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Biomedical subjects

W Scheithauer

Publications and source records attributed to W Scheithauer.

At least 55 records · Page 3Linked to original sources
PubMed1998

Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial.

BACKGROUND: Recently, the serotonin antagonist ondansetron has been reported to have a positive effect on cholestasis-associated pruritus. OBJECTIVES: To study the effect of orally administered ondansetron on pruritus in chronic liver disease in a randomized, placebo-controlled, double-blind, cross-over study. METHODS: Subjective severity of pruritus was assessed using a visual analogue scale (VAS) recorded four times daily by the patients. After a one week pretreatment baseline period the patients were randomized to receive ondansetron tablets 8 mg tds or placebo tablets tds for one week. Following a one week wash-out period patients were switched to the other treatment for one week. The study was ended by an additional follow-up week without medication. For each day peak VAS values were determined and the mean value of the last five days of each week was calculated and referred to as the composite peak VAS score. RESULTS: We observed a significant but moderate reduction of the composite peak VAS score of 1.34 points (CI(95%): 0.12-2.56; P=0.033) during treatment with ondansetron as compared to placebo (treatment effect). In addition, a period effect was observed: a reduction of composite peak VAS score by 1.26 points (C1(95%): 0.04-2.48; P=0.044) was seen in the second treatment period as compared to the first period, irrespective of the kind of treatment. Although under treatment with ondansetron a significant improvement of itching as assessed by the VAS score was demonstrated, this treatment was not preferred over placebo by the patients. CONCLUSIONS: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has a small, but significant positive effect on pruritus in chronic liver disease as compared to placebo.

Administration, Oral↗
PubMed1998

Iodine-123-vasoactive intestinal peptide receptor scanning in patients with pancreatic cancer.

UNLABELLED: Recent data demonstrated a high sensitivity (>90%) in the visualization of primary/recurrent pancreatic cancer as well as metastases by means of 123I-labeled vasoactive intestinal peptide (VIP). The aim of this study was to investigate the diagnostic value of radioiodinated VIP in patients suffering from adenocarcinoma of the exocrine pancreas. METHODS: Sixty consecutive patients (26 women, 34 men; mean age 59 yr) with histologically verified pancreatic cancer were investigated in this study. Twenty-one patients presented with organ-confined malignancy (19 at study entry and 2 during follow-up after initial surgery developed tumor recurrence), while 25 patients had distant metastases along with the local malignancy, and 7 patients had liver metastases after resection of the primary lesion (6 on study entry and 1 during follow-up showed tumor development). In 5 of these patients, abdominal lymph node metastases were present at the time of scanning. Of 10 patients, who had undergone potentially curative surgery for their cancer, 7 remained free of disease during follow-up until death or for at least 6 mo. Iodine-123-VIP (150-200 MBq; approximately 1 microg VIP) was administered to all patients. Scintigraphic results were evaluated as compared to conventional radiologic imaging methods and surgical exploration. RESULTS: Primary pancreatic tumors were visualized by 123I-VIP in 19/21 patients (90%) with disease confined to the pancreas and in 8/25 patients (32%) suffering both from locoregional and disease metastatic to the liver. The overall 123I-VIP scan sensitivity for primary pancreatic adenocarcinomas was 58% (27/46 scans). Liver metastases were imaged in 29/32 patients (scan sensitivity 90%) and abdominal lymph node metastases in 4/5 patients. In 5 patients, the VIP receptor scan indicated the malignant lesion before CT. In vitro results confirmed specific binding of 123I-VIP to primary pancreatic tumor cells as well as to PANC1 adenocarcinoma cells. CONCLUSION: Iodine-123-VIP receptor scanning has the potential to offer additional information to augment diagnostic standard methods and could influence the decision-making process in the treatment of pancreatic cancer.

Adenocarcinoma↗
PubMed1998

Indium-111-DOTA-lanreotide: biodistribution, safety and radiation absorbed dose in tumor patients.

