Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).

Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT-qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS-and PIK3CA-mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5-fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE-1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression-free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC-analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402-0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476-1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460-0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351-0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS- and PIK3CA-genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first-line irinotecan-based chemotherapy.

Evaluation of prognostic factors in liver-limited metastatic colorectal cancer: a preplanned analysis of the FIRE-1 trial.

BACKGROUND: Liver-limited disease (LLD) denotes a specific subgroup of metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: A total of 479 patients with unresectable mCRC from an irinotecan-based randomised phase III trial were evaluated. Patients with LLD and non-LLD and hepatic resection were differentiated. Based on baseline patient characteristic, prognostic factors for hepatic resection were evaluated. Furthermore, prognostic factors for median overall survival (OS) were estimated via Cox regression in LLD patients. RESULTS: Secondary liver resection was performed in 38 out of 479 patients (resection rate: 7.9%). Prognostic factors for hepatic resection were LLD, lactate dehydrogenase (LDH), node-negative primary, alkaline phosphatase (AP) and Karnofsky performance status (PS). Median OS was significantly increased after hepatic resection (48 months), whereas OS in LLD (17 months) and non-LLD (19 months) was comparable in non-resected patients. With the inapplicability of Koehne's risk classification in LLD patients, a new score based on only the independent prognostic factors LDH and white blood cell (WBC) provided markedly improved information on the outcome. CONCLUSION: Patients undergoing hepatic resection showed favourable long-term survival, whereas non-resected LLD patients and non-LLD patients did not differ with regard to progression-free survival and OS. The LDH levels and WBC count were confirmed as prognostic factors and provide a useful and simple score for OS-related risk stratification also in LLD.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Differential effect of high-dose methotrexate on erythropoiesis and granulocytopoiesis in humans.

The kinetics of erythroid and granulocytopoietic cell production were investigated during Courses 1 and 4 of high-dose methotrexate therapy with citrovorum factor rescue in a patient suffering from metastatic osteogenic sarcoma. Using the technique of quantitative 14C autoradiography, relative production rates were determined before, as well as 2, 24, 48, and 72 hr after, methotrexate infusion. There was only a minor decrease of the relative granulopoietic cell production 2 hr after methotrexate infusion followed by an overshoot reaction after 48 hr with a maximum of 3 to 4 times the pretherapeutic value. The relative erythropoietic cell production dropped to less than one-third of the pretherapeutic level during both courses and remained low during the period of postinfusion observation. The results indicate a severe and long-lasting impairment of the erythropoietic cell series, which is likely to include the committed stem cell pool. The impairment of granulocytopoiesis was much smaller and was followed quite soon by a reaction of recovery. The rate of DNA synthesis of individual cells was subnormal in all cell types investigated prior to Course 4 and was hardly affected by the methotrexate. Intracellular accumulation of methotrexate polyglutamates and differences in this pattern of accumulation between the red and white cell series are discussed as one possible explanation in this context.

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study.

PURPOSE: A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer. PATIENTS AND METHODS: Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. RESULTS: From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant). CONCLUSION: Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.

Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cell fractions enriched according to cell cycle stages by way of centrifugal elutriation.

Undifferentiated human lymphoblasts (culture LS-2) were separated according to cell size during their exponential growth phase by way of centrifugal elutriation. The cell fractions thus obtained were characterized in terms of different cell cycle stages by flow cytometric measurement of their deoxyribonucleic acid (DNA histogram), the [3H]thymidine labeling index, and by determining the rate of [3H]thymidine incorporation. In these cell fractions the activities of thymidine kinase, thymidylate synthase, DNA polymerase, dihydrofolate reductase, methionine synthase, and hexokinase were determined. The results showed that all the enzymes investigated exhibited activities in all cell fractions. With the exception of DNA polymerase, all of the enzymes exhibited the lowest level of activity in the fraction containing the highest proportion of G0 + G1 phase cells (fraction 2); the activity of thymidine kinase was particularly low. This would suggest that thymidine kinase is not active in G0 + G1 phase cells and that the activity measured in fraction 2 is perhaps attributable to contamination of this fraction by S and G2 + M phase cells.

Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cells separated according to DNA content by way of a cell sorter.

