Biomedical subjects

H Wilke

Publications and source records attributed to H Wilke.

At least 37 records · Page 2Linked to original sources

PubMed2000

[Infusiontherapy with 5-fluorouracil ("infusional" 5-FU) in solid tumors].

BACKGROUND: 5-FU is an important anticancer agent for many tumor entities. Because of the historical development of this compound it was predominantly administered as a bolus application, although it was well known that the antineoplastic activity of this antimetabolite is improved by prolonged administration schedules (protracted infusion ["infusional"] of 5-FU). Since port-a-cath systems and portable pumps became available, "infusional" 5-FU containing chemotherapies were intensively investigated in various tumors known to be susceptible to 5-FU. INDICATIONS: The largest experience with "infusional" 5-FU +/- folinic acid +/- other cytostatic drugs exists in gastrointestinal tumors. Meanwhile this way of 5-FU application is well established in the first- and second-line chemotherapy of metastatic colorectal and gastric cancer where it contributes to a clinically relevant improvement of the prognosis of these tumors. Other tumor entities where "infusional" 5-FU-based chemotherapies showed first positive results are i.e. breast cancer and esophageal cancers.

Antimetabolites, Antineoplastic↗

PubMed1999

Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: long-term results of a phase II trial.

Following mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22, IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52 months (30+ - 75+). Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

Adolescent↗

PubMed1999

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus.

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60-66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13-73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

Adult↗

PubMed1999

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Adolescent↗

PubMed1999

Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects.

PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.

Adult↗

PubMed1998

Implantable vascular access systems: experience in 1500 patients with totally implanted central venous port systems.

Totally implantable venous access systems are widely used, but large-scale studies evaluating these systems are lacking. In this study 1500 patients (719 male, 781 female) with an average age of 49 years (15-86 years) were fitted with subcutaneously implanted venous access systems, in most cases for long-term chemotherapy. All patients were observed until removal of the system, death, or the end of treatment. A retrospective analysis showed an average catheter life of 284 patient-days. A total of 1308 (87%) of the patients had no implant-related complications. Catheter infections occurred in 3.2% of the patients and catheter thromboses in 2.5%. Rarer complications, such as catheter malfunction, migration of the catheter, skin necrosis, catheter fracture, catheter disconnection, and pneumothorax, occurred in another 4.3% of the patients. The complications led to explantation of 178 access systems (11.9%). There was a significant difference (p < 0.05) between the low rate of infections and other complications in the group of patients with solid tumors (2% and 4%, respectively) and the rate in patients with hematologic diseases (6% and 8%, respectively). This study confirms the safety and convenience of using totally implantable venous access systems in patients on long-term chemotherapy.

Adolescent↗

PubMed1998

Pre-operative sequential chemo- and radiochemotherapy in locally advanced carcinomas of the lower oesophagus and gastro-oesophageal junction.

The purpose of this trial was to examine the feasibility of intensive, sequential chemo- and radiochemotherapy followed by surgery in patients with locally advanced carcinomas of the lower oesophagus and the gastro-oesophageal junction (GO junction). The chemotherapy consisted of two courses of 6 weekly administrations of 5-fluorouracil (5-FU) (2.0 g/m2, 24 h infusion) and folinic acid (FA) (500 mg/m2, 2 h infusion) combined with twice weekly cisplatin (50 mg/m2, 1 h infusion). Irradiation of 30 Gy was given concurrently with one course of cisplatin and etoposide. 25 patients with locally advanced (T3-T4 NX M0) squamous cell or adenocarcinoma of the lower oesophagus and GO junction were included and evaluated. Toxicity was usually mild to moderate (WHO grade 1 and 2) with mucositis as the most important side-effect of the pre-operative treatment. Of the patients, 94 and 88% completed the chemo- and radiochemotherapy according to the protocol, respectively. A major response (= partial remission with subjective improvement) to chemotherapy was achieved in 6/10 patients with squamous cell carcinoma and 10/15 with adenocarcinoma. 19 patients had subsequent surgery and complete resection was achieved in 16 (3 patients had intra-abdominal metastases observed at laparotomy). The operative mortality rate was 16% (3/19). 10 of the 16 patients with tumour resection had a pathological complete response. 15 patients (43%) remain alive at a median follow-up of 20 months and the median survival exceeds 16+ months. Our data suggest that this intensive pre-operative chemoradiotherapy programme is feasible and remarkably effective in patients with locally advanced carcinomas of the lower oesophagus or GO junction.

