Population-based patterns of care in the first-line treatment of patients with advanced esophagogastric adenocarcinoma in Germany.

BACKGROUND: Randomized studies proved the efficacy of new drugs for the systemic treatment of advanced gastric cancer in the past 5 years. However, little is known about the use of firstline chemotherapy in clinical practice in patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (AEG) and the stomach. We investigated temporal trends in therapy and factors influencing treatment decisions for these patients during a 4-year period. PATIENTS AND METHODS: 1058 patients (median age 67 years) with advanced AEG or gastric cancers undergoing treatment decisions were documented with the Therapiemonitor® in 2006-2009. Therapiemonitor collects population-based data regarding treatment decisions and strategies. Time trends of drug use and intensity in the first-line treatment were analyzed in the entire patient group and according to age (cut-off 65 years) and Karnofsky performance status (KPS; cut-off 80%). RESULTS: Over time, the use of oxaliplatin and docetaxel as well as capecitabine increased while cisplatin and irinotecan use slightly declined. The use of chemotherapy triplets rose from 10.1% in 2006 to 47.0% in 2009. Treatment patterns significantly varied by age and KPS: Older patients were significantly less likely to receive chemotherapy triplets, cisplatin and docetaxel but tended to more often receive oxaliplatin. Likewise, triplets, cisplatin and docetaxel were less frequently used in patients with KPS < 80%, while capecitabine and irinotecan were significantly more often used in this patient group. CONCLUSIONS: A clear tendency towards the use of more intensive chemotherapy regimens in patients with AEG and gastric cancer was observed over time. Older or less fit patients were treated preferably with monotherapy or chemotherapy doublets during 2006-2009. Oxaliplatin and docetaxel use has substantially risen.

Efficacy and safety of capecitabine in combination with docetaxel and mitomycin C in patients with pre-treated pancreatic, gallbladder, and bile duct carcinoma.

PURPOSE: Preclinical data indicate the improvement of the antitumor activity of capecitabine by mitomycin C and docetaxel through upregulation of thymidine phosphorylase activity. Therefore, we have established a combination regimen of these drugs (DocMitoCape), which demonstrated preliminary activity especially in bile duct and pancreatic carcinoma. METHODS: Here we report the safety and efficacy of the DocMitoCape regimen in pre-treated patients with gallbladder, bile duct, or pancreatic carcinoma. Treatment consisted of capecitabine (2,000 mg/m(2) days 1-14) in combination with docetaxel (40 mg/m(2) day 1) and mitomycin C (4 mg/m(2) day 1). Cycles were repeated on day 22. Toxicity was graded according to NCI-CTC criteria, and the antitumor activity was assessed by RECIST criteria. RESULTS: Twenty-eight pre-treated patients with a median age of 59 suffering from pancreatic, gallbladder, intra- (IHCCC) or extrahepatic (EHCCC) bile duct carcinoma were included. Eleven patients had received ≥2 lines of prior chemotherapy. A total of 183 and a median of six cycles were administered (range 1-21). The mean dose intensity was as follows (cycles 1-2/3-4; %): capecitabine 97/92, docetaxel 100/100, mitomycin C 99/100. Main adverse events grades 2/3/4 were (n): leukocytopenia 3/2/2, anemia 13/4/0, thrombocytopenia 3/1/0, nausea/vomiting 2/1/0, diarrhea 5/1/0, hand-foot-skin reaction 7/0/0. Six patients achieved partial and seven patients minor remissions, while six patients had stable disease adding to a tumor control rate of 68%. Median progression-free and overall survival was 4.5 (range 1.0-44.9) and 6.8 months (range 1.5-44.9), respectively, calculated from the start of treatment. CONCLUSION: In all, the DocMitoCape regimen exhibited a favorable safety profile and a high rate of tumor stabilizations in patients with pre-treated gallbladder, bile duct and pancreatic carcinoma. It might be considered after failure of standard regimens in these types of cancer.

Endoprotease profiling with double-tagged peptide substrates: a new diagnostic approach in oncology.

BACKGROUND: The measurement of disease-related proteolytic activity in complex biological matrices like serum is of emerging interest to improve the diagnosis of malignant diseases. We developed a mass spectrometry (MS)-based functional proteomic profiling approach that tracks degradation of artificial endoprotease substrates in serum specimens. METHODS: The synthetic reporter peptides that are cleaved by tumor-associated endopeptidases were systematically optimized with regard to flanking affinity tags, linkers, and stabilizing elements. Serum specimens were incubated with reporter peptides under standardized conditions and the peptides subsequently extracted with affinity chromatography before MS. In a pilot study an optimized reporter peptide with the cleavage motif WKPYDAADL was added to serum specimens from colorectal tumor patients (n = 50) and healthy controls (n = 50). This reporter peptide comprised a known cleavage site for the cysteine-endopeptidase "cancer procoagulant." RESULTS: Serial affinity chromatography using biotin- and 6xHis tags was superior to the single affinity enrichment using only 6xHis tags. Furthermore, protease-resistant stop elements ensured signal accumulation after prolonged incubation. In contrast, signals from reporter peptides without stop elements vanished completely after prolonged incubation owing to their total degradation. Reporter-peptide spiking showed good reproducibility, and the difference in proteolytic activity between serum specimens from cancer patients and controls was highly significant (P < 0.001). CONCLUSIONS: The introduction of a few structural key elements (affinity tags, linkers, d-amino acids) into synthetic reporter peptides increases the diagnostic sensitivity for MS-based protease profiling of serum specimens. This new approach might lead to functional MS-based protease profiling for improved disease classification.

