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.

Pharmacokinetics of 5-fluorouracil in patients heterozygous for the IVS14+1G > A mutation in the dihydropyrimidine dehydrogenase gene.

5-Fluorouracil (5FU) and capecitabine are two of the most frequently prescribed chemotherapeutic drugs for the treatment of patients with cancer. Administration of test doses of 5FU to eight patients heterozygous for the IVS14+1G > A mutation and five control patients showed that the AUC and clearance were weak parameters with respect to the identification of patients with a DPD deficiency. However, highly significant differences were observed for the terminal half life of 5FU between DPD patients and controls. Thus, a DPD deficiency could be predicted from 5FU blood concentrations measured after the administration of a test dose of 5FU.

[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.

Are serial CA 19-9 kinetics helpful in predicting survival in patients with advanced or metastatic pancreatic cancer treated with gemcitabine and cisplatin?

BACKGROUND: Serial kinetics of serum CA 19-9 levels have been reported to reflect response and survival in patients with pancreatic cancer undergoing surgery, radiotherapy, and chemotherapy. We prospectively studied serial kinetics of serum CA 19-9 levels of patients with locally advanced or metastatic disease treated with gemcitabine and cisplatin. PATIENTS AND METHODS: Enrolled in the study were 87 patients (female/male = 26/61; stage III/IV disease = 24/63). Patients received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 50 mg/m(2) on days 1 and 15, every 4 weeks. Serum samples were collected at the onset of chemotherapy and before the start of a new treatment cycle (day 28). RESULTS: 77 of 87 patients (88.5%) with initially elevated CA 19-9 levels were included for evaluation. According to imaging criteria, 4 (5.2%) achieved a complete remission and 11 (14.3%) achieved partial remission, yielding an overall response rate of 19.5%. 43 (55.8%) patients were CA 19-9 responders, defined by a > or = 50% decrease in CA 19-9 serum levels within 2 months after treatment initiation. Except for one, all patients who had responded by imaging criteria (n = 14) fulfilled the criterion of a CA 19-9 responder. Despite being characterized as non-responders by CT-imaging criteria (stable/progressive disease), 29 patients were classified as CA 19-9 responders (positive predictive value 32.5%). Independent of the response evaluation by CT, CA 19-9 responders survived significantly longer than CA 19-9 nonresponders (295 d; 95% CI: 285-445 vs. 174 d; 95% CI: 134-198; p = 0.022). CONCLUSION: CA 19-9 kinetics in serum serve as an early and reliable indicator of response and help to predict survival in patients with advanced pancreatic cancer receiving effective treatment with gemcitabine and cisplatin.

Capecitabine as second-line treatment for metastatic cholangiocarcinoma: a report of two cases.

BACKGROUND: The management of recurrent, metastatic cholangiocarcinoma still remains a problem since this tumor entity is classified as chemotherapy-resistant. When advanced or metastatic disease is diagnosed, the therapeutic efforts are essentially directed toward palliation. PATIENTS AND METHODS: We report on 2 patients suffering from metastatic cholangiocarcinoma. Both had received previous chemotherapy for metastatic disease, including hepatic artery infusion [5-fluorouracil (5-FU) / folinic acid (FA) and oxaliplatin] and a combination therapy consisting of 5-FU/FA and gemcitabine. Since a progression of the disease was diagnosed, both patients were started on oral capecitabine at a daily dose of 2,500 mg/m(2) in 2 divided doses for 2 weeks, followed by 1 week rest. RESULTS: Capecitabine was tolerated well and severe side effects were not observed. A stop of progression, documented by imaging procedures and tumor marker kinetics, was achieved in both patients. CONCLUSION: Capecitabine could potentially be used for secondline treatment in patients with progressive metastatic cholangiocarcinoma.

Weekly irinotecan in a patient with metastatic colorectal cancer on hemodialysis due to chronic renal failure.

BACKGROUND: The cytotoxic treatment of patients suffering from advanced or metastatic cancer undergoing hemodialysis due to chronic renal failure still remains a problem, since for those patients pharmacokinetic and pharmacodynamic data on most cytotoxic agents are lacking. CASE REPORT: We report a 45-year-old male who suffered from chronic renal failure and was diagnosed with stage-3 colorectal cancer (CRC) in February 2000. After surgical removal of the tumor an adjuvant chemotherapy of dose-reduced i.v. bolus 5-fluorouracil and folinic acid was begun (Mayo protocol). Due to excessive gastrointestinal toxicity, therapy was discontinued after the first cycle. In April 2000 liver metastases were diagnosed. The patient was then put on a weekly schedule of dose-reduced CPT-11 (50 mg/m(2), 80 mg total). No hematological or non-hematological toxicity grade 3/4 was observed. Due to excellent tolerability and lack of severe side effects the dose was increased up to 80 mg/m(2) (140 mg total) weekly. A dose escalation to 100 mg/m(2) (180 mg total) resulted in severe diarrhea (grade 4). Within 2 months of treatment the patient achieved a lasting partial remission until April 2001 (12 months). A significant progression of hepatic metastases required an alternative treatment regimen beginning in July 2001 (HAI, hepatic artery infusion). CONCLUSION: This case report demonstrates the feasibility and efficacy of a weekly treatment with dose-reduced CPT-11 in a patient with metastatic CRC on hemodialysis due to chronic renal failure.

