Bakgrund: Peritonealcarcinos är en allvarlig cancerform och cirka 250-300 svenskar varje år. Idag genomförs de omfattande operationerna CRS och HIPEC på en del av denna patientgrupp. Tidigare forskning visar att perioperativa samtal kan gynna patienter som genomgår omfattande kirurgiska ingrepp.     Syfte: Syftet med studien var att jämföra det postoperativa förloppet hos peritonealcarcinospatienter som fått perioperativa samtal med patienter som inte fått dessa samtal. Metod: Urvalet var konsekutivt och bestod av 89 journaler tillhörande peritonealcarcinospatienter. Interventionsgruppen bestod av patienter som genomgått CRS och HIPEC och som i samband med detta fått perioperativa samtal. Kontrollgruppen var patienter som genomgått samma ingrepp, men som inte fått perioperativa samtal. Datainsamlingsmetoden bestod av journalgranskning. Resultat: Behovet av psykosocialt stöd var något mindre hos interventionsgruppen än kontrollgruppen. Resultatet visade att interventionsgruppen konsumerade en mindre mängd smärtlindring än kontrollgruppen. Signifikanta skillnader mellan grupperna sågs dock endast vid VAS-skattning det sjätte postoperativa dygnet. Interventionsgruppens postoperativa vårdtid på universitetssjukhuset var ungefär ett dygn kortare än kontrollgruppens. Studien visade dock få statistiskt signifikanta skillnader mellan grupperna. Slutsats: De patienter som fått perioperativa samtal använde sig i mindre utsträckning av psykosocialt stöd, hade en lägre läkemedelskonsumtion samt tillbringade färre dygn på universitetssjukhuset, än de som inte fått perioperativa samtal. Resultatet visade endast få statistiskt signifikanta skillnader. De tendenser till skillnader som sågs bör trots detta ligga till grund för fortsatt forskning.

Ovarian cancer is the second most common, and first most lethal gynecological cancer. It will affect one in seventy-eight women, and is commonly diagnosed in the later stages of the disease. The majority of the cancer’s lifespan is spent within the peritoneal cavity. Hyperthermic intraperitoneal chemotherapy (HIPEC) is an innovative new treatment that has been proven as an effective treatment in other peritoneal cancers. There is strong scientific evidence to support HIPEC as an ideal treatment for advanced ovarian cancer. Over the past two decades, there has been an increase in the number of studies focused on the efficacy of HIPEC with regards to advanced ovarian cancer. These studies have shown great promise, with two very recent phase III studies showing resounding results. It is also clear that there is a need for standardization throughout these scientific studies in order to reasonably introduce HIPEC as a standard of treatment.

Introduction: Peritoneal carcinomatosis is an end stage sequela occurring in 10% of patients with colorectal cancer. Palliative approaches have evolved over the past several decades and the role for surgical cytoreduction with hyperthermic intraperitoineal chemotherapy (HIPEC) has proven efficacy in several studies. Optimization of HIPEC therapy includes the addition of adjuncts to the carrier solution of intraperitoneal chemotherapy to improve tumor cell killing. In this study the addition of vitamin C, selenium, and quercetin ("micronutrient combination") to mitomycin C is evaluated in-vitro, and a novel murine model of HIPEC is developed using a hyperthermic chemotherapy infuser device designed de novo and printed on a 3D resin printer. Methods: HCT-116 cells were grown in culture and divided into treatment groups including: control, micronutrient combination, mitomycin C, and mitomycin C + micronutrient combination. Groups were cultured up to 72 hours after treatment and then subjected to MTT assay, crystal violet assay, trypan blue synergy assay, clonogenicity assay, cell cycle assessment by flow cytometry with propidium iodide, and western blotting for cleaved caspase-3. The infuser device was designed in a CAD environment, printed on a 3D resin printer, and underwent fluid temperature stability analysis and flow experiments by infusing methylene blue into live mice followed by necropsy and analysis of dyeing patterns. Results: MCC treated cells proliferated at 32.7%, and tumor cells treated with MCC + MNC carrier solution proliferated at 27.3%. Normothermic MCC and the MNC alone caused a 26.8% and 33.3% reduction in cell survival, and MCC delivered to cells in the micronutrient combination solution decreased cell survival by 53.2%. 95.3% and 99% of cells treated with MCC or MNC alone demonstrated viability, and 85% of cells treated with MCC + MNC demonstrated short term viability, suggesting synergy. HCT-116 clonogenicity is disrupted by MCC and MNC individually, and nonexistent in the MCC + MNC treatment group. Cleaved caspase-3 mediated apoptosis is upregulated by MCC, and by MNC to a lesser extent. Flow cytometry apoptosis demonstrates increased S-phase cell cycle arrest in the MCC + MNC sample. The mouse infuser HIPEC apparatus demonstrated an thorough distribution of blue dye in predictable regions of the abdomen with an acceptable range of hyperthermic regulation.

