Gabriel Glockzin

Peritoneal carcinomatosis: patients selection, perioperative complications and quality of life related to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

BackgroundPeritoneal tumor dissemination arising from colorectal cancer, appendiceal cancer, gastric cancer, gynecologic malignancies or peritoneal mesothelioma is a common sign of advanced tumor stage or disease recurrence and mostly associated with poor prognosis.Methods and resultsIn the present review article preoperative workup, surgical technique, postoperative morbidity and mortality rates, oncological outcome and quality of life after CRS and HIPEC are reported regarding the different tumor entities.ConclusionCytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising combined treatment strategy for selected patients with peritoneal carcinomatosis that can improve patient survival and quality of life. The extent of intraperitoneal tumor dissemination and the completeness of cytoreduction are the leading predictors of postoperative patient outcome. Thus, consistent preoperative diagnostics and patient selection are crucial to obtain a complete macroscopic cytoreduction (CCR-0/1).

Targeting Heat Shock Protein 90 in Pancreatic Cancer Impairs Insulin-like Growth Factor-I Receptor Signaling, Disrupts an Interleukin-6/Signal-Transducer and Activator of Transcription 3/Hypoxia-Inducible Factor-1α Autocrine Loop, and Reduces Orthotopic Tumor Growth

Purpose: Inhibitors of heat-shock protein 90 (Hsp90) may interfere with oncogenic signaling pathways, including Erk, Akt, and hypoxia-inducible factor-1α (HIF-1α). Because insulin-like growth factor-I receptor (IGF-IR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways are implicated in the progression of pancreatic cancer, we hypothesized that blocking Hsp90 with geldanamycin derivates [17-allylamino-geldanamycin (17-AAG), 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)] would impair IGF-I– and interleukin-6–mediated signaling and thus reduce pancreatic tumor growth and angiogenesis in vivo. Experimental Design: Human pancreatic cancer cells (HPAF-II, L3.6pl) were used for experiments. Changes in signaling pathway activation upon Hsp90 blockade were investigated by Western blotting. Effects of Hsp90 inhibition (17-AAG) on vascular endothelial growth factor were determined by ELISA and real-time PCR. Effects of 17-DMAG (25 mg/kg; thrice a week; i.p.) on tumor growth and vascularization were investigated in a s.c. xenograft model and in an orthotopic model of pancreatic cancer. Results: 17-AAG inhibited IGF-IR signaling by down-regulating IGF-IRβ and directly impairing IGF-IR phosphorylation. Hypoxia- and IL-6–mediated activation of HIF-1α or STAT3/STAT5 were substantially inhibited by 17-AAG. Moreover, a novel IL-6/STAT3/HIF-1α autocrine loop was effectively disrupted by Hsp90 blockade. In vivo, 17-DMAG significantly reduced s.c. tumor growth and diminished STAT3 phosphorylation and IGF-IRβ expression in tumor tissues. In an orthotopic model, pancreatic tumor growth and vascularization were both significantly reduced upon Hsp90 inhibition, as reflected by final tumor weights and CD31 staining, respectively. Conclusions: Blocking Hsp90 disrupts IGF-I and IL-6–induced proangiogenic signaling cascades by targeting IGF-IR and STAT3 in pancreatic cancer, leading to significant growth-inhibitory effects. Therefore, we suggest that Hsp90 inhibitors could prove to be valuable in the treatment of pancreatic cancer.

Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo

Oncogenic signaling through activation of epidermal growth factor receptor (EGFR), HER-2, and hypoxia inducible-factor-1α (HIF-1α) has been implicated in gastric cancer growth and angiogenesis through up-regulation of vascular endothelial growth factor (VEGF). Recently, heat shock protein 90 (Hsp90) has been identified as a critical regulator of oncogenic protein stability, including EGFR, HER-2, and HIF-1α. We hypothesized that inhibition of Hsp90 impairs EGF- and hypoxia-mediated angiogenic signaling in gastric cancer cells and consequently inhibits angiogenesis and tumor growth. In vitro, the geldanamycin derivate 17-allylamino-17-demethoxygeldanamycin (17-AAG) led to marked reduction in constitutive and inducible activation of extracellular signal-regulated kinase 1/2, Akt, and signal transducer and activator of transcription 3 and decreased nuclear HIF-1α protein. In addition, EGFR and HER-2 were down-regulated after Hsp90 inhibition. With respect to regulation of angiogenic molecules, 17-AAG significantly reduced EGF-mediated VEGF secretion. Phosphorylation of focal adhesion kinase and paxillin were both abrogated by 17-AAG, which resulted in significant impairment of cancer cell motility. Interestingly, cytotoxic effects of 17-AAG in vitro were higher on cancer cells and gastric fibroblasts than on pericytes. In vivo, the water-soluble compound 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG; 25 mg/kg, thrice per week) significantly reduced s.c. xenografted tumor growth. By immunohistochemistry, 17-DMAG significantly reduced vessel area and numbers of proliferating tumor cells in sections. Furthermore, similar significant growth-inhibitory effects of 17-DMAG were achieved when administered as low-dose therapy (5 mg/kg, thrice per week). In conclusion, blocking Hsp90 disrupts multiple proangiogenic signaling pathways in gastric cancer cells and inhibits xenografted tumor growth in vivo. Hence, gastric cancer harbors attractive molecular targets for therapy with Hsp90 inhibitors, which could lead to improved efficacy of antineoplastic therapy regimens. [Mol Cancer Ther 2007;6(3):1123–32]

Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis and metastasis by effects on tumor cells, endothelial cells and pericytes in pancreatic cancer

Activation of receptor tyrosine kinases, such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and VEGF receptor (VEGFR), has been implicated in tumor progression and metastasis in human pancreatic cancer. In this study, we investigated the effects of TKI258, a tyrosine kinase inhibitor to FGFR, PDGFR, and VEGFR on pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa2, and L3.6pl), endothelial cells, and vascular smooth muscle cells (VSMC). Results showed that treatment with TKI258 impaired activation of signaling intermediates in pancreatic cancer cells, endothelial cells, and VSMCs, even upon stimulation with FGF-1, FGF-2, VEGF-A, and PDGF-B. Furthermore, blockade of FGFR/PDGFR/VEGFR reduced survivin expression and improved activity of gemcitabine in MiaPaCa2 pancreatic cancer cells. In addition, motility of cancer cells, endothelial cells, and VSMCs was reduced upon treatment with TKI258. In vivo, therapy with TKI258 led to dose-dependent inhibition of subcutaneous (HPAF-II) and orthotopic (L3.6pl) tumor growth. Immunohistochemical analysis revealed effects on tumor cell proliferation [bromodeoxyuridine (BrdUrd)] and tumor vascularization (CD31). Moreover, lymph node metastases were significantly reduced in the orthotopic tumor model when treatment was initiated early with TKI258 (30 mg/kg/d). In established tumors, TKI258 (30 mg/kg/d) led to significant growth delay and improved survival in subcutaneous and orthotopic models, respectively. These data provide evidence that targeting FGFR/PDFGR/VEGFR with TKI258 may be effective in human pancreatic cancer and warrants further clinical evaluation. Mol Cancer Ther; 10(11); 2157–67. ©2011 AACR.

Surgical treatment of substernal goiter: An analysis of 59 patients

PurposeSubsternal goiter is defined as a thyroid mass of which more than 50% is located below the thoracic inlet. In this article we report the diagnosis, symptoms, thyroid function, treatment, and postoperative complications of 59 patients with substernal goiter.MethodsBetween 1992 and 2005, 59 patients underwent surgery for substernal goiter at our institution. The indications for surgery were multinodular goiter in 46 cases, follicular adenoma in two cases, and Hashimoto’s thyroiditis in one case. Ten patients were operated on for recurrent thyroid disease.ResultsThe leading preoperative symptoms were dyspnea (49.2%), dysphagia (13.6%), hyperhidrosis (10.2%), and cardiac dysfunction (6.8%). All but two thyroid glands could be removed through a Kocher transverse collar incision. The most common postoperative complications were persistent (5.1%) or temporary (3.4%) paresis of the recurrent laryngeal nerve, transient hypocalcemia (3.4%), and hematoma (3.4%). A tracheotomy was required in one patient with bilateral vocal cord paresis (1.7%).Conclusions(1) We conclude that a subtotal thyroidectomy is also the treatment of choice for asymptomatic benign substernal goiter. (2) Transverse collar incision should be the standard approach for most patients. (3) The visual identification of at least two parathyroid glands is essential to prevent permanent postoperative hypoparathyroidism.