Exponentially growing human lymphoblasts (culture LS-2) were separated by cell sorting (FACS II, Becton Dickinson) according to their deoxyribonucleic acid (DNA) content, designating them at particular phases of the cell cycle. Prior to cell sorting the DNA has been fluorochrome-labeled with the Hoechst stain H 33342. Maximum cell enrichments of 94% for G0 + G1 cells, 96% for S cells and 74% for G2 + M cells could be achieved. The enzyme activities of thymidine kinase (TK), thymidylate synthase (TS), DNA polymerase (DNA-P), dihydrofolate reductase (FH2-R), methionine synthase (MS), and hexokinase (HK) were determined in the obtained cell fractions. Although incorporation of 3H-thymidine (3H-dTR) and the 3H-dTR labeling index were significantly inhibited by the dye, no evidence of cell staining's having a significant effect on the enzyme activities was found. The enzyme activities for approximately 100% pure G0 + G1, S, and G2 + M cells were computed. With exception of TK, all the enzymes under study were shown to exhibit activities--although of differing degree--in the G0 + G1, S, and G2 + M cells. No TK activity was shown in G0 and G1 cells; its activity, however, was approximately the same in S and G2 + M cells. This applies likewise for TS which, in contrast to TK, exhibits minor activity in G0 + G1 cells. DNA-P was highly active in G0 + G1 cells, but maximum activity was in S cells. FH2-R exhibited maximum activity in S cells, although the difference in activity between S and G2 + M cells was not significant. None of the observed differences in MS activity was significant, indicating equally high activity in cells of all cell cycle phases. HK activity is approximately twice as high in G2 + M cells as in G0 + G1 cells.

[Tumor markers--how they should be applied]. / Nur der gezielte Einsatz bringt Vorteile für den Patienten. Tumormarker gehören nicht zum Routine-Check-up.

Determination of a tumor marker is currently not suitable method for screening purpose (exception: PSA and thyroglobulin). Tumor marker determination cannot be employed to exclude the presence of a tumor. Prior to surgery, however, such determination is desirable, and in the case of germ cell tumors even mandatory. Postoperatively, or after termination of adjuvant chemotherapy and/or radiotherapy, determination of tumor markers as an individual baseline is necessary for the further disease course. During the course of the disease and for follow-up care, the kinetic development of tumor factors is, in comparison with the individual baseline values, of decisive importance. However, in order to ensue correct interpretation it is important to use the same test system.

Central nervous system as sanctuary site of relapse in patients treated with chemotherapy for metastatic testicular cancer.

Isolated central nervous system relapse in patients treated successfully with cisplatin-based chemotherapy for testicular cancer has been described infrequently. In a retrospective analysis we identified this complication in six of 417 patients. Five of the six patients had advanced pulmonary dissemination at onset of chemotherapy, and post-chemotherapy surgery did not reveal viable tumour tissue in any of these cases. All six patients developed a single cerebral metastasis during complete remission a median four months after discontinuation of chemotherapy. Five patients were treated with surgery and subsequent radiotherapy, one patient with irradiation alone. Three patients are alive relapse-free 19, 62 and 86 months after diagnosis of cerebral relapse. One patient was alive with cerebral disease for 12 months without evidence of systemic recurrence. Our data demonstrate that the brain may act as a sanctuary site in chemotherapy-treated testicular cancer. A review of the literature shows that an isolated cerebral relapse is an extremely rare complication, but carries a relatively favourable prognosis.

Clinical pharmacokinetics of fluorouracil and folinic acid.

This article deals with the pharmacokinetics of fluorouracil (5-FU) and folinic acid (CHO-THF). 5-FU kinetics are characterized by short serum half-life times of 4.5 to 13 minutes. The high body clearance is mainly caused by a rapid catabolism of 5-FU to dihydrofluorouracil (FUH2), alpha-fluoro-ureidopropionic acid (FUPA), and to alpha-fluoro-beta-alanine (FBAL). Due to an incomplete hepatic extraction, systemic 5-FU levels greater than 5 microM are determined even during hepatic artery infusion. 5-FU measurements during isolated liver perfusion revealed different phases of 5-FU clearance. With higher levels (greater than 430 microM) clearance behaves in accordance with zero-order kinetics, with lower concentrations (less than 150 microM) 5-FU is cleared according to first-order kinetics. The impact of 5-FU kinetics on the treatment with 5-FU is discussed. After administration of the commercially available d,l-folinic acid (d,l-CHO-THF), the biologically inactive d-form is cleared very slowly with a median half-life of 438 +/- 63 minutes. l-CHO has short elimination half-lives of 56.5 +/- 10.5 minutes. The high body clearance of 222 +/- 27 mL/min is partially caused by metabolism to l-methyltetrahydrofolic acid (l-CH3-THF). With bolus injection of 200 mg/m2 or short-term infusion of 300 mg d,l-CHO-THF, serum levels greater than 1 microM are attained for approximately 2 to 3 hours. Total reduced l-folates (l-CHO-THF plus l-CH3-THF) are above 5 microM for at least 3 hours. Continuous infusion of CHO-THF affords steady-state levels in the micromolar range for prolonged time periods. After application of the pure l-folinic acid, mean elimination half-live and area under the curve were in the same range as after administration of the d,l-CHO-THF. Higher doses of oral d,l-folinic acid are always absorbed incompletely. Since the amount of l-CHO-THF absorbed is converted rapidly to CH3-THF, serum levels of l-CHO-THF remain always below 0.1 microM. CH3-THF steady-state levels in the micromolar range, however, are attained with different oral d,l-CHO-THF protocols.

