Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomised clinical trial.

BACKGROUND: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. METHODS: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. RESULTS: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects. CONCLUSIONS: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS. CLINICALTRIALS: gov, number NCT01077427.

PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma.

UNLABELLED: We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). METHODS: Seventy-three patients underwent (18)F-FDG PET/CT before and after 2-4 cycles of neoadjuvant chemotherapy with RHT for STS. Progression-free survival (PFS) and time to local and distant progression were among other factors correlated with response according to PET Response Criteria in Solid Tumors (PERCIST 1.0) and Response Evaluation Criteria in Solid Tumors (RECIST 1.1). RESULTS: Metabolic response by PERCIST (n = 44/73) was an independent predictor for PFS (P = 0.002; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.18-0.68) and time to local or distant progression. Other independent predictors for PFS by multivariate analysis were adjuvant radiotherapy (P = 0.010; HR, 0.39; 95% CI, 0.20-0.80) and a baseline tumor size less than 5.7 cm (P = 0.012; HR, 0.43; 95% CI, 0.22-0.83). Response by RECIST 1.1 was seen in a small group of patients (n = 22/73) and allowed prediction of PFS for patients with sarcoma outside the abdomen (P = 0.048; HR, 0.13; 95% CI, 0.02-0.98). CONCLUSION: Metabolic response by (18)F-FDG PET predicts PFS and time to local and distant progression after 2-4 cycles of neoadjuvant chemotherapy plus RHT for STS.

Quality of life in peritoneal carcinomatosis: a prospective study in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND/AIMS: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (HIPEC) can improve survival in selected patients with peritoneal carcinomatosis, but bear a significant risk of perioperative morbidity. The aim of this study was to prospectively evaluate the quality of life (QoL) following cytoreduction and HIPEC. METHODS: In this study including 40 patients (65% females) with different primary tumors, the EORTC QLQ-C30 questionnaire was applied prior to CS and HIPEC as well as 3, 9, and 18 months postoperatively. RESULTS: Global health status was not impaired significantly following HIPEC. Scales and symptom scores that deteriorated 3 months postoperatively (p < 0.05), that is, physical, role, and social functions as well as fatigue, pain, dyspnea, insomnia, and diarrhea, all returned to preoperative values within 9 months. CONCLUSIONS: Following cytoreductive surgery and HIPEC, QoL returns to preoperative levels within 9 months. Selected patients that are likely to benefit oncologically from HIPEC should not be denied this option for fear of reduced postoperative QoL.

Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a subgroup analysis of a randomized phase-III multicenter study.

OBJECTIVE: To determine whether regional hyperthermia (RHT) in addition to chemotherapy improves local tumor control after macroscopically complete resection of abdominal or retroperitoneal high-risk sarcomas. BACKGROUND: Within the prospectively randomized EORTC 62961 phase-III trial, RHT and systemic chemotherapy significantly improved local progression-free survival (LPFS) and disease-free survival (DFS) in patients with abdominal and extremity sarcomas. That trial included macroscopically complete and R2 resections. METHODS: A subgroup analysis of the EORTC trial was performed and long-term survival determined. From 341 patients, 149 (median age 52 years, 18-69) were identified with macroscopic complete resection (R0, R1) of abdominal and retroperitoneal soft-tissue sarcomas (median diameter 10 cm, G2 48.3%, G3 51.7%). Seventy-six patients were treated with EIA (etoposide, ifosfamide, doxorubicin)+RHT (≥5 cycles: 69.7%) versus 73 patients receiving EIA alone (≥5 cycles: 52.1%, P=0.027). LPFS and DFS as well as overall survival were determined. RESULTS: RHT and systemic chemotherapy significantly improved LPFS (56% vs 45% after 5 years, P=0.044) and DFS (34% vs 27% after 5 years, P=0.040). Overall survival was not significantly improved in the RHT group (57% vs 55% after 5 years, P=0.82). Perioperative morbidity and mortality were not significantly different between groups. CONCLUSIONS: In patients with macroscopically complete tumor resection, RHT in addition to chemotherapy resulted in significantly improved local tumor control and DFS without increasing surgical complications. Within a multimodal therapeutic concept for abdominal and retroperitoneal high-risk sarcomas, RHT is a treatment option beside radical surgery and should be further evaluated in future trials.

