UNIVERSITY OF MEDICINE AND PHARMACY GRIGORE T. POPA IAȘI

Transcription

1 UNIVERSITY OF MEDICINE AND PHARMACY GRIGORE T. POPA IAȘI PhD Thesis Summary HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY ASSOCIATED WITH CYTOREDUCTIVE SURGERY IN PERITONEAL CARCINOMATOSIS OF GASTROINTESTINAL ORIGYN SCIENTIFIC COORDINATOR, PROFESSOR DR. SCRIPCARIU Viorel PhD STUDENT HUŢANU Ionuţ 2013

2 Research funded by the project Burse doctorale pentru creşterea competitivităţii în domeniul medical şi farmaceutic POSDRU/88/1.5/S/63117, cofounded from the European Social Fund through the Operational Program for Human Resources Development Main intervention field: 1.5 Doctoral and post-doctoral program supporting the research Project title: Doctoral fellowships for the increase of competitiveness in the medical and pharmaceutical field Beneficiary: Gr. T. Popa University of Medicine and Pharmacy of Iasi Partner : University of Medicine and Pharmacy of Timişoara The thesis consists of: - theory (40 pages )in four Chapters - personal research (95 pages) in five Chapters references - 63 pictures - 25 tables - 2 B+ aticles and 5 ISI indexed published or accepted In this abstract, the table of contents and the number for each figure is the same as in the thesis Key words Peritoneal carcinomatosis, HIPEC, peritonectomy, cytoreduction, pseudomyxoma peritonei, diffuse malingnant mesothelioma

3 Table of contents Personal motivations 9 General Part.Level of acknowledge 11 CHAPTER 1 Considerations on peritoneal carcinomatosis Anatomy and psysiopathology I. Ultrastructure of peritoneum II. Molecular biology of peritoneal carcinomatosis Clinical aspects in peritoneal carcinomatosis Imaging of peritoneal carcinomatosis 16 CHAPTER 2 Hyperthermic intraperitoneal chemotherapy Intraperitoneal assessment of the extent of peritoneal carcinomatosis Hyperthermic intraperitoneal chemotherapy (HIPEC) The evolution of the treatment of peritoneal carcinomatosis Peritonectomy procedures technique 22 CHAPTER 3 Role of HIPEC in the treatment of peritoneal carcinomatosis Colorectal cancer I. The incindence of colorectal peritoneal carcinomatosis II. Survival after systemic chemotherapy III. Survival after systemic chemotherapy associated with biologic agents IV. Survival after HIPEC V. Peritoneal carcinomatosis associated with liver metastases VI. Strategy in incidental findins of peritoneal carcinomatosis of colorectal origin VII. Cytoreductive surgery without HIPEC VIII Tumor relapse after HIPEC Gastric cancer Ovarian cancer Pseudomyxoma peritonei I. Pathology os pseudomyxoma peritonei II. Clinical aspects of pseudomyxoma peritonei III. Treatment of pseudomyxoma peritonei Diffuse malignant peritoneal mesothelioma 44 CHAPTER 4 Considerations on HIPEC Patient selection for HIPEC Morbidity and mortality after HIPEC Quality of life after HIPEC Costs of HIPEC procedure Learning curve in cytoreductie surgery 59 Personal contributions 61 CHAPTER 5. Morbidity and mortality after HIPEC for peritoneal carcinomatosis of colorectal cancer and pseudomyxoma peritonei. Experience of National Cancer Institute of Milano, Italy Aims of the study Material and methods Results 83 5,4. Discussions 93 CHAPTER 6 The role of circulating tumor markers in pseudomyxoma peritonei Aims of the study Material and Methods Results 105

4 6.4. Discussions 127 CHAPTER 7. Treatment of peritoneal carcinomatosis of gastro-intestinal origin-a retrospective study of 203 cases Introduction. Aim of the study Material and methods Results Discussions Conclusions 138 CHAPTER 8 The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy (HIPEC) Introduction. Aims of the study Material and methods Results Discussions 154 CHAPTER 9 Discussions and conclussions Discussions Conclusions 163 References 165 Addenda 185 Abbreviations 185 Informed Consent for HIPEC treatment 186 List of scientific papers issued during PhD studies 191

5 Personal Motivations Peritoneal carcinomatosis (PC) is a disease with a dismal prognosis, difficult to treat wich represent a permanent problem for surgeons, medical oncologists, and other specialities. Overall survival of the patiens with peritoneal carcinomatosis is very poor. It s natural history is very unpredicteble with long hospitalisation, low quality of life,, palleative surgery to treat various complications, ascites, and finally death. Primary peritoneal carcinomatosis is a very rare disease wich include diffuse malignant peritoneal mesothelioma and serous peritoneal carcinomatosis. Secondary pesitoneal carcinomatosis is more frecquent and coul be found in advanced intra or extraperitoneal disease. The most frecquent cancers are gastric, colorectal, pancreatic and ovarian. Rare cancers are billiary, prostatic, renal and breast cancer and a very rare appendicular cancer - pseudomyxoma peritonei. EVOCAPE study on 370 patients with PC of gastrointestinal origyn revealed aoverall survival of 3 to 9 month for the patients with 3 months for those with nodules greater than 2 cm and 9 months for those with nodules less tan 5 mm. [1]. Hiperthermic intraperitoneal chemotherapy (HIPEC) has become during the last 30 years standard therapy fost PC of colorectal origun and for pseudomyxoma peritonei and peritoneal mesothelioma. There are reports favoring the complex procedure for other entities like ovarian, gastric carcinomatosis. One of the concerning of this complex procedures reguard the lack of high evidence base medicine with only one randomised prospective study comparing the survival of patients with peritoneal carcinonamtosis of colorectal origyn with or without HIPEC. Other concernings are high morbidity and mortality, costs, quality of life, learning curve. In Romania HIPEC procedure is not performed. The aim of this study is to investigate the morbidity and mortality of this procedure, the morbidity and mortality of traditionally treated patient with carcinomatosis and various aspects of the treattment of pseudomyxoma peritonei and peritoneal diffuse mesothelioma.

