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A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial  [cached]
Glockzin Gabriel,Rochon Justine,Arnold Dirk,Lang Sven A
BMC Cancer , 2013, DOI: 10.1186/1471-2407-13-67
Abstract: Background Peritoneal 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/design The 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. Discussion The 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 registration ClinicalTrials.gov Identifier: NCT01540344, EudraCT number: 2009-014040-11
Peritoneal carcinomatosis of colorectal origin  [cached]
Antonio Macrì,Edoardo Saladino,Vincenzo Bartolo,Vincenzo Adamo
World Journal of Gastrointestinal Oncology , 2010,
Abstract: Peritoneal carcinomatosis is, after liver metastases, the second most frequent cause of death in colorectal cancer patients and at the present time, is commonly inserted and treated as a stage IV tumour. Because there is no published data that outlines the impact of new therapeutic regimens on survival of patients with peritoneal surface diffusion, the story of carcinomatosis can be rewritten in light of a new aggressive approach based on the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Also if these treatment perhaps allow to obtain better results than standard therapies, we suggest, that a large prospective randomised control trial is needed to compare long-term and progression-free survival under the best available systemic therapy with or without cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Cytoreductive approach to peritoneal carcinomatosis originated from colorectal cancer: Turkish experience  [PDF]
Füzün Mehmet,S?kmen Selman,Terzi Cem,Emre-Canda Aras
Acta Chirurgica Iugoslavica , 2006, DOI: 10.2298/aci0602017f
Abstract: Peritoneal carcinomatosis (PC) in contrast to lymph nodes and liver metastases was assumed as a terminal condition with no curative treatment options having a 5 to 9 months median survival rate until recently. Today, in properly selected patients, curative surgical treatment of PC is possible like resection of lymph nodes and liver metastases. Between 1996 and 2005, 29 patients who underwent cytoreductive surgery combined with intraperitoneal chemotherapy for PC originated from colorectal cancer (CRC) were analyzed prospectively at the Department of Surgery in Dokuz Eylul University Hospital. Mean age was 54 year (range, 23-75 years). There was no peroperative mortality in 29 patients. The morbidity rate was 41% (12/29) and 6 (20%) patients required reoperation(s) for major complications. Mean and median survival time was 34 and 21 months, respectively. The overall 1-year, 3-year, and 5-year survival rates were 72%, 13%, and 7%, respectively. Mean survival time was 56 months in patients with peritoneal cancer index (PCI) <10, and 22 months in patients with PCI >10 (P=0.075). The mean survival time was 62 months in patients with complete cytoreduction (CC)-0 score, 21 months in patients with CC-1 score, and 7 months in patients with CC-2 and 3 scores. Patients who had CC-0 score had better survival than patients having CC-1 and CC-2 scores (P = 0.003 and P = 0.000, respectively). Patients who had CC-0 and 1 scores had better survival than patients with CC-2 score (P = 0.000). The overall 1-year, 3-year, and 5-year survival rates for patients with CC-0 score were 87%, 37%, and 25%, respectively. There was a positive correlation between the PCI and CC score (P = 0.001, correlation coefficient = 0.585 with correlation is significant at level 0.01). Cytoreductive approach combined with intraperitoneal chemotherapy and systemic chemotherapy prolongs survival in selected patients with PC of CRC with acceptable morbidity and mortality. Prognosis is better in patients with limited disease and in whom complete cytoreduction is achieved. In patients with PC of CRC, the key issue is to select the patients in whom complete cytoreduction is feasible. Better patient assessment with new diagnostic tools such as (PET)-CT or PET-magnetic resonance imaging will be used to detect more precisely the patients with low tumor burden in the new feature.