A phase I trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that both folinic acid and interferon may enhance the efficacy of 5-fluorouracil (5-FU) in colorectal carcinoma. We therefore initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of the combination of recombinant interferon (IFN) alpha-2b with folinic acid (FA) and 5-FU. Seventeen patients with colorectal cancer who failed local chemotherapy received 5-FU as a 4-hour infusion, preceded by a bolus of FA and IFN. The 5-FU dose was escalated over the range of 400 to 650 mg/m2/d for a period of 7 days. Folinic acid was administered as a bolus in a fixed dose of 200 mg/m2/d and IFN as 5 million U/d subcutaneously on days 1 to 7. A total of 89 courses of therapy were completed for the 17 patients, of which there were 10 paired courses with a combination of 5-FU and IFN or 5-FU alone, being performed to analyze the pharmacokinetics and modulation of 5-FU by IFN. The maximum tolerated dose of 5-FU using this combination and a 4-hour schedule was 600 mg/m2/d for 7 days. The dose-limiting toxicity of this regimen was diarrhea. Mucositis and myelosuppression was not a marked problem at dose levels of 400 and 500 mg/m2/d for 7 days. However, at a dose level of 600 to 650 mg/m2/d for 7 days, grade 3 and 4 (WHO) leukopenia occurred in 50% and mucositis occurred in 33%. At a given dose of 5 million U, IFN did not significantly influence 5-FU serum levels. Mean steady-state serum levels of 5-FU at 500 mg/m2 given as a 4-hour infusion were 16.55 +/- 9.34 mumol/L and 18.23 +/- 12.77 mumol/L with and without IFN, respectively. Mean area under the curve (mumol/L x min) was 4,008 +/- 2,133 and 5,114 +/- 2,567 with and without interferon, respectively. Objective responses were seen in one of 17 of these heavily pretreated patients and stable disease was seen in seven of 17 patients. The recommended dose of 5-FU for use of phase II studies is 500 mg/m2/d for 7 days. We conclude that the toxicity of 5-FU plus FA with and without IFN alpha-2b can be reduced by using a 4-hour infusion instead of a bolus.

A phase II trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that folinic acid as well as interferon alpha-2b may enhance the antitumor activity of 5-fluorouracil (5-FU). In a phase I trial, we recently showed that interferon alpha-2b (IFN), folinic acid and 5-FU can be safely administered with a 4-hour infusion of 5-FU. We therefore initiated a phase II trial evaluating the efficacy and safety of these three drugs. Forty-five evaluable patients with advanced metastatic colorectal cancer, documented progressive disease, and previously unexposed to chemotherapy were treated with sequential IFN 5 MU/d subcutaneously and folinic acid 200 mg/m2/d as bolus on days 1 to 7 followed by 5-FU in a 4-hour infusion at a dose of 500 mg/m2/d, resulting in a total dose of 3,500 mg/m2/course. This schedule was repeated on day 21. A total of 204 courses of therapy were completed. One of 45 patients (2%) achieved a complete response, and 13 of 45 patients (29%) achieved a partial response. An additional 16 patients (36%) had stable disease. The median time to disease progression was seven months (2 to 24 months). Despite the relatively high-dose intensity of 5-FU, toxicity was very mild. Grade 3 or 4 myelosuppression, stomatitis, and nausea/vomiting occurred in only three of 45 patients (7%). Four of 45 patients (9%) suffered from severe (grade 3/4) diarrhea. Neurotoxicity and infections of grade 2 to 4 did not occur. From these data we conclude that modulation of 5-FU with both folinic acid and IFN induces an overall response rate of 31% in disseminated colorectal cancer. Using a 4-hour application schedule of 5-FU, the therapeutic index can be improved even for high-dose intensity and requires further evaluation in combination with other modulators.

Circulating nucleosomes in serum.

