Ann Surg Oncol (2009) 16:2744–2751 DOI 10.1245/s10434-009-0611-5

ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY

The Second Procedure Combining Complete Cytoreductive Surgery and Intraperitoneal Chemotherapy for Isolated Peritoneal Recurrence: Postoperative Course and Long-Term Outcome Antoine Brouquet, MD1, Diane Goe´re´, MD1, Je´re´mie H. Lefe`vre, MD1, Ste´phane Bonnet, MD1, Fre´de´ric Dumont, MD1, Bruno Raynard, MD2, and Dominique Elias, MD, PhD1 Department of Surgical Oncology, Gustave Roussy Cancer Institute, Villejuif Ce´dex, France; 2Intensive Care Unit, Gustave Roussy Cancer Institute, Villejuif Ce´dex, France

1

ABSTRACT Background. Complete cytoreductive surgery (CCRS) with intraperitoneal chemotherapy (IPC) is becoming the gold-standard treatment for resectable peritoneal carcinomatosis, when feasible. However, this approach has not yet been evaluated for isolated peritoneal re-recurrences after previous IPC. The aim of this study was to evaluate the postoperative course and long-term outcome after repeat (re-)CCRS ? IPC. Methods. From 1996 to 2007, 25 re-CCRS ? IPC were performed in 20 patients with isolated peritoneal re-recurrences, among 393 CCRS ? IPC performed during the same period in the department. Selection was based on the supposedly limited extent of the peritoneal disease and an interval of more than 12 months between the first CCRS ? IPC procedure and recurrence. After a re-CCRS, we used re-IPC modalities (method and/or drug) that were systematically different from those of the first IPC. The origins of the tumors were pseudomyxoma (n = 12), colorectal cancer (n = 4), mesothelioma (n = 3), and carcinoid tumor (n = 1). Results. At laparotomy, mean peritoneal index was 7.6 ± 4.8. Among the 25 procedures, hyperthermic intraperitoneal chemotherapy was used in 15 cases and early postoperative intraperitoneal chemotherapy in 10 cases. The postoperative mortality rate was 4% (n = 1) and six grade 3–4 postoperative complications occurred. The

Ó Society of Surgical Oncology 2009 First Received: 23 February 2009; Published Online: 21 July 2009 D. Goe´re´, MD e-mail: [email protected]

overall 5- and 10-year actuarial survival rates were 72.5% and 58%, respectively. The 5-year disease-free survival rate was 19%. The long-term outcome was not different, whatever the type of primary tumor. Conclusion. Re-CCRS ? IPC is feasible and yields prolonged survival in highly selected patients. Also, the switch to another type of IPC or regimen may have contributed to this prolonged survival.

Peritoneal carcinomatosis (PC), whatever its origin, is associated with a poor prognosis.1,2 Nevertheless, the prognosis of a few types of tumors (colorectal cancer, pseudomyxoma peritonei, peritoneal mesothelioma) has been improved considerably with use of an aggressive combined approach in selected patients. Indeed, the overall 5-year survival year rate following complete cytoreductive surgery (CCRS) with intraperitoneal chemotherapy (IPC) ranges from 22% to 51% in patients with colorectal PC, rises to 80% in patients with peritoneal pseudomyxoma, and reaches 29–63% for patients with peritoneal mesotheliomas.3–12 Different IPC procedures have been developed over time, including early postoperative intraperitoneal chemotherapy (EPIC) administered just after surgery for 5 consecutive days without hyperthermia, and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC).13,14 However, after CCRS ? IPC, 80% of patients treated for PC from colorectal carcinoma relapse, as do 40% of patients with mesothelioma, and 25–44% of patients treated for pseudomyxoma.9,15–18 In some cases, recurrences are strictly located in a few areas in the peritoneal cavity and, if cytoreduction was macroscopically complete, it can be hypothesized that IPC failed to cure