6 Level of aknowledge CHAPTER 1. Peritoneal carcinomatosis Mechanisms of peritoneal carcinomatosis Nowadays the mechanism of CP is incompletely understood. It is considered that it s different from the hematogenous or lymphatic pathways involved in the development of distant metastases in parenchymal organs or lymph nodes. In order to explain the occurrence of CP, there have been proposed several theories. One hypothesis suggests that the tumor cells once they are infiltrating the serous and once they are free into the peritoneal cavity, then they are able to generate the appearance of CP. In this process may be involved also the tumor manipulation during surgery or biopsy[10]. This theory can not explain, however, a rare occurrence of CP in T1 or T2 tumors [1]. It has been described the presence of free tumor cells in colorectal cancer in stage I before their surgical manipulation [11]. I.2. Clinical aspects in peritoneal carcinomatosis The clinical aspects in CP usually overlaps with the primary tumor signs and symptoms. To those pacients where the primitive tumor hasn t been diagnosed, it may occure signs as ascites, enlargement of the abdomen, weight, physical or intellectual ability loss, irritability, changes in eating habits, flatulence, presence of palpable tumors. Often, especially in pseudomixoma peritonei and ovarian cancer, the palpation of the abdomen reveals a central tumor mass because of the tumoral implants on the great omentum, also known as "omental-cake". In advanced cases, the patients become cachectic, and the clinical picture may be complicated by the appearance of intestinal obstruction because of the invasion of the small or large bowel, local peritonitis in case of tumor invasion or diastatic perforation, bleeding.sometimes clinical signs and symptoms may be lesions to other secondary (metastatic) sites: liver, lung, bone, brain.. CHAPTER 2. Hyperthermic intraperitoneal chemotherapy (HIPEC) treatment of peritoneal carcinomatosis 2.2. Hiperthermic intraperitoneal chemotherapy (HIPEC) Hiperthermic intraperitoneal therapy belongs to locoregional therapies. With other procedures like locoregional treatment of unresectable liver metastases [50-51], isolated limb perfusion for advanced tumors with the goal to preserve the function [52-53], intraoperative radiotherapy for advanced breast cancer [54] HIPEC provides high dose of chemotherapic agents locally avoiding systemic complications. In the last 3 decennia HIPEC proved its efficacity in various loaclly advanced tumors like colorectal cancer [55], ovarian [56], gastric [57-58] and has became golden standard for rare tumors like pseudomyxoma peritonei (PMP) [59-60] and peritoneal mesothelioma (MP) [61].

7 2.3. The evolution of the surgical treatment of peritoneal carcinomatosis The evolution of intraperitoneally administred chemotherapy [69]: Weisberger and col. in 1955 [70] administred nitrogen mustard for the threatment of ascites of in advanced ovarian cancer. Authors observed a good palliation of ascites but no improvements in survival pentru tratamentul ascitei neoplazice Spratt and col. [71] suggested intraperitoneal hiperthermic chemotherapy after animal studies.then they performed for the first time the procedure in a 37 years old male with pseudomixoma peritonei 1981 Spreyer and col. [72] described the farmacology of intraperitoneally adminiustred 5-florouracyl in liver cancer patients 1984 Hamazoe and col. [73] first study of hiperthermic intraperitoneal chemotherapy with Mitomicin C in patients with gastric and colorectal carcinomatosis proving the efficacity of the method 1985 Sugarbaker and col. [74] published the results of a randomized study (systemic chemotherapy vs intraperitoneal chemotherapy) for advanced colorectal cancer with no macroscopic carcinomatosis. Authors observed a low incidence of peritoneal carcinomatosis in patients treated with intraperitoneal chemotherapy Koga and col. [75] reported first study of prophylactic intraperitoneal chemotherapy with Mitomicin C in advanced gastric cancer (T3). The authors observed an improvement of survival Kiuchi and col. [76] reported an overall survival of 380 days and 62%-one year survival in a population of pacients with gadvanced gastric cancer treated with HIPEC and overall survival of 160 days and 16% one years survival in patients traditionally treated Sugarbaker [77] described peritonectomy procedure 2003 Verwaal and col. [78] published the results of the first randomized study on HIPEC in peritonel carcinomatosis of colorectal cancer. The authors observed an overall survival of 22 monts in patients treated with hiperthermic intraperitoneal chemotherapy and 12 month in patients treated with surgery plus systemic chemotherapy. CHAPTER 3. The role of HIPEC in the treatement of peritoneal carcinomatosis 3.1.The Colorectal cancer Colorectal cancer in Europe has estimated an incidence of cases per year. It is estimated that approximately patients die because of this neoplasia[105].cp is one of the most common ways of dissemination in colorectal cancer having symptoms which may overlay on the primary tumor condition, only if it s limited. It s diagnosed in 7-10% of patients who had surgery for colorectal cancer, it develops in 4-19% of patients who underwent surgery with curative visa and occurs in approximately 44% of patients with postoperative tumor recurrence.in a retrospective study of 3019 patients [106], 349 of them (13%) developed CP of which 214 (61%) had a CP synchronous and 135 (39%) CP metachronous.

