Andreas Hilbig

Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy)

BackgroundAdvanced pancreatic cancer, in addition to its high mortality, is characterized by one of the highest rates of venous thromboembolic events (VTE) as compared to other types of cancer. Enoxaparin, a low molecular weight heparin (LMWH), has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients. Results of some small studies suggest that this benefit might extend to patients with cancer, however, enoxaparin is not currently indicated for this use. This phase IIb study was designed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy.MethodsThe aim of this prospective multicenter trial is to compare concomitant treatment with enoxaparin to no anticoagulation in 540 patients. Primary endpoint is the incidence of clinically relevant VTE (symptomatic deep venous thrombosis (DVT) of the leg and/or pelvic and/or pulmonary embolism (PE)) within the first 3 months. Secondary endpoints include the incidence of symptomatic and asymptomatic VTE after 6, 9 and 12 months as well as remission at 3, 6, 9 and 12 months, overall survival and bleeding. Trial registration: isrctn.org identifier CCT-NAPN-16752, controlled-trials.com identifier: ISRCTN02140505.ResultsAn interim analysis for safety performed after inclusion of 152 patients revealed no increased risk of bleeding (5 pts vs. 6 pts, Chi2: 0.763).ConclusionPROSPECT is a pivotal study in elucidating the role of low molecular weight heparins in advanced pancreatic cancer. Its results will lead to a new understanding of the role of heparins in the prevention of venous thromboembolism and of their effect on survival, remission rates and toxicity of chemotherapeutic regimens.

Gemcitabine in the treatment of metastatic pancreatic cancer

Gemcitabine (2´,2´-difluorodeoxycytidine) is a deoxycytidine-analog antimetabolite with broad activity against a variety of solid tumors and lymphoid malignancies. It was approved as standard of care in patients with pancreatic cancer one decade ago, based primarily on improvement in clinical benefit response such as pain reduction, improvement in Karnofsky performance status and increase in body weight. This article gives an overview of the pharmacodynamics and pharmacokinetics of gemcitabine, highlights the clinical activity of gemcitabine and summarizes the treatment options in metastastic pancreatic cancer with focus on gemcitabine-based chemotherapy. The emerging role of combinations of gemcitabine with novel targeted agents, including small-molecule inhibitors and other investigational drugs, is also discussed.

Transforming growth factor beta in pancreatic cancer.

Pancreatic cancer has high incidence and mortality rates, and effective treatment remains a clinical challenge. As deregulation of the cytokine transforming growth factor beta (TGF-β) contributes to the progression of pancreatic carcinoma, the TGF-β pathway has been targeted using various strategies, including small molecule inhibitors of TGF-βRI, TGF-β-specific neutralizing antibodies and antisense compounds. As increased TGF-β2 levels in serum or tumor tissue of patients with pancreatic cancer correlated with poor prognosis, inhibition of TGF-β2 synthesis via the antisense oligonucleotide trabedersen (AP 12009) is a promising approach.

Second-Line Therapy in Refractory Pancreatic Cancer. Results of a Phase II Study

Background: This phase II trial investigated the efficacy and safety of oxaliplatin (O), 5-fluorouracil (5-FU), and folinic acid (FA) (OFF) as second-line treatment for patients with metastatic pancreatic adenocarcinoma after failure of first-line gemcitabine treatment. Patients and Methods: 37 patients with confirmed progressive disease on gemcitabine therapy were treated with OFF (O 85 mg/m2 days 8, 22; FA 500 mg/m2, followed by 5-FU 2,600mg/m2 days 1, 8, 15, 22) every 6 weeks. Patients were treated on an outpatient basis and remained on treatment until disease progression. Results: All patients were assessable for toxicity and effectiveness. We observed moderate hematotoxicity, the most common non-hematologic toxicity was neurotoxicity. A total of 12 patients had grade 3 nonhematologic toxicities: nausea and vomiting (4 patients), reversible neurotoxicity (5 patients), and diarrhea (3 patients). No grade 4 toxicities were observed. Median time to progression was 12 (1–125) weeks. Survival in second line was 22 (4–326+) weeks. Overall disease control rate was 49% (complete remission = 3%; partial remission = 3%; stable disease > 12 weeks = 43%). Conclusions: This regimen is feasible and active with an acceptable toxicity profile; it can be safely administered in an outpatient setting. There is an urgent need for further investigation in phase III trials.

