京都大学 / 新制・課程博士 / 博士(医学) / 甲第24883号 / 医博第5017号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中島 貴子, 教授 石見 拓, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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.

Peritoneal carcinomatosis (PC) is traditionally regarded as a terminal stage of disease with a poor prognosis and systemic chemotherapy is regarded as palliative treatment. In order to improve survival and even to achieve cure for selected patients with PC, cytoreductive surgery and intraperitoneal che-motherapy have been advocated. Despite complete macroscopic removal of tumour, residual microscopic malignant cells might result in recurrence. Intraperitoneal chemotherapy aims to kill residual malignant cells and thereby needs to be distributed in the entire peritoneal cavity. This aggres-sive combined loco-regional treatment has a high risk of morbidity and mor-tality. Whether the increased risks are acceptable to improve survival re-quires investigation and the impact of loco-regional treatment of PC on health-related quality of life (HRQL) needs to bee explored The overall aim of this thesis was to analyse the impact of cytoreductive surgery and intraperitoneal chemotherapy on patients with peritoneal carci-nomatosis. A significant survival improvement (median 32 months) was seen in 18 patients with PC of colorectal origin subjected to loco-regional treatment, in comparison to matched controls treated with systemic chemotherapy (me-dian survival 14 months, Paper I). The results of single-photon emission computer-tomography (SPECT) in 51 patients were correlated to the number of intraperitoneal chemotherapy courses that could be performed without further surgery (Paper II). Postoperative 30-days morbidity and 90-days mortality was investigated in 123 PC-patients after loco-regional treatment. Severe adverse events occurred in 51 (41%) patients. Five patients (4%) had treatment-related mortality. Stoma formation, duration of surgery, periopera-tive blood loss, and extent of PC was associated with morbidity (Paper III). HRQL was investigated in 64 patients. HRQL was negatively affected at 3 months but a partial recovery was seen at 8 months. 30-day morbidity did not have any impact on HRQL at 8 months (Paper IV). This treatment there fore appears justified despite considerable toxicity in view of possible life prolongation.

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.

Pseudomyxoma peritonei (PMP) is a rare disease characterized by mucinous peritoneal metastasis (PM). Different loco-regional treatment strategies, i.e. debulking surgery and cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC), have changed the prognosis for these patients. CRS is an aggressive surgical procedure with a long learning curve. PMP exists in different types; how many depends on which classification is used. The aims of this thesis were to investigate the time-frame of PMP development from an isolated appendiceal neoplasm, examine the learning process for CRS, evaluate the differences in treatment outcome between debulking surgery and CRS in combination with HIPEC, to evaluate a more detailed PMP classification and to investigate particularly interesting new cysteine-histidine (PINCH) protein as a prognostic factor for PMP. Retrospectively 26 PMP patients were identified as having had an appendectomy with a neoplasm in the appendix but with no evidence of PM at the appendectomy. They were treated for PMP within a median of 13.1 months (3.8-95.3) after the appendectomy. No difference was seen between the types of PMP regarding the time to a clinically significant development of PMP and how much tumour was found at treatment. CRS is a highly invasive treatment and stabilization in the learning curve was seen after 220±10 procedures. Patients treated with CRS+HIPEC had a better 5-year overall survival (OS) than patients treated with debulking surgery, 74% vs. 40%. CRS increased the rate of complete cytoreduction from 25% in patients treated with debulking surgery to 72%. The new four-grade PMP classification showed very good inter-rater agreement between two independent pathologists and a difference in survival rates was observed between the different grades. A positive PINCH staining was recorded in 83% of the tumours and that was associated with poorer survival.

ABSTRACT Background: Patients that have undergone cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) are a patient group with many complex nursing care needs, the recovery process is often long and challenging. However, there is no research on the patients experiences of the recovery on the ward. Aim: The aim was to describe how patients that have undergone CRS with or without HIPEC experiences the postoperative recovery at the ward, and if the nursing care they receive matches their individual needs. Method: A qualitative study with semi-structured interviews were conducted with seven patients on one gynecological- and one surgical ward. Data was analysed with qualitative content analysis. Result: Two categories were identified: A time filled with physical challenges but gradually returning to normal and A roller coaster of thoughts and emotions. The result showed both physical and mental challenges during the recovery process on the ward. The patients described nausea, tiredness and initially difficulties with mobilisation. They also shared feelings of concern, frustration and missing their relatives. The nursing staff had an important role in creating a safe environment during the treatment period by showing support, providing information and offering conversations. Conclusion: The result of the study shows that patients who have undergone CRS with or without HIPEC experiences both physical and mental challenges during the recovery process on the ward. Through support, information and conversations the nursing staff can meet the patient’s individual needs and in that way, optimize the recovery. By ensuring a high level of competence among the nursing staff, the safety of the patients can be guaranteed and good nursing can be carried out.