In selected patients, surgical treatments such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have enabled curative treatment options for previously incurable diseases, such as peritoneal carcinomatosis (PC). The introduction of resource demanding surgery could affect the work process, efficiency, and productivity within a surgical department and factors influencing patient postoperative recovery processes may have an impact on the efficiency of patient care after major surgery. The aim of this thesis was to investigate operating room efficiency from the perspective of both staff and leaders’ in two different settings (Papers I and II) and the early postoperative recovery of patients with peritoneal carcinomatosis (Papers III and IV). Interviews were held with 21 people in a county hospital and 11 members of the PC team in a university hospital, and a phenomenographic approach was used to analysis the data (Papers I and II). The patients’ postoperative recovery and pulmonary adverse events (AE) were determined from data retrieved from the electronic health records of 76 patients (Papers III and IV). The concept of efficiency was understood in different ways by staff members and their leaders (Paper I). However, when working in a team, the team members had both organisation-oriented and individual-oriented understanding of efficiency at work that focused on the patients and the quality of care (Paper II). The patients with PC regained gastrointestinal functions and could be mobilised during early postoperative recovery phase, although many patients suffered from psychological disturbances, sleep deprivation, and nausea (Paper III). Postoperative clinical and radiological pulmonary AE were common, but did not affect the early recovery process (Paper IV). In conclusion, leaders who are aware of the variation in understanding the concept of efficiency are better able to create the same platform for staff members by defining the concept of efficiency within the organisation. In a team organisation, the team members have a wider understanding of the concept of efficiency with more focus on the patients. The factors affecting postoperative recovery and pulmonary AE should be considered when designing individualised patient care plans in order to attain a more efficient recovery.

Introduction: Referral for CS/HIPEC is variable, and barriers encountered by referring physicians are unknown. Identification of such barriers is useful for the creation of tailored knowledge translation (KT) strategies. Methods: Interviews of 20 medical oncologists and surgeons in the New York (NY) area were completed to identify barrier topics, using the Pathman framework of uptake of innovations (awareness, agreement, adoption, adherence) at the various levels of the individual, practice group, and organization. Barriers were used to structure a survey for evaluation of prevalence at the population level of medical oncologists and surgeons in NY State. Results: Barrier topics of awareness included training at a CS/HIPEC center, and availability of multidisciplinary cancer conferences. Agreement barriers centered mainly on quality of published literature, and the paradigm shift of carcinomatosis as a systemic to locoregional disease process. Adoption barriers included knowledge of outcomes of a CS/HIPEC surgeon, and concerns with morbidity/mortality rates. Adherence barriers included the lack of reflection of CS/HIPEC in current CPGs, financial/resource and logistic concerns of referrals, and lack of quality measures for the procedure. For the survey, 119 responded (12% response rate), including 42 medical oncologist and 77 surgeons. The majority were aware of CS/HIPEC (n=113, 95%). Medical oncologists were less likely than surgeons to agree with CS/HIPEC related to published evidence (76% vs 92 %, p = 0.02). Surgeons were more likely to be aware of where to refer patients for the procedure, and were less likely to have concerns regarding morbidity/mortality, compared with medical oncologists (p = 0.05, p = 0.04). Representation of CS/HIPEC in CPGs and quality measures/outcomes data was felt to result in adherence to a regular referral practice. Discussion: This prospective study of stakeholders for CS/HIPEC is the first to evaluate and characterize barriers to referral for this complex and controversial surgical innovation, with prevalence at the population level. / Thesis / Master of Health Sciences (MSc) / This thesis identifies problems encountered with referring patients to a specialist surgeon for a procedure that involves both surgical removal of tumors and treatment of the abdominal cavity with chemotherapy. These problems are evaluated from interviews with specialists in the field, and then evaluated at a higher level of all practicing referring specialists through a survey. The results will be used to improve patient outcomes in the future.