Adenocarcinoma↗

PubMed1998

Phase I study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma.

The majority of patients with hepatocellular carcinoma will develop either unresectable or metastatic disease and, therefore, are candidates for systemic chemotherapy. Only a few chemotherapeutic agents have shown documented activity in the treatment of advanced hepatocellular carcinoma and there is clearly a need for the evaluation of new active drugs. Therefore, we performed a phase I trial with a weekly schedule of paclitaxel in patients with advanced hepatocellular carcinoma. 16 patients with documented progression of unresectable hepatocellular carcinoma were included. After premedication, paclitaxel was given as a 1 h infusion on days 1, 8, 15, 22, 29 and 36 representing one treatment cycle. The cycle was repeated every 50 days. The starting dose was 70 mg/m2 and the doses were escalated in steps of 10 mg/m2/week. A minimum of 3 patients were treated at each dose level. All treatment was given on an out-patient basis. Dose-limiting toxicity was reached at a dose of 100 mg/m2/week with 2 of 6 patients treated at that dose level having WHO grade 4 neutropenia. Other toxic side-effects were only mild. 1 partial response and 9 cases with disease stabilisation were observed in 16 patients with initially progressive disease. We, therefore, conclude that the recommended dose for a further phase II trial in patients with hepatocellular carcinoma is 90 mg/m2/week. These data indicate that paclitaxel given at this dose and schedule might have activity in hepatocellular carcinoma and further investigation in phase II trials is warranted.

Adult↗

PubMed1998

Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: results of a phase II study.

PURPOSE: To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m2 was administered additionally on days 1 and 22, q 50 days. RESULTS: We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3-22), median TTP eight months (2-22) and median survival time 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucositis, nausea and vomiting. CONCLUSIONS: Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluations.

Adult↗

PubMed1998

Phase II study with cisplatin and paclitaxel in combination with weekly high-dose 24 h infusional 5-fluorouracil/leucovorin for first-line treatment of metastatic breast cancer.

Results from our previous phase II study demonstrating high efficacy and low toxicity for a weekly schedule of 5-fluorouracil (5-FU)/leucovorin in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel and cisplatin to this regimen for a phase II study of outpatient first-line treatment of metastatic breast cancer. (MBC). Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant CTX in 24 out of 28 patients, but no prior CTX for MBC. Patients were treated with 5-FU 2 g/m2 (24 h infusion) plus leucovorin 500 mg/m2 (2 h infusion prior to 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29 and 36); in addition, paclitaxel 175 mg/m2 (3 h infusion) was administered on days 0 and 21, and cisplatin 50 mg/m2 (1 h infusion) on days 1 and 22 prior to 5-FU/leucovorin, repeated every 50 days. All patients were treated as outpatients using Port-a-Cath systems and portable pumps. Aside from common total alopecia, neutropenia was common but only of short duration. No episodes of febrile neutropenia occurred. Non-hematologic toxicities (NCl CTC grade, percent of patients) consisted of mild to moderate diarrhea (2+3, 47%), mucositis (2, 14%), and nausea and vomiting (2+3, 60%). Out of 28 patients with bidimensionally measurable disease 25% (seven out of 28) achieved a CR, 57% (16 out of 28) achieved a PR, 11% (three out of 28) had a SD and 7% (two out of 28) had a PD. Overall RR was 82% (95% confidence interval 66-100%). Median remission duration was 8 months, median time to progression 9 months and median survival time 28 months with a median follow-up of 21 months. We conclude that the combination of paclitaxel, cisplatin and 5-FU/leucovorin is an effective non-anthracycline-containing regimen for the first-line treatment of MBC.

