Perioperative Therapie des lokal fortgeschrittenen Rektumkarzinoms

The therapeutic approach for locally advanced rectal carcinoma should always comprise multimodality treatment instead of surgical intervention alone. The treatment strategy differs depending on which third of the rectum is affected. During recent years, neoadjuvant treatment concepts have replaced adjuvant chemoradiotherapy for locally advanced rectal cancer. In the current article, we summarize the state of the art in the treatment of locally advanced rectal cancer and discus perspectives of treatment.     

First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer

Purpose  

Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.     

Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer

We have investigated the prognostic value of two novel interim ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters in patients undergoing chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): one tumor parameter (maximal standardized uptake ratio rSUR) and one normal tissue parameter (change of FDG uptake within irradiated nontumor-affected esophagus ∆SUV_NTO). PET data of 134 European and Chinese patients were analyzed. Parameter establishment was based on 36 patients undergoing preoperative CRT plus surgery, validation was performed in 98 patients receiving definitive CRT. Patients received PET imaging prior and during fourth week of CRT. Clinical parameters, baseline PET parameters, and interim PET parameters (rSUR and ∆SUV_NTO) were analyzed and compared to event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Combining rSUR and ∆SUV_NTO revealed a strong prognostic impact on EFS, OS, LRC and FFDM in patients undergoing preoperative CRT. In the definitive CRT cohort, univariate analysis with respect to EFS revealed several staging plus both previously established interim PET parameters as significant prognostic factors. Multivariate analyses revealed only rSUR and ∆SUV_NTO as independent prognostic factors (p = 0.003, p = 0.008). Combination of these parameters with the cutoff established in preoperative CRT revealed excellent discrimination of patients with a long or short EFS (73% vs. 17% at 2 years, respectively) and significantly discriminated all other endpoints (OS, p < 0.001; LRC, p < 0.001; FFDM, p = 0.02), even in subgroups. Combined use of interim FDG-PET derived parameters ∆SUV_NTO and rSUR seems to have predictive potential, allowing to select responders for definitive CRT and omission of surgery.     

Cervical carcinoma antigen: distribution in neoplastic lesions of the uterine cervix and comparison to other tumor markers

Four antibodies (anti-CCA, anti-CEA, Ca-l, and anti-EMA) were used to study the distribution of antibody-binding sites in normal endocervical mucosa, metaplastic squamous epithelium, squamous epithelium exhibiting varying grades of intraepithelial neoplasia, and invasive squamous cell carcinoma. Anti-CCA, a novel monoclonal antibody raised against an extract of squamous cell carcinoma of the cervix, recognizes dysplastic, neoplastic, and metaplastic cervical epithelial cells. While anti-CCA and Ca-l rarely stained normal glandular epithelium, 31.4 and 45.7% of the samples stained positively for CEA and EMA, respectively. There did not appear to be significant differences between anti-CCA and the other antibodies in the frequency with which neoplastic conditions were stained. Based upon these observations, it appears that none of the antibodies tested can be regarded as a specific tumor marker.     

Malignant intestinal non-Hodgkin's lymphoma from the surgical point of view

BACKGROUND: Primary intestinal non-Hodgkin's lymphoma (I-NHL) is much less frequent than gastric lymphoma and has hardly been studied in prospective trails. To the surgeon, patients frequently present with abdominal emergencies. PATIENTS AND METHODS: A consecutive series of patients subjected to surgery because of I-NHL between 1998 and 1999 was evaluated retrospectively for characteristic clinical, radiographic and intraoperative findings. Patients with gastric lymphoma were not considered. RESULTS: 10 patients, 8 males and 2 females, with I-NHL were subjected to first-line surgery because of painful abdominal tumor, intestinal hemorrhage, obstruction or perforation. I-NHL was located most often in the small bowel (n = 7). It was rare in the colon (n = 2) and the duodenum (n = 1). Median postoperative follow-up was 28 months. Perioperative mortality was 10% (n = 1). Probability of survival 3 years after surgery was 60%. CONCLUSIONS: Patients with I-NHL frequently present with complications of tumor growth, requiring urgent surgical treatment. Irrespective of surgical complications we advocate surgery in cases of resectable disease as first-line treatment. Adjuvant treatment is indicated with respect to resection status and histopathological staging.     

Infusional 5-fluorouracil and mitomycin C: an effective regimen in the treatment of advanced gastric cancer

BACKGROUND: Weekly infusional 5-fluorouracil (5-FU) and folinic acid (FA) as part of multi-drug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective with low toxicity. The present analysis was carried out to evaluate the safety and efficacy of 5-FU/FA in combination with 3-weekly mitomycin C (MMC) in patients with advanced gastric cancer. PATIENTS AND METHODS: A total of 28 patients with AGC were analysed (first line n=23). They received weekly 24-h 5-FU 2,600 mg/m2 preceded by 2-h FA 500 mg/m2 for 6 weeks followed by a two week rest period. Bolus MMC 10 mg/m2 was applied on days 1 and 22. Patient characteristics were: m/f 17/11; median age 67 years (43-79). The most common metastatic sites were liver and peritoneum (n=12, respectively). RESULTS: A median of 3 and a total of 91 cycles were administered. Mean dose intensity in cycle I was: 5-FU 86%, MMC 87%. Responses were observed in 43%, no change was seen in 29% of the patients. Median overall survival was 9.7 months (10.7 months for patients treated first line). Non-haematological toxicities (NCI CTC grades 3 and 4) were observed in 2 patients, leukopenia and thrombocytopenia grades 3/4 were observed in 50 and 25% of the patients, respectively. CONCLUSIONS: Infusional 5-FU/FA plus MMC may safely be used in patients with AGC in the routine clinical setting. This regimen yields response rates and survival data comparable to platinum-based regimen.     

Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15-25-30-35 mg m(-2) corresponding to dose levels I-IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m(-2)) and sodium FA (500 mg m(-2), mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m(-2) on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n=3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m(-2) Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m(-2). Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer.     

Population Pharmacokinetics of Sibrotuzumab, A Novel Therapeutic Monoclonal Antibody, in Cancer Patients

Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5 mg/m(2) to an absolute dose of 100 mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1 ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6 ml/h (9.6); for the nonlinear clearance Vmax was 0.0338 mg/h (25) and Km 0.219 microg/ml (57). At serum concentrations between approximately 20 ng/ml and 7 microg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7 microg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration-time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.     

Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability

Tumorigenesis and tumor progression can be considered an evolutionary process. In order to deduce information on the mutational and selective pressures during melanoma progression we performed microsatellite analysis at 42 autosomal and two X-linked loci in a microdissected primary melanoma and its nine metastases. Loss of heterozygosity at locus D9S259 was the only genetic change observed in all metastases. The pattern of loss of heterozygosity at loci D9S162 and D9S171 within the region of common loss on chromosome 9p21 which encompasses the tumor suppressor gene p16ink4 enabled the distinction of four genetically different tumor cell populations. Three cell lineages showed homozygous loss of the p16ink4 gene, which evolved independently in each tumor cell population within the primary tumor. Additional allele losses could be demonstrated at markers D14S53 and DXS998. The fourth lineage did not demonstrate loss of heterozygosity at loci D9S162 and D9S171 and contained the wild type p16ink4 gene but was characterized by abundant microsatellite instability. The evolutionary approach towards tumorigenesis and tumor progression used in this study thus confirms the role of p16ink4 inactivation for melanoma progression but not for melanoma initiation; it suggests the existence of additional putative tumor suppressor genes located on 9p as well as on the long arm of chromosome 14 and shows that microsatellite instability may represent an alternative pathway of tumor cell evolution in malignant melanoma.