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Biomedical subjects

M Raderer

Publications and source records attributed to M Raderer.

At least 127 records · Page 7Linked to original sources
PubMed1997

Treatment of advanced colorectal cancer with doxorubicin combined with two potential multidrug-resistance-reversing agents: high-dose oral tamoxifen and dexverapamil.

On the basis of the overexpression of the MDR1 gene in human colorectal cancer, which may constitute a molecular basis for intrinsic drug resistance that can be reversed, and because of the limited therapeutic value of conventional cytotoxic treatment in this common disease, the present phase II study of P-glycoprotein-directed double modulation was initiated. Fifteen patients with measurable metastatic colorectal cancer, all of whom were refractory to first-line chemotherapy with 5-fluorouracil/leukovorin, were entered in this trial. Treatment consisted of 80 mg tamoxifen twice daily on days 1-9, oral dexverapamil every day on days 7-9, and 60 mg/m2 doxorubicin given by intravenous bolus injection on day 8. Courses were repeated every 4 weeks. After a median of three (between one and six) courses, none of the 14 evaluable patients had objective response, and 4 had stable disease. Adverse reactions consisted mainly of myelosuppression (WHO grade IV granulocytopenia was noted in 40%), and mild and reversible dexverapamil-related cardiovascular side-effects, specifically hypotension (47%). Our results suggest that, despite the histological demonstration of high levels of P-glycoprotein in colorectal cancer and administration of two potentially synergistic chemosensitizers, we were unsuccessful in circumventing its primary resistance to chemotherapy.

Administration, Oral↗
PubMed1997

Radiation doses deriving from patients undergoing 111In-DTPA-D-phe-1-octreotide scintigraphy.

The purpose of this study was to estimate the radiation doses to nursing staff, other patients, accompanying persons and family members deriving from patients undergoing 111In-DTPA-d-Phe-1-octreotide (111In-OCT) scintigraphy. Dose rates were measured from 16 patients who had received an intravenous injection of 140+/-40 MBq 111In-OCT. The measurements were performed at three different distances (0.5, 1 and 2 m) at 10-20 min, 5-7 h and 24 h (and in some cases, up to 48 h) after administration of 111In-OCT. The effective half-lives of the biexponential decrease of the dose rates were estimated to be 2.94+/-0.27 h (T1) and 65.17+/-0. 58 h (T2). The calculated maximum dose to other persons in the waiting area was 27.2 microSv, to family members 61.5 microSv, to nursing staff in a ward 24.1 microSv and to neighbouring patients in the ward 69.5 microSv. Our results clearly demonstrate that the calculated maximum radiation exposure to accompanying persons, personnel, family members and other patients is well below the maximum annual dose limit for non-professionally exposed persons.

Air Pollutants, Radioactive↗
PubMed1997

High levels of eosinophil cationic protein in wheezing infants predict the development of asthma.

BACKGROUND: In association with respiratory tract infections, infants may have episodes of wheezing, which represent the onset of asthma in some of them. Activated eosinophils play a central part in asthmatic inflammation. OBJECTIVE: We investigated whether, in infants experiencing their first episode of wheezing, eosinophil activation is present and can predict the development of asthma. METHODS: In a prospective trial, eosinophil activation was measured by eosinophil cationic protein (ECP) concentrations in serum from 33 nonatopic infants with their first episode of wheezing, 15 nonatopic infants with upper respiratory tract infection without wheezing, and 18 healthy nonatopic infants. One year later, the children were re-evaluated for a diagnosis of infantile asthma. RESULTS: Wheezing infants had higher median serum ECP levels (13.4 micrograms/L) than children with nonwheezy respiratory tract infection (7.6 micrograms/L, p < 0.005) or healthy subjects (7.1 micrograms/L, p < 0.005). In addition, wheezing infants (n = 13) with serum ECP concentrations greater than 20 micrograms/L were more likely to have asthma within 1 year than patients with ECP levels less than 20 micrograms/L (odds ratio = 12.4; confidence interval, 4.6-33.5). CONCLUSION: Eosinophil activation measured by serum ECP is present in infants with their first episode of wheezing illness, especially in those infants in whom asthma subsequently develops within 1 year. These data may indicate a predictive value of serum ECP measurements in children with wheezing to identify those patients in whom infantile asthma is developing. These findings probably also indicate that serum ECP may be used to identify the children who need early antiinflammatory treatment.

Asthma↗
PubMed1997

Treatment of advanced pancreatic cancer with epirubicin, 5-fluorouracil and 1-leucovorin: a phase II study.

