Palliative management of malignant esophageal strictures with endoprosthesis implantation

Palliative management of malignant esophageal strictures with endoprosthesis implantation Theses Dr. Ákos Balázs Semmelweis University Doctoral School of Clinical Medicine Supervisor: Dr. Péter Kupcsulik Ph.D. Opponents: Dr. Pál Vadász Ph. D. Dr. Tibor Oláh Ph. D. Chairman of the Final Examination Committee: Dr. József Sándor Ph.D. Members of the Final Examination Committee: Dr. András Bálint Ph.D. Dr. György Bodoky Ph.D. Budapest 2009

1. INTRODUCTION The malignant esophageal strictures develop from the tumors of esophageal, respiratory and mediastinal malignances. The incidence rate of esophageal and respiratory tumors, which play a role in the development of the disease, show a growing rate in Hungary over the past decades. The malignant process infiltrating the esophageal wall starts causing dysphagia after it has spread throughout 2/3 of the circumference. On this account the recognition of the condition is often delayed. Patients are able to tolerate the embossed tumors to the esophagus from respiratory and mediastinal malignances for a long time. A great part of the patients is already in an inoperable state by the time of the first diagnosis because of which the importance of palliative interventions are outstanding. Between the treatments with palliative aim is the palliative resection, bypass surgery, diversion-exclusion operations, irradiation, chemotherapy, surgery that enables implementation of supportive nutrition, and implantation of endoprosthesis. The goal of the palliation is to restore the patient`s swallowing ability, in case of esophago-respiratory fistulas sealing of the pathological communication. Resulting of this management improve the survival period and quality of life. 2. OBJECTIVES The aim of this study is to examine the methods of endoprosthesis implantings from the aspect of their applicability in cases of patients with malignant esophageal strictures in palliative management. 1. I intended to examine the change of the characteristics that influenced the palliative treatment of patients with malignant esophageal strictures at the 1 st Department of Surgery of the 2

Semmelweis University, in the period of time between 1984 and 2004. 2. I planned to examine the applicability of the method of implantation of the endoprosthesis according to the criteria of: possibility of successful execution solvability of the problems regarding swallowing acceptable measures of the forms and the number of complications manageability of the complications possibility of prevention of complications the improvement of the life quality of the patients that received the prosthesis the improvement of the survival-rate indicators of the patients treated successfully 3. I aimed to determine the place of the implantation of the endoprosthesis in the system of the palliative treatments. 4. My goal was to exactly determine the indications and contraindications. 5. The objective of the study was also to determine the factors that influence successfulness. 3. METHODS 3.1. The methods of statistical analysis I have supplemented the data of the prospective registration available between 1984 and 2004 with retrospective data collection. I have conducted the analysis using the SPSS 15.0 program (SPSS Inc., Chicago, IL., USA). I have evaluated the resulting data and averages numerically, and according to percentage, mean, range, standard deviation (SD), 95% confidence interval (CI). In the case of the patient group with esophago-respiratory fistulas originating from an esophageal tumor, I have conducted the comparison of the continous variables in pairs by Student t-tests and one way variance 3

analysis (Oneway ANOVA). The comparison of the non continuous quantitative variables was done according to the method of cross table analysis (Pearson Chi-Square test). I have evaluated the correlation by linear regression analysis. I have determined the frequency spread of the data of the patient group with esophageal tumors causing esophago-respiratory fistulas with the help of the histogram. The inhomogenity of the distribution of variables in the fistula group was examined using cluster analysis with the Ward method and then the values of the two segments were compared. I have compared the survival rates (uncensored data) with the Cochran, Mantel-Haenszel log rank test, and have determined a value of significance of p<0,05. All the p results are two sided. 3.2. Methods of treatment 3.2.1. Methods of implanting endoprosthesis by surgical procedure The surgical implantation was executed under general anesthesia. After the upper median or paramedian laparotomy, we performed a gastrostomy on the upper third of the stomach corpus. Through this we inserted a guide-wire until we reached the strictured tract of the esophagus where the tumor was. After this we dilatated the narrowed lumen with a series of probes pulled through the guide-wire. We attached a string to the guide wire as it reaches the oral cavity and we pulled the prosthesis attached to this string into the area that was strictured because of the tumor. The progress of the prosthesis and it s suitable position was controlled by X-ray equipment. After this we closed the gastrostomy in two layers and the incision on the abdomen. 4

