European Journal of Obstetrics & Gynecology and Reproductive Biology 172 (2014) 111–114

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Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of endometrial cancer with peritoneal carcinomatosis Je´roˆme Delotte a, Mariangela Desantis b, Me´lanie Frigenza a, Delphine Quaranta a, Andre´ Bongain a, Daniel Benchimol b, Jean Marc Bereder b,* a

Service de gyne´cologie-obste´trique, reproduction et de me´decine foetale, Centre hospitalier universitaire de l’Archet II, Universite´ de Nice-Sophia Antipolis, 151, route St Antoine de Ginestie`re, 06200 Nice, France b Service de chirurgie ge´ne´rale et cance´rologie digestive, Centre hospitalier universitaire de l’Archet II, Universite´ de Nice-Sophia Antipolis, 151, route St Antoine de Ginestie`re, 06200 Nice, France

A R T I C L E I N F O

A B S T R A C T

Article history: Received 8 June 2013 Received in revised form 6 October 2013 Accepted 26 October 2013

Objective: To investigate the benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of endometrial peritoneal carcinomatosis. Study design: Preoperative, intraoperative and postoperative data were collected prospectively for 13 patients treated in our University hospital. Results: Of the thirteen patients treated, one patient was lost to follow up. Three patients died within the first twelve months of treatment, and two patients died at respectively 12.4 and 19.4 months after the HIPEC procedure. Seven patients are alive, four of them without recurrence, between 1.5 and 124.8 months after surgery. The Peritoneal Cancer Index (PCI) and the Completeness of Cytoreduction-Score (CC-S) are prognostic factors for survival after HIPEC treatment for peritoneal carcinomatosis of endometrial origin. Conclusions: The significant survival time in selected patients should lead to a study of the management of peritoneal carcinomatosis of endometrial origin in a larger number of cases, and justifies a clinical trial on a larger scale. Crown Copyright ß 2013 Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: HIPEC Endometrial cancer Peritoneal carcinomatosis Cisplatin Doxorubicin

1. Introduction Endometrial cancer is the most common cancer of the female reproductive tract. It is the fifth most common cancer among French women in terms of incidence with about 7000 new cases and 2000 deaths per year [1]. Its incidence is increasing, particularly due to the current increase in the number of overweight patients. In 70% of cases, endometrial cancer is detected early (International Federation of Gynecology and Obstetrics (FIGO) stage I) and its treatment is surgical, either exclusively or in combination with brachytherapy and/or radiotherapy. In these cases, the prognosis is good, with approximately 90% survival at 5 years. In cases of peritoneal dissemination as carcinomatosis, whether primitive or as the result of recurrence, the management is more complex. It can involve surgery, systemic chemotherapy, brachytherapy, radiation or even hormone therapy. The prognosis of these

* Corresponding author. Tel.: +33 04 92 03 64 86; fax: +33 04 92 03 65 61. E-mail address: [email protected] (J.M. Bereder).

cases with peritoneal spread is poor, with a median survival of approximately one year [2]. The advantage of the combination of optimal surgical resection with hyperthermic intraperitoneal chemotherapy (HIPEC) in primary or secondary peritoneal tumors has been demonstrated in certain indications. HIPEC is therefore one of the treatments proposed for recurrent or persistent carcinomatosis secondary to, for instance, ovarian [3,4] or colonic [5] tumors. Some cases of peritoneal carcinomatosis of endometrial origin have been reported in the literature, justifying interest in this surgical technique for such poor prognosis lesions [2]. We report the largest series, to our knowledge, of peritoneal carcinomatosis of endometrial origin treated by cytoreductive surgery combined with HIPEC. 2. Materials and methods Data of all patients treated by cytoreduction and hyperthermic intraperitoneal chemotherapy in the University Hospital of Nice were collected prospectively. We extracted and analyzed retrospectively data of patients treated for peritoneal carcinomatosis of