BACKGROUND: Preclinical data suggest that the levorotatory isomer of leucovorin (1-LV) can augment the cytotoxic effects of 5-fluorouracil (5-FU) more effectively than racemic LV. A phase II study was initiated to evaluate the effect of a combination of the pure L-isomer of LV and 5-FU along with epirubicin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-eight consecutive, previously untreated patients with measurable metastatic adenocarcinoma of the pancreas were enrolled in this study. Treatment consisted of epirubicin 50 mg/m2 on day 1 and 5-FU 400 mg/m2 plus 1-LV 100 mg/m2 both administered on days 1 to 5. Treatment cycles were repeated every four weeks for a total of six months unless progressive disease was documented earlier. The study endpoints were survival, toxicity, objective response as well as palliative beneficial effects of the regimen in terms of performance status, body weight and pain. RESULTS: Six patients had a partial response (21%; 95% CI, 8% to 44%) and 10 (36%) stable disease (35%), while the remaining 12 patients (43%) progressed during treatment. The median time to treatment failure was 2.9 months (range 1.2-13.7 months), and the median survival time was six months (range 1.8-19 months), with three patients (11%) being alive after one year. Beneficial palliative effects in terms of performance status, body weight and/or pain were seen in 12 of 28 patients (43%): an improvement in performance status was recorded in four patients, pain was attenuated and/or analgetic consumption reduced by > or = 50% in eight patients, and five patients had weight gain of > 5% of their pretreatment body weight. Treatment-associated side effects were generally mild to moderate. Severe adverse reactions included (asymptomatic) granulocytopenia in five, mucositis and/or diarrhea WHO grade 3 in four patients. CONCLUSION: Our data suggest that epirubicin plus 5-FU and 1-LV is a tolerable regimen that has some positive effects in the treatment of pancreatic cancer. Since this regimen, however, is unlikely to offer any major therapeutic advantage compared to monochemotherapy or other combination regimens, the search for novel and more effective cytotoxic agents must continue.

Adenocarcinoma↗
PubMed1997

Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.

PURPOSE: To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier. RESULTS: There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms. CONCLUSION: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.

Adult↗
PubMed1997

Vasoactive intestinal peptide and somatostatin receptor scintigraphy for differential diagnosis of hepatic carcinoid metastasis.

We report a case of a hepatic carcinoid metastasis mimicking a hemangioma on ultrasound and on CT. Indium-111-DTPA-D-Phe-1-octreotide (111In-OCT) and 123I-vasoactive intestinal peptide (123I-VIP) receptor images suggested a carcinoid metastasis of the liver. The final diagnosis was established histopathologically. The differential diagnosis of liver lesions is discussed.

Carcinoid Tumor↗
PubMed1997

Distinction between hepatic focal nodular hyperplasia and malignant liver lesions using technetium-99m-galactosyl-neoglycoalbumin.

UNLABELLED: Distinction between hepatic focal nodular hyperplasia (FNH) and malignant liver lesions is essential because of the different therapy strategies, since FNH can be managed conservatively. The aim of this study was to describe the imaging pattern of FNH using the hepatocyte receptor ligand 99mTc-galactosyl-neoglycoalbumin 99mTc-NGA) and to assess the value of this receptor imaging agent in the differentiation of FNH from malignant liver lesions. METHODS: Twelve consecutive patients with histologically confirmed FNH were investigated. The FNH-lesions were asymptomatic and incidentally found by ultrasonography. Nine patients with histologically verified hepatocellular carcinomas and three patients with liver metastases spread from gastrointestinal adenocarcinomas served as controls. RESULTS: All FNH lesions showed normal or even increased uptake of 99mTc-NGA. Whereas malignant liver lesion-to-normal liver ratios amounted to 0.4 +/- 0.2 (mean +/- s.d.), FNH lesion-to-normal liver ratios were 1.7 +/- 0.3 (mean +/- s.d.). CONCLUSION: The receptor imaging agent 99mTc-NGA with concurrent use of SPECT is useful in the differential diagnosis of FNH and malignant hepatic tumors.

Adult↗
PubMed1996

Effective radiochemotherapy with cisplatin and etoposide for the management of patients with locally inoperable and metastatic esophageal carcinoma.