Peritoneal carcinomatosis (PC) is a common manifestation of both gastrointestinal and gynecologic malignancies. Until recently, this condition was considered beyond curative intent treatment. Since the 1980s, new treatment strategies combining cytoreductive surgery (CRS) with perioperative intraperitoneal and intravenous chemotherapy have emerged. The underlying hypothesis considers CRS responsible for the removal of the macroscopic disease and that perioperative chemotherapy should address the residual microscopic disease. These new treatment regimens have presented encouraging clinical results that contrast with prior failure. The parameters for perioperative chemotherapy are mainly extrapolated from literature on peritoneal dialysis and data from systemic chemotherapy. The overall aim of this thesis was to provide a pharmacokinetic and pharmacodynamic rationale for perioperative intraperitoneal (IP) and intravenous (IV) chemotherapy in PC patients and, to assess its toxicity. After intraoperative IV administration of 5-fluorouracil or ifosfamide, substantial levels of these drugs were found inside the peritoneal fluid and tumor nodules (Papers I and II). This created a pharmacologically advantageous situation whereby a normothermic administered IV drug was subject to the effect of the local hyperthermia in the peritoneal fluid and tumor nodule. High levels of 5-fluouracil, ifosfamide and doxorubicin were observed inside the tumor nodules (Papers I, II and III) and, the identical pharmacokinetic advantage (expressed as Area Under the Curve (AUC) IP/IV ratios)) resulted in different drug levels of doxorubicin according to the density of the tumor nodules (Paper III). These data stressed the importance of pharmacodynamic variables such as tumor nodule density, size, and, vascularity. Therefore, the tumor nodule is proposed as a more appropriate pharmacological endpoint than AUC ratios. After IP Mitomycin C administration in PC patients with a contracted abdomen, mitomycin clearance from the abdomen decreased (Paper IV), which indicated  these patients at risk of under-treatment. Consequently, these pharmacologic data indicate a change in dosimetry for these treatment protocols might be warranted according to the diffusion area. Although diffusional vectors are viewed the main driving force for these treatment protocols, only pharmacokinetic variables such as dose, volume and duration are considered. As pharmacodynamic variables are equally important in the pharmacological assessment of cytotoxic effect, the tumor nodule was proposed as the center of a new conceptual model (Paper I). Mitomycin C data on non-metabolizers ( Paper IV) indicated the cytotoxicity of these cancer chemotherapy protocols is at the level of the individual tumor nodules. The morbidity and mortality of a new bidirectional intraoperative chemotherapy regimen in PC patients was analyzed (Paper V) which provided a means for identifying subsets of patients at risk for increased toxicity. This thesis provides pharmacokinetic and pharmacodynamic guidance for improving perioperative chemotherapy treatment strategies in PC patients and reports its toxicity.