Treatment of Recurrent Peritoneal Carcinomatosis

residual nonvisible tumor.15,16 In patients with good general status following CCRS ? IPC, whose peritoneal recurrence is deemed completely resectable, a benefit from repeat CCRS ? IPC is questionable because recurrent peritoneal disease can be considered a failure of the first procedure. The aim of this study was to analyze the feasibility and results of repeat CCRS ? IPC in the treatment of peritoneal recurrence following CCRS ? IPC. METHODS Patients Eligibility criteria for repeat CCRS ? IPC were as follows: (1) patients previously treated with CCRS ? IPC for PC, (2) good general status, (3) peritoneal recurrence diagnosed on imaging without associated distant metastases, (4) an interval [12 months between the first IPC and the diagnosis of recurrence, (5) extent of peritoneal recurrence apparently limited to a few areas of the peritoneal cavity, and (6) signed consent for the repeat procedure. All but two patients had American Society of Anesthesiologists (ASA) status 2 or less. The two remaining patients had no major comorbidities, in particular heart or pulmonary disease; one had ‘‘borderline’’ nutritional status [body mass index (BMI) = 19 kg/m2] and the other experienced a temporary episode of arrhythmia after the first procedure. Any diagnosis of peritoneal recurrence that was highly suspected on preoperative imaging and/or based on elevated serum tumor markers was always confirmed at laparotomy. Before surgery, all patients had a chest and abdominal computed tomography (CT) scan in order to rule out extraperitoneal spread of disease, and the decision to perform re-IPC was confirmed during a multidisciplinary meeting including surgeons, radiologists, and oncologists. Surgical Procedure and Intraperitoneal Chemotherapy (IPC) At laparotomy, the peritoneal cavity was thoroughly explored to rule out contraindications for resection. The extent of recurrent peritoneal disease was evaluated using Sugarbaker’s peritoneal index, which ranges from 1 to 39.19 The first step was complete resection of tumor recurrences according to the principles described elsewhere, resulting in CC-0 status (i.e., no visible residual disease).20,21 IPC was only performed if all macroscopically detectable disease was completely resected, which is usually the case in our institute. In other cases, we considered that intraperitoneal chemotherapy was not effective enough to cure the residual disease. These patients underwent either only a laparotomy or a debulking procedure but were not treated by intraperitoneal chemotherapy. Clinical

2745

and biological parameters, procedure duration, extent of resection, and bleeding were recorded prospectively. We systematically chose a different re-IPC from the first IPC, changing the drugs and/or the procedure (HIPEC versus EPIC). HIPEC was performed intraoperatively with the open Coliseum technique. HIPEC regimens were as follows: (1) i.p. oxaliplatin alone (460 mg/m2) in 2 L/m2 5% dextrose (HIPEC oxali), (2) i.p. oxaliplatin (360 mg/ m2) plus irinotecan (360 mg/m2) in the same volume (HIPEC oxiri), (3) i.p. mitomycin C alone (10 mg/m2) in 3.5 L/m2 Ringer lactate solution (HIPEC mito), and (4) i.p. mitomycin C (20 mg/m2) and cisplatin (200 mg/m2) in 3.5 L/m2 Ringer lactate solution (HIPEC mito/cddp). During HIPEC, the mean intraperitoneal temperature was 43°C. It was higher than 42°C throughout the peritoneal cavity (four probes were placed intraperitoneally at different sites) over 30 min and patients received an intravenous perfusion of 5-fluorouracil (400 mg/m2) with leucovorin (20 mg/m2) just before starting the procedure. EPIC without hyperthermia began as soon as the wound was closed and included continuous intraperitoneal infusion of chemotherapy over 5 days. Each infusion lasted 23 h and the instillate was drained out over the next hour.13 EPIC regimens were as follows: (1) mitomycin C (10 mg/ m2) in 900 mL/m2 Ringer lactate solution on day 1 followed by 5-fluorouracil (15 mg/kg) from day 2 to day 6 (EPIC mito/5-Fu) and (2) cisplatin (15 mg/m2) and doxorubicin (0.1 mg/kg) diluted in 2 L Ringer lactate (EPIC doxo/cddp) from day 1 to day 6. Follow-Up of Patients After Repeat CCRS ? IPC Morbidity and mortality were investigated until discharge from the hospital. Complications were classified according to the Dindo classification.22 Patients were followed up every 3 months with a clinical examination, imaging examinations, and blood marker determination, except for patients with low-grade pseudomyxoma who were followed up every 6 months. No patient was lost to follow-up and no patient was excluded from the survival analysis (including postoperative deaths). Statistical Analysis Data were obtained from a prospective database containing clinical records, surgical reports, and regular systematic follow-up information. Quantitative data were expressed as mean ± standard deviation (SD) and qualitative data as frequency and percentage values. Concerning intraoperative characteristics and postoperative outcomes, data concerning the 25 procedures were analyzed. The survival rate of the 20 patients was analyzed. Survival curves were calculated using Kaplan–Meier method and