Complete pathological response to neoadjuvant pemetrexed/cisplatin in combination with regional hyperthermia in a patient with sarcomatoid peritoneal mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare disease. Although most patients eligible for surgery undergo cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy, the role of perioperative systemic chemotherapy still remains undefined. Here we report the case of a 52-year-old female patient with advanced sarcomatoid DMPM. After five cycles of systemic pemetrexed and cisplatin, along with two cycles of regional hyperthermia, tumor resection with histomorphological examination showed a complete pathological response. We therefore conclude that there is a subgroup of DMPM patients that might benefit from systemic neoadjuvant chemotherapy with pemetrexed and cisplatin.

Gender and sex hormones influence the response to trauma and sepsis: potential therapeutic approaches.

Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.

Gender and sex hormones influence the response to trauma and sepsis: potential therapeutic approaches

Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.

Uma série de estudos clínicos e experimentais demonstram a existência de dimorfismo sexual das respostas imunológicas e orgânicas, bem como da suscetibilidade e morbidade em relação ao choque, ao trauma e à sepse. Respostas imunes celularmente mediadas apresentam-se deprimidas em machos em resposta ao binômio trauma-hemorragia, mas conservados/enaltecidos em fêmeas em proestro. Adicionalmente demonstra-se que os hormônios sexuais são responsáveis por esta dicomotomia de resposta sexualmente específica, em condições cardiovasculares adversas. Estudos específicos indicam que os andrógenos produzem imunodepressão pós-trauma hemorragia em machos. Em contraste, esteróides sexuais femininos parecem exibir propriedades imunoprotetoras após episódios de trauma com ou sem perda importante de sangue. No terreno dos mecanismos subjacentes, foram identificados receptores para hormônios sexuais em várias células do sistema imunológico, sugerindo a existência de efeitos diretos destes hormônios sobre tais células. Alternativamente, observam efeitos indiretos de hormônios sexuais tais como modulação das respostas cardiovasculares das enzimas sintetizadores de andrógeno e estrógeno, que podem contribuir para as estas respostas sexualmente diferenciadas. Estudos recentes indicam que os hormônios sexuais, como por exemplo a dehidroepiandrosterona também modulam a função de células mononucleares da série branca em pacientes cirúrgicos. Assim, as propriedades imunomodulatórias de hormônios sexuais/antagonistas de receptores/enzimas sintetizadores de esteróides após a ocorrência de trauma ou de hemorragia sugerem o caminho para novas estratégias terapêuticas para o tratamento de imunodepressão em pacientes cirúrgicos.

Dehydroepiandrosterone restores depressed peripheral blood mononuclear cell function following major abdominal surgery via the estrogen receptors.

OBJECTIVE: Peripheral blood mononuclear cell (PBMC) dysfunction occurs following major abdominal surgery and correlates with an increased rate of septic complications. Studies have shown that dehydroepiandrosterone (DHEA) restores cell-mediated immune responses after trauma-hemorrhage in mice. Nonetheless, it remains unknown whether DHEA has any salutary effects on depressed PBMC function in surgical patients. DESIGN: Laboratory experiment. SETTING: University laboratory. PATIENTS: Fifteen patients undergoing major abdominal surgery. INTERVENTIONS: Blood samples were obtained preoperatively and 2 hrs postoperatively. MEASUREMENTS AND MAIN RESULTS: PBMCs were cultured with 33% plasma in the presence or absence of DHEA (10(-10) M, 10(-8) M physiologic concentration, 10(-6) M, 10(-5) M). In an additional set of samples, the estrogen receptor antagonist tamoxifen (10(-6) M) was added. The release of proinflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) was measured in the supernatants by enzyme-linked immunosorbent assay. Abdominal surgery resulted in depressed interleukin-1beta and tumor necrosis factor-alpha release by PBMC. Addition of DHEA to the culture medium, however, significantly improved the release of interleukin-1beta and tumor necrosis factor-alpha and stimulated the interleukin-6 release capacity of PBMC. This effect was most pronounced for a concentration of 10(-5)M DHEA. The immunomodulatory effect of DHEA on PBMC cytokine release was completely blocked by tamoxifen. In contrast, the modulatory effect of DHEA was enhanced by the addition of postoperative plasma. CONCLUSIONS: DHEA stimulates proinflammatory cytokine release capacities of human PBMCs following major abdominal surgery. The estrogen receptor appears to be involved in mediating the immunomodulatory effect of DHEA. Thus, DHEA might be a useful adjunct for preventing immunosuppression in surgical patients.

