Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24).

BACKGROUND: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors. PATIENTS AND METHODS: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery. RESULTS: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions. CONCLUSION: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease. CLINICAL TRIAL NUMBER: NCT00309556, www.clinicaltrials.gov.

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer.

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.

Experimental transmission of pospiviroid populations to weed species characteristic of potato and hop fields.

Weed plants characteristic for potato and hop fields have not been considered in the past as potential hosts that could transmit and lead to spreading of potato spindle tuber (PSTVd) and hop stunt (HSVd) viroids, respectively. To gain insight into this problem, we biolistically inoculated these weed plants with viroid populations either as RNA or as cDNA. New potential viroid host species, collected in central Europe, were discovered. From 12 weed species characteristic for potato fields, high viroid levels, detectable by molecular hybridization, were maintained after both RNA and DNA transfers in Chamomilla reculita and Anthemis arvensis. Low viroid levels, detectable by reverse transcription-PCR (RT-PCR) only, were maintained after plant inoculations with cDNA in Veronica argensis and Amaranthus retroflexus. In these two species PSTVd concentrations were 10(5) and 10(3) times, respectively, lower than in tomato as estimated by real-time PCR. From 14 weeds characteristic for hop fields, high HSVd levels were detected in Galinsoga ciliata after both RNA and DNA transfers. HSVd was found, however, not to be transmissible by seeds of this weed species. Traces of HSVd were detectable by RT-PCR in HSVd-cDNA-inoculated Amaranthus retroflexus. Characteristic monomeric (+)-circular and linear viroid RNAs were present in extracts from weed species propagating viroids to high levels, indicating regular replication, processing, and circularization of viroid RNA in these weed species. Sequence analyses of PSTVd progenies propagated in C. reculita and A. arvensis showed a wide spectrum of variants related to various strains, from mild to lethal variants; the sequence variants isolated from A. retroflexus and V. argensis exhibited similarity or identity to the superlethal AS1 viroid variant. All HSVd clones from G. ciliata corresponded to a HSVdg variant, which is strongly pathogenic for European hops.

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer.

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.

Biolistic inoculation of plants with viroid nucleic acids.

Parameters for biolistic transfer of viroid nucleic acids using a Helios Gene Gun device were assayed. The main achievement of this method is high efficiency of inoculation with linear monomeric viroid cDNAs and RNAs. This greatly facilitates the study of mutated sequence variants, viroid libraries and mixed populations. The lower limits for efficient inoculation of monomeric cDNA fragments with the sequence of potato spindle tuber viroid (PSTVd) and native PSTVd RNA as detected 21 days p.i. are in the range of 50 ng and 200 pg per tomato plant, respectively. At a higher dose, i.e. 2 ng of native RNA per plant, biolistic transfer causes drastic stunting compared to conventional mechanical inoculation, which points to higher PSTVd titers after the biolistic transfer. Infection is readily achieved with exact length monomeric RNA transcripts having 5'-triphosphate and 3'-OH termini in amounts ranging from 2 to 20 ng per plant, suggesting no need for any supplementary modifications of ends or RNA circularization. The biolistic transfer is efficient for viroid "thermomutants", which exhibit low or no infectivity with conventional mechanical inoculation with Carborundum. The biolistic inoculation is also efficient for two other members of the Pospiviroidae family, hop stunt and hop latent viroid.

Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients.

AIM: A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF. PATIENTS AND METHODS: Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre. RESULTS: After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups. CONCLUSIONS: Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.

The variability of hop latent viroid as induced upon heat treatment.

We have previously shown that heat treatment of hop plants infected by hop latent viroid (HLVd) reduces viroid levels. Here we investigate whether such heat treatment leads to the accumulation of sequence variability in HLVd. We observed a negligible level of mutated variants in HLVd under standard cultivation conditions. In contrast, the heat treatment of hop led to HLVd degradation and, simultaneously, to a significant increase in sequence variations, as judged from temperature gradient-gel electrophoresis analysis and cDNA library screening by DNA heteroduplex analysis. Thirty-one cDNA clones (9.8%) were identified as deviating forms. Sequencing showed mostly the presence of quadruple and triple mutants, suggesting an accumulation of mutations in HLVd during successive replication cycles. Sixty-nine percent of base changes were localised in the left half and 31% in the right half of the secondary structure proposed for this viroid. No mutations were found in the central part of the upper conserved region. A "hot spot" region was identified in a domain known as a "pathogenicity domain" in the group representative, potato spindle tuber viroid. Most mutations are predicted to destabilise HLVd secondary structure. All mutated cDNAs, however, were infectious and evolved into complex progeny populations containing molecular variants maintained at low levels.