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.

Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer.

BACKGROUND: To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. PATIENTS AND METHODS: Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2). RESULTS: Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). CONCLUSIONS: The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.

Nucleosomes in serum of patients with benign and malignant diseases.

High quantities of mono- and oligonucleosomes circulate in the blood of patients with malignant tumors. For their direct quantification in serum, we modified the Cell Death Detection(plus)-ELISA for its application in liquid materials. We examined sera samples from 590 persons, including 418 patients with malignant tumors, 109 patients with benign diseases and 63 healthy persons. We also observed the kinetics of the concentration of nucleosomes in serum samples from 20 patients undergoing chemotherapy and from 16 patients undergoing radiotherapy. Sera of patients with malignant tumors contained considerably higher concentrations of nucleosomes (mean = 350 arbitrary units [AU], median = 190 AU) compared with those of healthy persons (mean = 36 AU, median = 24 AU; p = 0.0001) and patients with benign diseases (mean = 264 AU, median = 146 AU; p = 0.072). Concerning the follow-up investigations, the concentration of nucleosomes in serum increased 24-72 hr after the first application of chemotherapy and 6-24 hr after the start of radiotherapy. A subsequent decrease was often correlated with regression of the tumor. In patients undergoing chemotherapy, an increase in the baseline values of circulating nucleosomes >50%, which were determined before each new therapeutic cycle, was correlated with progression of disease; all patients with disease regression showed a decrease >50% of the baseline values. In patients undergoing radiotherapy, an early decrease of the nucleosomal concentration (< or = 1 day after the initial peak during therapy) to low minimum levels (< or = 100 AU) correlated with good clinical outcome; a late decrease (>1 day) to higher minimum levels (>100 AU) was associated with a worse clinical outcome. Thus, the concentration of nucleosomes in serum might be a useful tool for monitoring the biochemical response during antitumor therapy, especially for the early estimation of therapeutic efficacy.

Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer.

BACKGROUND: This phase II study was initiated to determine the efficacy and safety of gemcitabine plus cisplatin in patients with pancreatic cancer. PATIENTS AND METHODS: Gemcitabine 1000 mg/m2 was given on days 1, 8, and 15 of a 28-day schedule, and cisplatin 50 mg/m2 on days 1 and 15 to chemonaive patients with locally advanced or metastatic pancreatic cancer. RESULTS: Of the 41 patients enrolled (median age 57, and 61% male), median Karnofsky performance status was 80%. Patients received a median of 4.2 cycles (range 1-11). In 35 evaluable patients, one complete response (CR) and three partial responses (PR) were observed, for an overall response rate of 11% (95% confidence interval (95% CI): 3.2% -26.7%). Stable disease (SD) > 3 months occurred in 20 (57%) patients; 6 survived > or = 1 year. Median time to progressive disease was 4.3 months (95% CI: 3.0-5.7 months). For all patients, median survival was 8.2 months (95% CI: 6.1-10.6 months) with a one-year survival rate of 27%. Therapy was well tolerated. Grade 3-4 neutropenia (no grade 3-4 infection), thrombocytopenia (no bleeding), nausea/vomiting, and alopecia were reported in 29%, 13%, and 2.6% of patients, respectively. CONCLUSIONS: The combination of gemcitabine and cisplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer without compromising tolerability.

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.

[Percutaneous implantation of port-catheter systems for intraarterial chemotherapy of the liver]. / Perkutane Implantation von Portsystemen in der Arteria hepatica.