8 Treatment of metastatic colorectal cancer is multimodal,surgery is the only curative intent, despite the new class of chemotherapy which significantly improved survival. 3.1.IV.Results in CP s multimodal treatment (cytoreduction + HIPEC) of colorectal etiology. In 1995, Sugarbaker et al. [81] published the first results of multimodal therapy including tumor cytoreduction associated with hyperthermic intraperitoneal chemotherapy in a group of 181 patients, who uderwent surgery for colo-rectal CP (51 patients), and for apendicular etiology for CP (130 patients). The authors identified colonic origin, nods status, tumor differentiation and extent of CP as negative prognostic factors. In those colo-rectal patients with incomplete cytoreduction, authors have reported a 3-year survival of 20%, significantly lower than those with a full cytoreductive (60%). There is only one study [119] randomized and completed so far on the colorectalcp treated by HIPEC. In this study, between february august 2001, 105 patients were randomized into two groups. All 105 patients had histological diagnosis of colo-rectal CP and no liver or extra-abdominal metastases, age under 71years old, with acceptable performance status and good renal, liver and bone marrowfunction. The patients were randomized to standard therapy or experimental treatment. The patients in the standard group (51 patients after randomization) went surgery only if there were casesof complications and in that situation they performed bypass, stenting and exceptional resection. Otherwise, in a total of 44 patients, there were performed standard chemotherapies from that that period in Netherlands, after a schema containing 5-Fluorouracil and Leucovorin. In the experimental group (54 patients after randomization) 49 patients wentsurgerypracticing tumor cytoreduction and hyperthermic intraperitoneal chemotherapy for a period of 90 minutes with mitomycin C.Subsequently these patients (33 patients) had systemic chemotherapy following the same pattern as those in the standard arm.all patients were subsequently re-evaluated every 3-6 months. Study results showed a median survival of 12 months in arm with systemic chemotherapy and 22 months in the experimental arm so a benefit of about 10 months 3.4. Pseudomixoma peritonei Pseudomixoma peritonei (PMP) is localized or generalized progressive accumulation of a gelatinous consistency ascite in the abdominal cavity, usually a consequence of chistadenoma appendix rupture.pmp is a generic term used to describe clinical and radiological syndrome, but not a histopathologic diagnosis. Rokitansky was the first to describe an appendix mucocel, he named it hydrops vermiform process [185]. In 1884 [186], Werth introduced the PMP term describing the first case in a patient with an ovarian tumor.in 1901 Frankel had described a case ofpmp associated with an appendicular cyst. PMP prevalence in the general population is difficult to assess. It is estimated at 1-2 cases per 1 million inhabitants.in a retrospective study [187] for a period of 10 years from appendectomies carried out in Holland in 1482 were found appendix tumors (0.9%) of which 574 were epithelial tumors. Because it is a rare

9 condition there is no prospective study on the treatment of this heterogeneous disease.nowadays,in the world are 8 reference centers with more than 100 patients [59], the greatest casework of 500 cases being reported in Basingstoke. CHAPTER 4. Considerations about HIPEC 4.1. Patient selection for HIPEC Patient selection for HIPEC is not easy. Surgical treatment decision should not belong to a single physician, it should be taken in consensus by a multidisciplinary team [222].Piso et al. [224] have sketched some indicative criteria for selection of patients with CP proposed for surgery by identifying factors related to tumor and patient: factors related tumors: primary tumor location, histological type and grading; presence of extra-abdominal metastatic disease, the presence of para-aortic lymph nodes metastasis, Peritoneal Cancer Index, bowel and hepatogastric ligamentinvolvement, bladder or ureteral stenosis, response to prior systemic chemotherapy. Other factors: ECOG performance status,patient comorbidities, the learning curve of the surgeon, the patient's informed consent, quality of life expected postoperatively Morbidity and mortality after HIPEC The complications, such as fistula or the perforation, are at a rate of 7-17% [88, ]. Compared to the 2-4% incidence of fistula in elective colorectal surgery [239] the relatively large number of anastomotic anastomotic fistulas is justified by thepatients status, often with a history of multiple interventions with postoperative adhesions that make dissection difficult,but also by the fact that in some cases, in order to obtain anproper cytoreductive result, we actually increase the risk of complications by performing a large number of anastomosis. Often we practice serous tumor cytoreduction in bowel or mesentery, which increase the risks of bowel necrosis and devascularisation The learning curve in cytoreductive surgery. Smeenk et al. [223] believes that learning curve peak is reached after approximately 130 cases.the authors have noticeda decreaing morbidity from 71 to 34%, a decrease in the length of stay for 24 to 17 days and an increased proportion of patients with complete cytoreductive from 35 to 65% in a group of 323 patients who went for surgery for colo-rectal CP or PMP, dividing the patients into 3 groups according to the period in which they were operating. In the group of patients the ultimate complications of gastrointestinal complications have been observed (32%), infection (20%), lung (13%), bone marrow suppression (12%).Post-operative mortality decreased from 8% to 4% for the first 75 patients operated on.one of the authors explanations for better results over time is related to a more rigorous selection of patients excluding patients with extensive abdominal CP (6-7 regions), becausecomplete citoreduction is difficult and because of

10 thepostoperator riscks and complications, due to large excision necessary for optimal cytoreduction.yan et al. [271] in a group of 140 patients operated by cytoreduction combined with HIPEC has been a net improvement in the parameters of the last 70 patients from the first 70 patients. PERSONAL PART CONTRIBUTIONS CHAPTER 5. Morbidity and mortality in patients operated after HIPEC with peritoneal carcinomatosis of colorectal etiology and Pseudomixoma peritonei at National Tumor Institute in Milan, Italy 5.1. The purpose of the study The main objective of this study is to identify the main risk factors for the occurrence of severe postoperative complications in patients with CR and PMP peritoneal carcinomatosis. The second objective is to evaluate the oncological outcome of patients with CR CP, when performind peritonectomie associated with intraperitoneal chemotherapy. 5.2.I. The group of patients The study was conducted on a group of patients operated at the National Cancer Institute (INT) in Milan between june march 2012.In this period went for surgery a total of 473 patients with various diseases of the peritoneum.all patients were operated by a single surgical team, having as principal surgeon the same surgeon (Marcello Deraco) who also performed patient selection for curative intervention visa. The decision was taken after surgery consent multidisciplinary team consisting of a surgeon, oncologist, pathologist, anesthesiologist and nutritionist. All patients were operated after a protocol developped by INT and met the following criteria: CR CP or PMP, good renal function, hepatic and hematopoietic, age under 75 years old, ECOG performance status less than 3, the absence of distant metastases and retroperitoneal lymphadenopathy blocks, imaging investigations that suggest the possibility of an optimal citoreductive surgery, signed informed consent of patients.

