Phase IB study of the EpCAM antibody adecatumumab combined with docetaxel in patients with EpCAM-positive relapsed or refractory advanced-stage breast cancer.

BACKGROUND: Targeted therapy options in HER2-negative breast cancer are limited. This open-label, multicenter phase IB dose-escalation trial was conducted to determine safety, tolerability, and antitumor activity of a combination of docetaxel (Taxotere) and increasing doses of adecatumumab, a human IgG1 antibody targeting epithelial cell adhesion molecule (EpCAM), in EpCAM-positive relapsed or primary refractory advanced-stage breast cancer. PATIENTS AND METHODS: Patients pretreated with up to four prior chemotherapy regimens received increasing adecatumumab doses either every 3 weeks (q3w) or weekly (qw) combined with docetaxel (100 mg/m(2) q3w). Primary end points were safety and tolerability. Antitumor activity was evaluated according to RECIST. Clinical benefit was defined as complete or partial response or stable disease for ≥24 weeks. RESULTS: Thirty-one evaluable patients were treated. Most adverse events were mild to moderate in severity. Neutropenia, leukocytopenia, lymphopenia, and diarrhea (dose-limiting) were the most frequent toxic effects. Maximum tolerated doses of adecatumumab given in combination with docetaxel were 550 mg/m(2) q3w and 360 mg/m(2) qw. Clinical benefit was observed in 44% of patients treated with q3w adecatumumab and docetaxel, increasing to 63% in patients with high EpCAM-expressing tumors. CONCLUSION: Combination therapy of adecatumumab and docetaxel is safe, feasible, and potentially active in heavily pretreated advanced-stage breast cancer.

Clinical significance of lymph vessel density in T3 colorectal carcinoma.

PURPOSE: The purpose of the present study is to characterise the lymphatic vessel density (LVD) in the T3 colorectal carcinoma and to correlate it with N status, grading and presence of tumour budding. METHODS: A total of 56 cases of T3 colorectal carcinoma were retrieved from the pathology's archive of Klinikum Augsburg. All slides were stained immunohistochemically with D2-40 (lymphatic endothelium) and with pancytokeratin to assess the tumour budding. Tumour budding and lymph vessel density were investigated independently by BM and CC. The highest density of lymphatic vessels was counted both in tumour centre (ILVD) and at the periphery of the tumour (PLVD) within an area of 0.24 mm(2). RESULTS: Due to the strong intra-observer (BM and CC) difference in ILVD and PLVD, all cases were re-evaluated establishing a consensus that has been used for the further analyses. There was a significant difference between PLVD and ILVD (12 ± 4 versus 6 ± 3; P < 0.001). Moreover, we found a non-significant trend towards high PLVD in the cases with nodal metastasis versus the negative one, 13 ± 5/hpf versus 11 ± 4 (P = 0.072). There was no association between tumour budding and ILVD and PLVD (P = 0.249 and 0.38). CONCLUSION: Colorectal carcinoma induces lymphangiogenesis. A higher PLVD could increase the capability of cancer cell to invade the lymphatic system. However, the obvious difficulties in immunohistochemical evaluation and the rather small differences between nodal positive and negative cases in T3 colorectal cancer seem to limit the clinical value of LVD evaluation.

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.

Tumour budding, uPA and PAI-1 are associated with aggressive behaviour in colon cancer.