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endometrial origin between January 2001 and January 2013. The minimum preoperative investigations included: physical examination, cardiopulmonary investigation with cardiac echography and pulmonary functional exploration, nephrological investigation with creatininemia and clearance of creatinine, biologic assessment of the hepatic function, assessment of nutritional state with the body mass index (BMI), and pro albuminemia–albuminemia, and extent of disease and staging with multisliced contrastenhanced computed tomography (CT), and if necessary FDG-PET, magnetic resonance imagery (MRI) or laparoscopic exploration. The inclusion criteria were: patients aged 18–75 years with peritoneal carcinomatosis of endometrial origin, giving informed consent to the procedure combining cytoreductive surgery and HIPEC, with no contraindications either to surgery or to HIPEC, and without any extra-abdominal lesion on preoperative evaluation. All surgical explorations and procedures were under the direction of one of the authors (JMB). All patients were judged to be completely resectable during surgical exploration except for two cases where HIPEC procedures were performed for palliative reasons, due to the quality of life impairment associated with recurrent ascites. The extent of carcinomatosis was assessed using the Peritoneal Cancer Index (PCI), a classification dividing the abdomen and the pelvis into twelve regions for which peritoneal implants are scored from 0 to 3 depending on their size. Thus, the evaluation of PCI results in a score ranging from 0 to 39 (Fig. 1) [6]. The surgeries were performed with the aim of obtaining the resection of all visible tumor nodules. Peritonectomy procedures were performed when the peritoneal surfaces were macroscopically affected. After completion of the surgical cytoreduction, the Completeness of Cytoreduction Score (CC-S) was evaluated by the surgeon before HIPEC perfusion and was classified as follows: CC0 = no macroscopic residual cancer, CC-1 = residual nodules 25 mm [7]. The HIPEC procedure was performed according to the procedure known as Coliseum [8]. The intraperitoneal chemotherapy protocol involved the combination of cisplatin (dosage: 50 mg/m2 in 2 l of dialysis fluid) and doxorubicin (dosage: 15 mg/m2 in 2 l of dialysis fluid). This mixture was placed in contact with the peritoneal cavity at a dose of 2 l per m2 of body surface for 60 min at a controlled temperature of 43 8C. The material used for the distribution and temperature control of chemotherapy was the Performer LRT1, RAND, Medolla (MO), Italy. Any gastrointestinal anastomoses were performed after the end of the HIPEC.

Preoperative, intraoperative and postoperative data were collected prospectively. The information collected included patient characteristics: age, BMI, and American Society of Anesthesiologists Physical Status (ASA-PS) score. Information about the history of the disease and the medical-surgical management was also collected: duration of tumor progression between the end of initial treatment and the HIPEC procedure, treatment applied before or after HIPEC, PCI during surgical exploration, resections performed during cytoreduction, the CC-S after surgery, duration of surgery, administration of blood transfusion, hospital stay, postoperative complications according to the common terminology criteria for adverse events (CTCAE) v3.0 of the National Institute of Health [9], and survival of patients with or without tumor recurrence. We used the Kaplan–Meier survival curves. The differences were analyzed by the log-rank test and considered significant if P < 0.05 [10]. Cox’s regression model was used for multivariate survival analysis. Statistics and graphics were performed using the ‘‘R software’’ version 2.15.1 (copyright 2012, the R Foundation for Statistical Computing). 3. Results From January 2001 to January 2013, 13 patients were treated by cytoreductive surgery and intraperitoneal chemotherapy for peritoneal carcinomatosis of endometrial origin. The average age of the patients during the HIPEC procedure was 66.5 years (range 51–75). The median BMI was 28 (mean 27.3, range values 20–37). The average duration of tumor progression between the end of initial treatment and the HIPEC procedure was 18.5 months (range 0–53). The median exposure to chemotherapy was of 1 line (mean 1.23, range values 0–3). The preoperative ASA score was 1 for 1 patient and 2 for the other 12. The PS average score was 1 (range 0–1). The median PCI at laparotomy was 12 (mean: 11.46; extreme values 3–24). The average number of organ resections in these HIPEC procedures was 2 (range 0–4). These organ resections involved a segment of the digestive tract for three patients (resection of small intestine, right or atypical colectomy), resection of other organs in five cases (splenectomy, hysterectomy with bilateral salpingo-oophorectomy, liver segmentectomy for parenchymal metastasis, partial cystectomy, resection of the right diaphragmatic dome). The CC-S after surgery was 0 for 8 patients, 1 for 3 patients and 2 in the last two cases. The median operative time was 300 min (mean 316, range values 217–480). One patient required the administration of three units of red blood cells

Fig. 1. Peritoneal Cancer Index [from Jacquet et al. [6]].

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Table 1 Patients’ characteristics. Patients

Histology

Primary management (P) or Recurrence (R)

Preoperative treatment

PCI

CCS

Time to relaps following HIPEC (months)

Duration of follow-up (months)

1 2 3

Type I Type II Type I

R P R

15 3 14

1 0 2

7 4 19.4

12.4 6.43 19.4

4 5 6 7 8

Type Type Type Type Type

I I I I I

R R P P R

17 13 5 24 5

0 0 0 2 0

4.76 5.66 No recurrence Lost of follow up No recurrence

47.36 12.60 59.13 1.9 59.36

Deceased Deceased Persistent disease Deceased Deceased Deceased Alive without recurrence Lost of follow up Alive without recurrence

9

Type I

R

5

0

No recurrence

124.83

Alive without recurrence

10

Type I

R

7

0

6.83

26.93

Alive with recurrence

11

Type I

R

Chemotherapy None Radiotherapy Chemotherapy Radiotherapy Chemotherapy None None Radiotherapy Chemotherapy Radiotherapy Chemotherapy Radiotherapy Chemotherapy Chemotherapy