11 Fig. 5.7 Right upper quadrant peritonectomy Collection of Dr. Marcello Deraco Fig Parietal and pelvic peritonectomy Collection of Dr. Marcello Deraco

12 TABLE 5.IV Risk factors for postoperative high grade mororbidity after HIPEC in PMP and colorectal peritoneal carcinomatosis patients Factors Morbidity Grade 3-5 Univariate Multivariate** analysis* p Odds Confidence interval P Ratio Tumor (Colon vs PMP) 0, Sex (Male vs Female) 0, Age >52 years 0, Body mass index <22 0, ( yes vs no) Performance status (0 vs 1-2) <0,01 3,73 1,50-9,30 <0,01 Charlson morbidity index > 3 (da vs nu) Histologic subtype (Colon + PMCA vs 0, DPAM) Prior surgical score 0-1 vs 2-3 0, Preoperative chemotherapy 0, (yes vs no) Preoperative albumin 0, (<3,5 vs >3,5) Preoperative lymphocite count < , (da vs nu) Preoperative platelets count > , ( da vs nu) Peritoneal Cancer Index (> 20 vs < 20) <0, Anastomoses( yes vs no) 0, Anastomoses > 2 (yes vs no) <0, Ttransfusions > 2 units ( yes vs no) Transfusion ( yes vs no) 0, Duration of procedure > 600 minutea ( yes vs no) Splenectomy (yes vs no) 0, Colectomy ( yes vs no) 0, Enterectomy ( yes vs no) 0,01 2,49 1,16-5,31 0,02 Histerectomy 0, Number of procedures > 8 0, (yes vs no) Complete cytoreduction 0, (yes vs no) CDDP intraperitoneal > 220 mg ( yes vs no) <0,01 2,96 1,31-6,67 <0,01

13 TABEL 5.V Risk factors fost postoperative fistulas after HIPEC in PMP and colorectal carcinomatosis patients Risk factors Fistulae Univariate analysis* Multivariate analysis** p Odds Confidence interval P Ratio (Colon vs PMP) 0, Sex (male vs female) 0, Age >52 (yes vs no) 0, BMI <22 ( yes vs no) 0, Performance status (0 vs 1-2) 0, Charlson comorbidity index 0, > 3 (yes vs no) (Colon + PMCA vs DPAM) 0, Prior surgical score 0-1 vs 2-3 0, Preoperative chemotherapy (da vs nu) 0, Preoperative albumin (<3,5 vs >3,5) 0, Preoperative lymphocitic count < 1500 (da vs nu) Preoperative platelets > ( da vs nu) <0,01 3,90 1,45-10,46 <0,01 0, Peritoneal Cancer Index >20 <0,01 4,57 1,40-14,56 0,01 (yes vs < no) Anastomoses ( yes vs no) 0, Anastomoses > 2 (yes vs no) <0, Intraoperative blood units > 2 unităti ( yes vs no) Blood transfusion ( yes vs no) 0, Durata operaţiei > 600 minute ( da vs nu) Splenectomy (yes vs no) 0, Colectomy ( yes vs no) 0, Enterectomy (yes vs no) <0,01 2,94 1,18-7,34 0,02 Histerectomie (yes vs no) 0, Nomber of procedures 0, > 8 ( yes vs no) CC score >1 (yes vs no) 0, Cisplatin dose > 220 mg ( yes vs no) <0,

14 5.4. Discussions Univariate analysis showed the following factors: ECOG performance status, preoperative lymphocyte count, Peritoneal Cancer Index> 20, enterectomy, colectomy, splenectomy, CDDP dose and complete cytoreduction. After performing multivariate analysis (logistic regression - backward conditional) only Peritoneal Cancer Index >20, enterectomy and preoperative lymphocytic count remained as independent factors. One explanation for Peritoneal Cancer could be : more involvement of peritoneal cavity implies more procedures and thus higher risk for bleeding, fistulas, anastomotic leak. Preoperative albumin, number of procedures, perioperative blood transfusion were not amongst the independent factors. CHAPTER 6. Circulating tumor markers: predictors of incomplete cytoreduction and powerful determinants of outcome in pseudomyxoma peritonei 6.1. Introduction Pseudomyxoma peritonei (PMP) is a rare condition characterized by a slow accumulation of peritoneal deposits of mucinous tumors and mucin. With systemic chemotherapy and palleative surgery overall survival is limited. The aim of this study is to evaluate the ability of preoperative serum markers (Ca125, CEA, and Ca19-9) to predict incomplete cytoreduction in patients PMP patients elected eligible to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy deemed for hyperthermic intraperitoneal chemotherapy associated with peritonectomy.the secondary aim of this study is to evaluate their prognostic role for oncologic outcome Results Mean follow up was 42 months (1-170). 30 patients died (mean follow-up 31 months range patients were alive (mean follow-up 46 months range ). Five year overall survival was 73%. Mean age was 53 years (±13,6). There were 60 males and 96 females. Mean Charlson comorbidity index was 3,6 (±1). Preoperative serum albumin was 4.3 g/dl (±0,7). PSS was 0 to1 in 47% patients and was > 2 in 53% of patients. 23% patients underwent preoperative systemic chemotherapy. 34% patients had PMCA/PMVA-I histologic type. Mean Peritoneal Cancer Index was 22,6 (±11,1). Most frecquent procedure was omentectomy. (TABLE 6.I) 14 patients (9%) underwent incomplete cytoreduction. Mean operative time was 600 minutes ( minute). During the intervention were recquired 3 units of blood (range 0-37) Mean lenght of stay was 18 days (7-101). One patient presented postoperative leukopenia ( TABLE 6.II) 6.4. Discussions Univariate analysis revealed the following negative prognostic factors: Charlson comorbidity index >4, male gender, ECOG performance status >2 preoperative systemic chemotherapy, histologic subtype PMCA, preoperative albumin < 3,5mg/dl, Peritoneal Cancer Index >20, incomplete cytoreduction, Ca125>125 U/ml, Ca19,9 >89 U/ml. After multivariate analysis (multivariate logistic regression)