BACKGROUND: The limited therapeutic value of available chemotherapeutic drug combinations in patients with advanced esophageal carcinoma, the documented synergistic activity of etoposide and cisplatin, which might be further enhanced by simultaneous radiotherapy, and promising though only preliminary therapeutic results with this combination regimen have stimulated the present Phase II trial. The specific aim of the study was to determine the efficacy and tolerance of this combined treatment approach in previously untreated patients with either local regional unresectable or metastatic esophageal carcinoma. METHODS: Thirty patients with Stage IIIB or IV squamous cell or adenocarcinoma of the esophagus were entered in this study between October 1992 and November 1994. Chemotherapy was comprised of cisplatin, 30 mg/m2, combined with etoposide, 120 mg/m2, both given intravenously on 4 consecutive days. Treatment courses were repeated every 4 weeks. Radiation therapy (total dose, 5000 centigray) was administered concurrently during the 2nd and 3rd chemotherapy course, during which both drugs were given with a 25% dose reduction. RESULTS: After a median of 4 chemotherapeutic treatment courses (range, 1 to 6 courses), 3 patients had a complete response for 5, 8, and 11.5 months, and 9 patients had a partial response lasting for a median duration of 5.3 months (range, 2.5 to 7.5 months), yielding an overall response rate of 40% (95% confidence interval, 23-59%). The response rates tended to be higher for squamous cell carcinomas (11 of 23; 48%) than for adenocarcinomas (1 of 7), as well as for locoregional disease (7 of 13; 54%) than for patients with disseminated disease (5 of 17; 29%). For the entire study population, median time to progression was 5.4 months (range, 1.5 to 13.5 months), and median survival was 9.2 months (range, 1.5 to 28 months), with 4 patients still alive at the time of this report. Clinically, the most important toxic effect was myelosuppression. Grade 3-4 granulocytopenia occurred in 16 patients (53%), severe thrombocytopenia in 11 (37%), and Grade 3 anemia in 5 (17%). There were four hospitalizations among three patients for the management of fever during neutropenia. Other nonhematologic side effects were generally mild or modest, and most commonly included nausea/emesis (40%), mucositis and/or esophagitis during simultaneous radiotherapy (40%), and alopecia (43%). CONCLUSIONS: Combined radiochemotherapy with cisplatin and etoposide is active against advanced esophageal carcinoma, but can be associated with significant hematotoxicity. Although the therapeutic potential of this regimen appears to be comparable to other, conventional fluorouracil/cisplatin-based chemotherapy, less toxic and more effective regimens need to be identified.

Adenocarcinoma↗
PubMed1996

Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T lymphocytes.

The physiological role of the multidrug resistance P-glycoprotein (P-gp), which is expressed by normal human T lymphocytes, is still largely unknown. To investigate whether or not P-gp is involved in the transport of cytokines, peripheral blood lymphocytes were stimulated with phytohemagglutinin (PHA) in the absence or presence of P-gp inhibitors, and concentrations of cytokines (interleukin-2 [IL-2], IL-4, IL-6, interferon-gamma [IFN-gamma]) in the supernatants of these cultures were quantitated by enzyme-linked immunosorbent assay. P-gp inhibitors included verapamil (Ver), tamoxifen (Tmx), and the P-gp specific monoclonal antibody UIC2. Release of IL-2 was significantly suppressed by these inhibitors at concentrations that were also effective in blocking efflux of Rhodamine-123 from normal T lymphocytes. IL-2 mRNA expression in lymphocytes was not different between PHA control and the cultures with P-gp inhibitors. Ver and Tmx did not interfere with T-cell activation as determined by CD25 and CD69 expression. In a nonhematological model, the P-gp expressing HCT-8 adenocarcinoma cell line, exogenously added IL-2 was shown to exert an inhibitory effect on P-gp mediated Rhodamine-123 efflux. In addition, transepithelial transport of IL-2 by electrophysiologically tight and polarized HCT-8 monolayers was examined. A time-dependent flux of IL-2 across dense monolayers, which was partially inhibited by Ver, was observed. We also investigated whether or not P-gp inhibitors suppressed release of other cytokines produced by activated T cells (IL-4, IL-6, IFN-gamma). Release of IL-4 and IFN-gamma was significantly inhibited by Ver, Tmx, and UIC2; however, release of IL-6 remained unaffected. These data show P-gp mediated transmembrane flux of IL-2 in T lymphocytes and HCT-8 cells. We conclude that P-gp participates in the transport of cytokines (IL-2, IL-4, and IFN-gamma) in normal peripheral T lymphocytes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

In vitro and in vivo studies of three radiolabelled somatostatin analogues: 123I-octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-D-Phe-1-OCT.

