Cytoreductive Surgery for Peritoneal Carcinomatosis from Endometrial Cancer - A Case Report and Literature Review

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1 : Copyright Celsius Case Report Cytoreductive Surgery for Peritoneal Carcinomatosis from Endometrial Cancer - A Case Report and Literature Review N. Bacalbaæa 1, C. Anghel 2, I. Barbu 2, I. Dudus 2, M.I. Ionescu 2, M. Pautov 2, M. Motthor 2, Irina Bãlescu 3, V. Braæoveanu 2,4 1 Carol Davila University of Medicine and Pharmacy Bucharest, Romania 2 Dan Setlacec Department of General Surgery and Liver Transplantation Fundeni Clinical Institute, Bucharest, Romania 3 Ponderas Hospital, Bucharest, Romania 4 Titu Maiorescu University, Faculty of Medicine, Bucharest, Romania REZUMAT Citoreducåie chirurgicalã pentru carcinomatoza peritonealã din cancerul endometrial - prezentare de caz æi revizia literaturii Neoplasmul de endometru reprezintã una din cele mai fercvente malignitati ale tractului genital feminin, prezentând incidenåã în creætere mai ales din cauza cresterii numarului de persoane supraponderale. În timp ce cazurile diagnosticate æi operate în stadii precoce ale bolii au evoluåie favorabilã, lucrurile stau cu totul altfel în cazurile diagnosticate în stadii avansate. În orice caz, pacientele care prezintã diseminãri peritoneale la momentul diagnosticului beneficiazã de un abord chirurgical agresiv, similar cu cel practicat în neoplasmul ovarian avansat. Prezentãm cazul unei paciente de 67 ani diagnosticatã cu carcinomatozã peritonealã de origine endometrialã la care principiile chirurgiei citoreductive au fost aplicate cu success. Cuvinte cheie: neoplasm endometrial, carcinomatozã peritonealã, citoreducåie ABSTRACT Endometrial cancer is one of the most common malignancies of the female reproductive tract, with increasing incidence particularly due to the increase proportion of the overweight persons. While cases diagnosed in an early stage of the disease report an excellent outcome, things significantly change when it comes to advanced stages. However it seems that women who already present peritoneal seeding at the moment of diagnosis benefit most from an aggressive surgical approach, similar to the one performed in advanced stage ovarian cancer. We present the case of a 67 year old patient diagnosed with peritoneal carcinomatosis from endometrial cancer in which the principles of cytoreductive surgery were successfully applied. Key words: endometrial cancer, peritoneal carcinomatosis, cytoreductive surgery Corresponding author: Nicolae Bacalbaæa, MD Dimitrie Racoviåã Street, no. 2, Bucharest, Romania nicolae_bacalbasa@yahoo.ro

Cytoreductive Surgery for Peritoneal Carcinomatosis from Endometrial Cancer 173 INTRODUCTION Endometrial cancer is one of the most common malignancies of the genital tract in women, with an

The most important prognostic factors are thought to be diabetes, estrogen secreting tumors, nulliparity and the higher number of overweight persons (2).

have a poor prognosis associated with low rates of survival - 67% and 23%, respectively, for cases with regional or distant disease (3).

2 Cytoreductive Surgery for Peritoneal Carcinomatosis from Endometrial Cancer 173 INTRODUCTION Endometrial cancer is one of the most common malignancies of the genital tract in women, with an increasing incidence in the last few years. The reported incidence in the United States surpassed cases/year while the death rate reached almost 7500 deaths/year (1,2). The most important prognostic factors are thought to be diabetes, estrogen secreting tumors, nulliparity and the higher number of overweight persons (2). While up to 70% of patients are diagnosed in an early stage of the disease and report an excellent outcome (5 year overall survival of 90%), patients diagnosed in an advanced stage of the disease have a poor prognosis associated with low rates of survival - 67% and 23%, respectively, for cases with regional or distant disease (3). However, in these cases it seems that an aggressive surgical approach similar to the one performed in advanced ovarian cancer is perfectly justified (2,4). Figure 1. Initial aspect disseminated peritoneal tumors associated with an uterine tumor CASE REPORT A 67 year old, nulligesta, nullipara, obese patient presented for abdominal and pelvic diffuse pain associated with vaginal bleeding. Local examination revealed the presence of a distended slightly painful abdomen, with no palpable tumor mass. A bioptic uterine curettage was performed and the histopathological findings revealed a poorly differentiated endometrial adenocarcinoma. Abdomino-pelvic computed tomography revealed the presence of disseminated tumor masses all over the peritoneal surface. The patient was submitted to surgery; intraoperatively a large uterine tumor and diffuse peritoneal carcinomatosis were found, so the patient was operated according to the principles of ovarian cytoreductive surgery. A radical total hysterectomy en bloc with bilateral adnexectomy, total omentectomy, total colectomy, pelvic and parietal peritonectomy, pelvic and lymph node dissection were performed (Fig. 1-9). The histopathological findings confirmed the presence of a poorly differentiated endometrial adenocarcinoma. DISCUSSIONS The efficacy of debulking surgery and minimal residual disease after cytoreductive surgery in ovarian cancer encouraged the surgeons to apply the Figure 2. Cmplete mobilization of the uterine body Figure 3. Tumoral nodules involving the mesosigmoid same principles in other advanced abdominal malignancies in order to obtain a better outcome in