15 only the following factors remained: ECOG performance status, serum albumin < 3,5 mg/dl, Ca125 >125 and Ca19.9 > 89 TABLE 6.II. Changes in laboratory values after HIPEC Creatini >1,3mg/dl 36 Creatin > 3mg/dl 5 TGO 276 ( ) TGP 311 ( ) Total bilirubin 1 (0,4-4,49) Amilase 239 ( ) Leukopenia <3000 /mmc 1 Anemia <8 ghb/dl 31 Platelets count < mmc 9 TABLE 6.V Risk factors for death in PMP patients after HIPEC Factors Univariate analysis Cox regression (Log-Rank) p HR ( p Gender (Male vs Female) 0,03 NS Age ( > 52 vs 52) 0,8 - Preoperative chemotherapy (Yes vs 0,03 NS No) Histologic subtype ( DPAM vs <0,01 NS PMCA) Serum albumin ( 3,5mg/dl vs >3,5 <0,01 3,9 (1,45-10,49) <0,01 mg/dl) Ca 125 ( Ca125 >125U/ml vs 125 <0,01 4,56 (1,98-10,51) <0,01 U/ml CA 19.9 ( CA19.9 > 89U/ml vs 0,04 2,82 (1,17-6,71) 0,02 89 U/ml) ACE ( > 18ng/dl vs 18 ng/dl) 0,35 - Performance status ECOG (1-2 vs 0,03 NS 0) Charlson Index ( >3 vs 3) 0,30 - Preoperative platelets (> vs 0, ) Prior Surgical Score ( 2-3 vs 0-1) 0,75 - Peritoneal Cancer Index ( >20 vs <0,01 NS 20) No procedures ( >8 vs 8) 0,38 - Cytoreduction <0,01 8,15 (2,73-23,86) <0,01 (CC0-1 vs CC2-3) Postoperative morbidity (grade III-IV vs 0-II) 0,19 -

16 The following variables were proven to be independently associated with shorter PFS: charlson comorbidity index >4, preoperative systemic chemotherapy, incomplete cytoreduction, morbidity G3-5, and Ca125>125 U/ml. On the other hand, variables independently associated with shorter OS were as follows: ECOG performance status >2, serum preoperative albumin<3.5 g/dl, CC, Ca125>125U/ml, and Ca19-9>89U/ml. Neither the histological subtype nor the PCI>20 were proven to be independent predictors of survival. Despite presenting a reasonable discriminant power in predicting incomplete cytoreductive surgery others clinicopathlogic data are more important. On the other hand preoperative Ca125 and Ca19.9 were proven to be important oncological prognostic markers of poor prognosis in operated PMP patients. CHAPTER 7. Treatment of peritoneal carcinomatosis of gastro-intestinal origin a retrospective study on 203 cases 7.1. Introduction.Aim of the study Peritoneal carcinomatosis of gastrointestinal origin (PC-GI) is an advanced digestive tumor and is found in 10-30% of patients (P) with primary surgery for cancer (C) and up to 50% of C recurrences. Patients with peritoneal carcinomatosis of gastrointestinal origyn have a very poor prognosis. With systemic therapy the overall survival is limited to 3 to 9 months. New drugs improved the survival of colorectal patients to 22 monts. The aim of this studz is to evaluate the main characteristics, ethio-pathogenesis, prognosis and imaging to track of P with PC-GI admitted to the Third Surgical Clinic, "St. Spiridon" Hospital, Iaşi Material and methods A retrospective study was carried out on series of 203 patients admitted in the period June March The patients were aged between years (average 62), with a women/men ratio of 95/108. The duration of hospitalization was between 1 and 61 days, with an average of 13.5 days for emergency cases and 15 days for elective cases. The data from observation files, the operating protocols, pathology reports and follow-up files were collected and analyzed Results 136 patients were hospitalized with synchronous PC (the most common gastric N = 60) and 67 with metachronous PC (the most common colon N = 29). Imaging investigations consisted of ultrasound and computer tomography that showed a sensibility and specificity of 80% and 73% respectively, mainly in regard to ascites but less in assessing the presence of peritoneal deposits. The most common

17 complication was septic shock and mortality was 9.5% (17 patients). Average survival was 5.7 months. The ethiology of sincronous peritoneal carcinomatosis is summarised in TABLE 7.II TABLE 7.II Ethiology of syncronous carcinomatosis 136 patients with syncronous carcinomatosis Stomac 60 Colon 31 Right 14 Trasverse 4 Left 13 Pancreas 19 Head 5 Rectum 8 Esophagus 6 Duodenum 2 Liver 4 Billiary tree 7 Small bowell 1 Others 6 Body and tail 14 The ethiology os metacronous carcinomatosis is summarised in TABLE 7.III 53 patients with metacronous carcinomatosis were operated TABLE 7.III Ethiology of metacronous carcinomatosis 67 patients metacronous carcinomatosis Stomac 13 Colon 29 Right 10 Transverse 5 Left 14 Pancreas 7 Head 5 Rectum 8 Esophagus - Duodenum 3 Liver - Billiary tree - Others 7 Body and tail 2

18 7.4. Discussions Intraperitoneal normothermic chemotherapy was performed only in 5 patients 2 with right colon cancer with sincronous peritoneal carcinomatosis and 3 with metactonous carcinomatosis). One patient presented a transitory renal failure. Two patient were lost to follow-up and the other three survived between 6 to 9 months. Conclusion PC-GI is a disease with a poor prognosis, posing difficulties in early diagnosis, establishing the surgical indication and protocol. Consistent advances in systemic and locoregional chemotherapy, surgical techniques, intraoperative radiotherapy, as well as immunotherapy are expected to improve prognosis. CHAPTER 8. The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy 8.1.Introduction. Aim of the study Peritoneal mesothelioma is a rare disease with an incidence of 1-2 cases per million in western countries.70% of all mesotheliomas arises from pleura, 20-25% from peritoneum and in very rare cases the disease arises from pericardum or from tunica vaginalis testis. It is a disease with a poor prognosis- overall survival with systemic chemotherapy is one year [327]. There is no gold standard therapy for this disease. Best systemic chemotherapy includes cisplatin and doxorubicin. HIPEC has became in the last 30 years standard therapy for diffuse malignat mesothelioma with 5 years survival exceeding 50% [328]. Despite good results this aggresive method is still performed in only a few centers. High costs, high morbidity and mortality long learning curve are arguments for the centralisation of this procedure[329]. The aim of this study was to evaluate the effects of perioperative systemic chemotherapy on short-term surgical and long-term oncologic results in diffuse malignant peritoneal patients treated with HIPEC at National Cancer Institute of Milan Results There were 116 with diffuse malignant peritoneal mesotheliomapatients operated between February 1995 and October 2011, 60 males and 56 females. Main characteristics are summarized in TABLE 8.I. Main procedures during the intervention are summarized in TABLE 8.II