Src Kinase and Pancreatic Cancer

The c-Src non-receptor tyrosine kinase is overexpressed in a large number of human malignancies. It is linked to tumour development and progression to distant metastases by promoting cell proliferation, invasion, and motility. Recently, promising anticancer therapeutics targeting c-Src have been developed that are under clinical investigation.

Value of Carbohydrate Antigen 19-9 in Predicting Response and Therapy Control in Patients with Metastatic Pancreatic Cancer Undergoing First-Line Therapy

BACKGROUND Serum carbohydrate antigen 19-9 (CA 19-9) has been shown to be a sensitive and specific serum marker for pancreatic cancer. Little has been published about correlations between baseline CA 19-9 level or changes to CA 19-9 level and median overall survival (mOS). Its impact on monitoring treatment efficacy remains under discussion, however. METHODS CA 19-9 serum level was measured in 181 consecutive patients with advanced pancreatic cancer (APC) being treated with gemcitabine-based first-line chemotherapy. We separated the patients into several groups depending on baseline CA 19-9 levels and the CA 19-9 response after 6-8 weeks of treatment. Evaluations were made using SPSS 19.9. RESULTS Median baseline CA 19-9 level was 1,493 U/ml (range 40-1,043,301). Patients with baseline CA 19-9 ≤1,000 U/ml had a mOS of 14.9 months (95% CI: 11.36:18.44), whereas patients with CA 19-9>1,000 U/ml had a mOS of 7.4 months [(95% CI: 5.93:8.87) p < 0.001, HR 2.12]. With regard to the change in CA 19-9 after 6-8 weeks of treatment: patients with increased CA 19-9 levels had a mOS of 8.1 months, those with stabilized CA 19-9 levels 11.6 months, and those with decreased CA 19-9 levels 11.1 months (p < 0.019). CONCLUSION CA 19-9 levels can separate patients with differing mortality risks at baseline. Patients with stabilization or high response of CA 19-9 after 6-8 weeks of treatment had no significant differences in survival rates, whereas patients with increased CA 19-9 had significantly lower survival rates, indicating an early treatment failure.

Adjuvant therapy of pancreatic cancer

Pancreatic adenocarcinoma is one of the most aggressive tumors, with a high potential for early dissemination and a relatively poor sensitivity to radiation therapy and cytotoxic agents. Complete resection of the tumor is currently the only curative option but only 10–15% of patients present with localized, potentially resectable disease at the time of diagnosis. Median overall survival for all resected patients (R0 and R1) averages between 11 and 23 months, 5-year overall survival ranges from 10 to 25% (R0) and 0 to 5% (R1), leading to a case–fatality index of 95%. Despite the latest trend toward adjuvant chemotherapy with gemcitabine due to the results from the Charité Onkologie-001 trial, there is no broad consensus regarding the adjuvant regimen that should be applied. Early data from the European Study Group for Pancreatic Cancer-3(v2) trial revealed no difference in terms of overall survival between 5-fluorouracil/folinic acid and gemcitabine after resection of pancreatic cancer.

