Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110).

BACKGROUND: The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. PATIENTS AND METHODS: In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. RESULTS: Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS = 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS = 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS = 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P = 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P = 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P = 0.022). CONCLUSION: We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.

Efficacy, safety and quality-of-life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial.

INTRODUCTION: Trifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted. METHODS: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). A validated questionnaire, EORTC QLQ-C30, was employed to assess HRQoL. Secondary endpoints included OS, PFS and safety. RESULTS: Of 194 eligible patients, 185 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. On the other hand, treatment with FTD/TPI was associated with maintained HRQoL. Median OS was 6.9 months [95% confidence interval (CI) 6.1-8.2 months] and median PFS was 2.5 months (95% CI 2.1-2.9 months). The most frequent treatment-emergent adverse events were neutropenia (27.6%) and anaemia (22.7%). Febrile neutropenia occurred in 1.1%. CONCLUSIONS: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression but also with maintained HRQoL.

Relevance of baseline carcinoembryonic antigen for first-line treatment against metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).

PURPOSE: Increased baseline carcinoembryonic antigen (CEA) serum level is associated with inferior overall survival (OS) in metastatic colorectal cancer (mCRC). However, limited data exist on its predictive relevance for targeted therapies. Therefore, we analysed its relevance in FIRE-3, a randomised phase III study. EXPERIMENTAL DESIGN: FIRE-3 evaluated first-line FOLFIRI plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumour (i.e. wild-type in KRAS and NRAS exons 2-4). Herein, the impact of CEA on patient outcome was investigated. RESULTS: Of 400 patients, 356 (89.0%) were evaluable for CEA. High CEA (>10 ng/ml; N = 237) compared to low CEA (≤10 ng/ml; N = 119) was associated with shorter OS in the FOLFIRI/Bev arm (hazard ratio [HR] = 1.50; P = 0.036), while no significant OS difference was observed in the FOLFIRI/Cet arm (HR = 1.07; P = 0.74). In patients with high CEA, FOLFIRI/Cet compared to FOLFIRI/Bev showed a greater OS benefit (HR = 0.56; P < 0.001) than in patients with low CEA (HR = 0.78; P = 0.30). Furthermore, FOLFIRI/Cet exhibited significantly superior objective response rate in patients with high CEA (odds ratio = 2.21; P = 0.006) in contrast to patients with low CEA (odds ratio = 0.90; P = 0.85). CONCLUSION: In patients with RAS-WT mCRC receiving first-line chemotherapy with FOLFIRI/Cet versus FOLFIRI/Bev, elevated CEA was associated with inferior survival in the bevacizumab arm, while this was not the case when cetuximab was applied. Comparison of OS and objective response rate according to treatment arms indicated that cetuximab was greatly superior to bevacizumab in patients with elevated CEA, while this effect was markedly lower and lost statistical significance in patients with low CEA.

Evaluation of survival across several treatment lines in metastatic colorectal cancer: Analysis of the FIRE-3 trial (AIO KRK0306).

BACKGROUND: We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment. PATIENTS AND METHODS: OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time. RESULTS: The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75]). CONCLUSION: The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.

Palliative home care for patients with advanced haematological malignancies-a multicenter survey.

Patients with advanced haematological malignancies in non-curative settings suffer from complex physical symptoms and psychosocial distress, comparable to patients with solid tumour entities. Nevertheless, numerous problems at the interface between haematology and palliative home care have been described. From January 2011 until October 2014, we performed a retrospective, multicenter analysis of all patients with haematological malignancies (ICD 10: C81-C95) being treated by the respective specialized palliative home care (SAPV) team. Three SAPV teams were surveyed. Disease entity, physical symptoms, psychosocial distress, number of hospital admissions, therapeutic interventions and other items were analysed descriptively. Of 3,955 SAPV patients, 1.8% (n = 73) suffered from haematological malignancies. Main problems were deterioration of general condition, pain or psychological problems. Thirty-seven percent developed new symptoms during SAPV, mainly pain, psychological distress or deterioration of general status. In 33%, patients were referred to hospital, mainly due to deterioration of general condition or pain. Seventy percent died within 3 months after beginning SAPV care; 83% died at home or in a nursing home. Patients suffering from advanced haematological malignancies were statistically underrepresented in SAPV, and SAPV was installed rather at the very last days of life. By far, more patients were able to die outside a hospital as compared to reference cohorts of haematological patients not being treated in SAPV. The spectrum of documented problems is comparable to other patient cohorts being treated in SAPV; therefore, the options and benefits of palliative home care should be incorporated in palliative haematological treatment concepts more vigorously and consequently.

Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study.

BACKGROUND: RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear. METHODS: Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR). RESULTS: Overall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively. CONCLUSIONS: In BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).