19 Fig. 8.2 Diffuse malignant mesothelioma. Peritoneal Cancer Index 36. Operative time 870 minutes. Collection of dr. Marcello Deraco TABLE 8.I. Clinicopathologic characteristics of DMPM patients Characteristics Age xx 58 (22-76) Sex (m\f) 60\56 BMI xx 24 (15-56) ECOG 0-1 vs >2 105\11 Hystological type epitelial \byphasic + sarcomatos 104\12 Albumin (g/dl) xx 4,03 (2,5-5,7) Total Proteins (g/dl) xx 7,2 (5,7-8,8) Preoperative platelets /mmc xx ( ) Hospitalisation xx 25 (9-110) Morbiditz grade III-V x 47 ( 40,5%) Mortality ( grade V) x 3 (2,5%) Follow-up (months) xx 39 (1-119)

20 TABLE 8.IV. Univariate and multivariate analysis of risk fators for severe morbidity and incomplete cytoreduction in patients operated for diffuse malignant peritoneal mesothelioma Factor Morbidity (Grade III-V) Optimal cytoreduction vs incomplete cytoreduction Univariate x Multivariate xx Univariat e x Multivariate xx p OR p p OR p Age 0,53 0,47 Sex 0,28 0,57 ECOG 0,03 5,29 (1,27-22,6) Charlson index (> 3 vs <4) Prior surgical score ( > 2 vs < 2) 0,9 0,7 0,02 <0,01 4,25 (1,03-17,47) 0,72 0,34 0,045 ( epiteliod vs biphazic/sarcomat os) Platelet preoperatice > Yes vs no Preoperative chemotherapy (da vs nu) Peritoneal cancer index > 20 (Yes vs No) Anastomosis (yes vs no) No. Procedures > 7 (Yes vs no) Optimal cytoreduction (Yes vs No) 0,71 0,07 NS 0,39 0,08 NS 0,41 0,14 0,06 NS 0,01 5,64 (1,45-21,89) 0,02 3,49 <0,01 0,87 (1,51-8,2) 0,01 4,25 <0,01 0,26 (1,43-12,6) 0,44 0,1 X chi-square test/ Fisher exact test xx - multivariate logistic regression

21 8.4.Discussions With the setting up of the division for peritoneal diseases at INT Milano, patients form all Italy have been examined and treated. After the finalizations of the investigations the patients are put on waiting lists. The waiting time is approximately 6 months. Some of them have received therapeutic schemes before arriving at INT and smaller percentage underwent chemotherapy between first medical evaluation and the surgical intervention time. The analysis of risk factors in the studied patient group for postoperative complications and incomplete cytoreduction reveals together with the disease extension through the peritoneum (Peritoneal Cancer index) the role of the ECOG performance status. The disease extension quantified by the peritoneal cancer index usually translates in patients with high values, a diffuse involvement of the peritoneal cavity, therefore the necessity of complex surgical gesture with the possibly of visceral multiple resection. Other important complications are the prolonged intraoperative time, intra and postoperative bleeding, fistula, due to intestinal serosa peritonectomy or due to the necessity of anastomosis creation after intestinal or colic resection. ECOG performance status role is most obvious for low performance status patients, which means limited organism resources and deficient nutritional status. On the studied group of patients preoperative chemotherapy did not influence the optimal cytoreduction possibilities and post operative morbidity. Unlike the ovarian cancer or the hepatic metastasis originating in colorectal cancer, where neoadjuvant chemotherapy might lead to diminishing tumor dimensions and therefore raise the cytoreduction possibilities, chemotherapy didn t influence the optimal treatment possibilities. One of the explanations might be the relative chemoresistence of PM.[336].

22 CHAPTER 9. Discussions and conclusions 9.1. Discussions The survival of cancer patients already found in the metastatic phase has been reported taking into consideration all types of metastasis. Therefore there is a lack of data regarding the survival of the peritoneal metastatic disease patients. Tumor biological variety and different evolutionary paths can lead to cerebral, hepatic, pulmonary, bone, retroperitoneal and quite frequent peritoneal metastasis. Due to ease of management the general therapeutic approach has been that of treating all these entities as metastatic disease. In reality all these locations can have a different impact over survival rate. The existence of 1 cm cerebral metastasis can significantly influence the patient survival, sometimes limited to only a few weeks in the absence of a surgical gesture. One, a few centimeters large, hepatic metastasis can evolve without any clinical symptoms for several years. Due to intestinal lumen proximity PC can also have an unforeseeable evolution. Occasionally a small singular nodule located on the small bowel serosa can cause serious complications, whereas sometimes patients can present multiple intraperitoneal nodules that do not concern the intestinal peritoneum. Apparently these do not generate transit changes and sometimes even the imagistic diagnosis is challenging. There is no standard treatment for PC. It is a disease with a poor prognosis and for a long time patients underwent treatment only for palliative purposes. Once new chemotherapeutic agents were introduced the ovarian and colorectal PC prognosis has been improved. In spite of a good initial response most patients present cancer recurrence and five year survival cases are extremely rare. The idea of bringing tumorous cells into contact with the chemotherapeutic agent had to undergo several stages before being accepted by most surgeons. The first data concerning the cytoreduction benefits in ovarian cancer drew interest for further research regarding the PC s biology and made possible the development of new techniques designed to achieve the maximum therapeutic benefits for patients [341]. Another goal of the conducted studies has been indentifying patients that could best benefit from surgical interventions. Few I and II phase and only one III phase study that were carried out according to Spratt intraperitoneal chemotherapy scheme in the case of a young patient with PMP have shown obvious benefits as far as survival and life quality in patients suffering from PC RC and PMP is concerned, using the complex procedure that includes both cytoreduction and HIPEC. Intraoperative chemotherapy initially normothermic and afterwards done hyperthermicly in association or not with postoperative intaperitoneal chemotherapy has become a complex multidisciplinary treatment method in PC. This change represents an alternative to systemic chemotherapy used with palliative purposes. Numerous retrospective studies have shown the advantages of the method for PMP, peritoneal malignant mezothelioma, primary peritoneal tumors. Unfortunately the complex treatment method has not yet been proven through prospective randomized or multicentric studies. The majority of the studies are in reference to