3.2.2. Method of endoscopic esophageal intubation The endoscopic prosthesis implant was carried out after premedication according to need, whilw the patient was awakw. In the process, first we pin pointed the location of the stricture and marked it with a signal that provides an x-ray shadow (metal plate placed on the chest wall), then we pulled a guide- wire through the stricture. Dilatation was carried out in the needful measurement of the affected area by implementing either a Eder-Puestow (Keymed House Southend on sea, England) or a Savary-Gilliard (Wilson-Cook Medical Inc. Winston-Salem,USA) tools, with the help of a guide-wire. After this we inserted the prosthesis into place using either a rigid Storz-endoscope or a Savary-Gillard introducer. In case of self-expanding stents there was often no need for further widening. The whole procedure was performed under constant x-ray picture enhancer monitoring. The follow up of the prothesis s position and incidental complications were carried out using swallowing X-ray examination with absorbeable contrast material. 3.2.3. Method of endoscopic intubation in operative situation In case of irresecable conditions whilst surgically exploring the tumor (laparotomy, thoracotomy, collaris mediastinotomy, laparoscopic exploration) if the level of dysphagia makes the implantation of endoprosthesis necessary we performed the procedure according to the method listed at the endoscopic procedure. 5

3.3. Interventions During the time interval examined, from the 2092 esophagus strictures caused by malignant tumors (1996 tumors of the esophagus, 71 tracheobronchiatic and 25 mediastinal tumors) 1604 patients were inoperable. In 1292 cases, the cause of implementation of endoprosthesis was dysphagia as a consequence of the strictures. The presence of esophagorespiratory fistulas made the implantation of an endoprosthesis necessary in 234 cases. The procedures were performed surgically 41 times, but in 824 cases the endoscopic method was used. In 133 cases the implantation was combined with irradiation therapy and in 56 instances with chemotherapy. In 3 cases respiratory tract stents were implanted, and 2 patients had undertaken laser recanalization. 127 patients received probes that enabled feeding the patient (gastrostomy in 146, PEG in 15, and jejunostomy in 8 cases).- 612 patients received only conservative supportive treatments. 4. RESULTS From the 1526 cases that needed palliation the implantation of an endoprosthesis was performed successfully in 865 patients, and has resulted in immediate and permanent disappearance of nutritional disorders in case of 768 patients. Because of untreatable complications the success of the procedure was temporarily in 73 cases. In 29.1% of the procedures performed there were complications like: migration of the prosthesis (117 cases 12.4%), perforation (7 cases 0.7%), hemorrhage (17 cases 1.8%), respiratory compression syndrome (7 cases 0.7%), early unexpected death (21 cases 2.2%), food bolus impactation (12 cases 1.3%), tumor overgrowth and ingrowth (29 cases 3.1%), fistula formation and neoformation (8 cases 0.7%), aspiration (5 cases 0.5%), reflux (28 cases 3.2%). The procedure related complications was 9,1%. Lethal 6

complications occurred in 2.8% of all cases. The percentage of complications in surgically implanted prosthetic devices was 21.9%. The average survival time of patients who received a prosthesis was 5.4 (0-60) months. The survival time of patients treated with gastrostomy, percutan endoscopic gastrostomy, jejunostomy, enabling them to feed was 3,6 (0-36) months. The survival time of patients that received only conservative supportive treatment was 3.2 (0-25) months. The difference between the survival of the group that received a prosthesis and the other two groups in which patients had not received one, is significant. The difference between the life expectancy of the two groups that had not received a prosthesis is not significant. 5. CONCLUSIONS 5.1. The characteristics of the patients treated of the malignant esophageal stricture 1. The number of patients that suffered from malignant strictures of the esophagus almost doubled between 1984 and 2004. 2. The relative percentage of women grew in between the patients. 3. The percentage of adenocarciomas compared to cases of squamos cell carcinomas has not grown in spite of the global statistic trends. 4. 66,3% of the esophago-respiratory fistulas in patients suffering from esophageal tumors, had end stage characteristics, and 33,7% was the result of a fast progressing aggressive tumor. 5. The majority of the patients were in a late stage of their illness. 50.7% was in 7-8-9 stage of Karnofsky performans index, 35% was in T3 and 61.6% in T4 clinical TNM 7