A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial

BackgroundPeritoneal carcinomatosis is regarded as a common sign of advanced tumor stage, tumor progression or local recurrence of appendiceal and colorectal cancer and is generally associated with poor prognosis. Although survival of patients with advanced stage CRC has markedly improved over the last 20 years with systemic treatment, comprising combination chemotherapy +/− monoclonal antibodies, the oncological outcome—especially of the subgroup of patients with peritoneal metastases—is still unsatisfactory. In addition to systemic therapy, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are specific treatment options for a selected group of these patients and may provide an additional therapeutic benefit in the framework of an interdisciplinary treatment concept.Methods/designThe COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial investigating perioperative systemic polychemotherapy including cetuximab in combination with CRS and HIPEC patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal carcinomatosis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), perioperative morbidity and treatment-associated toxicity, feasibility of the combined treatment regimen, quality of life (QoL) and histopathological regression after preoperative chemotherapy.DiscussionThe COMBATAC trial is designed to evaluate the feasibility and efficacy of the combined multidisciplinary treatment regimen consisting of perioperative systemic combination chemotherapy plus cetuximab and CRS plus bidirectional HIPEC with intraperitoneal oxaliplatin.Trial registrationClinicalTrials.gov Identifier: NCT01540344, EudraCT number: 2009-014040-11

Quality of life after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with high morbidity. The Quality of Life (QoL) assessment in this patient group with a limited life expectancy and high recurrence rate is important. Published data show an impairment of postoperative Quality of Life at 3 months postoperatively with an improvement over 6–12 months at levels higher than the baseline. Standardized instruments QoL have to be included in clinical trials assessing the efficacy of CRS and HIPEC. J. Surg. Oncol. 2009;100:317–320.

Current status and future directions in gastric cancer with peritoneal dissemination.

Peritoneal carcinomatosis arising from gastric cancer is mostly associated with poor prognosis. Despite the improvement of survival with modern polychemotherapy, the results are still unsatisfactory. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy might provide an additional therapeutic option for highly selected patients with gastric cancer and peritoneal metastasis leading to improved prognosis. Considering the increased rate of perioperative morbidity and the crucial prognostic role of complete macroscopic cytoreduction, adequate preoperative diagnostics and patient selection are strongly recommended. Further prospective randomized trials are needed to determine the roles of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as part of an interdisciplinary treatment concept.

American Society of peritoneal surface malignancies opinion statement on defining expectations from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer

JESUS ESQUIVEL, MD,* POMPILIU PISO, MD, VIC VERWAAL, MD, THOMAS BACHLEITNER-HOFMANN, MD, OLIVIER GLEHEN, MD, SANTIAGO GONZÁLEZ-MORENO, MD, MARCELLO DERACO, MD, JOERG PELZ, MD, RICHARD ALEXANDER, MD, AND GABRIEL GLOCKZIN, MD Department of Surgical Oncology, Cancer Treatment Centers of America, Philadelphia, Pennsylvania Division of Surgical Oncology, Hospital Barmherzige, Regensburg, Germany National Cancer Institute, Amsterdam, The Netherlands Vienna University Hospital, Vienna, Australia Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Pierre-Benite, France Department of Surgical Oncology, MD Anderson Cancer Center, Madrid, Spain Department of Surgery, National Cancer Institute, Milan, Italy Department of Surgery, University of Wuerzburg, Wuerzburg, Germany Department of Surgical Oncology, University of Maryland, Baltimore, Maryland Department of Surgical Oncology, Regensburg University Hospital, Regensburg, Germany

Patient selection for a curative approach to carcinomatosis

Abstract:There is an increasing evidence showing that in selected patients with peritoneal carcinomatosis cytoreductive surgery and hyperthermic intraperitoneal chemotherapy may improve survival. Adequate patient selection is crucial to obtain a complete macroscopic cytoreduction, a leading predictor of patient outcome. However, selection is a very difficult process and is associated with a significant learning curve. Many selection criteria have to be assessed in each patient: performance status, comorbiditites, response to previous chemotherapies, histology grading, and presence of extra-abdominal or liver metastases, small bowel involvement, and tumor volume assessed by the peritoneal cancer index. All these factors have to be discussed interdisciplinary and with the patient to create an individualized treatment strategy. It is difficult to decide the relative importance of each selection criteria. However, completeness of cytoreduction, tumor volume, and histology grading are most important in many multivariate analysis independent prognostic factors. For appropriate selected patients with peritoneal carcinomatosis arising from appendiceal and colon cancer, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be considered standard of care.