In the nucleus of eukaryotic cells, DNA is associated with several protein components and forms complexes known as nucleosomes. During cell death, particularly during apoptosis, endonucleases are activated that cleave the chromatin into multiple oligo- and mononucleosomes. Subsequently, these nucleosomes are packed into apoptotic bodies and are engulfed by macrophages or neighboring cells. In cases of high rates of cellular turnover and cell death, they also are released into the circulation and can be detected in serum or plasma. As enhanced cell death occurs under various pathologic conditions, elevated amounts of circulating nucleosomes are not specific for any benign or malignant disorder. However, the course of change in the nucleosomal levels in circulation of patients with malignant tumors during chemotherapy or radiotherapy is associated with the clinical outcome and can be useful for the therapeutic monitoring and the prediction of the therapeutic efficacy.

Pharmacokinetics of erythrocyte methotrexate after high-dose methotrexate.

Erythrocyte methotrexate (MTX) concentrations were determined in 10 patients with metastatic osteogenic or soft tissue sarcoma after 52 cycles of high-dose methotrexate (HDMTX). In contrast to serum MTX, pharmacokinetics of erythrocyte MTX showed three distinct phases: A rapid decrease to a nadir 2-3 days after MTX was followed by a significant rise of erythrocyte MTX until days 10-14. Subsequently there was a third phase, with a definite decrease of erythrocyte MTX concentrations with half-lives of 30-40 days. Short-term repititions of HDMTX had considerable influence on the first two phases of the kinetics. Each curve surpassed that of the previous therapy, and erythrocyte MTX concentrations increased continuously to the values measured at the end of the HDMTX infusion. The following mechanisms of MTX enrichment in erythrocytes is discussed: In erythro- and normoblasts MTX is converted to polyglutamate forms, which are retained inside the cell and are probably the reason for the relatively high sensitivity to MTX. Upon resumption of erythropoiesis the release of freshly prepared erythrocytes containing MTX and predominantly MTX polyglutamates causes the renewed increase in blood MTX levels.

Pharmacokinetics of reduced folates after short-term infusion of d, 1-folinic acid.

After the use of d,1-folinic acid (d,1-CHO-THF), pharmacokinetic measurements should take into account 1-CHO-THF and its metabolite 1-methyltetrahydrofolic acid (1-CH3-THF) as well as d-CHO-THF. For this purpose, we developed a simple and rapid assay by combining reversed-phase HPLC to determine total levels of d,1-CHO-THF and CH3-THF and chiral HPLC to separate the biologically active 1-CHO-THF from the inactive d-CHO-THF. We investigated the pharmacokinetics after short-term infusion of 300 mg d,1-CHO-THF in ten healthy volunteers. With a mean of 56.5 min, 1-CHO-THF exhibits a rapid body clearance of 222 ml/min, about 60% of which is caused by metabolism to CH3-THF and 40%, by renal excretion. CH3-THF has a terminal half-life of 208 min and a total body clearance of 88.9 ml/min, which is essentially the same as the renal clearance. Due to the lower clearance of CH3-THF, its AUC (2,132 microM x min) exceeds that of 1-CHO-THF (1445 microM x min) by approximately 50%. In contrast to that of the reduced 1-folates, the total body and renal clearance of d-CHO-THF is very low, with values of 13.2 and 12.9 ml/min, respectively. This results in a very high AUC of 24, 269 microM x min, which is higher by factors of 17 and 11 than those of 1-CHO-THF and CH3-THF, respectively. The implications of the distinct kinetics of the reduced 1-folates and d-CHO-THF for the efficacy of folinic acid/5-fluorouracil therapy and adequate protocols for the treatment of advanced colorectal cancer are discussed.

Biochemical control of high-dose methotrexate/Leucovorin rescue therapy.

High-dose methotrexate/Leucovorin rescue therapy is based on the assumption of differences in the transport system for folate compounds between normal and malignant proliferating cells. Thus, under normal conditions, methotrexate (MTX) and Leucovorin (citrovorum factor, CF) in low doses can enter the cells by an active transport system, whereas in some malignancies - such as osteosarcoma - these substances only penetrate through the cell membrane by passive diffusion if they are given in very high doses. Therefore, after high-dose MTX treatment, the cytotoxic effect of the folate antagonist is compensated for by rescue with Leucovorin in low doses only in the normal cell system. The consequence of this kind of treatment is a selective antitumor effect. To avoid cytotoxic side effects, this therapeutic regimen must be monitored carefully. The decrease of the ratio of 3H-deoxyuridine (dUR) beta H-thymidine (dTR) incorporation into the DNA of the cells is a good biochemical parameter for estimating the MTX effect on rapidly proliferating cell systems. Using this indicator, it was shown that the usually administered dose of Leucovorin is not sufficient for an effective rescue of the bone marrow cells as long as the MTX serum concentration is equal or higher than 10(-6) M. If in critical cases the MTX elimination is retarded, a rescue can only be achieved by Leucovorin at doses tenfold higher than the actual amount of MTX in the whole body system. The Leucovorin rescue does under such circumstances can be calculated according to the formula Leucovorin (mg) = 10 x MTX (mg/l) x 0.76 x body weight (kg).