Adult↗

PubMed1998

Paclitaxel plus ifosfamide in advanced ovarian cancer: results of a phase I study.

Patients with advanced ovarian carcinoma and an inadequate response to first-line platinum-based combination chemotherapy (CTX) have a very poor prognosis and effective salvage regimens are clearly needed. This phase I study was performed in order to determine the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of the combination paclitaxel (P) and ifosfamide (IFO). After premedication, patients received P as a 3 h i.v. infusion on day 1; IFO was given as 1 h i.v. infusion with the standard dose of mesna i.v. on days 2-5, q day 22. The following dose levels (dl) were investigated: (mg/m2/day) dl1, P 135/IFO 1500; dl2, P 135/IFO 2000; dl3, P 175/IFO 2000; and dl4, P 175/ IFO 1500. Eighteen patients with advanced ovarian cancer entered this trial. In eight patients treated with an IFO dose of 2000 mg/m2 during dl2 and 3, two required treatment interruptions because of CNS toxicity CTC grade 3 and one patient experienced nephrotoxicity CTC grade 3, Therefore the MTD of IFO used in combination with P and given over 4 days is reached with 2000 mg/m2/day. In the fourth dl we escalated the P dose up to 175 mg/m2, reduced the IFO dose to 1500 mg/m2 and treated an additional five patients. No DLT occurred at that dl. Objective responses were observed at all dls. The combination of P and IFO is feasible and active in pretreated advanced ovarian carcinoma. dl4 is the recommended dose for phase II trials.

Adult↗

PubMed1998

Comparison between short or long exposure to 5-fluorouracil in human gastric and colon cancer cell lines: biochemical mechanism of resistance.

Recent preclinical and clinical data indicate that the main mechanisms of 5-fluorouracil (5-FU) cytotoxicity depend on the mode of administration. To gather further insight into the major causes of acquired 5-FU resistance, drug-sensitive human gastric (M2), colon (HT29) and breast (MCF7) cancer cell lines were repeatedly exposed to a fixed concentration of 5-FU given either for 1 or 24 h. Although equieffective doses (IC50) of 5-FU were used, resistance to a 1 h exposure of 5-FU developed faster in all models than to a 24 h exposure. Cell lines with acquired resistance to a 1 h application of 5-FU were only partly cross-resistant to a 24 h exposure, whereas lines with resistance to protracted application of 5-FU displayed significant cross-resistance to the 1 h schedule. Resistance to methotrexate was only seen in cell lines with acquired resistance to 24 h of 5-FU. All 5-FU-resistant cell lines showed reduced incorporation of 5-FU into cellular RNA. Furthermore, elevations of thymidylate synthase were seen in all cell lines with resistance to 24 h of 5-FU but also in one cell line with resistance to a bolus schedule. No alterations in folylpolyglutamate synthase developed in the resistant cell lines. These data support the concept that the main mechanisms of 5-FU cytotoxicity depend on the mode of application. Incorporation of fluorouridine triphosphate into RNA appears to be the most important mechanism of action for 5-FU bolus schedules, whereas inhibition of thymidylate synthase becomes more important as the infusion time is prolonged. These data could have implications on the interaction of 5-FU given at different schedules with various other cytostatic agents.

Adenocarcinoma↗

PubMed1998

Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer.

PURPOSE: To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates. RESULTS: The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%). CONCLUSION: Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.

Adult↗

PubMed1998

Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial.