Peritoneal carcinomatosis of colorectal origin. Current treatment: Review and update
Gómez Portilla,A.; Cendoya,I.; López de Tejada,I.; Olabarría,I.; Martínez de Lecea,C.; Magrach,L.; Gil,A.; Echevarría,J.; Valdovinos,M.; Larrabide,I.;
Revista Espa?ola de Enfermedades Digestivas , 2005, DOI: 10.4321/S1130-01082005001000005
Abstract: colorectal cancer is the most frequent tumor of the digestive tract. the high incidence of abdominal dissemination; the poor prognosis of these patients, with median survival consistently ranging from 5 to 9 months in all studies of peritoneal carcinomatosis from colorectal cancer; the failure of adjuvant systemic chemotherapy treatment with a maximal survival of 18 months despite the development of new cytostatic drugs, and new combinations of use, make it crucial to search for and develop new treatment strategies. we review the principles of sugarbaker′s treatment protocol, which involves the combination of maximum cytoreductive radical oncological surgery for the treatment of all macroscopically disseminated disease with maximum perioperative intraperitoneal intensification chemotherapy to treat residual microscopic disease. we present the results of several scientific papers, all of them phase ii studies with more than 10 patients treated, published in the medical literature by the main groups working in this line of treatment, together with the only phase iii study reported and published so far, and finally the results of a recently reported retrospective international multicenter study. with this new alternative therapeutic approach, overall mean survival is 40% at 36 months, and 20% at 5 years. based on these results, this new therapeutic approach is proposed as the treatment of choice for these unfortunate patients.
Peritoneal Colorectal Carcinomatosis Treated with Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy  [PDF]
Antonios-Apostolos K. Tentes, Odysseas Korakianitis, Nikolaos Pallas, Christos Mavroudis, Panagiotis Sarlis, Anastasios Liberis, Athanasios Pagalos, Stephanos Popidis
Surgical Science (SS) , 2012, DOI: 10.4236/ss.2012.32013
Abstract: Background-Aims: Peritoneal colorectal carcinomatosis is a potentially curative disease. The purpose of the study is the retrospective analysis of survival of the patients with peritoneal colorectal carcinomatosis that underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy and the identification of prognostic variables of the disease. Patients-Methods: Patients with primary or recurrent colorectal cancer and peritoneal carcinomatosis were included in the study. Clinical variables were correlated to survival, recurrence, hospital mortality, and morbidity. Results: From 2000-2010, 28 patients underwent 33 cytoreductive operations. The hospital mortality and morbidity rate was 9.1% and 45.5% respectively. The overall 5-year and median survival time was 29.2% and 19 months respectively. The extent of peritoneal carcinomatosis (p = 0.0003) and the completeness of cytoreduction (p = 0.0002) were related to survival. The completeness of cytoreduction (p = 0.003) was the single prognostic variable of survival. The recurrence rate was 42.4% and the use of systemic chemotherapy was identified as the single prognostic variable of recurrence (p = 0.047). Conclusions: Patients with limited extent of peritoneal colorectal carcinomatosis who undergo complete cytoreduction may be offered long-term survival.
Intraperitoneal chemotherapy for prevention and treatment of peritoneal carcinomatosis from colorectal origin
E. de Bree,, F.A.N. Zoetmulder, J. Romanos, A.J. Witkamp, D.D. Tsiftsis
Annals of Gastroenterology , 2007,
Abstract: SUMMARY The peritoneal surface remains an important failure site for patients with colorectal cancer. Peritoneal metastases of colorectal cancer are at present considered equal to distant metastatic disease. Consequently, peritoneal carcinomatosis is treated with systemic chemotherapy and surgery only to palliate complications such as obstruction. Despite the development of new chemotherapeutic agents and combinations, the results remain disappointing with a limited impact on survival. Colorectal carcinoma cells are relatively resistant to chemotherapy. Intraperitoneal chemotherapy seems to be an attractive approach in the treatment of highrisk colorectal cancer and peritoneal carcinomatosis of colorectal origin providing high local drug concentration with limited systemic side effects. Adjuvant early postoperative intraperitoneal chemotherapy is worthwhile considering as a treatment option after resection of high-risk colorectal cancer. Meta-analysis of randomized trials demonstrates a positive impact of this adjuvant treatment on overall survival and regional tumor control. In the treatment of peritoneal carcinomatosis postoperative intraperitoneal chemotherapy leads to inadequate exposure of the peritoneal surface. Only intraoperative continuous peritoneal perfusion chemotherapy performed with direct cytotoxic drugs such as MMC and cisplatin may overcome this problem. The limited limited drug penetration in tissue implies the need for extensive cytoreductive surgery. Additionally, the latter form of regional chemotherapy can be performed under hyperthermic conditions. Hyperthermia has a direct cytotoxic effect and enhances the activity and penetration depth of many cytotoxic drugs. The results of phase II studies of cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin suggest that an increased median survival can be achieved with this approach, especially in patients with no macroscopic or small volume residual disease.