3 174 N. Bacalbasa et al Figure 4. Tumoral nodules involving the transverse mesocolon Figure 5. Performing parietal peritonectomy Figure 6. The final aspect after resection, pelvic and para-aortic lymph node dissection Figure 7. Parietal peritonectomy Figure 9. The specimens: total hysterectomy with bilateral adnexectomy, total colectomy and total omentectomy Figure 8. The final aspect of the pelvic cavity after resection

4 Cytoreductive Surgery for Peritoneal Carcinomatosis from Endometrial Cancer 175 terms of survival. Several studies demonstrated the efficacy of cytoreductive surgery associated with other therapeutic strategies such as hypertermic intraperitoneal chemotherapy (HIPEC) in colon cancer and endometrial cancer (2, 4-6). Delotte et al included in their study 13 patients diagnosed with advanced stage endometrial cancer with peritoneal disseminations who were submitted to complete resection and HIPEC. During cytoreductive surgery, an average of 2 organs were resected, the most frequently performed resections being bowel resection, atypical hepatectomies, splenectomies, partial cystectomy or partial frenectomy. They reported a disease free survival of 11,4 months and a median overall survival of 19,4 months. An important conclusion of this study was that association of HIPEC was able to offer a significant increase of survival when compared to cytoreduction alone (19,4 months vs. 12 months) (2). Some other studies also consider that aggressive cytoreduction remains the most important prognostic factor related to an increased overall survival, while other authors consider that the evolution of these cases in strongly correlated to histopathological features and to the initial extent of the disease (7,8). Bakrin et al reported a case series of 5 patients with advanced endometrial cancer with peritoneal carcinomatosis treated by the same principles and reported improved outcomes: 2 patients were free of disease after 2 and 3 years while the other 2 patients were living with recurrence after 1 and 3 years (4). Abu Zaid et al included in their study 6 patients diagnosed with advanced stage endometrial cancer who were treated by cytoreductive surgery and HIPEC from November 2010 to August Cytoreductive surgery consisted of peritonectomy and visceral resections in order to provide a complete elimination of the tumor masses from the abdomino-pelvic Cavity while HIPEC was performed with Cisplatin and Doxorubicin at 41 to 42,2 C for 90 minutes. Postoperatively all patients were submitted to systemic chemotherapy based on carboplatin and paclitaxel regimens. Two cases developed recurrent disease during the next 6 months, one of them being dead because of the disease 5 months after surgery, while the other 4 patients were alive and free of any recurrence at 7,34,35 and 19 months (9). There are authors who consider that endometrial cancer consist in fact of two different tumor types: type 1 endometrial cancer has a primary lymphatic spread by pelvic lymph nodes especially obturatory fossa lymph nodes and only secondarily to iliac lymph nodes, while type 2 has a peritoneal pattern of spread (10). According to these two different patterns of spread, studies have shown that for type 1 stage IV endometrial cancer complete debulking can be achieved only in 44-72% and only patients with good biological status should be candidates for this surgical approach (11,12,13). Bristow et al conducted a study on 65 patients diagnosed with advanced endometrial cancer who were submitted to surgery between January 1990 and December Complete R0 cyotreduction was defined as the absence of residual disease larger than 1 cm; they demonstrated that the overall survival was significantly higher in cases submitted to R0 resection (34,3 months) when compared to those with >1 cm residual disease (11 months, p=0,0001). Other factors associated with improved outcomes were higher performance status, age under 58 years, adjuvant chemo-irradiation. On multivariate analysis age (p=0,023), performance status (p=0,043) and residual disease (p=0,0001) were independent predictors of survival (13). When it comes to patients in whom type 2 stage IV endometrial cancer is encountered, it seems that this subtype resembles most with advanced ovarian cancer and its propagation via transperitoneal route; in consequence, these patients should benefit most from an aggressive surgical approach similar with debulking surgery in advanced stage ovarian cancer (14-21). In order to increase the rate of complete cytoreduction some authors recommended the administration of 3 cycles of neo-adjuvant chemotherapy (22); however patients who report a poor response to neoadjuvant treatment might also not benefit from cytoreductive surgery too (23). When it comes to association of adjuvant treatments such as radiotherapy, studies have shown that it might be useful in the postoperative course. Administrated pre-operatively, radiation therapy seems to interfere with the adequate tumor staging without improving the outcomes (23,24). In order to increase the overall survival, adjuvant chemotherapy can be associated; most authors sustain the association of taxanes- platinum salts regimens (25-27). Randall et al included in their study 388 patients diagnosed with stage IV endometrial cancer who were submitted first to cytoreductive surgery (with maximum residual disease < 2 cm); after surgery, the patients were randomly assigned to doxorubicin and cisplatin chemotherapy for seven courses or