Scintigraphy with long-acting somatostatin (SST) analogues may be useful for the localization of tumours expressing receptors (R) for SST. In this study we have analysed the in vitro and in vivo binding properties of three SST analogues, 123I-octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-d-Phe-1-OCT. In vitro binding studies performed with a variety of primary tumours (n=48) as well as with several tumour cell lines (A431, HT29, PANC1, COLO320, HMC1, KU812) indicated significant in vitro binding of these three radiolabelled SST analogues to two subpopulations of SSTR, high (Kd 0.2-2.0 nM) and low (Kd 5-15 nM) affinity ones. The number of SSTR on tumour cells was at least a 1000-fold higher as compared with normal peripheral blood cells. Comparative scintigraphic studies using 123I-OCT and/or 123I-Tyr-3-OCT and/or 111In-DTPA-d-Phe-1-OCT were performed in 21 patients with histologically verified intestinal carcinoid tumours. Corresponding scintigraphic results were obtained in 18 of 21 patients investigated with two different SSTR ligands, either 123I-OCT/123I-Tyr-3-OCT (four of five), 123I-OCT/111In-DTPA-d-Phe-1-OCT (eight of nine), or 123I-Tyr-3-OCT/111In-DTPA-d-Phe-1-OCT (six of seven). We conclude that various tumours express high amounts of SSTR which are recognized by three radiolabelled SST analogues: 123I-OCT, 123I-Tyr-3-OCT and 111In-DTPA-d-Phe-1-OCT. Differences between these SST analogues in their in vitro binding and/or in vivo scanning properties are observed in a minority of patients. Thus, the labelling of OCT with iodine may be an alternative approach for those nuclear medicine departments for which 111In-DTPA-d-Phe-1-OCT is not easily available, or is too expensive.

Adolescent↗
PubMed1996

123I-vasoactive intestinal peptide (VIP) receptor scanning: update of imaging results in patients with adenocarcinomas and endocrine tumors of the gastrointestinal tract.

Recent data suggest that functional receptors (R) for vasoactive intestinal peptide (VIP) are expressed on various tumor cells. The high-level expression of VIPR on tumor cells provided the basis for the successful use of 123I-labeled VIP for the in vivo localization of intestinal adenocarcinomas and endocrine tumors. We here report an update of our imaging results using 123I-VIP (150-200 MBg/1 microgram/patient) in 169 patients. In patients with pancreatic adenocarcinomas without liver metastases, the primary/recurrent tumor was visualized in 16 of 18 patients (89%) and liver metastases were imaged in 15 of 16 patients. In 11 of 12 patients with colorectal adenocarcinomas, the primary/recurrent tumor (92%) was imaged by 123I-VIP. Also, in 21 of 25 patients, liver metastases (84%); in 3 of 6 patients, lung metastases (50%); and in 4 of 5 patients, lymph-node metastases (80%) were imaged by 123I-VIP. In 10 of 10 patients with gastric adenocarcinomas, the primary/recurrent tumor; in 3 of 4 patients, liver metastases; and in 2 of 2 patients, lymph-node metastases were visualized by 123I-VIP. 123I-VIP localized primary intestinal carcinoid tumors in 15 of 17 patients (88%) and 8 of 10 primary insulinomas (80%). We conclude that the 123I-VIPR scintigraphy localizes intestinal adenocarcinomas and endocrine tumors as well as metastatic tumor sites.

Adenocarcinoma↗
PubMed1996

Effective treatment of advanced breast cancer with vinorelbine, mitomycin C plus human granulocyte colony-stimulating factor.

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between October 1992 and July 1994, 55 patients entered this trial. Nine patients had locally advanced disease and 46 had distant metastases, including 14 who had received previous palliative chemotherapy with (n = 9) or without anthracyclines (n = 5). Therapy consisted of VNB 40-50 mg m(-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and MMC 15 mg m(-2) administered by intravenous bolus injection every 6 weeks. G-CSF was given at 5 microg kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was continued in case of response or stable disease for a total of six courses. The overall response rate was 73% for all 55 patients (95% confidence interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD), and only two (4%) progressed. All nine patients with locally advanced disease were rated responsive (two pCR, seven PR) and underwent surgery with curative intent. Eight out of nine remain disease free after a median observation period of 18 months (range, 13.5-28 months). Among the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second-line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+ months) in previously untreated patients with disseminated disease, and 6.0 months (range, 2-22 months) in those who had failed prior chemotherapy. After a median follow-up time of 20 months, 24 patients with distant metastases are still alive with disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: six (11%) and ten patients (18%) had World Health Organization grade 3, and eight (14%) and nine patients (16%) had grade 4 leucopenia and granulocytopenia respectively. Severe (WHO grade 3) non-haematological toxicities included nausea/vomiting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectious episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data suggest that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumour activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or anthracycline regimens. Apart from reversible, acute pulmonary toxicity, a rare adverse reaction that had previously been described for VNB, as well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at the initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and salvage therapy of advanced breast cancer.