Peritoneal carcinomatosis of colorectal origin. Current treatment: Review and update Carcinomatosis peritoneal de origen colorrectal. Estado actual del tratamiento: Revisión y puesta al día  [cached]
A. Gómez Portilla,I. Cendoya,I. López de Tejada,I. Olabarría
Revista Espa?ola de Enfermedades Digestivas , 2005,
Abstract: Colorectal cancer is the most frequent tumor of the digestive tract. The high incidence of abdominal dissemination; the poor prognosis of these patients, with median survival consistently ranging from 5 to 9 months in all studies of peritoneal carcinomatosis from colorectal cancer; the failure of adjuvant systemic chemotherapy treatment with a maximal survival of 18 months despite the development of new cytostatic drugs, and new combinations of use, make it crucial to search for and develop new treatment strategies. We review the principles of Sugarbaker′s treatment protocol, which involves the combination of maximum cytoreductive radical oncological surgery for the treatment of all macroscopically disseminated disease with maximum perioperative intraperitoneal intensification chemotherapy to treat residual microscopic disease. We present the results of several scientific papers, all of them phase II studies with more than 10 patients treated, published in the medical literature by the main groups working in this line of treatment, together with the only phase III study reported and published so far, and finally the results of a recently reported retrospective international multicenter study. With this new alternative therapeutic approach, overall mean survival is 40% at 36 months, and 20% at 5 years. Based on these results, this new therapeutic approach is proposed as the treatment of choice for these unfortunate patients. El cáncer colorrectal es el tumor más frecuente del tracto digestivo. La alta incidencia de diseminación abdominal, el pobre pronóstico de estos pacientes con una mediana de supervivencia entre 5 y 9 meses demostrada repetidamente en todos los estudios de carcinomatosis peritoneal por cáncer colorrectal, el fracaso de los tratamientos sistémicos adyuvantes con quimioterapia con supervivencias máximas de 18 meses independientemente del desarrollo de nuevas drogas citostáticas y las nuevas combinaciones o formas de uso, hacen crucial la investigación y el desarrollo de nuevas estrategias de tratamiento. Revisamos los principios del protocolo del tratamiento de Sugarbaker, que contempla la combinación de la máxima cirugía radical oncológica citorreductora para el tratamiento de la enfermedad macroscópica diseminada con la máxima quimioterapia de intensificación intraperitoneal perioperatoria para el tratamiento de la enfermedad microscópica residual. Se presentan los resultados de las publicaciones científicas, de todos los estudios fase II con más de 10 pacientes tratados publicados en la literatura médica por los principales grupos de
Brain-Derived Neurotrophic Factor (BDNF)-Induced Tropomyosin-Related Kinase B (Trk B) Signaling Is a Potential Therapeutic Target for Peritoneal Carcinomatosis Arising from Colorectal Cancer  [PDF]
Koji Tanaka, Yoshinaga Okugawa, Yuji Toiyama, Yasuhiro Inoue, Susumu Saigusa, Mikio Kawamura, Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Masato Kusunoki
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096410
Abstract: Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal metastatic nodules was found to be reduced, as compared with control mice. BDNF/TrkB signaling may thus be a potential target for treating peritoneal carcinomatosis arising from colorectal cancer.