PURPOSE: To evaluate the feasibility and efficacy of an intensive multimodality approach with combination chemotherapy, hyperfractionated accelerated chemoradiotherapy, and definitive surgery in prognostically unfavorable subgroups of locally advanced non-small-cell lung cancer stages IIIA and IIIB (LAD-NSCLC). PATIENTS AND METHODS: Following staging, including mediastinoscopy, 94 patients with inoperable LAD-NSCLC were treated preoperatively with chemotherapy (three courses of split-dose cisplatin and etoposide [PE]) followed by concurrent chemoradiotherapy (one course of PE combined with 45 Gy hyperfractionated accelerated radiotherapy). After repeat mediastinoscopy, patients underwent surgery 4 weeks postradiation. RESULTS: Of 94 consecutive patients (52 stage IIIA [> or = two lymph node levels involved] and 42 stage IIIB [no pleural effusion, no supraclavicular nodes]), 62 (66%) completed induction and underwent surgery. Complete resection (R0) was achieved in 50 (53% of all patients) and pathologic complete response (PCR) in 24 (26%). After a median follow-up of 43 months, the median survival time was 20 months for IIIA, 18 months for IIIB, and 42 months for R0 patients. Calculated survival rates at 4 years were 31%, 26%, and 46%. Two patients died of sepsis preoperatively and four died postoperatively of pleural empyema (n = 1), stump insufficiency (n = 2), and cardiac failure (n = 1). Other toxicities were acceptable-mainly hematologic during chemotherapy or chemoradiotherapy and esophagitis during chemoradiotherapy. CONCLUSION: This intensive multimodality treatment is feasible and demonstrates high efficacy in prognostically unfavorable LAD-NSCLC subgroups with high R0 rates and improved long-term survival compared with historical controls

Adult↗

PubMed1998

Fluorouracil-based combinations in the treatment of metastatic breast cancer.

Although combination chemotherapy regimens may prolong survival for selected patients with metastatic breast cancer, few, if any, are cured. The standard regimens used in treatment, e.g., CMF (cyclophosphamide, methotrexate, and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), and FEC (5-FU, epirubicin, and cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (e.g., high-dose chemotherapy with peripheral stem-cell support). An important alternative approach to increasing therapeutic efficacy focuses on altering the administration schedules of well-known chemotherapeutic agents and introducing active new agents. One of the most frequently used cytotoxic drugs, fluorouracil (5-FU), has documented activity in a variety of malignancies, most notably, breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience with 5-FU, our knowledge about the mechanisms of resistance to the various administration schedules used is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using alternative schedules, in particular, a protracted infusion. This article discusses our clinical experience with weekly high-dose 24-hour infusions of 5-FU in combination with folinic acid (leucovorin) alone and together with paclitaxel (Taxol) for the treatment of advanced breast cancer.

Adult↗

PubMed1998

[Hypothetical and reliable aspects of pre-, intra- and postoperative adjuvant therapy of stomach carcinoma].

The results of surgical therapy of gastric cancer could not be improved in recent years. Therefore, different perioperative modalities were investigated for this tumor. A series of studies could not show any survival benefit using postoperative adjuvant radio- or chemotherapy after complete resection of the tumor. Data available about preoperative chemotherapy in locally advanced tumor stages may demonstrate an increased R0-resection rate after objective remission resulting in a prolonged survival compared to surgery alone. Furthermore, in others trials intraoperative radiation or intraperitoneal chemotherapy could decrease the incidence of locoregional recurrence or peritoneal carcinomatosis and improve the overall survival rate. These treatment modalities, above all preoperative chemotherapy, must be proven in precisely defined patient populations within prospective trials to achieve clearcut data in the future.

Combined Modality Therapy↗

PubMed1997

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study.

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.

Adult↗

PubMed1997

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma.

PURPOSE: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m2 i.v. 15-minute infusion followed by methotrexate 200 mg/m2 i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m2 i.v. push on day 2. Folinic acid was given at 15 mg/m2 p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks. RESULTS: Thirty patients with advanced chemotherapynaive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27-72); median PS 1 (0-2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients. CONCLUSIONS: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.

Adenocarcinoma↗