Introduction. L’efficacité de la chimiothérapie intracavitaire dépend de la pénétration du produit au sein du péritoine (CHIP) ou de la plèvre. L’hyperthermie et l’hyperpression peuvent augmenter cette pénétration. Ce travail étudie leur effet intrapéritonéal, puis établit la méthode optimale pour les délivrer. L’étude de la faisabilité et de la tolérance d’une hyperpression intrapleurale est essentielle pour transposer ces bénéfices à la cavité thoracique. Méthodes. Quatre groupes de porcs ont reçu une CHIP ouverte avec de l’oxaliplatine à une concentration constante (150 mg/l) pendant 30 minutes en normothermie ou hyperthermie (42-43°C) ; et en pression atmosphérique ou hyperpression (25 cmH2O). Deux groupes ont reçu une procédure fermée en hyperthermie et hyperpression ou forte hyperpression (40 cmH2O). L’absorption systémique et tissulaire d’oxaliplatine a été étudiée. La tolérance d’une perfusion pleurale a été étudiée chez 21 porcs avec ou sans résection associée, avec ou sans chimiothérapie (cisplatine + gemcitabine), à divers niveaux de pression de 15 à 25 cmH2O. Résultats. L’hyperthermie augmente les concentrations de platine dans les surfaces viscérales (p=0.0014), alors que l’hyperpression l’augmente dans les surfaces viscérales et pariétales (respectivement p= 0.0058 et p= 0.0044). L’association des deux facteurs permet d’obtenir les concentrations les plus importantes dans le péritoine viscéral (p= 0.00001) et pariétal (p= 0.0003). Les concentrations obtenues lors des procédures fermées sont inférieures à celles obtenues en ouvert, même lorsque la pression atteint 40 cmH2O. Une chimiothérapie intrapleurale à 20 cmH2O sans résection associée est le niveau maximal toléré durant 60 minutes. Conclusion. Au cours d’une CHIP, l’hyperthermie augmente la pénétration d’oxaliplatine dans le péritoine viscéral, alors que l’hyperpression est efficace dans le péritoine viscéral et pariétal. Leur association est synergique et la procédure ouverte semble la meilleure pour la délivrer. Une chimiothérapie intrapleurale est faisable à 20 cmH2O dans ce modèle. / Introduction. In order to achieve a good effect, chemotherapy drugs need to penetrate into the peritoneal (HIPEC) or pleural tissue. Hyperthermia and high-pressure may enhance this penetration. The aim of this study was to evaluate their peritoneal effect and to establish the best technique to it. A feasibility study of an intrapleural high-pressure was an essential step to export these effects to the thoracic space. Methods. Four groups of pigs underwent an open HIPEC with a constant concentration (150 mg/l) of oxaliplatin during 30 minutes either in normothermia, or in hyperthermia (42-43°C); and either with atmospheric pressure or with high-pressure (25 cmH2O). Two more groups underwent a closed procedure with hyperthermia and either high-pressure or very high-pressure (40 cmH2O). The systemic and tissue absorption of oxaliplatin were studied. The haemodynamic and respiratory tolerance of a pleural infusion was also tested in 21 pigs with and without associated resection; with and without chemotherapy infusion (cisplatin + gemcitabin) and at various levels of pressure (from 15 to 25 cmH2O). Results. Hyperthermia enhances the concentrations of platinum in visceral surfaces (p=0.0014), whereas high-pressure enhances it both in visceral and in parietal surfaces (p= 0.0058 and p= 0.0044, respectively). Their association obtains the highest concentrations both in the visceral (p= 0.00001) and the parietal peritoneum (p= 0.0003). The concentrations obtained during closed procedure are lower than those achieved with the open technique, even with 40 cmH2O of pressure. A 60-minutes intrapleural chemotherapy perfusion with 20 cmH2O of pressure without any lung resection was the maximal tolerated level. Conclusion. During HIPEC, hyperthermia improves the penetration of oxaliplatin in the visceral peritoneum, whereas high-pressure is effective in both peritoneal surfaces. Their association is synergic and the open technique seems to be the best one to deliver it. An intrapleural chemotherapy with a 20 cmH2O pressure is feasible in this model.

The diploma thesis deals with the protection of personnel in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, focusing on non-medical healthcare workers - anesthetist nurses. The aim of the work was to analyze the knowledge of anesthesia nurses in the use of personal protective equipment, the specifics of selection for the given performance, the use of an electrocautery with integrated suction, the availability of decontamination aids In case of an accident of cytotoxic substances and if the staff is afraid of their own health. The data was obtained through a questionnaire. For the research were selected anesthesia nurses working in operating theaters in selected health care facilities in the Czech Republic. The total number of respondents who participated in the research was 35. The results of the survey revealed that the staff did not find out what PPEs are recommended for this type of operation. It's either because the staff is less linguistically equipped or does not know EBN / EBP or EBM. The staff only uses those PPEs that are available to them. As a good result, 49% of respondents use an integrated electric exhaust system. With regard to the availability of decontamination aids, I have found that most of the staff does not know whether these utilities are available at...