5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice
Yongsheng Wang, Changyang Gong, Li Yang, Qinjie Wu, Shuai Shi, Huashan Shi, Zhiyong Qian, Yuquan Wei
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-402
Abstract: A biodegradable PEG-PCL-PEG (PECE) triblock copolymer was successfully synthesized. The biodegradable and temperature sensitive hydrogel was developed to load 5-FU. Methylene blue-loaded hydrogel were also developed for visible observation of the drug release. The effects and toxicity of the 5-FU-hydrogel system were evaluated in a murine CRPC model.The hydrogel system is an injectable flowing solution at ambient temperature and forms a non-flowing gel depot at physiological temperature. 5-FU-hydrogel was subsequently injected into abdominal cavity in mice with CT26 cancer cells peritoneal dissemination. The results showed that the hydrogel delivery system prolonged the release of methylene blue; the 5-FU-hydrogel significantly inhibited the peritoneal dissemination and growth of CT26 cells. Furthermore, intraperitoneal administration of the 5-FU-hydrogel was well tolerated and showed less hematologic toxicity.Our data indicate that the 5-FU-hydrogel system can be considered as a new strategy for peritoneal carcinomatosis, and the hydrogel may provide a potential delivery system to load different chemotherapeutic drugs for peritoneal carcinomatosis of cancers.Peritoneal carcinomatosis (PC) is one of the most common causes of incurability of intra-abdominal cancers, among which colorectal peritoneal carcinomatosis (CRPC) is a result of transcoelomic invasion by the primary cancer or intraperitoneal seeding during surgical manipulation. Approximately 8% of patients have isolated peritoneal seeding at the time of primary surgery, and 25% of patients with recurrence have disease confined to the peritoneal cavity [1,2]. Neither systemic chemotherapy nor intraperitoneal chemotherapy alone had any significant impact on survival [3]. The current goal of treatment for most abdominal/peritoneal metastases is palliative, rather than curative. It is imminent to sought new strategies to improve the therapeutic effects of intraperitoneal chemotherapy. Intraperitoneal infusion of
Surgical Treatment of Peritoneal Carcinomatosis from Gastric Cancer  [PDF]
Kiran K. Turaga,T. Clark Gamblin,Sam Pappas
International Journal of Surgical Oncology , 2012, DOI: 10.1155/2012/405652
Abstract: Peritoneal carcinomatosis from gastric cancer is considered a fatal disease with limited treatment options. Recent advances in the understanding of the disease process, systemic chemotherapy, and application of cytoreductive surgery and hyperthermic chemoperfusion have shown promising results in the management of this difficult disease. Novel therapies such as extensive intraperitoneal lavage and intraperitoneal targeted agents are being applied in the management of this disease. We review the current literature in this field and describe the rationale behind some of these advances. 1. Introduction Gastric cancer is the second leading cause for cancer-related mortality worldwide with almost 22,280 patients being diagnosed with gastric cancer annually in the United States [1, 2]. Peritoneal dissemination occurs commonly in patients with gastric cancer by means of intracoelomic dissemination or due to tumor spillage at the time of an operation [3]. High risk of peritoneal carcinomatosis from gastric cancer has led to common use of laparoscopy in the management of patients with gastric cancer. Unfortunately, systemic chemotherapy has not been shown to have a significant benefit to patients with peritoneal carcinomatosis. Despite short-duration response rates (43%) for visceral metastases with epirubicin-, cisplatin-, and 5-fluorouracil-based regimens, the response rate for peritoneal carcinomatosis is less than 14% [3, 4]. The blood peritoneal barrier which is 90? m wide prevents a high concentration of intravenous chemotherapy from accumulating in the peritoneal surface, and this has led to increased interest in locoregional treatment for peritoneal carcinomatosis (PC) from gastric cancer [3]. Surgery has been the mainstay for treatment of gastric cancer without peritoneal dissemination, but advances in neoadjuvant chemotherapy with the MAGIC trial have led to significant survival benefits for patients [5]. This strategy demonstrated an effective use of multimodality therapy for patients with gastric cancer. The application of hyperthermic intraperitoneal chemoperfusion or HIPEC to gastric cancer has been described by several groups over the last decade [3, 6, 7]. This technique refers to the combination of extensive cytoreductive surgery performed by an experienced team to remove all visible tumor, followed by intraoperative circulation of heated chemotherapy in the abdominal cavity during the procedure. This technique is currently considered standard of care for patients with PC from colorectal cancer, pseudomyxoma peritonei, and mesotheliomas [8].
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