Immunomodulatory effects of dehydroepiandrosterone in proestrus female mice after trauma-hemorrhage.

Studies indicate that administration of the adrenal steroid dehydroepiandrosterone (DHEA) after trauma-hemorrhage in male mice improved cellular immune functions and reduced mortality rates from subsequent sepsis. There is evidence, however, that DHEA is converted to estrogens in males and that estrogens are immunoprotective after trauma-hemorrhage (TH). In contrast, DHEA in females can be converted to testosterone that has deleterious effects on immune functions. The aim of our study, therefore, was to determine whether administration of DHEA in proestrus females after TH would deteriorate immune responses. Proestrus female C3H/HeN mice (age 7-8 wk) were subjected to laparotomy (i.e., soft tissue trauma induced) and hemorrhagic shock (35 +/- 5 mmHg for 90 min) or sham operation. The mice then received DHEA (100 micro/25 g body wt) or vehicle subcutaneously followed by fluid resuscitation (4x the shed blood volume). Plasma IL-6, splenocyte proliferation, splenocyte IL-2, IL-3, IFN-gamma, IL-10 release, and splenic Mphi IL-1beta, IL-6, IL-10, and IL-12 release were determined 24 h after TH. Plasma IL-6 levels were significantly increased in vehicle-treated females, and DHEA administration markedly attenuated this response. In vehicle-treated females, splenocyte proliferation, IL-2, IL-3, and IFN-gamma release, and splenic Mphi IL-1 beta, IL-6, and IL-12 release were maintained or slightly enhanced after TH. In DHEA-treated females, however, these immune functional parameters were either unaltered compared with vehicle-treated animals or even further enhanced, but surprisingly were not depressed. Moreover, DHEA reduced splenocyte and splenic M phi anti-inflammatory cytokine (i.e., IL-10) production after TH compared with vehicle-treated females. Because DHEA further enhances the immune responsiveness in proestrus females after TH, this hormone might be a useful adjunct even in females for further enhancing immune responses and decreasing the mortality rate after trauma and severe blood loss.

Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer.

HYPOTHESIS: Preoperative radiochemotherapy for advanced rectal cancer results in fewer lymph nodes detected in the tumor-bearing specimen. DESIGN: Nonrandomized control trial with analysis of a prospective perioperative database. SETTING: Department of Surgery of a large-volume university hospital. PATIENTS: All patients who underwent conventional open surgery to cure rectal cancer between January 1, 1996, and March 31, 2001. INTERVENTIONS: During the study period 184 patients (81%, control group) underwent surgery without receiving preoperative radiochemotherapy. Forty-two patients (19%, study group) who had advanced rectal cancer (modified Dukes stages B [tumors that have penetrated the muscle layer of the bowel wall or have gone through the bowel] or C [tumors that have spread to the lymph nodes in the same region]) received preoperative radiochemotherapy (2 cycles of fluorouracil, 4500 rad) during this period. Most patients underwent anterior rectal resection in both groups (77.7% of those who did not receive preoperative radiochemotherapy and 71.8% of those who did), the remaining patients were treated with abdominoperineal resection. RESULTS: A mean (SEM) of 19 (1) lymph nodes per specimen were detected in the control patients, while significantly fewer lymph nodes were detected in study patients (13 [1]; P<.05). The rate of inadequate lymph node staging (pNx) increased from 7% in the control group to 12% in the study group (P =.06). Pathological lymph node staging disclosed that significantly more study patients who received preoperative radiochemotherapy had modified Dukes stage A (tumors that are found only in the inner wall or rectum) cancer when compared with the control group (17% vs 0%, respectively; P<.05). CONCLUSIONS: Preoperative radiochemotherapy for advanced rectal cancer results in a significant decrease of lymph nodes detected within the tumor-bearing specimen. Preoperative radiochemotherapy induces significant downstaging with fewer positive lymph nodes and more patients presenting with Dukes stage A rectal cancer. Great care must be taken to remove an adequate number of lymph nodes and more sophisticated pathological techniques of lymph node detection are required since the tumors of ever-increasing numbers of patients are inadequately classified.