Point mutations in SP1 motifs in the upstream regulatory region of human papillomavirus type 18 isolates from cervical cancers increase promoter activity.

Evidence of the functional significance of two naturally occurring mutations at nt 40 or 41 in the Sp1 motif in the promoter proximal segment of the upstream regulatory region (URR) of human papillomavirus (HPV) type 18 is presented. In electrophoretic mobility shift assays, Sp1 protein bound more efficiently to the Sp1 mutant motifs than to the prototype; while in both HeLa and HT3 cells, luciferase activity controlled by the mutant URRs was upregulated 2- and 3-fold, or 4- and 6-fold, in comparison with the prototype URR or HeLa cell-derived URR respectively. The HeLa URR represents a more appropriate baseline for promoter activity, containing a series of point mutations representative of most HPV-18 cancer isolates, including one in the Yin Yang 1 (YY1) site at the P105 promoter. The effect of the Sp1 mutations was found to be largely maintained in the context of the HeLa URR containing the prototype YY1 site.

Very low-dose adjuvant chemotherapy in steroid receptor negative stage I breast cancer patients. Austrian Breast Cancer Study Group.

A randomised clinical trial was performed to test whether or not low-dose chemotherapy lasting only 35 days improves the outcome of breast cancer patients with stage I disease and negative oestrogen and progesterone receptors (ER-, PgR-). Between 1984 and 1990, 277 stage I breast cancer patients with tumours negative for both oestrogen and progesterone receptors were randomised to receive either low-dose short-term chemotherapy or no chemotherapy. Chemotherapy consisted of one cycle of doxorubicin, vincristin (AV) and one cycle of cyclophosphamide, methotrexate, fluorouracil (CMF). Patients were stratified for tumour stage, type of surgery, menopausal status and participating centre. Results were analysed both by univariate and multivariate statistical. After a median length of follow-up of 84 months, disease-free (DFS) and overall survival (OS) did not differ significantly between patients having received adjuvant chemotherapy and the control group. Uni- and multivariate analysis did not show any significant prognostic or therapy related factor. A low-dose short-term adjuvant chemotherapy is insufficient to improve the prognosis of patients with breast cancer stage I with ER-, PgR-tumours.

RNA structural features responsible for potato spindle tuber viroid pathogenicity.

The native structure of potato spindle tuber viroid (PSTVd) contains a series of short double helices and small internal loops that are organized into five structural domains. Nucleotides within the pathogenicity domain are known to play a critical role in modulating PSTVd symptom expression, and it has been suggested that disruption of a comparatively unstable "premelting region" within the pathogenicity domain may be required for disease induction. We have used a combination of quantitative bioassays, temperature gradient gel electrophoresis of circularized RNA transcripts, and thermodynamic calculations to compare the biological and structural properties of 12 representative PSTVd sequence variants. Certain mutations appeared to act indirectly, downregulating pathogenicity by suppressing the rate of PSTVd replication/accumulation. The effects of other mutations appeared to be more direct, but there was no consistent correlation between symptom severity and melting temperature. Taking into account the three-dimensional shape of RNA helices, comparison of the optimal secondary structures for these variants point to major differences in the geometry of their pathogenicity domains; i.e., variants producing intermediate symptoms possess a linear arrangement of three consecutive helices, whereas for variants producing mild or severe symptoms this domain is bent in opposing directions. Such alterations in RNA structure together with concomitant alterations in RNA-protein interaction(s) may be the primary cause of viroid pathogenicity.

Description of RNA folding by "simulated annealing".