classification, 87.7% was in the III-IV stage of AJCC classification. 5.2 The observations concerning the applicability of the implantation an endoprosthesis 1. The implantation of the endoprosthesis was possible in 56.7% of cases of necessary palliation. 8 % was unsuccessful. 2. The implantation of the endoprosthesis solved all the swallowing problems definitivly in 88.8% of all cases, in 8.4% of all cases it proved to be a temporary solution. The score of dysphagia lowered from 1,93 to 0,38. 3. The occurrences of complications were limited to 29,1% of all cases, of these 2,8% were fatal. 57.9% of all complications could have been solved by endoscopic reintervention. 4. The number of complications can be limited by concentrating on the indications and contraindications, by evaluating the morphologic anomalies, and thus by choosing the adequate tactic whilst implanting the prosthesis. 5. After implanting the prosthesis the life quality of the patients became acceptable compared to the circumstances. 6. The survival time of the patients was significantly longer than of the patients that had not received such a prosthetic treatment. In conclusion of all of the above it can be said that the implantation of an endoprosthesis in successful cases can meet all the expectations of palliation in strictures of the esophagus caused by tumors. 5.3. Conclusions regarding the method of implanting the endoprosthesis 1. The endoscopic technique of implantation has overshadowed the surgical method but it has not made it obsolete. 8

2. The endoscopic method of implanting the endoprosthesis is technically simple, tolerable for the patients and can be applied with a small chance of complications. 3. The endoscopic method can be applied in short term medical attendance or in outpatient treatment cost effectively. 5.4. Conclusions regarding the indications of endoprosthesis implantation 1. The implantation of an endoprosthesis is indicated in cases of malignant strictures of the esophagus in which the dysphagia prevents the patient to consume mashy or fluid consistence food and is also indicated in cases of esophago respiratory fistulas. 2. The treatment is contraindicated in cases that carry the danger of complications. It is also contraindicated with patients that have a serious cardiac- or pulmonary condition where the expected benefit is outweighed by the foreseeable complications of the procedure. 3. The implantation of the prosthesis can be relatively contraindicated if the patient refuses to collaborate. 4. The prosthesis might not be implantable at the upper entry tract of the esophagus in cases of strictures that emerged too high and have approached the line of the musculus chiropharingeus with less than 2cm, and in cases when the stricture affects the cardia in which cases the wall of the stomach can dislocate the implanted prosthesis. 5.5. The influencing factors of the effectiveness of endoprosthesis implantation 1. The radio-morphological characteristics of the stricture greatly determine the success of the implantation. Knowledge and suitable assessment of these have fundamental importance. 9

2. The selection of the type and size of prosthesis that is to be implemented, the selection of the implantation method are key factors in the success of the procedure. 10

