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Herpes zoster (HZ) is a frequent complication after autologous stem cell transplantation (ASCT). The option of zoster prophylaxis with an antiviral drug is described in the literature, but there is no consensus on the drug and the dosage.We analyzed the records of 310 patients treated with ASCT who were controlled regularly regarding HZ inter alia for at least 24 months following ASCT. Since 01/2015 patients received prophylactic low-dose acyclovir (400 mg per day) during the first 12 months following discharge after ASCT (n = 107).Twenty percent of patients without this kind of prophylaxis and 2.8% of patients with prophylaxis developed HZ (p .001). No patient with this prophylaxis developed HZ in the first year after ASCT, 2.8% of patients in the second year after ASCT. A prognostic factor was the kind of diagnosis: 30% of lymphoma patients and 14% of myeloma patients developed HZ in the first 24 months after ASCT without prophylaxis, but only 6.3% and 0% of patients with prophylaxis, respectively. Neither an increase of HZ cases following prophylaxis nor acyclovir refractory HZ cases were observed.Zoster prophylaxis with low-dose acyclovir over 12 months after ASCT is effective and well tolerated.

OBJECTIVE To contribute data on long-term outcome and potential curative impact of ASCT in FL, especially following HDT with the BEAM protocol (BCNU, etoposide, cytarabine and melphalan), given very limited data on this topic in the literature. PATIENTS AND METHODS Patients with FL (n = 76) were treated in our institution with HDT and ASCT. In the case of long-term remission (≥8 years), peripheral blood was tested for minimal residual disease by t(14;18)- and IGH-PCR, including the last follow-up. RESULTS 10-year overall survival, progression-free survival, and freedom from progression (FFP) after first-line ASCT (n = 20) were 80%, 60%, and 69%, after second-line ASCT (n = 48, following BEAM) 66%, 38%, and 41%, after third/fourth-line ASCT (n = 8) 33%, 25%, and 25%, respectively. Prognostic factors for FFP were treatment line and FLIPI (Follicular Lymphoma International Prognostic Index). 10-year FFP for second-line ASCT and low-risk FLIPI at relapse was 69%, intermediate-risk 28%, and high-risk 25% (P

Colorectal cancer is a clinically and molecularly heterogeneous disease. Currently, extended RAS and BRAF mutation testing is obligatory in routine clinical practice before starting any treatment in the metastatic setting. Treatment decision making also includes assessment of the clinical condition of the patient, definition of the treatment goal, and consideration of the primary tumor site. Biological treatment is part of the first-line drug combination unless contraindicated. Mutational status is significantly associated with the outcome of patients and is strongly predictive for anti-EGFR-targeted therapy. The prognosis of RAS mutant CRC is clearly inferior to wild-type cases. RAS remains an elusive target, and specific treatment options are not yet available. Recently, promising results of a direct KRAS G12C inhibitor have been reported; however, further confirmation is needed. The biomarker landscape in mCRC is evolving; new promising markers are awaited with the chance of more precise targeted treatment.

Purpose: The BRCA1-like profile identifies tumors with a defect in homologous recombination due to inactivation of BRCA1. This profile has been shown to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break-inducing chemotherapy. We tested the predictive potential of the BRCA1-like profile for adjuvant non-myeloablative, intensified dose-dense chemotherapy in the GAIN trial. Methods: Lymph node positive breast cancer patients were randomized to 3 × 3 dose-dense cycles of intensified epirubicin, paclitaxel, and cyclophosphamide (ETC) or 4 cycles concurrent epirubicin and cyclophosphamide followed by 10 cycles of weekly paclitaxel combined with 4 cycles capecitabine (EC-TX). Only triple negative breast cancer patients (TNBC) for whom tissue was available were included in these planned analyses. BRCA1-like or non-BRCA1-like copy number profiles were derived from low coverage sequencing data. Results: 119 out of 163 TNBC patients (73%) had a BRCA1-like profile. After median follow-up of 83 months, disease free survival (DFS) was not significantly different between BRCA1-like and non-BRCA1-like patients [adjusted hazard ratio (adj.HR) 1.02; 95% confidence interval (CI) 0.55–1.86], neither was overall survival (OS; adj.HR 1.26; 95% CI 0.58–2.71). When split by BRCA1-like status, DFS and OS were not significantly different between treatments. However, EC-TX seemed to result in a trend to an improvement in DFS in patients with a BRCA1-like tumor, while the reverse accounted for ETC treatment in patients with a non-BRCA1-like tumor (p for interaction = 0.094). Conclusions: The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