2746

A. Brouquet et al.

compared using the log-rank test. Survival time was calculated from the repeat CCRS ? IPC. A P value \0.05 was considered significant. Data were analyzed using StatViewÒ software (version 9.1; SAS Institute, Cary, NC). RESULTS Patient and Tumor Preoperative Characteristics From 1996 to 2007, 25 repeat CCRS ? IPC for isolated peritoneal tumor recurrence were performed in 20 patients in our institute. The mean age of patients was 47 ± 10 years. These 20 patients represented a highly selected population: 393 patients underwent a CCRS ? HIPEC or EPIC between 1996 and 2007, 263 of them relapsed (67%), and approximately one-third (n = 89) of these relapses were inside the peritoneum. Only 20 of these 89 (22.4%) patients fulfilled the selection criteria. The origins of the primary tumors were: peritoneal pseudomyxoma (n = 12; 11% of the patients with pseudomyxoma underwent CCRS ? IPC during the study

TABLE 1 Preoperative clinical characteristics of 20 patients who underwent 25 repeat CCRS plus IPC for recurrent peritoneal carcinomatosis

period), colorectal cancer (n = 4; 4% of patients with PC from colorectal cancer underwent CCRS ? IPC during the study period), malignant mesothelioma (n = 3; 10% of patients with mesothelioma underwent CCRS ? IPC during the study period), and carcinoid tumor (n = 1; 1% of patients with a miscellaneous tumor underwent CCRS ? IPC during the study period). Preoperative patient and tumor characteristics are summarized in Table 1, with the extent of resected PC during the first procedure. The mean interval between the previous CCRS ? IPC and the diagnosis of peritoneal recurrences was 24.7 ± 19 months. Eight patients had received adjuvant chemotherapy after the first procedure. These patients had PC from colorectal cancer (n = 3) or grade 3 pseudomyxoma (n = 5). At diagnosis of recurrence, systemic chemotherapy was administered before repeat CCRS ? IPC in only three patients. Of these patients, two had pseudomyxoma and one patient had mesothelioma. These patients received preoperative chemotherapy because their recurrence occurred less than 2 years after the first procedure. Two of these patients

n = 25

Median (range)

Agea

47 ± 10

49 (28–61)

Gender (M:F)

7:18

ASA scorea

2.1 ± 0.27

2 (2–3)

BMI (kg/m2)a

22 ± 3.5

21 19–33)

Primary tumor (n = 20) Malignant mesothelioma

3

Colorectal cancer

4

Pseudomyxoma peritonei Carcinoid

12 1

Grading of pseudomyxoma (Ronnett)a

2.13 ± 0.64

2 (1–3)

Number of previous cytoreductive surgical procedures followed by HIPEC or EPIC 1

20

2

3

3

1

4

1

Intraoperative findings at time of previous procedure with IPC Number of invaded areasa

10.75 ± 3.9

13 (3–13)

Peritoneal indexa

16.9 ± 11.3

15 (2–31)

Adjuvant therapy after previous IPC FU-based/oxali-based/iri-based chemotherapy Number of cyclesa Interval between previous CCRS ? IPC and diagnosis of recurrence (months)a

8 5/1/2 8.3 ± 3.1

6 (6–12)

24.7 ± 19

17 (12–85)

Preoperative chemotherapy Number of patients

a

Mean ± SD

3

FU-based/oxali-based/iri-based chemotherapy

0/0/3

Number of cyclesa

5.3 ± 1.2

6 (4–6)