6. PUBLICATIONS 6.1. Thesis-related publications Kupcsulik P.,Balázs Á.,Miklós I.,Kokas P.: Inoperabilis nyelőcsődaganatok palliativ kezelése endoskópos tubuslevezetéssel. Magyar Onkológia 1990,34,3:155-164 Kupcsulik P.,Balázs Á.,Vigváry Z.,Miklós I.: Endoscopos tubuslevezetés és intracavitalis irradiatio inoperabilis nyelőcsődaganatok palliativ kezelésére. Orvosi Hetilap 1991,132,7:347-353 Kupcsulik P.,Miklós I.,Balázs Á.,Kokas P.: New method for ambulatory intubation of nonresectable esophageal tumours.experience in 247 consecutive cases. Ambulatory Surgery 1993,1,3:141-145 Balázs Á.,Kupcsulik P.,Vigváry Z.,Miklós I.,Forgács A.,Kokas P.: Intraluminalis after-loading radioterápiás (IALR) módszer nyelőcsőtumorok kezelésére. Magyar Sebészet 1994,47,3:135-148 Balázs Á.,Kupcsulik P.,Vigváry Z.,Miklós I., Kokas P., Forgács A.: Preoperativ intraluminalis after-loading radioterápia (IALR) eredményei nyelőcsőtumorok kezelésében. Magyar.Sebészet 1997,50,3:137-142 Balázs Á.,Kupcsulik P.,Vigváry Z.,Miklós I.,Kokas P.,Forgács A.: Palliativ intraluminalis after-loading radioterápia (IALR) eredményei nyelőcsőtumorok kezelésében. Magyar Sebészet 1997,50,2:71-75 11

Balázs Á.,Kupcsulik P.,Vigváry Z.,Mikós I.,Kokas P.,Forgács A.: Posztoperativ intraluminalis after-loading radioterápia (IALR) eredményei nyelőcső és cardia tumorok kezelésében. Magyar Sebészet 1998,51,1:11-16 Balázs Á.,Kokas P.,Miklós I.,Kupcsulik P.: Nyelőcsőtumoros betegek klinikánk szakambulanciáján. Orvosi Hetilap 2004,145,6:267 276 Balázs Á.,Galambos Z.,Kupcsulik P.: Tumoros eredetű oesophago-respiratorikus fisztulák. Magyar Sebészet 2005,58,5:297 304 Balázs Á.,Kupcsulik P K.,Galambos Z.: Nyelőcsőtumoreredetű oesophago-respiratoricus fistulák kórtani jellemzői. Magyar Onkológia 2008,52,2:163 170 Balázs Á.,Kupcsulik P K.,Galambos Z.: Esophago-respiratory fistulas of tumorous origin. Non-operative management of 264 cases in a 20-year period. European Journal of Cardio- Thoracic Surgery 2008,34,5:1103 1107 IF:2,011 Balázs Á.,Lukovich P.,Kokas P.,Kupcsulik P.: A nyelőcső stenosisát okozó inoperabilis légúti tumorok palliatív kezeléséről. Medicina Thoracalis 2008,61,6:299 306 Balázs Á.,Galambos Z.,Kupcsulik P K.: Characteristics of esophago-respiratory fistulas resulting from esophageal cancers. A single-center study on 243 cases in a 20-year period. World Journal of Surgery 2009,33,5:994-1001 IF:1,778 12

Balázs Á.,Kupcsulik P,K.,Galambos Z.: Reply to Lajos Kotsis (Reply to the Letter to the Editor) European Journal of Cardio- Thoracic Surgery 2009,36,1:226 Summarized impact factor: 3,789 6.2. Thesis-related abstracts Kupcsulik P.,Balázs Á.,Miklós I.: Complex Palliativ Treatment of Esophageal Tumors. Hepato-gastroenterology 1989,36,4:303 IF : 1.00 Miklós I.,Kupcsulik P.,Balázs Á.,Kokas P. : Ambulant Endoscopic intubation of tumors causing esophageal stenoses. Zeitschrifft für Gastroenterologie 1991,29,5:194 IF : 0,538 Miklós I.,Kupcsulik P., Kokas P.,Balázs Á.,Márton E.,Poller I.: The complex palliative treatment of patients with nonoperable oesophagus tumor. Zeitschrifft für Gastroenterologie 1992,30,5:294 IF : 0,681 Balázs Á.,Kupcsulik P.,Vigváry Z.,Miklós I.,Kokas P., Forgács A.: Preoperative Intraluminal Radiotherapy of Esophageal Cancer. Zeitschrifft für Gastroenterologie 1996,34,5:302 IF : 0,958 Vigváry Z.,Tarján Zs.,Makó E.,Haj H.,Kupcsulik P.,Balázs Á.: Long Term Experiences with LDR After-loading Irradiation of Esophageal Tumors Zeitschrifft für Gastroenterologie 1997,35,5:412 IF : 1,021 13