23 personal experience which is rarely constituted by more than 100 cases of operated patients. Furthermore most of them are not considered high reference points. Wervaal and col s [119] randomized prospective study is the only EBM first class study that has yet been published. Numerous systematic reviews [231,342] have shown the method s advantages in comparison to systemic chemotherapy associated with palliative surgical intervention. In the retrospective study Treatment of peritoneal carcinomatosis of gastrointestinal origin--a retrospective study of 203 cases (Rev Med Chir Soc Med Nat Iasi Jan-Mar;116(1):150-6 PMID: ) [343] conducted at III Surgical Clinic of Sf Spriridon Hospital Iaşi, data about morbidity and mortality has been assessed after the admission of 203 patients over a period of 5 years. There have been numerous problems in conducting the study. The patient lot has been heterogenic electively admitted patients or as emergencies with PC of different etiology but with GC and RC predominance with or without preoperative chemotherapy. The retrospective nature of the study didn t allow the evaluation of some clinical and epidemiological factors such as nutritional and performance status, postoperative complications in CTCAE classification and tumor markers. The relatively small patient lot with a heterogenic pathology has not permitted uni/multivariate analysis to identify the risk factors for postoperative complications. During hospitalization patients were not given life quality questionnaires. Also the postoperative follow up has not been done actively therefore data about life quality, undertaken chemotherapy and other possible surgeries, is missing. Patient or family compliance to the sent questionnaires and also the difficulties in the collaboration process with the Population Evidence Bureau have not allowed survival estimation with Kaplan Meier curve. Due to patient group heterogeneity and lacking data we could not make a comparison with the witness group. In the absence of a regional or national register for cancer patients and in the absence of a proactive systematic follow up, the retrospective recuperation of data was deficitary. One of the observations made after the study regarded the mortality during patient hospital admission which was rather high 9,5% and did not include 30 or 60 days mortality according to recommendations for accurately done estimations over postoperative mortality. One of the reasons for high mortality could be the specific of the department that has many emergencies cases. For occlusive RC and cephalic cancer the absence of minimally invasive palliative treatment through stent implantation has probably influenced the immediate survival of these patients. Many of these patients underwent surgery regardless of the performance status which may have lead to discrepancies between the high mortality rate and the reported rate for ample interventions such as HIPEC. The patient group cannot be compared to a witness group treated with intaperitoneal chemotherapy because of data inconsistency due to the small number of intraperitoneal chemotherapy conducted (5 patients).

24 During the time spent at the National Institute for Tumors in Milano as part as the Doctoral scholarship I have conducted several studies, most of them retrospective. The Circulating tumor markers: Predictors of incomplete cytoreduction and powerful determinants of outcome in pseudomyxoma peritonei. [344] (J Surg Oncol May 29. doi: /jso.23329) evaluates the role of the tumoral markers in the management of the patients that underwent surgery for PMP. There is little mentioning in medical literature of the tumoral markers in PMP. In 2007 Barrati and col. [345] published a retrospective study on a 62 patient group that underwent surgery at INT underlining the preoperative role of Ca125 in optimal cytoreduction possibility prediction and prognostic role of Ca In the present study there were included 156 patients with PMP treated at INT. With the help of ROC curve un useful instrument in evaluating the diagnosis capacity of a test we have established threshold limits of the main tumor markers CEA ca 125 and Ca19.9. The analysis on a larger group of patients highlighted the minor preoperative role of tumoral markers in the prediction of optimal cytoreduction possibility. The preoperative value of tumoral markers didn t significantly influence the tumoral cytoreduction possibilities. In the group of patients with optimal cytoreduction, a value of the Ca 125 and Ca 19.9 markers over the threshold limit represented a negative prognosis factor with a precocious apparition of tumoral recurrence and also a shorter survival rate. Even though the patient group is small and patient subgroups with histological different subtypes are small, the study shows the importance of tumoral markers in the oncologic prognosis of PMP patients operated by HIPEC. Even if some patients had an optimal cytoreduction they had tumoral recurrence and a continuously evolving disease. One of the possibilities for future research might be the role of neoadjuvant chemotherapy in patients with high levels of tumor markers at the moment of diagnosis. The study could not follow the tumoral markers dynamic through the pre and post operative period nor could it follow the impact of perioperative chemotherapy in these patients. Although MP is not a digestive disorder, this rare pathology is one of the HIPEC beneficiaries. The low incidence of the disorder in the Western countries is probably underrated due to the lack of diagnosis of all types of the disorder and to confusing it with other disorders whose starting point are the abdominal parts. Between 2003 and 2011, while I was working within the III Surgical Clinic of Sfantul Spiridon Hospital of Iasi only 2 MP patients have been diagnosed and treated. This slightly low number of patients treated in a surgical clinic with addressability from a region with more than 4 million people contradicts the incidence of the illness for our country. Considering that in real life a high number of MP patients receive an inaccurate diagnosis, I was interested in this pathology during my external traineeship with INT Milano. The department of peritoneum disorders within INT is a reference centre in Italy for this disorder and probably one of the first four centres in the world in terms of number of operated patients. In the research The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and