Cetuximab-based treatment of metastatic anal cancer: correlation of response with KRAS mutational status.

BACKGROUND: No standard chemotherapy regimen can be defined for patients with metastatic squamous cell carcinoma of the anus due to the low incidence of this disease and the high cure rate of localized tumors. Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far. METHODS: We report on 7 patients with metastatic anal cancer treated with cetuximab - a chimeric antibody against EGFR - on a compassionate use basis along with the results of KRAS mutational analysis. RESULTS: Marked tumor shrinkage was noted in several patients using cetuximab monotherapy or cetuximab/irinotecan combination as first or subsequent treatment line (usually after failure of cisplatin-based regimens). Two out of seven patients harbored KRAS mutations. Both patients had progressive disease receiving cetuximab, while the remaining 5 patients had either a partial remission (n = 3), a minor remission (n = 1) or no change lasting > or =6 months after previous rapid tumor progression. CONCLUSION: Cetuximab-based treatment appears to be a valuable treatment option for patients with metastatic KRAS wild-type anal cancer after failure of or as an alternative to cisplatin/5-fluorouracil-based therapy.

Alpha-fetoprotein expressing metastastic adenocarcinoma of the esophago-gastric junction responding favorably to capecitabine and oxaliplatin.

Alpha-fetoprotein-producing metastatic adenocarcinoma of the stomach or the esophago-gastric junction usually exhibits either no or only short-term remission while receiving palliative chemotherapy. We report on a 76-year-old male patient suffering from an unresectable alpha-fetoprotein-producing adenocarcinoma of the esophago-gastric junction with several liver metastases. He was treated with capecitabine and oxaliplatin-based combination therapy. A long-lasting major remission was observed resulting in a survival of 18.5 months.

Oxaliplatin and capecitabine-based chemoradiotherapy for gastric cancer--an extended phase I MARGIT and AIO trial.

PURPOSE: Adjuvant 5-fluorouracil-based chemoradiotherapy has been shown to improve the prognosis of gastric cancer. To optimize these results, in the present study oxaliplatin and capecitabine were used instead of 5-fluorouracil. We sought to determine the maximum tolerated dose and the dose-limiting toxicities (DLT) of these drugs in combination with intensity-modulated radiotherapy. METHODS AND MATERIALS: Patients with resected adenocarcinoma of the stomach or the gastroesophageal junction were included. They received two cycles of induction chemotherapy (oxaliplatin and capecitabine [XelOx] regimen). Using standard Phase I methodology, patients received 45 Gy in 1.8-Gy fractions either in combination with capecitabine 825 mg m(-1) twice a day (Dose Level [DL] I) or capecitabine in combination with weekly oxaliplatin 40 or 50 mg m(-1) (DL II and III). After the completion of chemoradiation, two additional cycles of XelOx were scheduled. RESULTS: A total of 32 patients were recruited. Only 1 of 6 patients evaluable on DL I had DLT. Of the first 6 patients on DL II, 1 patient experienced DLT, and 3 of the remaining patients had Grade 3 toxicity. Therefore, DL II was defined as the maximum tolerated dose and a total of 20 patients were treated at this DL. The most frequently observed toxicities (Common Toxicity Criteria Grades 1, 2 and 3) were, respectively, leukocytopenia in 5, 5, and 4 patients; nausea in 3, 7, and 3; and diarrhea in 4, 0, and 1. CONCLUSIONS: In summary, capecitabine 825 mg m(-1) twice a day (Days 1-33) and weekly oxaliplatin 40 mg m(-1) was safe and tolerable in combination with intensity-modulated radiotherapy. Furthermore, four cycles of XelOx could be applied before and after chemoradiotherapy in two thirds of the patients.

Expression of the mutated transketolase TKTL1, a molecular marker in gastric cancer.

The nonoxidative pentose phosphate pathway allows glucose conversion to ribose for DNA or RNA synthesis and glucose degradation to lactate controlled by transketolase enzyme reactions. It has been postulated, that this pathway is of the utmost importance in tumors for the proliferation process. We detected a strong upregulation of the mutated transketolase transcript (TKTL1) in a considerable number of patients with gastric cancer (GC) or cancer of the gastroesophageal junction (GEJ). While only 10.8% of the cancer tissues revealed a significant mRNA upregulation, 36.9% of the cancer tissues demonstrated a protein overexpression. We propose that TKTL1 upregulation is a common phenomenon in GC and cancer of the GEJ leading to an enhanced, oxygen-independent glucose usage which might contribute to a more aggressive tumor growth. Since molecular targeted inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis, TKTL1 could be a relevant target for anti-transketolase therapies in gastric cancer.