ABSTRACT The VEGF- (bevacizumab) and EGFR- (cetuximab and panitumumab) targeting monoclonal antibodies have become integral components of the first-line treatment strategies for patients with metastatic colorectal cancer (mCRC). Increasingly combination chemotherapy, with or without a targeted agent, is being used to facilitate curative liver resection and improve survival rates in patients with initially unresectable but potentially resectable mCRC. Currently, the only selective marker for the treatment of patients with mCRC is tumor RAS mutational status. BRAF status is a strong prognostic indicator. Medical and clinical oncologists from Central Asia, Russia, the Middle East, Africa and Turkey reviewed data for the use of targeted agents in the treatment of patients with mCRC and have formed recommendations for the biological of choice first-line for patients with mCRC.

In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log10(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

BackgroundIn the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (QoL) was assessed, and associations with tumour response and survival were investigated.Patients and methodsThe European Organization for Research and Treatment of Cancer QoL questionnaire-core 30 was used, focusing on global health status (GHS)/QoL and social functioning scales. Radiological response was assessed by an independent review committee.ResultsQoL was evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/QoL (P=0.12) and social functioning scores (P=0.43) between the treatment arms. In additional analyses: early skin reactions in patients receiving cetuximab did not significantly affect these QoL scales, and tumour response was more common (58% versus 40%, P=0.0002) and survival longer (Hazard ratio 1.68, P

The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests.In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p0.001) and ORR (odds ratio 2.16; p0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Purpose The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2mut in a large cohort of patients with AML in the context of other AML-associated aberrations. Patients and Methods Samples from 783 younger adult patients with AML were analyzed for the presence of TET2mut (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome. Results In total, 66 TET2mut were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (P < .001). TET2mut were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2mut-associated biology. TET2mut did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2mut and/or IDHmut revealed shorter overall survival (P = .03), although this association was not independent from known risk factors. Conclusion TET2mut were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDHmut, which supported recent data on a common mechanism of action that might obscure the impact of TET2mut if compared against all other patients with AML.

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+ patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of −5/5q−, −7, 7q−, abnl(12p), abnl(17p), −18/18q−, −20/20q−, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK+. Response to induction therapy and overall survival in MK+ patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.

Fur das kolorektale Karzinom haben sich in den letzten Jahren deutliche Verbesserungen der Behandlung ergeben. Neben der Einfuhrung verschiedener neuer Medikamente beobachten wir auch einen Zuwachs an Metastasenchirurgie. Medikamentose und operative Behandlungsansatze wachsen zunehmend zusammen. Auch bei primar resektablen Lebermetastasen, die eine hohe Rezidivwahrscheinlichkeit haben, kommen neoadjuvante oder adjuvante Chemotherapiekonzepte zum Tragen. Bei bislang irresektablen Metastasen kann eine hocheffektive Chemotherapie eine Resektion ermoglichen und bei etwa einem Drittel der Patienten, die primar nicht operabel waren, zu einer R0-Resektion fuhren. Bei KRAS-Wildtyp-Tumoren hat hier die Chemotherapie in Kombination mit EGF-Rezeptor-Antikorpern einen besonderen Stellenwert erlangt.

Background Patient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016. Methods We searched PubMed and Embase (January 2005 – June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007. Results Sixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5–18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%–100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%–25%). We identified 29 different stratification factors (median: 3 [range: 1–9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4–11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007. Conclusions We observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.