25 hyperthermic intraperitoneal chemotherapy (Ann Surg Oncol, 2013 Apr; 20(4): , two: /s x) [2013] on a batch of 150 operated patients I assessed the role of chemotherapy in MP patients subject to HIPEC. Considering that the role of perioperative chemotherapy has not been studied before, the research data, under the limitation caused by the low number of cases, showed a small impact of chemotherapy on the survival rate of the patients, but there was highlighted a survival rate of approximately 50% in patients with optimal cytoreduction. The low incidence of the disorder in general population, namely 1-2 cases in one million of inhabitants, should not be a counter-argument to the utility of setting up a HIPEC programme in Romania. At least in theory, this disorder has an incidence that equals those in the Western countries, where it is estimated that the incidence peak will be reached in In Romania, by dropping the use of asbestos materials later, the peak of this incidence will probably occur after this year. Between the period May 2012 and March 2013 in the I Surgical Clinic of the Regional Institute of Oncology Iasi 2 MP patients were operated. A 70-year-old patient was investigated for undetermined etiology ascites. The laparascopic examination diagnosis with biopsy of peritoneal nodules raised the suspicion of CP with digestive, maybe pancreatic starting point. Under the paliative treatment applied with Gemcitabina, the condition of the patient improved after 2 chemotherapy sessions. A re-assessment of the biopsy parts revealed suggestive aspects of peritoneal mesothelioma biphasic type. Three months after the surgery, the patient was undergoing systemic chemotherapy. Another patient, aged 56 years, operated in another service for a right retroperitoneal tumour with anatomopathologic examination suggested an extra digestive neuroendocrine tumour, under chemotherapeutic treatment, has been assessed in the I Clinic for a relapse retroperitoneal tumour. The patient was suggested for surgical intervention taking into consideration the tumour cytoreduction in order to facilitate the systemic chemotherapy. Due to the surgery, there were revealed a large retroperitoneal tumour that was making common block with the ascending colon and the last ileal ansa, as well as several peritoneal nodules located on the great epiploon and on the mesentery serosa. It was applied an expanded right hemicolectomy and an epiplonectomy, and the anatomopathologic examination revealed an epithelioid mesothelioma aspect with a low degree of differentiation. Four months after the surgery, the patient undergoes systemic chemotherapy. In the 6 th chapter of the paper there were investigated the post-surgery morbidity and mortality on the patients operated at the National Institute of Tumours in Milano for CP of CR and PMP etiology. Although there had been concerns in the CP treatment of gastric etiology, they were abandoned at the end of 2000 because of the unsatisfactory results of the operated patients. Intraperitoneal chemotherapy for gastric cancer should be reserved according to the opinion of the doctors responsible of experimental trials within INT. Another suggestion of the European research is that once CP occurs in a case of gastric cancer, chemotherapy would have limited benefits. Intraperitoneal chemotherapy should be practised when there are no peritoneal tumours, when there is no tumour residue, but patients have an increased risk of relapsing with localisation in the peritoneum only (T3, T4, N+ tumours).

26 The two types of pathologies included in the research are chiefly different. The PMP diagnosis is different from the CP CR one. On the other hand, within PMP there are also histological subtypes with different diagnoses PMCA has a reserved diagnosis similar to the CP CR one. The two entities were included in the research because the batches with CP CR or PMP patients were similar from point of view of the clinical-epidemiological features, the number of intra-operative procedures being similar in both cases. It would have been impossible to carry out a study only on the batch of patients with CP CR because of the low number of patients. Although it is a more complex intervention, the tumoral cytoreduction associated to intraperitoneal chemotherapy for the batch of patients from INT has not been followed in the postoperative period by increased morbidity or mortality. The data is comparable to the data available in literature for HIPEC [233, ], with severe morbidity of 23% and intrahospital mortality of 3.5%. The multi-varied analysis of the risk factors for the postoperative severe morbidity identified a factor related to the patient and to the physician that carries out the selection for the patient ECOG performance status, a factor that is related to the extension of the peritoneal affectation the number of performed enterectomies and a physician-related factor the dosage of the chemotherapy used. The performance status during the preoperative period is highly important since it probably reflects the duration of the illness evolution, functional reserves and the ability of the patient to recover during the postoperative period. It is arguable whether a patient who needs recovery in bed for more than 12 hours or a patient who is incapable of taking care of himself can be submitted to a large intervention. In relation to the number of anastomoses carried out it is obvious in every surgical intervention that every anastomosis with various localisations can increase the occurrence risk of the anastomotic fistula. There is not much data known about the role of chemotherapy applied intraoperatively on anastomoses. Research conducted on animals revealed a more difficult recovery of anastomoses under hyperthermia [348]. All anastomoses are carried out at INT before performing regular chemotherapy on the small intestine, generally mechanic suture in cases of ileotransverse, colocolical and colorectal or ileorectal anastomosis, with protective ileostomy in the last case. In the research The Importance of the Learning Curve and Surveillance of Surgical Performance in Peritoneal Surface Malignancy Programs (Surg Oncol Clin N Am, 2012 Oct; 21 (4):559-76, two: /j.soc ) [244] the assessment was retrospectively on the cases operated within the National Institute for Tumours in Milano between 1995 and The learning curve is a concept that appeared almost 30 years ago in medical practice and mainly refers to the stages necessary to reach expertise in a field when starting from scratch. It is a rough guide, but it has a subjectivity degree. It is hard to believe that a surgeon does only a certain type of surgeries in order to gain experience. While earning experience, the surgeon assists other colleagues as well or performs other interventions and thus he always makes progress. There are few studies related to the learning curve in cytoreductive surgery. Since in most retrospective cases the learning curve is assessed by dividing the batch into periods or sub-batches selected arbitrarily, there can be discrepancies between the capacity of the surgeon reflected on his position on the learning curve and the