12

0

11.4

14.53

Alive with recurrence

12 13

Type II Type I

P R

None Radiotherapy Chemotherapy

17 12

1 1

No recurrence 4.53

1.56 28.10

Alive without recurrence Alive with recurrence

Current status

intraoperatively, the remaining 12 patients being not transfused. The median duration of hospitalization was 13.4 days (median 12, range values 10–21). One patient had a grade II complication in the course of hospitalization, but no patient showed any complication of grade III or IV. No patient died during surgery or during the initial hospitalization. Post operatively, all patients who scored CC1 and CC-2 received chemotherapy, but none with CC-0. Two patients had persistent disease at the end of the procedure. Seven patients had recurrences, five of whom died of these recurrences. Three are alive with recurrence and four are alive without recurrence. One patient with persistent disease at the end of the procedure was lost to follow up two months after the HIPEC. The median overall survival is 19.4 months and the median disease-free survival is 11.4 months (range values 1.5– 124.83). Table 1 summarizes the characteristics of patients, and Figs. 2 and 3 schematically show the survival curves of the patients according respectively to the PCI and the post-resection CC-S. 4. Comment Fig. 2. Survival curve based on the Peritoneal Cancer Index (PCI).

Fig. 3. Survival curve based on the Completeness of Cytoreduction (CC) Score.

The current standard for the treatment of peritoneal carcinomatosis of endometrial origin depends on the evolution of the disease, and the feasibility of treatment in elderly patients where co-morbidities are common. Treatment may include, alone or in combination, surgery, chemotherapy, hormone therapy in the case of positive receptors or slowly progressive disease, or even an external conformal radiotherapy depending on the location of the lesions. The morbidity of such treatments is not negligible and the overall prognosis of this disease remains poor, with a median survival of about a year without much change for many years, despite new protocols of chemotherapy or surgery [11–13]. Some studies concluded that in women with stage IV endometrial cancer, histologic features and extent of disease are more important determinants of outcomes than any kind of treatment, in opposition to other studies which highlighted the effect of cytoreductive surgery on survival rate [11,14]. Thus, treatment strategies for such patients remain controversial. The fact is that the development of peritoneal carcinomatosis was the main cause of death in these patients; so the use of a technique aimed at the elimination of peritoneal invasion should be able to favorably impact the prognosis of these patients. It is in this context that some teams specialized in the treatment of carcinomatosis proposed the implementation of

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HIPEC procedures. For example, Bakrin et al. reported a series of 5 patients with carcinomatosis of endometrial origin: 2 patients were without recurrence after 2 and 3 years and 2 patients were living with recurrence after 1 and 3 years [2]. The high rate of survival in these patients with particularly poor prognosis raises the question of the possible role of HIPEC in tumors of endometrial origin [15]. In our series of 13 patients, which is, to our knowledge, the largest to date, HIPEC was performed as first line treatment in four cases and in the context of a peritoneal recurrence in the remaining nine cases. The chemotherapy used was doxorubicin + cisplatin combination for two reasons. The first is a pathological reason: this is the chemotherapy used for serous papillary adenocarcinomas and, by analogy, it seemed legitimate to use it against peritoneal implants of endometrial origin. The second is a technical reason: the effectiveness of such chemotherapy has been largely demonstrated during these procedures. Cisplatin, when used in HIPEC, notably allows high tumor concentration to be achieved with low systemic effect, causing an intense cytotoxic effect [16]. Surgical morbidity was represented by a single complication of grade II, a wall abscess, which resolved with percutaneaous drainage, but no complication of grade III or IV. No intraoperative or early postoperative deaths were noted. Survival times with or without recurrences following HIPEC are high compared to the standard prognosis of this disease. Of the thirteen patients treated, one patient was lost to follow up. Three patients died within the first twelve months of care, and two others died, respectively at 12.4 and 19.4 months after the HIPEC procedure. Seven patients are alive, four of them being without recurrence between 1.5 and 124.8 months after surgery. There seem to be prognostic factors for this disease after HIPEC. Just like carcinomatosis of other origins, CC-S tends to be correlated with median survival (Fig. 3). This is entirely consistent with the very concept of HIPEC since the hyperthermic intraperitoneal chemotherapy procedure is intended to facilitate the destruction of peritoneal micrometastatic lesions and does not allow the destruction of macroscopic lesions. The preoperative PCI is a major prognostic factor. As shown in Fig. 2, if the PCI was greater than 10, patients all died within 48 months following the HIPEC procedure. In contrast, for patients whose PCI was less than 10, the median survival was not reached, and, for one of them, survival exceeded 120 months. Our study is observational and because of the lack of control group, we had to compare our results with data in the literature, where the median survival is approximately one year [2,11–13]. This long survival in our subgroup of patients with endometrial peritoneal carcinomatosis leads to three reflections. The first is that it is legitimate to have an ‘‘aggressive’’ surgical attitude in carcinomatosis where the aim is to obtain a complete absence of postoperative residue. The second is that peritoneal extension, considered as metastatic in endometrial cancer (FIGO 2009 and

tumor-node-metastasis (TNM) 2009 classifications), could be treated in a specific manner and entail long-term survival in selected patients with low tumor burden (PCI