We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab.We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival.A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P0.001), infusion-related reactions (in 2.5% vs. 0%, P0.001), and diarrhea (in 15.7% vs. 10.5%, P=0.008).First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.)

Purpose To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m2 twice daily on days 1 through 14 plus Gem 1,000 mg/m2 in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for ≥ 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight. Results Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05). Conclusion There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.

Item does not contain fulltext Disease-free survival is increasingly being used as the primary endpoint of most trials testing adjuvant treatments in cancer. Other frequently used endpoints include overall survival, recurrence-free survival, and time to recurrence. These endpoints are often defined differently in different trials in the same type of cancer, leading to a lack of comparability among trials. In this Commentary, we used adjuvant studies in colon cancer as a model to address this issue. In a systematic review of the literature, we identified 52 studies of adjuvant treatment in colon cancer published in 1997-2006 that used eight other endpoints in addition to overall survival. Both the definition of these endpoints and the starting point for measuring time to the events that constituted these endpoints varied widely. A panel of experts on clinical research on colorectal cancer then reached consensus on the definition of each endpoint. Disease-free survival--defined as the time from randomization to any event, irrespective of cause--was considered to be the most informative endpoint for assessing the effect of treatment and therefore the most relevant to clinical practice. The proposed guidelines may add to the quality and cross-comparability of future studies of adjuvant treatments for cancer.

Purpose This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent. Results A total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms. Conclusion GemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

Gemcitabine (2',2'-difluorodeoxycytidine) is a cytotoxic agent with a low toxicity profile and proven activity against a number of solid tumors. It is not known whether gemcitabine is safe to administer to patients with kidney failure, and if dose adjustment is necessary. We determined the tolerability and pharmacokinetics of gemcitabine and its noncytotoxic metabolite 2',2'-difluorodeoxyuridine (dFdU) in a patient with end-stage renal disease on maintenance hemodialysis therapy.A 64-year-old patient with pancreatic cancer and end-stage renal disease received two cycles of gemcitabine at a standard dose of 1000 mg/m(2) given as a 30-min infusion on days 1 and 10. A regular 3.5-h hemodialysis treatment was performed 24 h after each infusion. Plasma and dialysate concentrations of gemcitabine and dFdU were determined by HPLC. The tolerability of gemcitabine treatment was assessed by clinical and laboratory parameters.For gemcitabine, the maximal plasma concentration, terminal half-life (t(1/2)) and area under the concentration-time curve (AUC) were similar to those reported for patients with normal renal function. In contrast, end-stage renal disease resulted in a five- to tenfold prolongation of terminal half-life and a distinct increase in the AUC of plasma dFdU in this patient. Plasma dFdU was effectively eliminated by hemodialysis treatment. Both cycles of gemcitabine were tolerated well with no unexpected side effects observed.Gemcitabine treatment in end-stage renal disease with intermittent standard hemodialysis treatment is safe and well tolerated. The pharmacokinetic data suggest that dose adjustment of gemcitabine should be avoided to ensure its full cytotoxic activity, and that hemodialysis treatment should be initiated 6-12 h after its administration to minimize the potential side effects of the metabolite dFdU.

The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.

Summary Background Colorectal cancer is usually diagnosed in patients around 70 years of age With a continuous increase in life expectancy we may expect a higher number of elderly patients in the future Because patients above 70 or 75 years are often excluded there is uncertainty as to what extent systemic adjuvant and palliative treatment should be offered to elderly patients. Methods We reviewed the available literature on adjuvant and metastatic colorectal cancer in order to identify reports on elderly patients treated within chemotherapy trials Results Only about 20% of patients entering clinical trials belong to the age group of over 70 years and represent the minority of the very fit patients Compared to their younger counterparts 5-FU-based treatment appears to be equally effective and more toxic according to some reports Data regarding raltitrexed, oral fluoropyrimidines, topoisomerase 1 inhibitors or DACH-platin derivates are limited but suggest no age-specific differences in activity or toxicity. Conclusions Elderly patients should not be excluded from clinical trials and studies in unfit elderly patients are warranted Elderly patients need more attention regarding their functional, social and mental status Fit elderly patients should be offered adjuvant or palliative chemotherapy