Zielsetzung: Das Ovarialkarzinom ist die häufigste Krebstodesursache innerhalb der gynäkologischen Malignome. Im Rahmen dieser retrospektiven Arbeit werden die klinischen Ergebnissen von 84 Patientinnen dargestellt, die an Ovarialkarzinom erkrankten und im Krankenhaus im Friedrichshain in Berlin behandelt wurden. Das Ziel dieser Studie war die Analyse des Einflusses verschiedener Prognosefaktoren auf das Gesamtüberleben, Identifikation unabhängiger Prognosefaktoren und Erarbeitung von Prognoseregeln in Bezug auf das Gesamtüberleben sowie Beurteilung des Therapieerfolges und kritische Diskussion des second-look Verfahrens. Methodik: Zur Bestimmung der kumulierten Überlebensraten wurde die Kaplan-Meier-Methode verwendet, zur Identifikation unabhängiger Prognosefaktoren die multivariate Analyse. Als statistisch signifikant galten Ergebnisse mit einer Irrtumswahrscheinlichkeit von p < 0,05. Ergebnisse: Das mediane Alter zum Zeitpunkt der Erstdiagnose betrug 61 Jahre. Die kumulierte Fünfjahresüberlebensrate betrug 53 %. Die kumulierten Fünfjahresüberlebensraten lagen für die Stadien FIGO I, II, III bzw. IV bei 93 %, 83 %, 20 % bzw. 11 %. Seitens der Histologie handelte es sich überwiegend um serös-papilläre Karzinome. Die Rezidivrate lag bei 36 %. Der Median bis zum Auftreten eines Rezidivs betrug 11,5 Monate. Schlussfolgerungen: Eine gute Prognose ergibt sich bei geringem Alter bei Erstdiagnose, gutem Allgemeinzustand, normwertigem präoperativem Tumormarker CA 125, fehlendem Aszites bzw. möglichst geringer Aszitesmenge, hochdifferenzierten Tumoren, möglichst vollständiger Tumorentfernung und Lymphonodektomie. Als unabhängige Prognosefaktoren haben sich nur das FIGO-Stadium, Alter und Grading erwiesen. Anhand der unabhängigen Prognosefaktoren lässt sich die prognostizierte Überlebenswahrscheinlichkeit angeben. / Objective: Ovarian carcinoma is the most frequent reason of the cancer death among malignant gynaecological tumours. The clinical outcome of 84 patients, who had ovarian carcinoma and underwent the treatment in "The Hospital in Friedrichshain" in Berlin, is presented in this retrospective study. The objective of this study was to analyse the influence of different prognostic factors related to overall survival, to identify the independent prognostic factors, to set up prognostic rules for patients with ovarian carcinoma related to overall survival, to assess the benefit of the therapy and the critical discussion of the second-look operation. Methods: The Kaplan-Meier method was applied in order to estimate overall survival rates and multivariate analysis in order to evaluate the independent prognostic factors. The results with p < 0,05 were of statistic significance. Results: The median age at diagnosis was 61 years. The cumulated 5-year survival rate was 53 %. The cumulated 5-year survival rates for the stages FIGO I, II, III and IV were 93 %, 83 %, 20 % and 11 %, respectively. Concerning histology there were mostly serous-papillar carcinomas. The recurrence rate was 36 %. The median until the recurrence occurred was 11,5 months. Conclusions: A good prognosis is associated with lower patient age at diagnosis, good performance status, normal preoperative serum CA-125 level, absence or minimal presence of ascites, well differentiated tumours, minimal size of the residual disease after primary cytoreductive surgery and lymphadenectomy. However, on multivariate analysis, only tumour stage, patient age and tumour grade retained prognostic significance as independent prognostic factors. Due to independent prognostic factors the survival probability can be predicted.

