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.

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.

The novel tribody [(CD20)(2)xCD16] efficiently triggers effector cell-mediated lysis of malignant B cells.

Bispecific antibodies (bsab) offer a promising approach for optimizing antibody-based therapies. In the present study, [(CD20)(2)xCD16], a recombinant CD20- and CD16-directed bsab in the tribody format, was designed to optimize recruitment of FcγRIII (CD16)-positive effector cells. [(CD20)(2)xCD16] retained the antigen specificities of the parental monoclonal antibodies and binding to FcγRIIIa was not compromised by the F/V polymorphism at amino-acid position 158. [(CD20)(2)xCD16] mediated potent lysis of lymphoma cell lines and freshly isolated tumor cells from patients, even at low picomolar concentrations (∼10 pM). Irrespective of the CD16a allotype, potency as well as efficacy of lysis obtained with the tribody was significantly higher than lysis triggered by rituximab. Tumor cell killing also occurred when autologous NK cells were used as effector cells. Compared with rituximab, the tribody demonstrated depletion of autologous B cells in ex vivo whole blood assays at 100-fold lower antibody concentration. In mice with a reconstituted humanized hematopoietic system, established by transplantation of human CD34-positive cord blood cells, this novel tribody significantly depleted autologous human B cells. Thus, tribodies such as [(CD20)(2)xCD16], recruiting CD16-positive effector cells, may represent promising candidates for clinical development.

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.

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer.

BACKGROUND: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. PATIENTS AND METHODS: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. RESULTS: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombocytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. CONCLUSION: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2).

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer.

BACKGROUND: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. PATIENTS AND METHODS: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles (3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. RESULTS: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses (median cumulative dose 339 mg/m(2)) was administered (range: 2-18). The overall response rate was 48.1% (95% CI: 34-61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months (intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. CONCLUSION: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status.

Health economic analysis of fluoropyrimidine-based therapies of colorectal cancer from the perspective of statutory sickness funds.

AIMS: 1) to identify the treatment costs of different standard fluoropyrimidine-based therapies, i. e., the Mayo-Clinic and AIO/Ardalan regimens, under real-life conditions in settings routinely used for chemotherapy administration in Germany (inpatient, day-clinic or office-based oncologists) and 2) to investigate the cost implications of the routine use of capecitabine, an oral alternative for the treatment of metastatic colorectal cancer. METHODS: We analysed the actual fee-listings of office based oncologists and projected the results to several hospital-based treatment settings and to oral treatment with capecitabine from the perspective of statutory sickness funds. RESULTS: Office-based setting: the highest quarterly treatment costs of 9.874 were found for the AIO/Ardalan-regimen, followed by the Mayo-Clinic regimen, which incurred costs of 2.497. The cheapest treatment option was capecitabine with quarterly costs of 1.610. Day-clinic setting: the costs of the Mayo-Clinic protocol amounted to 2.036 in a municipal hospital and 8.455 in a university hospital. The respective costs for the AIO/Ardalan regime were 1.294 and 5.374. In-patient setting: the Mayo-Clinic protocol costs were 3.143 in a municipal hospital and 10.5609 in a university hospital. The respective costs found for the AIO/Ardalan-regimen were 1.998 and 6.717. CONCLUSION: From a health economic perspective, substantial cost savings for health insurance may be realised if patients with colorectal carcinoma were treated in the office-based setting with capecitabine instead of a hospital-based treatment. Economic consequences would be positive for municipal hospitals (avoided losses) and negative for university hospitals. Further savings could be realised if drug prices in hospital and retail pharmacies were harmonized.

Comment on Re B (Adult: Refusal of Medical Treatment) [2002] 2 All England Reports 449.

The judgment handed down in the case of Ms B confirms the right of the competent patient to refuse medical treatment even if the result is death. The case does, however, raise some interesting legal points. The facility for conscientious objection by doctors has not previously been explicitly recognised in case law. More importantly perhaps is that the detailed inquiry by the court into Ms B's reasons for refusing treatment, apparently as a precondition for finding her competent, seems to contradict earlier case law where it has been asserted that competent patients can refuse treatment for no reason at all.

Causal authorship and the equality principle: a defence of the acts/omissions distinction in euthanasia.

This paper defends the acts/omissions distinction which underpins the present law on euthanasia, from various criticisms (including from within the judiciary itself), and aims to show that it is supported by fundamental principles. After rejecting arguments that deny the coherence and/or legal relevance of the distinction, the discussion proceeds to focus on the causal relationship between the doctor and the patient's death in each case. Although previous analyses, challenging the causal efficacy of omissions generally, are shown to be deficient, it is argued that in certain cases of causing death by omission the causal authorship of the doctor lapses. The final part of the paper examines why this should be morally significant and proposes an answer in terms of the principle of equality. Assuming all other factors are equal, the infringement of this principle provides an additional reason against actively killing a patient, which is not present in cases of passively letting die.