An algorithm is proposed which describes the thermodynamically as well as the kinetically controlled folding process of RNA. The algorithm, based on a special Monte Carlo procedure known as "Simulated Annealing", takes into account the probabilities for opening and closing of single base-pairs. Thus, the algorithm is able to reach structures and structure distributions near the global minimum of structure space, and is not restricted by the tendency to halt in local minima. Three types of structural folding processes may be analysed by this algorithm. Firstly, using thermodynamic data, structure ensembles comparable to those obtained by dynamic programming are achieved. Secondly, using kinetic data, the processes of structure formation and structural rearrangement may be simulated. Thirdly, additionally taking into account RNA polymerase chain elongation rates, the process of "sequential folding" during transcription may be described. Analysis of all types of structural folding and refolding is performed for RNA sequences related to potato spindle tuber viroid (PSTVd). The computed results are in accordance with experimental data and biological functions known for PSTVd.

Interdependence of pathogenicity and replicability with potato spindle tuber viroid.

After the unexpected appearance of lethal symptoms on tomato plants infected with the PSTVd strain Intermediate Di, viroids were isolated and sequenced. It was found that a new strain, named RG 1, had been generated spontaneously in our greenhouse. In a different series of plant passages two new strains, named QF A and QF B, were detected which coexisted with the wild-type strain Di. Strains QF A and QF B showed intermediate symptoms when inoculated separately. In order to confirm the working hypothesis that the more pathogenic strain outcompetes the less pathogenic strain but strains of similar pathogenicity might coexist in the host, strains of different pathogenicity were mixed for inoculation in a ratio from 1:1 to 1:100 (more pathogenic:less pathogenic). The concentrations of the individual strains were determined 6 weeks postinfection with the method of nondenaturing polyacrylamide gel electrophoresis, and the working hypothesis was confirmed. The total concentrations of viroids in infected plants were very similar, irrespective of whether severe, intermediate, or mild strains or mixtures of different strains were present. The mutations in all new strains (3 in RG 1, 2 in QF A, 3 in QF B) were located in the so-called virulence-modulating region. The mutations of strain RG 1 influenced dramatically the thermodynamic stability of the native rod-like structure, as determined experimentally by temperature-gradient gel electrophoresis. Since during replication a multihairpin structure is generated transiently which is transformed afterwards into the rod-like structure, a lower thermodynamic stability of the rod-like structure leads to a higher accumulation of the transient structure. It is assumed that the transient structure, which is active in replication as shown earlier, is essential also in pathogenesis. This model explains the experimentally determined interdependence between pathogenicity and replicability of PSTVd strains.

[Primary (preoperative, neoadjuvant) chemotherapy of colon cancer--a therapeutic alternative?]. / Primäre (präoperative, neoadjuvante) Chemotherapie beim Coloncarcinom--eine Therapiealternative?

Primary chemotherapy is an established treatment in selected patients with osteosarcoma and locally advanced breast cancer. In several other tumor entities this therapeutic approach is under clinical investigation. In contrast, colon carcinoma has been believed to be chemoresistant for a long period of time. Thus, no therapeutic approaches dealing with preoperative therapy have been initiated yet. Recent studies showing remission rates as high as 40% in advanced colon cancer and the proof of efficacy for postoperative adjuvant chemotherapy must now lead to reevaluation of the therapeutic approach to this tumor entity. Data from animal models as well as several tumor biologic hypotheses also point to a possible advantage for preoperative therapy in order to ameliorate relapse-free survival and overall survival in these patients. In this work we discuss potential advantages and disadvantages of primary, neoadjuvant strategies of treatment for colon cancer. Based on these pros and cons, clinical studies for a preoperative therapeutic approach appear to be justified and necessary in patients with locally advanced disease and in patients with metastases at the time of diagnosis.

Folate absorption in Crohn's disease.

An oral folate absorption test was performed in 100 consecutive patients with Crohn's disease (CD) and 20 healthy individuals to investigate the frequency of abnormal folate absorption in regard to the site of the disease and to investigate the possibility of defining a subgroup of patients requiring parenteral folate supplementation. The described oral folate absorption test can be performed quickly on an outpatient basis and is capable of distinguishing patients with altered folate absorption from those with normal folate absorption. In 25 patients, abnormal folate absorption was detected. 16 patients showed impaired folate absorption as indicated by a marked but insufficient increase in serum folate levels after oral folate intake, whereas no increase of the serum folate levels was detected in the remaining 9 patients. Abnormal folate absorption was not correlated with disease extent or activity. In patients with only impaired folate absorption, it might be sufficient to increase dietary intake of folates. In the remaining patients with no measurable increase of serum folate levels after oral folate intake, i.e. about 10% of all patients with CD, parenteral folate supplementation could be considered.