Vigváry Z.,Makó E.,Tarján Zs.,Kupcsulik P.,Faller J.,Balázs Á.: Long term results with pre-, postoperative and palliative LDR after-loading irradiation of esophageal tumours. Br.J.Surg. 1998,85,Suppl 2:185 IF : 2,381 Balázs Á.,Kokas P.,Galambos Z.,Kupcsulik P.: Esophagorespiratory fistulas of tumorous origine Zeitschrift für Gastroenterologie 2001,39,5:382 IF : 0,803 Schiszler T.,Tarján Zs.,Kiss K.,Vighváry Z.,Balázs Á.,Makó E.: Oesophageal stent implantation: role of radiological examination European Radiology 2002,Suppl.1,12:366 IF : 1,37 Balázs Á.,Kokas P.,Miklós I.,Lukovich P.,Kupcsulik P.: Problems of the management of the esophageal cancer in our outpatient service Zeitschrift für Gastroenterologie 2003,41,5:430 IF :1,076 Lukovich P.,Kupcsulik P.,Balázs Á.,Kokas P.,Frank E.: Therapy of anastomotic leak and its complications after exstirpation of the oeseophagus. Zeitschrift für Gastroenterologie 2005,43,6:500 IF :0,800 Summarized impact factor of abstracts: 10,627 14

6.3. Thesis-related citable abstracts in Hungarian reviews Balázs Á.,Kupcsulik P.,Miklós I.,Flautner L.,Kiss K.: Endoscopos tubusbeültetés nyelőcsőrtumoros betegek palliativ kezelésére. VIDEOFILM Magyar Onkológia 1997,41,4:283 Balázs Á.,Kupcsulik P.,Kokas P.,Miklós I.,Forgács A., Márton E.: Tumoros eredetü oesophago-respiratórikus fistulák kezelése endoscopos tubusbeültetéssel ( Videófilm) Magyar Sebészet 1998,51,3:177 Schisler T.,Magyar Cs.,Balázs Á.,Kiss K.,Karlinger K.,Makó E.: A radiológiai vizsgálat szerepe a nyelőcső endoprothesis behelyezés indikációjában Magyar Radiológia Supplementum 2000,1:160 Szűcs O.,Galambos Z.,Balázs Á.,Kupcsulik P.: Az operabilitás egyes kérdései a nyelőcső tumoros betegeknél Magyar Sebészet 2002,55,3:124 Lukovich P.,Kupcsulik P.,Balázs Á.,Kokas P.,Farkas Sz.,Tóth A.,Udud K.: Malignus tumorok okozta nyelésképtelenség miatt végzett endoscopos- radiológiai minimálisan invasiv beavatkozások. Magyar Onkológia 2004,48,Suppl.1:6 Galambos Z.,Balázs Á.,Kupcsulik P.: Malignus nyelőcsőtumorok epidemiológiai változásai az elmúlt két évtizedben Magyarországon. Magyar Sebészet 2006,59,4:232 Balázs Á.,Galambos Z.,Lukovich P.,Kupcsulik P.: Nyelőcsőtumoros eredetű oesophago-respiratorikus fisztulák kórtana. Magyar Sebészet 2008,61,3:147 15

6.4. Other publications Balázs Á.,Pulay I.,Faller J.: Acut pancreatitis szövődményeként kialakult transitorikus vakság esete. Magyar Sebészet 1985,38,3:182-186 Balázs Á.,Forgács A.,Flautner L.,Kupcsulik P.: Colon transversum mellkasi herniatiójának esete transhiatalis oesophagektomia ritka szövődményeként. Orvosi Hetilap 1997,138,40:2535-2538 Kupcsulik P.,Flautner L.,Pinkola K.,Darvas K.,Balázs Á., Winternitz T.: Májdaganatok sebészete Magyar Sebészet 1998,51,6:325-329 Balázs Á.,Lukovich P.,Flautner L.: A femoralis regióra terjedő retroperitonealis pancreatogen abscessus. Orvosi Hetilap 2000,141,5:241-264 16