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Background: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. Methods: Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. Results: Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. Conclusion: The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.

In resectable gastric and gastroesophageal junction cancer, adding durvalumab to perioperative chemotherapy improved event-free survival and pathological complete response, with no major increase in high-grade adverse events.

SummaryBackgroundThe evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients’ age and sidedness of primary tumour.MethodsThe study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.ResultsOverall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).ConclusionsIn FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.Clinical trialFIRE-3 (NCT00433927).

Purpose: The aim of this study was to assess whether the reduction in the total dose of pegylated liposomal doxorubicin (PLD) per cycle from 50 mg/m2 every 4 weeks to 40 mg/m2 every 4 weeks can effectively lower the incidence of treatment-related palmar-plantar erythrodysesthesia (PPE) and mucositis. Methods: Patients received PLD 40 mg/m2 every 4 weeks, and were evaluated for toxicity prior to each treatment and for response every 8 weeks. Results: All patients were previously treated with at least one chemotherapy regimen for metastatic disease, and 72% of the patients had a prior exposure to an anthracycline. Forty-six evaluable patients received a median of four PLD cycles, with a median dose intensity of 10 mg/m2/week and a median cumulative dose of 160 mg/m2. No National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 PPE was observed in these patients. NCI-CTC grade 3 or 4 mucositis occurred in 4.3% of patients, only. Response rates and survival results observed here were comparable to those observed with PLD 50 mg/m2 every 4 weeks in a matched patient population. However, patients treated with PLD 40 mg/m2 every 4 weeks experienced less PPE and mucositis and required clearly less dose reductions and treatment delays. Conclusion: The favorable safety profile observed in this study leads us to recommend the use of PLD 40 mg/m2 every 4 weeks for patients with advanced breast cancer. [PUBLICATION ABSTRACT]

We describe the development of a three-dimensional in vitro organ culture model for bronchial carcinoma using bronchial mucosa organ cultures and three different human non-small cell lung cancer cell lines. During precultivation, bronchial fragments obtained as biopsies during routine bronchoscopy had regenerated a complete epithelial covering with a well-preserved organotypic architecture around a nucleus consisting of connective tissue. To create cocultures, different types of confrontation between tumor cells and organ cultures were applied. Histologic light microscopy and scanning electron microscopy were used in analysis. When tumor cells were confronted with completely epithelialized organ cultures, they showed a low incidence of attachment. When organ cultures were wounded before confrontation, tumor cells always attached to the wounded side and showed a progressive invasion into the stromal tissue. Measurements of the penetration depth of tumor cells into the organ cultures after different incubation times permitted the quantitative evaluation of invasion. Histologic studies revealed well-differentiated normal epithelium in spite of long culture periods. Histologic features of the tumors were those of an invasive undifferentiated carcinoma and showed marked similarities to the situation in vivo. The coculture model permits internal controls because it contains both normal human epithelium and human tumor cells in the same organotypic culture. Therefore it offers opportunities for various in vitro investigations on therapeutic and diagnostic modalities of lung cancer, as indicated in this paper by an example of photodynamic procedures with 5-aminolevulinic acid.