Physical activity level during a round of golf on a hilly course.

BACKGROUND: Regular physical activity plays a role in preventive medicine. Our study aimed at establishing the duration of different levels of exercise intensity during a round of golf. PARTICIPANTS: we studied 21 male and 9 female golfers (mean age 53 +/- 11 and 54 +/- 13 years respectively) volunteering for a round of golf on a hilly course. MEASURES: we recorded mean heart rate (HR) of every 15 seconds. Blood pressure was taken on each tee. Maximum HR (HRmax) reserve of each subject was calculated from the difference between pre-exercise and maximum HR attained during a test to volitional exhaustion on a cycle ergometer. A percentage of this value was added to the resting HR and was expressed as a percentage of HRmax reserve. RESULTS: Before start mean HR (+/- SD) was 86 +/- 11 beats per minute (BPM), during play 113 +/- 18, and during rest after play 100 +/- 24 BPM. Mean maximal HR of holes were 135 +/- 21 BPM. Mean systolic blood pressure was 145 +/- 30 before play, 137 +/- 31 on tees during play and 119 +/- 15 mmHg after play. A mean of 82 +/- 51 minutes was spent at 50-74% of HRmax reserve. 21 +/- 27 and 23 +/- 38 minutes were spent in the two higher intensity classes. An average of 106 +/- 77 minutes were spent at or above the individual heart rate equivalent of 100 W, the mean heart rate for this time was 128 +/- 17 BPM. Creatine kinase (+47%; p < 0.001), uric acid (+9%; p < 0.001) and HDL-cholesterol (+6%; p < 0.05) increased, triglycerides decreased by 18% (p < 0.01). CONCLUSIONS: The HR level during the golfround not using an electric cart relative to the maximum attained on the ergometer reaches the exercise intensity of 50 to > 85% HRmax reserve for a mean of over 2 hours, much longer than the 20-60 min recommended for endurance training.

Impaired granulocytic function in patients with acute leukaemia: only partial normalisation after successful remission-inducing treatment.

In vivo chemotaxis and phagocytic activity of polymorphonuclear neutrophils (PMN) were evaluated in 20 patients with acute myeloid leukaemia (AML), and in 10 patients with acute lymphoblastic leukaemia (ALL). For comparison, 20 healthy individuals were investigated. A skin-chamber technique and a phagocytosis test were used to quantify the neutrophil functions. The local leucocyte mobilisation in the skin-chamber was significantly lower in untreated patients with AML and ALL than in healthy individuals (P < 0.05). Patients with acute leukaemia in remission showed an increase in chemotactic parameters though they remained below normal levels. The phagocytosis index (PI) of peripheral blood PMN was lower than 30% (normal individuals: 60%) in untreated AML and ALL; this difference was significant (P < 0.05). The PI of peripheral blood PMN in patients with acute leukaemia in remission returned to the normal level. Investigation of granulocytic function in patients with acute leukaemia in remission may reveal evidence for reduced protection by these cells against infections and lead to adequate therapy.

Effect of felodipine on regional blood supply and collateral vascular resistance in patients with peripheral arterial occlusive disease.

This double-blinded, randomized, placebo-controlled study was designed to investigate the acute effect of felodipine on regional blood supply and collateral vascular resistance in patients with peripheral arterial occlusive disease (PAOD). Thirty men with PAOD were treated with a single dose of 5 mg felodipine or placebo. Systolic blood pressure (SBP), Doppler ankle pressure (DAP), calf blood flow (CBF) by venous occlusion plethysmography and calf transcutaneous oxygen tension (tcpO2) were measured during a cycle ergometry. Felodipine reduced SBP significantly (from 149 to 136 mmHg, p < 0.05), while placebo did not. DAP increased slightly but not significantly in both groups. The pressure gradient between SBP and DAP fell significantly in the felodipine group (60 vs 39 mmHg, p < 0.01) but not in the placebo group (59 vs 56 mmHg). There was a trend for lower velocity in tcpO2 decrease during the stress test and higher velocity of tcpO2 increase during recovery from exercise in the felodipine group although the differences between both groups were not significant. In the felodipine group, CBF increased by 35.6% (p < 0.05) whereas it did not change in the placebo group. In conclusion, while lowering SBP, felodipine increased slightly, or at least maintained, the blood supply to the calves in PAOD patients, which probably results from reducing collateral vascular resistance.

The legal concept of medical negligence.

Where a patient suffers injury in the course of receiving medical care, he/she may resort to legal action in order to gain compensation. If it can be shown that he/she did not really consent to the procedure, then an action in battery may lie. Much more often, the patient's complaint will be that the particular treatment administered was, in terms of its execution, deficient in some respect. Here, at least for NHS patients, this will involve bringing a claim in medical negligence. (For patients in the private sector, an alternative would be to bring an action for breach of contract; however, the salient legal principles remain virtually the same.)