PURPOSE: The objective of this study was to determine the usefulness, safety and acceptance of a new technique of percutaneous implantation of port-catheter-systems (PIPS) for locoregional intraarterial chemotherapy of the liver. MATERIAL AND METHODS: In 50 patients with malignant hepatic disease, 52 percutaneously implantable port-catheter systems were implanted for intraarterial chemotherapy of the liver as an interventional radiological technique. A commercially available angiographic catheter was placed in the hepatic artery under fluoroscopic control via a transfemoral approach and connected to a Port-A-Cath situated in the groin. This procedure was done on an outpatient basis; no medical treatment was administered. RESULTS: Percutaneous placement of the port-catheter system was successful in all cases, also in those with a hepatomesenteric trunk. No peri- and post-interventional complications occurred. The median patency was 312 days (13-547 days). The catheter-related complication rate was 12%. The function could be restored by replacement or an interventional procedure in all but one case (2%). Infection and leakage did not occur. The system had been withdrawn without complications in 7/52 cases for a variety of reasons (e.g. hemihepatectomy, desire of the patient or clinician, dissection after intervention, replacement). CONCLUSION: Percutaneous placement of a port-catheter system is a safe and easy alternative to the surgical placement of port systems for hepatic intraarterial chemotherapy. Long-term complication rates are comparable. The option of easy withdrawal and interventional correction of dysfunction as well as lower costs are additional advantages.

Nuclear mitotic apparatus protein (NuMA) in benign and malignant diseases.

Nuclear mitotic apparatus protein (NuMA) is a 239 kDa internal nuclear matrix protein described to be elevated in cancer patients, especially in colorectal carcinoma and early colorectal cancers. We tested the significance of NuMA as tumour marker in colorectal cancer and also the sensitivity/specificity profile in general. Therefore, we investigated in a retrospective clinical study 507 sera from patients suffering from solid tumours, with the main emphasis on colorectal carcinoma, and 418 sera from patients with benign diseases and healthy individuals. Testing was done with a double monoclonal enzyme immunoassay detecting head and rod domain of NuMA and results were compared to the established tumour associated antigens. Based on a specificity of 95% versus the benign reference group of gastrointestinal diseases, we found--at the time of primary diagnosis--a sensitivity for colorectal cancer of 8% for NuMA, 36% for CEA and 17% for CA 19-9. Regarding T-stages of colorectal cancer no marker detected T1 when regarding 95% specificity-cut-off value but NuMA showed little more sensitivity when based on a 95% specificity cut off value versus healthy. This could not be shown in Dukes' stages. Regarding all other solid tumours tested--all based on a specificity of 95% for the corresponding benign reference groups--no advantage of NuMA in sensitivity for all other solid tumours investigated was found. No additional sensitivity could be observed. Based on our results, the NuMA-assay in its present form has no clinical relevance.

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.

CA 242 in comparison with established tumour markers in colorectal, pancreatic and lung cancer.

In a prospective study (N = 566) we investigated the tumour associated carbohydrate-protein CA 242, focusing on the question whether CA 242 (CaNAG, Sweden) expression in carcinoma patients is distinctly higher than in benign disorders, especially when compared to CA 19-9 (EIA Roche Germany). A second point of interest was if CA 242 is expressed to a higher extent in early stages of colorectal cancer than CEA (MEIA Abbott, USA) and CA 19-9 are, and third its behavior in pancreatic and lung cancer. We found CA 242 values comparable in healthy individuals and benign gastrointestinal disorders, thus CA 19-9 remains the marker of first choice for pancreatic cancer and CEA for colorectal cancer. CA 242 shows no advantage in lung cancer as compared to the established markers (CEA, CYFRA 21-1 (EIA Roche Germany) and NSE (EIA Hoffmann LaRoche, Switzerland) and no clearly higher expression in early colorectal cancer. Overall, the combination of CEA and CA 242 shows the best sensitivity in colorectal cancer.

Pro-gastrin-releasing peptide (ProGRP)--a useful marker in small cell lung carcinomas.

Gastrin-releasing-peptide (GRP), the mammalian counterpart of amphibian bombesin, has been reported to be produced by cells of SCLC. Using recombinant ProGRP Yamaguchi et al developed an enzyme immunoassay for the measurement of this more stable precursor of GRP. We focused our interest on the comparability of ProGRP to neuron specific enolase (NSE), CYFRA 21-1 and CEA. For this purpose we investigated the sera of 272 patients with histologically proven carcinomas of the lung (87 SCLC, 185 NSCLC). The sera of 74 patients with benign diseases of the lung and smokers served as a reference group. At a specificity of 95% ProGRP and NSE possessed comparable sensitivities (47% versus 45%) in small cell lung carcinomas. ProGRP showed only a few more positive test results than NSE, but reached much higher value levels than NSE. ProGRP and NSE showed a clear additive sensitivity of about 20%. In NSCLC CYFRA 21-1 was the leading marker with 63% sensitivity, whereas ProGRP seldom showed a "false positive" test result. ProGRP proved a very high specificity and good sensitivity for small cell lung carcinomas and therefore enables diagnosis of small cell lung carcinoma in patients with lung tumours of unknown origin as well as good control of efficiency of therapy.