Multimodale palliative Behandlung des Pankreaskarzinoms

ZusammenfassungDas Pankreaskarzinom ist bei stetig steigender Inzidenz die vierthäufigste krebsbedingte Todesursache in der westlichen Welt. In Deutschland erkranken jährlich mehr als 4900 Männer und 5500 Frauen, was etwa 3% aller Krebsneuerkrankungen ausmacht. Aufgrund der unspezifischen Symptomatik wird das Pankreaskarzinom in etwa 80–90% der Fälle erst im fortgeschrittenen oder metastasierten Stadium diagnostiziert. Eine potenziell kurative Resektion kommt deshalb nur bei ca. 20% der Patienten infrage; die 5-Jahres-Überlebensrate nach einer kompletten Resektion liegt bei 20%. Beim fortgeschrittenen bzw. metastasierten Pankreaskarzinom gilt eine palliative systemische Chemotherapie inzwischen als Standard. Der Wert der Radio-Chemo-Therapie wird aktuell in mehreren laufenden Phase-III-Studien evaluiert. Weitere wichtige Therapiesäulen in der palliativen Situation sind die adäquate Schmerztherapie gemäß WHO-Stufenplan sowie eine frühzeitig begonnene unterstützende Ernährungstherapie.AbstractExhibiting a rising incidence, pancreatic carcinoma is the fourth most common cause of death in the Western world. In Germany more than 4900 men and 5500 women suffer from pancreatic carcinoma every year, about 3% of all newly diagnosed cases of cancer. Because of the non specific symptoms, pancreatic carcinoma is detected in 80–90% of cases in an advanced or metastatic stage. In only 20% of all patients is an operation possible and after complete resection the 5-year survival rate is 20%. Palliative chemotherapy is supposed to be the standard treatment in advanced and metastatic pancreatic carcinoma. The value of radiochemotherapy is currently being evaluated in several phase III studies. In the palliative situation sufficient analgesic treatment is necessary as well as early initiation of nutritional support.

Abstract 5506: Trabedersen (AP 12009) for the treatment of patients with advanced tumors: A phase I/II study

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Transforming growth factor-beta 2 (TGF-β2) regulates key mechanisms of carcinogenesis, in particular immunosuppression and metastasis. The antisense oligonucleotide trabedersen (AP 12009) specifically inhibits TGF-β2 expression. A randomized and active-controlled phase IIb study in high-grade glioma patients showed a clear survival benefit for intratumoral treatment with trabedersen over standard chemotherapy. In this study we evaluate the maximum tolerated dose (MTD), safety, pharmakokinetics, and efficacy of intravenous trabedersen treatment in patients with advanced solid tumors. Methods: In the open label, multicenter, Phase I/II study, 33 patients with advanced pancreatic carcinoma (PancCa, stage III/IV, N=23), malignant melanoma (stage III/IV, N=5), or colorectal carcinoma (stage III/IV, N=5) were enrolled in cohorts for dose-escalation. Patients were treated intravenously with trabedersen as 2nd to 4th-line therapy as monotherapy with escalating doses in 2 treatment schedules (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). After completion of dose-escalation, further patients were enrolled for the treatment with one defined dose in the Phase II part of the study. Results: Trabedersen showed excellent safety and tolerability. The only expected adverse reaction identified is non-serious, transient and moderate thrombocytopenia. Within the 1st schedule, MTD was established at a dose of 160 mg/m2/d. In the 2nd schedule (4d on, 10d off) a well tolerated dose (140 mg/m2/d) was identified and subsequently further 14 PancCa patients were treated with this regimen. The median overall survival of PancCa patients treated 2nd-line with the 2nd schedule-140 mg/m2/d regimen (N=9) has not yet been reached and currently is 9.2 months (status Oct 2010). Further promising efficacy data include: one PancCa patient had a complete, sustained response of liver metastases and is alive 61 months after monotherapy with trabedersen; another patient is alive 31 months after treatment start (status Oct 2010). Promising efficacy was also observed in malignant melanoma patients with a current median overall survival of 13.8 months. Conclusions: Currently the study continues with the treatment of 12 patients with malignant melanoma with the 2nd schedule-140 mg/m2/d regimen. A randomized, active-controlled study in PancCA patients is in preparation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5506. doi:10.1158/1538-7445.AM2011-5506