BACKGROUND: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PATIENTS AND METHODS: CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. RESULTS: Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. CONCLUSION: In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. CLINICAL TRIALS NUMBER: NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.

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.

Nutrition care in patients with cancer: A retrospective multicenter analysis of current practice - Indications for further studies?

BACKGROUND & AIMS: Weight loss and malnutrition are frequent problems in oncology patients. The aim of this study was to get a perspective of the current practice of parenteral nutrition (PN) care in an outpatient setting and to improve patient-centered nutritional care. METHODS: Fifty-three outpatient oncology centers participated in this observational study performed between July 2010 and March 2011. All participating centers entered data online into a web-based documentation form, containing a number of oncology patients, diagnoses, and detailed data about oncology patients receiving PN. RESULTS: Two cohorts were analyzed. First cohort consisted of all oncology patients in quarter 04/2010. Second cohort consisted of patients with PN during the whole studying period. In the first cohort 2.46% (n = 626) of 25,424 oncology patients received PN. Most frequent diagnoses of patients receiving PN were gastric cancer (n = 119) and colorectal cancer (n = 104), however most stated diagnosis was "other" (n = 163). In the second cohort (n = 1137), a common indication for PN was impaired gastrointestinal passage (n = 177), although here again most stated reason was "other" (n = 924). In the course of the PN treatment, patients (n = 1137) showed a stable or slowly increasing body mass index (from 21.6 ± 3.8 kg/m(2) to 21.8 ± 3.5 kg/m(2)). CONCLUSION: This is the largest study outlining the characteristics of oncology patients in the context of PN in German ambulatory centers. They confirm the important role of PN in the care of gastrointestinal cancer. Further studies have to be performed to identify if other indications than those mentioned in relevant guidelines can trigger initiation of PN.

[The Oncologic and Palliative Network Landshut: a problem-solving approach to oncological and palliative care in structurally weak rural areas, with special emphasis on outpatient and inpatient networking]. / Das Onkologische und Palliativmedizinische Netzwerk Landshut. Lösungsansatz für die zukünftige ambulante und stationäre Versorgung von onkologischen und palliativmedizinischen Patienten in strukturschwachen ländlichen Gebieten.

The Oncologic and Palliative Network Landshut is a problem-solving approach to structurally weak rural areas to improve an a dequate care of critically ill patients, especially by a close involvement of outpatient and inpatient care providers. These networks not only improve the medical and nursing care of patients, but can also be cost-effective.

[The Oncologic and Palliative Network Landshut: a problem-solving approach to oncological and palliative care in structurally weak rural areas, with special emphasis on outpatient and inpatient networking]. / Das Onkologische und Palliativmedizinische Netzwerk Landshut. Lösungsansatz für die zukünftige ambulante und stationäre Versorgung von onkologischen und palliativmedizinischen Patienten in strukturschwachen ländlichen Gebieten.

The Oncologic and Palliative Network Landshut is a problem-solving approach to structurally weak rural areas to improve an adequate care of critically ill patients, especially by a close involvement of outpatient and inpatient care providers. These networks not only improve the medical and nursing care of patients, but can also be cost-effective.

A prospective cohort study on the impact of darbepoetin alfa on quality of life in daily practice following anemia treatment guideline revisions.

OBJECTIVE: This study aimed to evaluate the impact of darbepoetin alfa (DA) on hemoglobin (Hb) levels and quality of life (QoL) in cancer patients with anemia in current daily practice following several revisions of anemia treatment guidelines. METHODS: This was a prospective, multi-center, observational study across Germany in non-myeloid cancer outpatients with chemotherapy-induced anemia treated with DA. Age, sex, cancer type, stage, and therapy, performance status, anemia status and treatment, and Hb concentrations were recorded for up to 18 weeks in a web-based registry. Optional QoL assessments were collected at baseline and at the end of DA treatment. MAIN RESULTS: Of 984 eligible patients, 978 had complete anemia data, 492 also had complete QoL data. In the 978 patients, mean age was 64 (standard deviation, SD 12) years, 62% of patients were women. Breast (26%) and gastrointestinal (22%) cancer were most prevalent. Therapy was palliative in 44% of patients and initiated with curative intent in 29%. Mean baseline Hb was 9.5 (SD 0.9) g/dL, which increased by an average of 1.2 g/dL. In 67% of patients Hb increased either to 10-12 g/dL or by ≥2 g/dL; no Hb response was seen in 219 patients (22%); increases of 0 to 1, >1 to 2, and >2 g/dl were seen in 216 (22%), 265 (27%), and 278 (28%) patients, respectively. Anemia treatment did not result in any significant differences of performance status. However, QoL improvements were significantly greater in Hb responders, although a linear relationship with Hb increments was lacking. None of 47 fatal cases was considered related to treatment with DA. CONCLUSION: Patients treated with DA in routine clinical practice had increases in Hb and reported improvement in QoL. Due to the uncontrolled design, no conclusions can be made regarding causality to treatment and the clinical relevance of the improvement.