Adult↗
PubMed1996

Comparison of iodine-123-vasoactive intestinal peptide receptor scintigraphy and indium-111-CYT-103 immunoscintigraphy.

UNLABELLED: Recently, we have shown that the expression of receptors for vasoactive intestinal peptide (VIP) on intestinal adenocarcinomas can be used for in vivo targeting of primary or metastatic tumor sites using 123I-labeled VIP. Several other receptors and antigens including the TAG-72 protein have also been implemented for in vivo localization purposes. In this study, we have compared the in vitro and in vivo binding of 123I-VIP and of the 111In-labeled monoclonal antibody (MAb) directed against TAG-72 (OncoScint; 111In-CR-103) in patients with intestinal adenocarcinomas in a single-blinded, prospectively randomized trial. METHODS: Twenty patients were administered either 123I-VIP (150-200 MBq; 1 microgram) or 111In-CYT-103 (150 MBq; 1 mg) for one imaging study. After interim analysis demonstrated superior imaging with 123I-VIP, the next 10 patients (accounting for a total of 50 patients) enrolled in this trial underwent both studies in random order to allow for a direct comparison. RESULTS: In total, 123I-VIP scans were true-positive in 28 of 30 patients (93%) versus 17 of 30 patients administered 111In-CYT-103 (56%). In the subgroup of 10 patients enrolled in the second part of the study, primary intestinal adenocarcinomas were imaged in five of five patients with 123I-VIP and in only two of these patients with 111In-CYT-103. Liver metastases were visualized in five of six patients by 123I-VIP receptor scanning and in four of these patients with 111In-CYT-103. The in vitro results indicated significant binding of 123I-VIP to primary colorectal tumors as well as to HT29 and COLO320 adenocarcinoma cells. In vitro, adenocarcinoma cells also expressed abundant numbers of the TAG-72 antigen. CONCLUSION: Intestinal adenocarcinomas co-express VIP receptors and the IAG-72 antigen. Despite significant in vitro binding of both agents, however, the VIP receptor scan is more sensitive in localizing intestinal adenocarcinomas and metastatic spread.

Adenocarcinoma↗
PubMed1995

Phase I/II trial of dexverapamil, epirubicin, and granulocyte-macrophage-colony stimulating factor in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose (MTD) of a cytotoxic regimen consisting of the second-generation chemosensitizer dexverapamil (DVPM), high dose epirubicin, and recombinant human granulocyte-macrophage-colony stimulating factor (GM-CSF) in pancreatic carcinoma. PATIENTS AND METHODS: Twenty-eight previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were studied. Treatment consisted of oral DVPM at a dose of 1000-1200 mg/day for 3 days, epirubicin administered as an intravenous bolus injection on Day 2 with an initial dose of 90 mg/m2, and a dose of GM-CSF of 400 micrograms administered subcutaneously from Day 5s through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of four to eight patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. RESULTS: Hematologic toxicity, specifically granulocytopenia, constituted the dose-limiting toxicity with an MTD of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, four, two, and five patients experienced Grade 4 granulocytopenia during their first two treatment courses at levels 105, 120, and 135 mg/m2, respectively. Grade 4 granulocytopenia was observed in two, three, and one additional patients during subsequent courses with these levels. Nonhematologic toxicity was uncommon, generally modest, and did not correlate clearly with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Nine of 28 patients achieved partial responses to this therapy. Stable disease was observed in nine patients, and tumor progress occurred in 10. CONCLUSION: The MTD of epirubicin for this regimen with DVPM and GM-CSF was 120 mg/m2 every 3 weeks. Though it remains uncertain whether the encouraging response activity observed in this disease-oriented Phase I study was, in fact, due to successful modulation of multidrug resistance, these results suggest that this regimen is likely to be an effective and tolerable treatment strategy for patients with pancreatic cancer, which should be evaluated further.

Adenocarcinoma↗
PubMed1995

Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma.

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000-1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m2, and 400 micrograms granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of 4-8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m2 respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial reponses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m2 every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.

Adenocarcinoma↗