Purpose: This study was performed to investigate the activity and safety of high dose 5-fluorouracil (5-FU) given as a weekly 24-hour infusion in combination with folinic acid plus mitomycin C in patients with advanced gastric cancer. Patients and Methods: Chemonaive patients with locally advanced inoperable, recurrent or metastatic gastric cancer were treated with 15 mg/m2 i.v. mitomycin C as bolus on day 1 of a 7-week cycle followed by a 2-hour infusion of folinic acid (500 mg/m2) and a 24-hour infusion of 5-FU (2,600 mg/m2) given on days 1, 8, 15, 22, 29, and 36 as outpatient treatment. Results: Thirty evaluable patients (median age 58 years and median ECOG performance status 1) received 1–4 cycles (median 3). 53% of the patients had liver metastases. Treatment-related toxicity was low with 10% of patients experiencing diarrhea ≥grade 3, 3% mucositis grade 3 and 3% nausea grade 3 (CTC). Hematological toxicity was mild with 13% thrombopenia grade 3 and no leukopenia grade 4. Eleven patients achieved a partial remission (major response rate 37%; 95% confidence interval 22–53%). Median time to progression was 5 months and median overall survival time was 7 months. Conclusion: This regimen is a well-tolerated outpatient treatment for patients with advanced gastric cancer with efficacy being comparable to other chemotherapy protocols.

Background: To evaluate the therapeutic activity of 24-hour continuously infused 5-fluorouracil (5-FU) modulated by high-dose folinic acid in patients with metastatic colorectal cancer who had recurred or progressed following mainly bolus 5-FU/folinic acid chemotherapy. Patients and Methods: Forty-two patients with a median age of 59 years (45–76) were enrolled. Karnosfky status was 90% (80–100), previous chemotherapy regimen bolus 5-FU/folinic acid (n = 33, 79%) or 24-hour continuous 5-FU ± interferon α2 (n = 9, 21%). Chemotherapy was given as a weekly infusion of 500 mg/m2 folinic acid over 2 h followed by a 24-hour continuous infusion of 2,600 mg/m2 5-FU for 6 consecutive weeks followed by a 2-week rest period. Results: No complete but 6 partial responses were observed (ORR: 14%, CI95%: 3.5–25.1%) with a median response duration of 7.3 months (range: 1.4–10.6). The median survival from the start of continuous infusion of 5-FU was 11.6 months (range: 2–27, CI95%: 9.4–13.8) and the 1-year survival rate was 46%. Disease stabilization and minor responses were achieved in another 25 patients (61%). WHO grade III/IV diarrhea occurred in 26% of patients, mucositis, nausea/vomiting and hand-foot syndrome in 5% each. Two cases of WHO grade III anemia and leukocytopenia were observed (5% each). Dose reductions had to be performed in 11 patients because of unacceptable diarrhea with subsequent stop of treatment in 2 patients. Progressive disease while receiving previous bolus 5-FU chemotherapy was associated with a lower response rate, shorter progression-free interval and overall survival compared to response and survival of patients who had achieved temporary disease stabilization during previous bolus 5-FU therapy. Conclusions: Continuous infusion of 5-FU/folinic acid displays activity in pretreated and refractory colorectal cancer with acceptable toxicity. Patients who had achieved disease stabilization or objective remission with previous 5-FU bolus therapy appear to be more likely to benefit from second-line treatment. Questions remaining to be addressed include the optimal starting dose of continuously infused 5-FU and whether the dose of folinic acid can be reduced or completely eliminated with respect to toxicity and health economics.