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial.

PURPOSE: AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients. PATIENTS AND METHODS: Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation. RESULTS: Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed. CONCLUSION: Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy.

EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104.

BACKGROUND: We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study. METHODS: AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash. RESULTS: Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash. CONCLUSION: The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.

Treatment of older patients with mantle-cell lymphoma.

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306.

BACKGROUND: The AIO KRK-0306 trial compares the efficacy of infusional 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). In October 2008, an amendment terminated the inclusion of patients with KRAS-mutated tumours. This subgroup of patients is evaluated in the present analysis, while the study is ongoing for patients with KRAS wild-type tumours. METHODS: Patients were randomly assigned to FOLFIRI (Tournigand regimen) every 2 weeks plus cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly=arm A) or bevacizumab (5 mg/kg every 2 weeks=arm B). Among 336 randomised patients, KRAS mutation was demonstrated in 100 assessable patients. The primary study end point was objective response rate (ORR). RESULTS: ORR was 44% [95% confidence interval (CI) 29% to 59%] in arm A versus 48% (95% CI, 33% to 62%) in arm B. Progression-free survival was 7.5 versus 8.9 months (hazard ratio: 1.0) and overall survival was 22.7 versus 18.7 months (hazard ratio: 0.86) in arms A versus B, respectively. CONCLUSIONS: This is the first head to head comparison of cetuximab versus bevacizumab in first-line treatment of mCRC. In the present evaluation of patients with KRAS-mutated tumours, neither strategy demonstrated a clearly superior outcome.

Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial.

BACKGROUND: The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy. METHODS: Patients with mCRC were randomised to cetuximab (400 mg m(-2), day 1, followed by 250 mg m(-2) weekly) plus CAPIRI (irinotecan 200 mg m(-2), day 1; capecitabine 800 mg m(-2), twice daily, days 1-14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m(-2), day 1; capecitabine 1000 mg m(-2), twice daily, days 1-14, every 3 weeks). RESULTS: Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand-foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1-3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1-3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend. CONCLUSION: This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.

A prospective multicenter phase II study of oral and i.v. vinorelbine plus trastuzumab as first-line therapy in HER2-overexpressing metastatic breast cancer.

BACKGROUND: To evaluate the efficacy and safety of oral and i.v. vinorelbine plus trastuzumab as first-line regimen in a patient-convenient application for human epidermal growth factor receptor 2 (HER2)-overexpressing patients with metastatic breast cancer. PATIENTS AND METHODS: Forty-two women were enrolled in a multicenter study. The patients received i.v. vinorelbine at a dose of 25 mg/m(2) on day 1 followed by oral vinorelbine at a dose of 60 mg/m(2) on days 8 and 15 in a 3-week cycle. Standard dose trastuzumab was given at 3-week intervals. RESULTS: Complete response was observed in 7 patients (18.9%) and partial response in 19 patients (51.4%), for an overall response rate of 70.3% [95% confidence interval (CI) 53.0-84.1]. The disease control rate reached 91.9% (95% CI 78.1-98.3). The median time to progression was 9.3 months, while median overall survival reached 35.6 months. Hematological and non-hematological toxic effects were acceptable with grade 3-4 leukopenia of 14% and neutropenia of 38%; cardiac toxicity did not reach the level of clinical relevance. CONCLUSION: The combination of i.v. and oral vinorelbine plus trastuzumab demonstrates high activity and good tolerability in first-line treatment of HER2-overexpressing metastatic breast cancer. In addition, it offers convenience for the patients with only one i.v. treatment every 3 weeks.

Weekly docetaxel monotherapy for advanced gastric or esophagogastric junction cancer. Results of a phase II study in elderly patients or patients with impaired performance status.

BACKGROUND: Three-weekly docetaxel is active in patients with advanced esophagogastric cancer but myelosuppression may make this schedule unsuitable for some patient groups such as elderly, pretreated, or poor performance status patients. PATIENTS AND METHODS: Eligible patients were chemonaive with Karnofsky index < or =70% and/or had received prior platinum-based chemotherapy. Docetaxel 35 mg/m(2) was administered on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. The primary endpoint was disease stabilization rate. RESULTS: Of 46 patients (median age, 68.5 years; 47% > or =70 years) included, 87% had Karnofsky index < or =70 and 50% had prior treatment. The safety profile was acceptable. Principal grade 3/4 toxicities were leukopenia (9%) and fatigue (14%). Fifteen patients experienced no progression for > or =100 days (disease stabilization rate: 36%). Overall response rate was 9%; median overall survival was 7.0 months. CONCLUSIONS: Weekly docetaxel was well tolerated and achieved disease stabilization in one-third of difficult-to-treat patients.