Treatment of Recurrent Peritoneal Carcinomatosis

2747

had an objective response or disease stabilization, whereas the tumor progressed in the last one. Intraoperative Findings, Surgical Procedure, and IPC Intraoperative findings and the characteristics of procedures are summarized in Table 2. Eleven patients underwent only peritonectomies without intestinal resection. In the remaining patients, intestinal resections were as follows: six rectal resections, six small bowel resections, five ileocolic resections, three degastrogastrectomies, and one subtotal colectomy. Concerning IPC protocols, 15 HIPEC and 10 EPIC were performed during these repeat CCRS ? IPC. The re-IPC protocols used in our patients are summarized in Table 3. We systematically switched to another IPC protocol and/or regimen for the repeat procedures. Postoperative Mortality and Morbidity One patient (4%) died before discharge from hospital. He died on day 120, of post-inhalation lung infection. The postoperative morbidity rate was 48.1% (12 patients). There were six grade IV complications (three anastomotic leaks, two intra-abdominal abscesses, one acute respiratory distress syndrome). Four patients required reoperation. Median hospital stay was 15 days (range 7–120 days) (Table 4).

free survival rate was 19%. Survival curves are reported in Fig. 1. Overall and progression-free survival were not significantly different whatever the origin of the PC. Finally, 12 patients (60%) developed re-recurrences. The re-recurrence rate was 17% (1/6) among the 6 patients who had an interval exceeding 24 months between the first and the repeat procedure, and was 78.5% (11/14) among the 14 patients who had an interval shorter than 24 months between the first and the repeat procedure (P = 0.22) The origins of PC in patients who developed re-recurrences were as follows: pseudomyxoma in eight, and colorectal cancer and mesothelioma in the remaining patients, with the same incidence whatever the origin. Rerecurrences in patients with pseudomyxoma were peritoneal in all cases, and four of these patients had only pelvic lesions. Among the 12 patients who developed re-recurrences, 9 had isolated peritoneal disease at relapse and, among these 9 patients, 3 underwent a third CCRS ? IPC (2 patients with colorectal cancer and 1 with pseudomyxoma). Two of these three patients are free of disease 3 years after the last procedure. Three patients had extraperitoneal recurrences: lung metastases in two and the remaining patient developed liver metastases and peritoneal recurrence from colorectal cancer 15 months after surgery and underwent a liver resection and CCRS for peritoneal deposits. This patient had a prolonged survival duration and died 31 months after the hepatectomy. DISCUSSION

Survival and Recurrences Median follow-up was 63 months (range 12–145 months). Five- and 10-year overall survival rates were 72.5% and 58.1%, respectively, and the 5-year progressionTABLE 2 Intraoperative findings and surgical procedures in the 20 patients who underwent 25 repeat CCRS ? IPC for recurrent peritoneal carcinomatosis

In this short series of patients with peritoneal recurrence, who had already undergone CCRS ? IPC for peritoneal dissemination, repeat CCRS ? IPC resulted in 5-year overall and progression-free survival rates of 72% and

n = 25 Intraoperative findings

Median (range)

a

Number of invaded areasa

3.72 ±2.9

3 (1–11)

Peritoneal index

7.6 ± 4.8

6 (2–18)

Number of resected organs

1.5 ± 1.3

2 (0–4)

Number of anastomoses

0.9 ± 1

1 (0–4)

Number of lateral sutures

1.9 ± 1.9

2 (0–5)

Number of procedures including only peritonectomies (%)

11

Number of procedures including resections of organs and digestive sutures

14

Blood loss (mL)a

770 ± 646

Intraoperative blood pack transfusion requirement

3

500 (200–2,880)

Type of intraperitoneal treatment HIPEC

10

EPIC

15

a

Among the 13 areas defined by Sugarbaker et al.12

b

Mean ± SD

Mean operating time (min)b

387 ± 126

380 (150–640)