Contexte: La chirurgie de cytoréduction combinée à la chimiothérapie hyperthermique intrapéritonéale (CHIP) à l'oxaliplatine (OX) est un standard de traitement pour certains patients sélectionnés atteints de carcinose péritonéale d'origine colorectale. Puisque le 5-FU potentialise l'action de l'OX lorsqu'administrés en intraveineux (IV), plusieurs groupes combinent empiriquement le 5-FU IV avec la CHIP à l'OX, mais cette pratique n'est pas soutenue par des données précliniques. Chez le rat, nous avons étudié l'impact du 5-FU IV sur la concentration péritonéale de l'OX dans le contexte d'une CHIP. Méthodes: Sous anesthésie générale, 24 rats Sprague-Dawley furent soumis à 4 différentes doses de 5-FU IV (0, 100, 400 et 800 mg/m²) et une dose fixe de CHIP à l'OX (460 mg/m²) perfusée à 40°C pendant 25 minutes. À 25 minutes, des échantillons de différents compartiments furent prélevés (péritoine, veine porte et veine cave) et les concentrations de 5-FU et OX furent mesurées par Chromatographie Liquide à Haute Performance. Résultats: La concentration péritonéale d'OX a augmenté significativement (17.0, 20.1, 34.9 et 38.1 nmol/g, p < 0.0001) avec chaque dose croissante de 5-FU (0, 100, 400 et 800 mg/m², respectivement). La concentration péritonéale d'OX a atteint un plateau entre les doses de 400 et 800 mg/m² de 5-FU IV. Conclusion: Le 5-FU IV potentialise la concentration péritonéale de la CHIP à l'OX. La dose optimale de 5-FU IV à administrer en combinaison avec la CHIP à l'OX semble être 400 mg/m². / Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is a standard of care for selected patients with peritoneal carcinomatosis of colorectal origin. Because 5-FU is mandatory to improve efficacy of OX when used by systemic route, several teams now empirically combine intravenous (IV) 5-FU with HIPEC OX, but this practice has yet to be supported by preclinical data. Using a murine model, we studied the impact of IV 5-FU on peritoneal concentration of HIPEC OX. Methods: Under general anesthesia, 24 Sprague-Dawley rats were submitted to 4 different doses of IV 5-FU (0, 100, 400 and 800 mg/m²) and a fixed dose of HIPEC OX (460 mg/m²) perfused at 40°C during 25 minutes. At 25 minutes, samples in different compartments were harvested (peritoneum, portal vein and systemic blood) and the concentrations of 5-FU and OX were measured by high performance liquid chromatography. Results: Peritoneal concentration of OX was significantly higher (17.0, 20.1, 34.9 and 38.1 nmol/g, p < 0.0001) with increasing doses of 5-FU (0, 100, 400 and 800 mg/m², respectively). Peritoneal concentration of OX reached a plateau between 400 and 800 mg/m² of IV 5-FU. Conclusion: IV 5-FU enhances peritoneal concentration of HIPEC OX. The most efficient dose of IV 5-FU to be used in combination with HIPEC OX seems to be 400 mg/m².

Gastric cancer (GC) is one of leading causes of death in the world, and peritoneal metastases (PM) are a major site of recurrence. PM from GC implies a poor prognosis, with median overall survival (mOS) approximately 3 months and no survival at five years. The aims of this thesis were to explore the incidence and evaluate prognostic factors for mOS of PM from GC in a defined population; to investigate the outcome of a new multimodal treatment; to analyse the treatment costs, and to investigate differences in drug sensitivity between individual patient samples and between various tumours. The incidence of loco-regional advanced GC was 3.8 per 100,000 person-years. Synchronous loco-regional GC in combination with synchronous distant metastasis was a negative prognostic factor while chemotherapy and good performance status, and radiotherapy plus chemotherapy were positive prognostic factors . There were no significant differences in mOS for the group of patients included during the period 2000-2004 versus 2005-2009, and this lack of improvement in mOS during the past decade justifies new treatment approaches. In a Phase II study of patients treated with neoadjuvant systemic chemotherapy followed by cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, mOS was 14.3 months and for patients with macroscopically radical surgery mOS was 19.1 months. The mean overall cost of the loco-regional treatment was $145,700 compared to $59,300 with systemic chemotherapy treatment. In an ex vivo chemo-sensitivity test, it was determined that GC samples were equivalent to colorectal cancer in chemo-sensitivity to standard drugs and targeted drugs, whereas ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the drugs, arguing for individualized drug selection. The incidence of loco-regional advanced GC was more common than previously reported and there were no improvements in mOS over the past decade. The mOS for patients with neoadjuvant systemic chemotherapy followed by macroscopically radical cytoreductive surgery + hyperthermic intraperitoneal chemotherapy was better than in recent reports on treatment with systemic chemotherapy. Treatment of advanced GC patients is costly irrespective of treatment modality. The GC samples varied considerably between individuals in terms of sensitivity to increasing concentrations of the drugs and were comparable to colorectal cancer in chemo-sensitivity.