Updated German guideline on diagnosis and treatment of squamous cell carcinoma and adenocarcinoma of the esophagus.

Diagnosis and therapy of esophageal carcinoma is challenging and requires a multidisciplinary approach. The purpose of the updated German guideline "Diagnosis and Treatment of Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus-version 3.1" is to provide practical and evidence-based advice for the management of patients with esophageal cancer. Recommendations were developed by a multidisciplinary expert panel based on an extensive and systematic evaluation of the published medical literature and the application of well-established methodologies (e.g. Oxford evidence grading scheme, grading of recommendations). Accurate diagnostic evaluation of the primary tumor as well as lymph node and distant metastases is required in order to guide patients to a stage-appropriate therapy after the initial diagnosis of esophageal cancer. In high-grade intraepithelial neoplasia or mucosal carcinoma endoscopic resection shall be performed. Whether endoscopic resection is the definitive therapeutic measure depends on the histopathological evaluation of the resection specimen. Esophagectomy should be performed minimally invasive or in combination with open procedures (hybrid technique). Because the prognosis in locally advanced esophageal carcinoma is poor with surgery alone, multimodality therapy is recommended. In locally advanced adenocarcinomas of the esophagus or esophagogastric junction, perioperative chemotherapy or preoperative radiochemotherapy should be administered. In locally advanced squamous cell carcinomas of the esophagus, preoperative radiochemotherapy followed by complete resection or definitive radiochemotherapy without surgery should be performed. In the case of residual tumor in the resection specimen after neoadjuvant radiochemotherapy and R0 resection of squamous cell carcinoma or adenocarcinoma, adjuvant immunotherapy with nivolumab should be given. Systemic palliative treatment options (chemotherapy, chemotherapy plus immunotherapy, immunotherapy alone) in unresectable or metastastic esophageal cancer depend on histology and are stratified according to PD-L1 and/or Her2 expression.

Phase I study of matuzumab in combination with 5-fluorouracil, leucovorin and cisplatin (PLF) in patients with advanced gastric and esophagogastric adenocarcinomas.

BACKGROUND: To evaluate the safety and tolerability of two different weekly doses of the fully humanized epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab combined with high-dose 5-fluorouracil, leucovorin and cisplatin (PLF) in the first-line treatment of patients with EGFR-positive advanced gastric and esophagogastric adenocarcinomas. METHODS: Patients were treated in two matuzumab dose groups with the first cohort of patients receiving 400 mg matuzumab in combination with PLF. Based on the safety observations the next cohort of patients received 800 mg matuzumab. The study was conducted in two parts, with phase A, designed to assess the safety and tolerability of the combination, and phase B designed to be a treatment continuation for those patients benefiting from treatment. Treatment cycles were 7 weeks each. Each patient received the dose of matuzumab they were assigned to at study entry for the duration of the study. RESULTS: Fifteen EGFR-positive patients were enrolled into the two matuzumab dose groups; 400 mg dose n=7; 800 mg dose n=8. All patients experienced at least one adverse event (AE). No patient experienced any serious AE which was considered to be related to matuzumab. Two grade 3 AEs possibly related to matuzumab occurred in 2 different patients (13.3 %), both in the 800 mg dose group. No dose-limiting toxicity (DLT) was observed in the 400 mg group. The maximum tolerated dose of matuzumab was not reached. The best confirmed overall response rate was 26.7 %. CONCLUSION: Matuzumab, in combination with PLF, demonstrated an acceptable safety profile with modest anti-tumor activity.