5 176 N. Bacalbasa et al whole-abdominal radiotherapy with 30 Gy in 20 fractions and a pelvic boost of 15 Gy. Although the recurrence rate was similar (55%) in the pelvis and abdomen in both groups, 2-year progression-free survival was better with chemotherapy (59% vs 46%) as was the overall survival (70% vs 59%; p_0 01) (27). However, the largest meta-analysis conducted on the subject of advanced stage endometrial cancer and recurrent endometrial cancer, performed by Barlin et al on 14 studies came to demonstrate that improved survival was positively associated with complete surgical cytoreduction (each 10% increase improved survival by 9.3 months, p = 0.04) and receiving postoperative radiation therapy (each 10% increase improved survival by 11.0 months, p= 0.004); the same meta-analysis concluded that an increasing proportion of patients receiving chemotherapy was negatively associated with survival (each 10% increase decreasing survival by 10.4 months, p= 0.007) (28). CONCLUSIONS The most appropriate therapeutic protocol in advanced endometrial cancer is not well established due to the paucity of data and due to the limited number of patients included in the studies published on this topic so far. However, almost all studies come to sustain the benefit of cytoreductive surgery as part of an aggressive surgical approach; similarly to advanced ovarian cancer, in advanced endometrial cancer one of the most important prognostic factors is the absence of macroscopic residual disease at the end of resection. Other therapies such as HIPEC seem to improve the outcomes without increasing the early postoperative morbidity and mortality. Association of adjuvant chemo-irradiation might also play a role but further studies are still needed. REFERENCES 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics. 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Hyperthermic intraperitoneal chemotherapy using oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective multicentre trial. CHIPOVAC study. Eur J Surg Oncol 2010;36: [5] 7. Tanioka M, Katsumata N, Sasajima Y, et al. Clinical characteristics and outcomes of women with stage IV endometrial cancer. Med Oncol 2010; 27: Einstein MH, Rice LW. Current surgical management of endometrial cancer. Hematol Oncol Clin North Am 2012;26: Abu-Zaid A, Azzam AZ, AlOmar O, Salem H, Amin T, Al-Badawi IA, Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for managing peritoneal carcinomatosisfrom endometrial carcinoma: a single-center experience of 6 cases, Ann Saudi Med Mar-Apr;34(2): doi: / Benedetti-Panici P, Maneschi F, Cutillo G, et al. Anatomical and pathological study of retroperitoneal nodes in endometrial cancer. Int J Gynecol Cancer 1998; 8: Goff B, Goodman A, Muntz H, et al. 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Is there a role for neoadjuvant chemotherapy in the treatment of stage IV uterine papillary serous carcinoma? Int J Gynecol Cancer (in press). 23. Amant, F., Moerman, P., Neven, P., Timmerman, D., Van Limbergen, E., Vergote, I., Endometrial cancer, com Vol 366 August 6, Einhorn N, Trope C, Ridderheim M, Boman K, Sorbe B, Cavallin Stahl E. A systematic overview of radiation therapy effects in uterine cancer (corpus uteri). Acta Oncol 2003; 42: Fleming G, Brunetto V, Cella D. et al. Phase III trial of doxorubicin plun cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2004; 22: Hoskins P, Swenerton K, Pike J, Wong F, Acquino-Parsons C, Lee N. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 2001; 19: Randall ME, Brunetto G, Muss HB, et al. Whole abdominal radiotherapy versus combination doxorubicin-cisplatin chemotherapy in advanced endometrial carcinoma: a randomized phase III trial of the Gynecologic Oncology Group. Proc Am Soc Clin Oncol 2003; 22: Barlin, J., Puri, I., Bristow, R. Cytoreductive surgery for advanced or recurrent endometrial cancer: A meta-analysis; Gynecologic Oncology 118 (2010) 14 18

Prof. Dr. Aydın ÖZSARAN

Prof. Dr. Aydın ÖZSARAN Adenocarcinomas of the endometrium Most common gynecologic malignancy in developed countries Second most common in developing countries. Adenocarcinomas, grade 1 and 2 endometrioid