□Studienauswertung: Docetaxel (Taxotere®; Rhone-Poulenc Rorer) wurde in der ersten Halfte der neunziger Jahre bei einem breiten Spektrum von Tumoren untersucht. In den 32 Phase-II-Studien aus Europa, Nordamerika und Japan, auf deren Ergebnisse sich diese Ubersicht im wesentlichen bezieht, wurden die folgenden Tumorarten behandelt: Kopf-Hals-Tumoren, Ovarial- und Zervixkarzinome, Weichteilsarkome, gastrointestinale Adenokarzinome, Nieren- und Urothelkarzinome sowie das Melanom und Glioblastom. Aktuelle Ergebnisse von Studien, die eine hohe Effektivitat einer Kombinationschemotherapie mit Cisplatin sowohl beim unvorbehandelten Kopf-Hals-Karzinom als auch beim Ovarialkarzinom aufzeigten, werden ebenso referiert. □Ergebnisse: Eine bemerkenswerte Wirksamkeit der Substanz als Monotherapie zeigte sich in der Palliativtherapie nach Rezidiv von Kopf-Hals-Karzinomen (Ansprechrate 27 bis 42%) sowie beim Versagen einer platinhaltigen Therapie beim fortgeschrittenen Ovarialkarzinom, wo die Effektivitat von Docetaxel mit der von Paclitaxel oder Topotecan vergleichbar zu sein scheint. Eine vielversprechende antineoplastische Aktivitat konnte auserdem beim Magen-, Pankreas- und Urothelkarzinom sowie dem malignen Melanom in mehreren Studien beobachtet werden. Schlusfolgerung: Docetaxel erwies sich als neues Zytostatikum mit einem breiten Wirkungsspektrum bei den verschiedensten soliden Tumoren. Sein Stellenwert im direkten Vergleich zu etablierten Behandlungsschemata sowie im Rahmen von Kombinationschemotherapien sollte deshalb in weiteren Studien untersucht werden.

Purpose Colorectal cancer predominantly occurs in the elderly, but approximately 5% of patients are 50 years old or younger. We sought to determine whether young age is prognostic, or whether it influences efficacy/toxicity of chemotherapy, in patients with advanced disease. Methods We analyzed individual data on 6,284 patients from nine phase III trials of advanced colorectal cancer (aCRC) that used fluorouracil-based single-agent and combination chemotherapy. End points included progression-free survival (PFS), overall survival (OS), response rate (RR), and grade 3 or worse adverse events. Stratified Cox and adjusted logistic-regression models were used to test for age effects and age-treatment interactions. Results A total of 793 patients (13%) were younger than 50 years old; 188 of these patients (3% of total patients) were younger than 40 years old. Grade 3 or worse nausea (10% v 7%; P = .01) was more common, and severe diarrhea (11% v 14%; P = .001) and neutropenia (23% v 26%; P < .001) were less common in young (younger than 50 years) than in older (older than 50 years) patients. Age was prognostic for PFS, with poorer outcomes occurring in those younger than 50 years (median, 6.0 v 7.5 months; hazard ratio, 1.10; P = .02), but it did not affect RR or OS. In the subset of monotherapy versus combination chemotherapy trials, the relative benefits of multiagent chemotherapy were similar for young and older patients. Results were comparable when utilizing an age cut point of 40 years. Conclusion Young age is modestly associated with poorer PFS but not OS or RR in treated patients with aCRC, and young patients have more nausea but less diarrhea and neutropenia with chemotherapy in general. Young versus older patients derive the same benefits from combination chemotherapy. Absent results of a clinical trial, standard combination chemotherapy approaches are appropriate for young patients with aCRC.