AIMS: The proteases PAI-1 and uPA play a major role in extracellular matrix degradation, which facilitates tumour progression. Tumour budding is a histomorphological expression of enhanced tumour cell migration. MATERIALS AND METHODS: To investigate their prognostic value for and correlation with colon cancer, a prospective study was performed. We analysed tissue levels of uPA and PAI-1 of 55 colon cancer tumours employing a commercially available enzyme-linked immunosorbent assay (ELISA). Tumour budding was analysed on cytokeratin-stained slides. RESULTS: There was a strong correlation between uPA and tumour budding (R = 0.440; P < 0.001). uPA levels were increased in high grade tumours, whereas PAI-1 was elevated in cases with venous invasion (P = 0.004 and P = 0.028). PAI-1 values and tumour budding are associated significantly with the occurrence of distant metastases (P < 0.001 and P = 0.034, respectively). Tumour budding was significantly associated with lymph node metastases (P = 0.034). Multivariate analysis revealed PAI-1 and lymph node metastases to be independently predictive of distant metastases (P = 0.007 and P = 0.004, respectively). CONCLUSIONS: The results of our study show that tumour budding and the plasmin/plasminogen system are related. PAI-1 was independently predictive for the occurrence of distant metastasis.

High antileukemic efficacy of an intermediate intensity conditioning regimen for allogeneic stem cell transplantation in patients with high-risk acute myeloid leukemia in first complete remission.

The goal of this analysis was to define the role of the moderate-intensity fludarabin Ara-C amsacrin (FLAMSA)-reduced intensity conditioning (RIC) regimen for patients with high-risk AML undergoing allogeneic SCT (alloSCT) in first CR1. High-risk was defined by (1) AML secondary to MDS or radio/chemotherapy, (2) unfavorable cytogenetics or (3) delayed response to induction chemotherapy. A total of 23 of 44 AML patients referred to the University of Munich for alloSCT in CR1 between 1999 and 2006 fulfilled these criteria and received FLAMSA chemotherapy, followed by RIC (4 Gy TBI/cyclophosphamide/ATG) for alloSCT. Twenty-two patients engrafted, one died in aplasia. Two-year cumulative incidences for relapse and nonrelapse mortality (NRM) were 4.6 and 22.5%, respectively. Four-year overall and leukemia-free survival was 72.7% (median follow-up among survivors: 35 months). The results of this high-risk cohort were compared to the outcome of 21 consecutive standard-risk patients <55 years, who had received standard, myeloablative sibling SCT in CR1 AML within the same center and time period. Survival and cumulative incidences of relapse and NRM were identical in both groups. In conclusion, the FLAMSA-RIC regimen produces long-term remission in a high proportion of patients with high-risk AML transplanted in CR1. In this cohort, FLAMSA-RIC showed equivalent antileukemic activity as compared to the standard protocols.

Early allo-SCT for AML with a complex aberrant karyotype--results from a prospective pilot study.

In AML, a complex aberrant karyotype is associated with poor response to chemotherapy and dismal prognosis. We prospectively studied the concept of allogeneic haematopoietic SCT (HSCT), performed early and regardless of response to induction treatment in patients with complex karyotype AML (CK-AML). The preparative regimen consisted of fludarabine, Ara-C and amsacrine (FLAMSA) chemotherapy, followed by reduced intensity conditioning (RIC) 3 days later. In vivo T-cell depletion by anti-thymocyte globulin was used to protect from early GvHD, and prophylactic donor lymphocyte transfusion was given from day+120 to augment the GvL effect, once tolerance was established. Eighteen consecutive patients with CK-AML (median age: 53 years) received HSCT from related (n=7) or unrelated (n=11) donors. Before FLAMSA-RIC, nine patients each had received one and two induction courses. Stage at start of FLAMSA-RIC was CR/CRi (n=8) or persistent disease (n=10). Following HSCT, 16 patients achieved CR. After a follow-up of 51 months, 11 patients are alive in CR, whereas seven have died in remission (n=3), or from leukaemia (n=4). Cumulative incidence of relapse, non-relapse mortality, acute GvHD≥II and chronic GvHD were 0.222±0.098, 0.235±0.104, 0.367±0.120 and 0.481±0.123, respectively. Four-year survival from HSCT is 61%. Early HSCT following FLAMSA-RIC may improve the outcome of this unfavourable AML subgroup.

[A 65-year-old female patient with breast cancer accompanied by thrombocytopenia and hyperfibrinolysis]. / 65-jährige Patientin mit Thrombopenie und Hyperfibrinolyse bei Mammakarzinom.