Double modulation of 5-fluorouracil by high-dose leucovorin and interferon alpha 2b in advanced colorectal cancer: a phase I and a phase II study of weekly administration.

In an attempt to evaluate the feasibility of 5-fluorouracil (FU) treatment modulated by (R,S)-leucovorin (LV) and interferon alpha (IFN alpha) in patients with advanced colorectal cancer, we conducted a phase I trial with increasing doses of subcutaneous IFN alpha (3 x 1 x 10(6) U, 3 x 3 x 10(6) U, 3 x 3 x 10(6) U, 3 x 5 x 10(6) U and 3 x 10 x 10(6) U/week) and 500 mg/m2 LV i.v. as a 2-h infusion with 600 mg/m2 FU i.v. as a midpoint injection. Unacceptable side-effects occurred in all 3 patients at the highest dose level of IFN alpha, while toxicity was tolerable at 3 x 5 x 5 x 10(6) U IFN alpha/week. Thus, this dose was defined as the maximal tolerable dose for IFN alpha in combination with FU and LV. In a subsequent phase II study a total of 83 treatment courses (median: 2.8, range: 2-10) were administered to 30 evaluable patients. Side-effects were acceptable with no WHO grade IV toxicities. Grade III toxicities consisted in thrombopenia (2/30), stomatitis (2/30), diarrhoea (3/30) and nausea/vomiting (4/30). After a median observation time of 17 months (range: 8-22 months), no complete remission was observed and 9 patients experienced a partial response lasting for a median of 6.6 months (range: 3-13+ months), for an overall response rate of 30% (95% confidence interval: 15%-49%). These results show that the described regiment of FU doubly modulated by LV and IFN alpha is active in colorectal cancer and can be safely administered in an out patient setting with acceptable toxicity. Thus, this regimen is suitable to be used for further evaluation in clinical trials.

GM-CSF in the treatment of a patient with severe methotrexate intoxication.

This case report describes the successful treatment of severe methotrexate intoxication in a 72-year-old female patient. Following two prior uneventful courses of a polychemotherapy regimen including low-dose intravenous (i.v.) methotrexate, the patient presented with fever, polymucositis, incipient pyodermia, acute renal failure and pancytopenia 9 days after the third application. Severe methotrexate overdose was confirmed by serum levels. Using a polypragmatic treatment approach focusing on renal function and including granulocyte-macrophage-colony-stimulating factor (GM-CSF) this life threatening and nearly fatal intoxication was successfully treated. This case report demonstrates that GM-CSF might contribute to rapid reconstitution of leukopoiesis once methotrexate serum levels are in the subtoxic range.

Inhibition of potato spindle tuber viroid (PSTVd) infection with DNA oligonucleotides.

The effects of DNA oligonucleotides complementary to potato spindle tuber viroid (PSTVd) on viroid infection were investigated. The oligonucleotides were used to form hybrids with PSTVd in the infection mixture. A 75% reduction of viroid infection was found when an oligonucleotide complementary to nucleotides 79-110 of PSTVd was hybridized with PSTVd at a molar ratio of approximately 5000:1, respectively. A total inhibition of PSTVd infection was observed using an oligonucleotide complementary to nucleotides 42-78 at the same molar excess of DNA over PSTVd, although a 200-fold molar excess was found to be sufficient for the complete blocking of infection by PSTVd. This oligonucleotide caused a significant reduction (about 83%) of viroid infection even if the hybridization was done at a low (30 degrees C) temperature. Shorter oligonucleotides containing 22 and 15 bases corresponding to position 42-62 and 63-78, respectively, exhibited a significant effect only at a high (80 degrees C) initial temperature of molecular hybridization. Heteroduplexes formed between PSTVd RNA and antisense DNA were found to be less stable in a crude nuclease extract from tomato leaves as compared with PSTVd RNA alone. RNase H was demonstrated to cleave the molecular hybrids in vitro.