Colorectal cancer is a disease of the elderly, with 70% of patients being aged 65 years or older. In Western countries, the total number of elderly patients with this disease is expected to further increase in the future. Since the incidence of adverse physical or socioeconomic conditions in the elderly is higher than in younger patients, a thorough assessment of the patient's suitability for therapy should be performed before a decision is made. Using a Comprehensive Geriatric Assessment (CGA) to subdivide the population of elderly cancer patients into three groups can help to guide treatment decisions. Both in the adjuvant and in the palliative setting, there are sufficient data supporting the use of fluorouracil-based chemotherapy in fit elderly patients who can tolerate cytotoxic treatment. Systemic chemotherapy has been shown to effectively reduce mortality in the adjuvant situation and to be of clinical benefit for patients with metastatic disease in terms of longer survival, control of symptoms and quality of life. In recent years, new substances such as oxaliplatin or irinotecan have shown significant activity in the treatment of patients with metastatic colorectal cancer. However, information on how to guide the use of these new drugs in elderly patients is still lacking. Limited data from clinical trials indicate treatment efficacy in selected elderly patients comparable to that observed in younger patients, with overall manageable toxicity. Clearly, further clinical trials in elderly patients with colorectal cancer are necessary as well as the incorporation of aspects of geriatric medicine into the teaching programme of medical oncologists.

It is remarkable that patients 1 and 2 developed progressive disease under tamoxifen maintenance (after 17 and 7 months, respectively), but remained in complete remission following local therapy (exstirpation of a kidney metastasis and an adrenal body in patient 1; irradiation of the lumbar spine, the sacrum and the right humerus in patient 2) and continuation of tamoxifen therapy. Four out of these 6 patients had liver metastases, usually indicating a particularly poor prognosis. 2 of them (patients 1 and 2) have shown a continuous complete remission for 16 and 13 years, respectively. Up to now, to our knowledge, there has been only 1 case published with a continuous complete remission of liver metastases for 10 years (following vindesine and interferon) [1]. As potential action mechanisms of tamoxifen in malignant melanoma, induction of apoptosis and inhibition of angiogenesis [2], inactivation of the insulin-like growth factor-1 receptor [3], or inhibition of tumor cell invasion and metastasis through suppression of the PKC/MEK/ERK and PKC/PI3K/ Akt pathways [4] have been discussed. Tamoxifen monotherapy in metastatic melanoma has been reported to induce remissions in about 5% of the patients, in some cases after progression of the disease in the first months of therapy [5]. In combination with chemotherapy, tamoxifen failed to exert an additional therapeutic effect in most studies [6]. But, to our knowledge, no results are published about tamoxifen maintenance following chemotherapy. Given the good tolerability and low costs of the drug, it would be worthwhile to start a clinical trial with a larger number of patients to investigate the potential of tamoxifen maintenance in metastatic malignant melanoma, if possible.

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.

PURPOSE: To determine the prognostic value of the central downstream apoptosis effector BAX in relation to its upstream regulator p53 in R0-resected hepatic metastases of colorectal cancer. PATIENTS AND METHODS: Retrospective analysis of 41 patients who underwent potentially curative resection of liver metastases from colorectal cancer was performed. Tumor DNA was screened for p53 mutations by single-stranded conformational polymorphism polymerase chain reaction and for BAX frameshift mutations by fragment length analysis. Protein expression of BAX, p21, and p53 was investigated by immunohistochemistry. RESULTS: Overall median survival was 40.2 months. Tumors with BAX frameshift mutations were considered microsatellite mutator phenotype–positive and were excluded from further prognostic analyses. Patients with high BAX protein expression had a median survival of 53.6 months compared with 35.4 months for patients with low BAX expression (P < .05). The negative prognostic value of low BAX expression was more evident in those patients with wild-type p53 (median survival, 54.0 v 23.3 months for BAX-negative tumors; P < .01). Low BAX expression was an independent negative prognostic marker in multivariate regression analysis for all patients independent of the p53 status (relative risk, 3.03, P = .03), especially for p53 wild-type tumors (relative risk, 8.21; P = .0095). CONCLUSION: We conclude that low BAX expression is an independent negative prognostic marker in patients with hepatic metastases of colorectal cancer. The best survival was seen in patients with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors. Thus, analysis of apoptosis signaling pathways (here, p53 in concert with its downstream death effector, BAX) might yield more prognostic power in future studies as compared with analysis of single genes such as p53 alone.