Tumor diseases can be accompanied by paraneoplastic syndromes. Low platelet counts and hyperfibrinolysis led to the diagnosis of recurrent breast cancer in this case. A tumour disease with disturbed hemostasis caused by both plasmatic coagulation and thrombocytopenia has not yet been reported.

Sequential immunotyping and genotyping of tumor cells in bone marrow of cancer patients: a model study.

Epithelial cells can be detected in bone marrow or peripheral stem cell preparations of patients with various kinds of cancer and their presence in bone marrow is of prognostic significance. Characterization of these cells has been hampered by their low frequency. Here we present a method that may allow sequential immunophenotyping and genotyping of epithelial cells in bone marrow. To simulate in vivo situations, cells from the colon cancer cell line HT29 were seeded into bone marrow and were first detected by the Fab fragment of the A45-B/B3 anticytokeratin antibody. Expression of Ki67, p53, Her-2/ neu (c-erbB2), and 17-1A could be detected on A45-B/B3-stained cells by immunofluorescence using a fluorescein-labeled anti-mouse immunoglobulin specific for the Fc part of mouse immunoglobulins. Reactivity for all antigens except for Ki67 persisted after A45-B/B3 labeling even when a scoring step for the presence of epithelial cells was performed before proceeding with the immunophenotyping. After immunophenotyping, numerical chromosomal aberrations and amplifications of the Her-2/neu oncogene could be assessed by fluorescence in situ hybridization in the same A45-B/B3-stained cells. This combination of immunophenotyping and genotyping may help in establishing the role of epithelial cells in bone marrow or peripheral stem cell harvests for tumor relapse and formation of metastases.

Combination of high-dose chemotherapy and monoclonal antibody in breast-cancer patients: a pilot trial to monitor treatment effects on disseminated tumor cells.

BACKGROUND: Tumor relapse occurring in high-risk breast cancer patients after high-dose chemotherapy (HDC) and autologous stem-cell transplantation may arise from cells resistant to chemotherapy, as well as from tumor cells reinfused with autologous stem cell grafts. This pilot study was designed to investigate whether ex vivo immunomagnetic purging of PBSC and subsequent immunotherapy with MAb 17-1A is feasible and can reduce the number of disseminated tumor cells in BM. METHODS: Twelve high-risk breast-cancer patients, seven in Stage II/III and five in Stage IV (UICC breast cancer classification) underwent surgery of the primary tumor and received two cycles of induction chemotherapy, followed by HDC. After each cycle of induction chemotherapy PBSC were collected and incubated with Ab-coated immunomagnetic beads, to remove contaminating tumor cells. Prepared stem-cell grafts were transplanted 24 h after completion of HDC. After recovering from HDC all 12 patients received a total dose of 900 mg MAb 17-1A within 4 months. The effect of in vivo purging with MAb 17-1A after HDC was controlled by examining bone aspirates of the patients with an immunocytochemical assay, allowing the detection of one cytokeratin-positive tumor cell in 10(6) total nucleated cells (TNC). RESULTS: Tumor cells were found in 5/12 BM aspirates prior to chemotherapy and even after HDC. Further monitoring of BM aspirates for cancer cells during Ab therapy showed a consistent reduction of tumor cells in four out of these five patients. After a median clinical follow-up of 41 (32-48) months all four patients are alive. These results are different from those of a historical control group of six patients with breast cancer treated with the same chemotherapy schedule, but without 17/1A consolidation. In comparison with the patients from the study group, all patients of this control group revealed a significantly increased number of tumor cells in BM (p < 0.01) after HDC during follow-up of 5 (3-7) months. These preliminary results indicate that induction chemotherapy, followed by HDC, may reduce disseminated tumor cells in BM. DISCUSSION: Immunotherapy with MAb 17-1A after HDC may further eliminate residual disease without severe toxicity.