UNLABELLED: Imaging with radiolabeled somatostatin/vasoactive intestinal peptide analogs has recently been established for the localization diagnosis of a variety of human tumors including neuroendocrine tumors, intestinal adenocarcinomas and lymphomas. This study reports on the biodistribution, safety and radiation absorbed dose of 111In-1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA)-lanreotide, a novel peptide tracer, which identifies hSST receptor (R) subtypes 2 through 5 with high affinity, and hSSTR1 with low affinity. METHODS: The tumor localizing capacity of 111In-DOTA-lanreotide was initially investigated in 10 patients (3 lymphomas, 5 carcinoids and 2 intestinal adenocarcinomas). Indium-111 -DOTA-lanreotide was then administered to 14 cancer patients evaluated for possible radiotherapy with 90Y-DOTA-lanreotide (8 neuroendocrine tumors, 4 intestinal adenocarcinomas, 1 Hodgkin lymphoma and 1 prostate cancer). After intravenous administration of 111In-DOTA-lanreotide (approximately = 150 MBq; 10 nmol/patient), sequential images over one-known tumor site were recorded during the initial 30 min after peptide application. Thereafter, whole-body images were acquired in anterior and posterior views up to 72 hr postinjection. Dosimetry calculations were performed on the basis of scintigraphic data, urine, feces and blood activities. A comparison with 111In-DTPA-D-Phe1-octreotide (111In-OCT) scintigraphy was performed in 8 of the patients. RESULTS: After an initial rapid blood clearance [results of biexponential fits: T(eff1) 0.4 min (fraction a1 80%) and T(eff2) 13 min (fraction a2 14%)], the radioactivity was excreted into the urine and amounted to 42% +/- 3% of the injected dose (%ID) within 24 hr and 62% +/- 6%ID within 72 hr after injection of 111In-DOTA-lanreotide. In all patients, tumor sites were visualized during the initial minutes after injection of 111In-DOTA-lanreotide. The mean radiation absorbed dose amounted to 1.2 (range 0.21-5.8) mGy/MBq for primary tumors and/or metastases. The effective half-lives of 111In-DOTA-lanreotide in the tumors were T(eff1) 4.9 +/- 2.2 and T(eff2) 37.6 +/- 6.6 hr, and the mean residence time tau was 1.8 hr. The highest radiation absorbed doses were calculated for the spleen (0.39 +/- 0.13 mGy/MBq), kidneys (0.34 +/- 0.08 mGy/MBq), urinary bladder (0.21 +/- 0.03 mGy/MBq) and liver (0.16 +/- 0.04 mGy/MBq). The effective dose was 0.11 +/- 0.01 (range 0.09-0.12) mSv/MBq. During the observation period of 72 hr, no side effects were noted after 111In-DOTA-lanreotide application. The 111In-DOTA-lanreotide radiation absorbed tumor dose was significantly higher (ratio 2.25 +/- 0.60, p < 0.01) when directly compared with 111In-OCT. CONCLUSION: Indium-111 -DOTA-lanreotide shows a high tumor uptake for a variety of different human tumor types, has a favorable dosimetry over 111In-OCT and is clinically safe.

Adenocarcinoma↗
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

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↗
PubMed1996

Serum tumor markers after renal transplantation.

The overall incidence of malignancy in renal transplant recipients is 100-fold higher compared with age matched controls. Routine clinical evaluation therefore often includes the determination of serum tumor markers AFP, CA19-9, CEA, CA125, CA15-3, PSA, and calcitonin. We evaluated the specificity and the sensitivity of these markers in 575 renal allograft recipients. Specificity varied between 0.69 (CA 125) and 0.96 (PSA) in 532 patients without cancer. Cyclosporine therapy and excretory allograft function did not affect marker concentration; impaired liver function was associated with significantly elevated AFP, CA19-9, CA125, and CA15-3 levels. In 43 patients with malignancies the sensitivity of the markers ranged between 0.2 (CEA) and 1 (CA 125, CA 15-3). We therefore conclude that routine screening of the transplant population with serum tumor markers is not useful because of the low sensitivity and specificity of these tests.

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

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↗