Pharmacokinetics of methotrexate during regional hyperthermia in a pig model.

In the pig model, regional hyperthermia in the gluteus was combined with the infusion of 150 mg MTX over a period of 100-120 min. The pharmacokinetic data reveal that this approach is capable of simulating the situation that is necessary and achievable in medium-dose MTX therapy of human tumours. Under MTX infusion, serum levels in the region of 10(-5) M are attained. As an expression of a renal and hepatic MTX excretion, high levels of MTX are found both in the urine and in the bile. Especially high concentrations of MTX are found in the liver and kidney tissue. In the normothermic and hyperthermic muscle, very low MTX levels are found. The pharmacokinetic data obtained show that the selected model is suitable for the future investigation of the effect of regional hyperthermia and MTX on transplanted tumours.

Adjuvant chemotherapy of stage-ii nonseminomatous testicular cancer.

85 patients with resected stage II non-seminomatous testicular cancer were treated with adjuvant cisplatin-based chemotherapy. Only one patient developed a relapse 14 months after discontinuation of adjuvant chemotherapy, which was successfully treated with salvage chemotherapy. One patient developed a contralateral testicular tumor 6 years after primary therapy. After a median observation time of 6 years (range 2 months to 13 years) 84 patients are alive without evidence of testicular cancer; one died from an unrelated cause. In conclusion, adjuvant cisplatin-based chemotherapy for resected stage Il nonseminomatous testicular cancer almost always prevents relapse.

Hepatic arterial infusion with oxaliplatin, folinic acid, and 5-fluorouracil in patients with hepatic metastases from colorectal cancer: role of carcino-embryonic antigen in assessment of response.

BACKGROUND: Therapy for patients with hepatic metastases from colorectal cancer (CRC) remains controversial and may be improved by regional oxaliplatin which proved to be effective when administered systemically to patients with advanced CRC. METHODS: During the current study, which aims to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetics of oxaliplatin applied as hepatic intra-arterial infusion combined with folinic acid and 5-fluorouracil in patients with hepatic metastases from CRC, serial levels of carcino-embryonic antigen were determined and their relationship to response to therapy was assessed. RESULTS: Toxicity mainly consisted of nausea, pain, mucositis, sensorial neuropathy, diarrhoea, and thrombocytopenia. The results of tumor marker analyses suggest that progressive disease may be detected early by increasing CEA levels and responsive disease may be characterized by low or decreasing values. CONCLUSIONS: Further analyses are warranted to determine the role of CEA in the assessment of response as compared to imaging techniques.

CA19-9: a pedictor of response in pancreatic cancer treated with gemcitabine and cisplatin.

The question was asked whether kinetics of CA19-9 would serve as a predictor of chemotherapeutic outcome in advanced pancreatic cancer treated with gemcitabine and cisplatin. Twenty one patients, 5 females and 16 males (median age 56 yrs, range 36-71 yrs) suffering from adenocarcinoma of the exocrine pancreas were analysed. Chemotherapy was applied for a median of 6 courses (range 2-21). Four patients achieved a complete remission, four a partial remission (OR = 38%), while stable disease was documented in 8 and progressive disease in 5 patients. Among 4 CR patients, all demonstrated a significant decline of CA 19-9 levels during the initial three treatment courses with apparent half-lifes of 15, 18, 24, and 33 days. At a cut-off level of 37 U/mL, all CR patients reached normal values in the course of treatment. All patients achieving PR showed a decrease of CA 19-9 values at apparent half-lifes of 9, 16, 88 and 89 days. Among patients with stable disease, CA19-9 transiently decreased in 7/8 patients and remained stable in 1 patient. However, values increased later in all patients after a median of 3 treatment courses (range 2-9). In patients with disease progression, CA 19-9 initially increased in 4/5 patients, while a further patient did so only beyound 100 days of treatment. In conclusion, kinetics of CA19-9 serum concentration may serve as an early indicator of response to gemcitabine/cisplatin chemotherapy in advanced pancreatic cancer.