Depuis 20 ans, certains patients porteurs d’une carcinose péritonéale sont traités par une chirurgie de cytoréduction combinée avec une chimiohyperthermie intrapéritonéale (CHIP). Bien que l’oxaliplatine (OX) soit couramment utilisée lors de CHIP, une telle utilisation chez l’humain n’est supportée que par des études de phase II et il n’y a pas d’études précliniques caractérisant les propriétés de l’OX dans le contexte d’administration intrapéritonéale. L’objectif de ce projet de maîtrise est d’étudier l’effet de la température sur l’absorption tissulaire et systémique de l’OX administrée par voie intrapéritonéale chez le rat. Nous avons procédé à une perfusion intrapéritonéale de 3 différentes doses d’OX à 3 différentes températures pendant 25 minutes chez une total 35 rats Sprague-Dawley, puis effectué le dosage des concentrations d’OX dans différents compartiments. Nous avons observé une augmentation linéaire (p<0,05) entre la dose d’OX administrée et sa concentration dans tous les compartiments (péritoine, mésentère, sang portal et systémique). De plus, avec l’augmentation de la température de perfusion, nous avons observé une augmentation de la concentration d’OX dans le péritoine mais une diminution de sa concentration dans les compartiments systémique et portal (p<0,05). Ces résultats démontrent donc que la dose et l’hyperthermie augmentent indépendamment la pénétration tissulaire de l’OX et que l’hyperthermie limite son absorption systémique. Ces observations suggèrent que l’hyperthermie pourrait réduire la toxicité systémique de l’OX. Pour connaître la cinétique de l’OX, des études subséquentes doivent être faites. / Over the last twenty years, certain patients afflicted with peritoneal carcinomatosis have been treated with a combination of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. Supported by phase II studies only, Oxaliplatin (OX) is commonly used in this context. However, pre-clinical studies to characterize its properties in such conditions are lacking. The purpose of this project is to study the effect of temperature on tissue and systemic absorption of OX when administered by intraperitoneal route in the rat. By intraperitoneal route, we administered 3 different doses of OX at 3 different temperatures for 25 minutes on 35 Sprague-Dawley rats. Samples from selected compartments were harvested and OX concentration was measured using high performance liquid chromatography. We obtained a linear correlation (p<0.05) between OX dose and tissue concentration in every compartments analyzed (peritoneum, mesentery, systemic and portal blood). With hyperthermia, we observed an increase in peritoneum and mesentery concentration of OX, but a decrease it its systemic and portal concentration (p<0.05). Intraperitoneal administration of OX leads to high concentration of drug in local tissues. Hyperthermia enhances tissue absorption and minimizes systemic absorption suggesting it could reduce systemic toxicity. Additional studies are needed to further define the pharmacokinetics of OX administered by intraperitoneal route.

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.

Depuis 20 ans, certains patients porteurs d’une carcinose péritonéale sont traités par une chirurgie de cytoréduction combinée avec une chimiohyperthermie intrapéritonéale (CHIP). Bien que l’oxaliplatine (OX) soit couramment utilisée lors de CHIP, une telle utilisation chez l’humain n’est supportée que par des études de phase II et il n’y a pas d’études précliniques caractérisant les propriétés de l’OX dans le contexte d’administration intrapéritonéale. L’objectif de ce projet de maîtrise est d’étudier l’effet de la température sur l’absorption tissulaire et systémique de l’OX administrée par voie intrapéritonéale chez le rat. Nous avons procédé à une perfusion intrapéritonéale de 3 différentes doses d’OX à 3 différentes températures pendant 25 minutes chez une total 35 rats Sprague-Dawley, puis effectué le dosage des concentrations d’OX dans différents compartiments. Nous avons observé une augmentation linéaire (p<0,05) entre la dose d’OX administrée et sa concentration dans tous les compartiments (péritoine, mésentère, sang portal et systémique). De plus, avec l’augmentation de la température de perfusion, nous avons observé une augmentation de la concentration d’OX dans le péritoine mais une diminution de sa concentration dans les compartiments systémique et portal (p<0,05). Ces résultats démontrent donc que la dose et l’hyperthermie augmentent indépendamment la pénétration tissulaire de l’OX et que l’hyperthermie limite son absorption systémique. Ces observations suggèrent que l’hyperthermie pourrait réduire la toxicité systémique de l’OX. Pour connaître la cinétique de l’OX, des études subséquentes doivent être faites. / Over the last twenty years, certain patients afflicted with peritoneal carcinomatosis have been treated with a combination of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. Supported by phase II studies only, Oxaliplatin (OX) is commonly used in this context. However, pre-clinical studies to characterize its properties in such conditions are lacking. The purpose of this project is to study the effect of temperature on tissue and systemic absorption of OX when administered by intraperitoneal route in the rat. By intraperitoneal route, we administered 3 different doses of OX at 3 different temperatures for 25 minutes on 35 Sprague-Dawley rats. Samples from selected compartments were harvested and OX concentration was measured using high performance liquid chromatography. We obtained a linear correlation (p<0.05) between OX dose and tissue concentration in every compartments analyzed (peritoneum, mesentery, systemic and portal blood). With hyperthermia, we observed an increase in peritoneum and mesentery concentration of OX, but a decrease it its systemic and portal concentration (p<0.05). Intraperitoneal administration of OX leads to high concentration of drug in local tissues. Hyperthermia enhances tissue absorption and minimizes systemic absorption suggesting it could reduce systemic toxicity. Additional studies are needed to further define the pharmacokinetics of OX administered by intraperitoneal route.