Gefitinib in combination with capecitabine as second-line therapy in patients with advanced colorectal cancer (aCRC): a phase I/II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: This phase I/II study was conducted to assess the maximal tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of gefitinib in combination with capecitabine in patients with advanced colorectal cancer (aCRC). PATIENTS AND METHODS: After failure of a 1st-line therapy, patients with aCRC received escalating doses of gefitinib once daily in combination with capecitabine twice daily: dose level (DL) 1: gefitinib 250 mg and capecitabine 1,000 mg/m(2), DL 2: gefitinib 250 mg and capecitabine 1,250 mg/m(2), DL 3: gefitinib 500 mg and capecitabine 850 mg/m(2). DLTs were determined after 6 weeks of treatment. RESULTS: A total of 16 patients were enrolled. On DL1 (n = 6), 1 patient developed a DLT (hand-foot syndrome, HFS n = 1). On DL2 (n = 7), DLTs were observed in 3 patients (exanthema n = 2, HFS n = 1), and on DL3 (n = 3), DLT occurred in 1 patient (HFS n = 1) resulting in recruitment stop at DL3. No patient showed an objective tumor response. Disease stabilization was observed in 6 patients. CONCLUSION: The combination of gefitinib and capecitabine resulted in significant skin toxicities such as exanthema and HFS. As 2nd-line treatment of patients with aCRC, this combination showed no substantial efficacy.

[Palliative treatment for colorectal cancer]. / Palliative Therapie des kolorektalen Karzinoms.

Before a decision is made to give a particular drug treatment, first of all the best strategy for the individual patient must be determined. In a patient with an aggressive tumour, for whom a secondary curative approach by means of metastasis resection is not an option, the preferred first-line treatment will generally be a triple combination therapy containing bevacizumab - and this is also true in KRAS/BRAF wild-type patients, since the main aim here is to achieve the longest possible survival time with a minimum of side effects. If an epidermal growth factor receptor (EGFR) antibody (cetuximab or panitumumab) is to be used in first-line or later therapy, then the presence of a KRAS mutation must be excluded beforehand. It is very likely sensible also to exclude a BRAF mutation. Second-line treatment after a first-line therapy containing bevacizumab may be a combination chemotherapy or, in patients who are KRAS wild-type (and possibly also BRAF wild-type), irinotecan plus cetuximab. Locoregional treatments such as chemoembolisation, selective internal radiation therapy (SIRT), and stereotactic

Morphological and functional evaluation of angiogenesis of a xenografted human sarcoma in nude mice.

The implantation of tumour cells in normal tissues and the subsequent induction of angiogenesis by the growing xenograft were studied by means of immunohistochemistry and digital image analysis. Tumour growth was induced by injection of a human spindle cell sarcoma (ES3) into the subcutis of HsdCpb:NMRI-nu/nu mice. In vivo injection of Hoechst 33342 was used as a marker of perfusion. The vasculature was stained with specific antibodies and subsequently analysed by digital image analysis. Starting at day 3 up to day 6, angiogenesis could be detected and the relative amount of perfusion within the investigated area reached a peak at day 6. This method, which allows investigation of both functional and morphometric characteristics of human xenograft vasculature, serves as an excellent assay for evaluation of antiangiogenic therapies in translational research of experimental tumours.

Docetaxel plus gemcitabine or docetaxel plus cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group.

PURPOSE: To define the efficacy and toxicity of docetaxel plus gemcitabine or docetaxel plus cisplatin for advanced pancreatic carcinoma. PATIENTS AND METHODS: Chemotherapy-naive patients with measurable disease and WHO performance status less than 2 were randomly assigned to receive 21-day cycles of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 (arm A) or docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 (arm B). Primary end points were tumor response and rate of febrile neutropenia grade. RESULTS: Of 96 randomly assigned patients (49 patients in arm A and 47 patients in arm B), 70 patients were analyzed for response (36 in arm A and 34 in arm B) and 89 patients were analyzed for safety (45 in arm A and 44 in arm B). Confirmed responses were observed in 19.4% (95% CI, 8.2% to 36.0%) of patients in arm A and 23.5% (95% CI, 10.7% to 41.2%) in arm B. In arm A, the median progression-free survival (PFS) was 3.9 months (95% CI, 3.0 to 4.7 months), median survival was 7.4 months (95% CI, 5.6 to 11.0 months), and 1-year survival was 30%. In arm B, the median PFS was 2.8 months (95% CI, 2.6 to 4.6 months), median survival was 7.1 months (95% CI, 4.8 to 8.7 months), and 1-year survival was 16%. Febrile neutropenia occurred in 9% and 16% of patients in arms A and B, respectively. CONCLUSION: Both regimens are well tolerated and show activity in advanced pancreatic carcinoma. The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation.