Effects of random mutagenesis upon potato spindle tuber viroid replication and symptom expression.

A combination of random chemical mutagenesis plus temperature gradient gel electrophoresis was used to isolate a collection of 57 potato spindle tuber viroid (PSTV) cDNAs containing mutations distributed throughout the entire 359 nucleotide genome. Although the presence of multiple mutations was often associated with a loss of cDNA infectivity, infectious PSTV cDNAs containing as many as four unlinked alterations could be isolated. Several mutations in the pathogenicity domain and left terminal loop were stably maintained in the resulting progeny, but those which affect base pairing in secondary hairpins I and II were either lethal or rapidly reverted to wild-type. One stable C----U substitution which may promote significant structural rearrangement within the right side of the pathogenicity domain had no detectable effect upon symptom expression. The variable domains of several noninfectious mutants contained an A----G substitution which is likely to inhibit the in vitro formation of secondary hairpin II via stabilization of the native structure, and the lethal nature of this mutation was confirmed by oligonucleotide-directed mutagenesis. Several lines of evidence now point toward an essential role for secondary hairpin II in the replication of PSTV and related viroids.

Formation of a thermodynamically metastable structure containing hairpin II is critical for infectivity of potato spindle tuber viroid RNA.

The functional relevance of a hairpin II-containing structure of viroid RNA was studied by site-directed mutagenesis, thermodynamic calculations, experimental denaturation curves and infectivity tests. Hairpin II is formed during thermal denaturation of circular viroids or as part of a metastable structure during synthesis of viroid replication intermediates. In potato spindle tuber viroid (PSTVd), eight single-site mutations were generated in the segments which form hairpin II. From the mutated viroid cDNA clones, linear RNA transcripts of PSTVd unit length were synthesized. The relevance of hairpin II for the mechanism of denaturation was confirmed quantitatively by optical denaturation curves and temperature-gradient gel electrophoresis. Infectivity tests showed that the mutations in the core region of hairpin II reverted to the wild type sequence whereas the mutations in the peripheral regions of hairpin II remained genetically stable. These data are in accordance with the natural variance of hairpin II in other viroids of the PSTVd class. Thus, the integrity of the core of hairpin II is critical for infectivity. Hairpin II exhibits a strong similarity in sequence as well as in three-dimensional structure to certain DNA GC-clusters found in the 5'-upstream regions of some genes in man, animals, viruses and plants. A hypothesis about a function of hairpin II as a binding site for host cell transcription factors is proposed.

[Current status of adjuvant therapy in patients with colorectal cancer: report and commentary on the Consensus Conference, 16-18 April 1990, National Cancer Institute, Bethesda, Maryland]. / Gegenwärtiger Stand der Adjuvanstherapie bei Patienten mit kolorektalem Karzinom: Bericht und Kommentar zur Consensus-Konferenz, 16. bis 18. April 1990, National Cancer Institute, Bethesda, Maryland, U.S.A.

This is a report on the Consensus Development Conference on adjuvant therapy for patients with colorectal carcinoma, which was held at the National Cancer Institute of the National Institutes of Health (NIH) in Bethesda, Maryland between April 16th and 18th 1990. Based on statistically significant results of a clinical trial adjuvant therapy with 5-fluorouracil (5-FU) and levamisole was recommended outside controlled clinical studies for patients with Dukes C colon carcinoma, but because no optimal form of adjuvant therapy yet exists there is still the need for further trials. No recommendations were given for patients with Dukes B colon carcinoma. For patients with Dukes B + C rectal cancer combined radiation therapy and 5-FU-based chemotherapy was considered "standard therapy" according to the consensus panel, but this recommendation seems to be still worth discussing. Since there is need of further evaluation of newly-recognized prognostic factors and also to optimize adjuvant strategies the panel stated that further prospective randomized studies are warranted. Hence, the establishment of a multicentre study group also in Austria appears to be an essential application of such trials in order to contribute towards ameliorating the prognosis of patients with colorectal carcinoma.