2-aroylindoles, a novel class of potent, orally active small molecule tubulin inhibitors.

2-Aroylindoles with 5-methoxy-1H-2-indolyl-phenylmethanone (D-64131) as the lead structure were discovered as a new class of synthetic, small molecule tubulin inhibitors. By competitively binding with [(3)H]colchicine to alphabeta-tubulin and inhibiting microtubule formation, cycling cells were arrested in the G(2)-M phase of the cell division cycle. The proliferation of tumor cells from 12 of 14 different organs and tissues was inhibited with mean IC(50)s of 62 nM and 24 nM by D-64131 and D-68144, respectively, comparable with the potency of paclitaxel with mean IC(50) of 10 nM. By measuring the cytotoxicity in a human colon carcinoma cell model with ectopic ecdysone-inducible expression of the cyclin-dependent kinase inhibitor p21(WAF1), specificity toward cycling cells was demonstrated. In contrast to microtubule inhibitors from natural sources, 2-aroylindoles did not alter the polymerization-dependent GTPase activity of beta-tubulin and are not substrates of the multidrug resistance/multidrug resistance protein efflux pump. No cross-resistance toward cell lines with multidrug resistance/multidrug resistance protein independent resistance phenotypes became evident. In animal studies, no signs of systemic toxicity were observed after p.o. dosages of up to 400 mg/kg of D-64131. In xenograft experiments with the human amelanoic melanoma MEXF 989, D-64131 was highly active with treatment resulting in a growth delay of 23.4 days at 400 mg/kg. Therefore, D-64131 and analogues have the potential to be developed for cancer therapy, replacing or supplementing standard therapy regimens with tubulin-targeting drugs from natural sources.

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.

Molecular mechanisms and targeting of colorectal cancer.

Targeted therapies that are approved for metastatic colorectal cancer are divided into two groups: those affecting vascular endothelial growth factor (VEGF) known to interrupt tumor growth and metastasis (also called neo-angiogenesis), and agents that affect the tumor directly by interrupting the epidermal growth factor (EGF) and its receptor. Anti-angiogenic VEGF therapies are divided into two categories: one affecting the VEGF ligand, such as bevacizumab, and those that inhibit the VEGF receptor, such as PTK/ZK. Epidermal growth factor receptor (EGFR) therapies are divided into monoclonal antibodies that affect EGFR, such as cetuximab, and EGFR tyrosine kinase inhibitors, such as gefitinib. Both VEGF and EGFR areas of treatment have shown promising efficacy in first-line, combination therapy settings. Future targeted therapeutic strategies include gene profiling, combinations of capecitabine and oxaliplatin, with bevacizumab and/or cetuximab therapies.

Clinical response to induction chemotherapy predicts local control and long-term survival in multimodal treatment of patients with locally advanced esophageal cancer.

PURPOSE: From 1991 to 1994 we performed a phase II study with intensive preoperative chemoradiation in locally advanced squamous cell carcinoma and adenocarcinoma of the esophagus. We now report on a multivariate analysis of prognostic factors based on the long-term results at a median follow-up of 6.5 years. PATIENTS AND METHODS: Eighty-eight patients were treated. Prognostic factors for overall survival and local tumor control were identified by univariate and multivariate analysis. RESULTS: Median overall survival reached 17 months, and the survival rate at 5 years was 22% (95%-confidence interval: 18-26%). Response to induction chemotherapy was the only independent factor predicting local tumor control and--beside weight loss prior to treatment--it also proved to be an independent prognostic factor for long-term survival. CONCLUSIONS: Intensive chemoradiation followed by surgery seems to be appropriate to improve long-term survival of high-risk patients with locally advanced esophageal cancer. In our trial, local tumor control and prognosis were best correlated with response to induction chemotherapy. These results may help to guide decisions regarding surgery in multimodal treatment of EC. Further efforts are needed to increase the number of treatment responders and to predict tumors not responding to chemo(radio)therapy earlier.

Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer.

Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by next-generation sequencing ("tumor tissue" cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent "liquid biopsy" cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584.

PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.

Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie.

PURPOSE: This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. PATIENTS AND METHODS: A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. RESULTS: Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. CONCLUSION: Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.