2748

A. Brouquet et al.

TABLE 3 Protocols and regimens used for intraperitoneal chemotherapy Case

Origin of carcinomatosisa

Diagnosis of PCb

First procedure

Second procedure

1

P

1992

HIPEC mitoc

EPIC mito/5-Fu

2

C

1992

HIPEC mito

3

Carcinoid tumor

1993

EPIC mito/5-Fu

4

P

1993

HIPEC mito/cddpe

5

P

1994

HIPEC mito

HIPEC mito/cddp

6

P

1994

HIPEC oxalif

HIPEC mito/cddp

7 8

C P

1995 1996

HIPEC mito HIPEC mito

EPIC mito/5-Fu HIPEC oxiri

9

P

1998

HIPEC oxali

HIPEC mito/cddp

10

C

1999

HIPEC oxali

HIPEC oxiri

11

C

1999

EPIC mito/5-Fu

HIPEC mito

12

P

1999

HIPEC oxali

EPIC mito/5-Fu

13

P

2000

HIPEC oxali

EPIC mito/5-Fu

14

M

2003

HIPEC oxali

EPIC mito/5-Fu

15

P

2003

HIPEC oxirig

HIPEC oxiri

16

P

2003

HIPEC oxiri

EPIC mito/5-Fu

17

M

2003

HIPEC oxiri

HIPEC oxali

18

P

2003

HIPEC oxiri

HIPEC oxiri

19

M

2004

HIPEC oxiri

EPIC doxo/cddph

20

P

2005

HIPEC oxiri

EPIC mito/5-Fu

HIPEC mito/cddp d

Third procedure

Fourth procedure

Fifth procedure

EPIC mito/5-Fu

EPIC MITO

EPIC mito/5-Fu

HIPEC mito HIPEC mito

a

P pseudomyxoma, C carcinomatosis from colorectal cancer, M mesothelioma

b

Peritoneal carcinomatosis

c

HIPEC with intraperitoneal mitomycin ? intravenous 5-FU

d

EPIC with intraperitoneal mitomycin ? intravenous 5-FU

e

HIPEC with intraperitoneal mitomycin and CDDP ? intravenous 5-FU

f

HIPEC with intraperitoneal oxaliplatin ? intravenous 5-FU

g

HIPEC with intraperitoneal oxaliplatin and irinotecan

h

EPIC with intraperitoneal adriamycin ? intravenous 5-FU

19%, respectively, with acceptable mortality and morbidity results. Consequently, we can conclude that it was beneficial to the highly selected patients who underwent these repeat procedures (Table 4). Only a few studies (Table 5) have been published on this topic.15,16,23 The series of Verwaal et al. and of Kianmanesh et al. included 15 and 11 patients, respectively, but did not specify whether resection of recurrence was complete, nor did they provide clear results about survival.15,23 On the contrary, Sugarbaker’s group reported on 26 cases of complete (CC0) repeat CCRS ? IPC for pseudomyxomas, and 16 similar procedures for colorectal cancer.16 Selection criteria were more severe in our study, which resulted in only 5% of reoperated patients (20 of the 393 patients) compared with 26% in Sugarbaker’s series (124 of the 472 patients) and better long-term survival. However, we can conclude that the results were good in both series, and that the principle of repeat CCRS ? IPC is justified in highly selected cases.

HIPEC oxali

HIPEC oxiri

Completeness of cytoreductive surgery appears to be a prognostic factor for long-term survival in patients who underwent CCRS?IPC.24 However, after CCRS ? IPC, the recurrence rate remained elevated and limited to the peritoneal cavity in only 13/54 patients (24%) who underwent R1 resection (no residual macroscopic tumor) in the study of Verwaal.15 We observed the same rates of recurrence, since among 393 patients who underwent CCRS?IPC 89 developed recurrence only inside the peritoneum (22.6%). Recurrent peritoneal disease following CCRS ? IPC can be considered a failure of either the surgical procedure or intraperitoneal chemotherapy. Our policy is to perform IPC (HIPEC or EPIC) exclusively in patients with completely resected disease (CC0). It is noteworthy that 4/12 patients operated on for recurrent pseudomyxoma only developed a pelvic recurrence. Prior to the first CCRS ? IPC, these four patients were treated in another institution for an erroneous diagnosis of ovarian cancer and had undergone cytoreductive surgery including

Treatment of Recurrent Peritoneal Carcinomatosis Cumulative Survival (Percent) 100

2749

Overall survival Progression-free sruvival

80

60

40

20

0

12

24

36 Months

48

60

72

20 20

17 14

12 8

10 3

7 2

6 2

4 1

Patients at Risk

FIG. 1 Overall and disease-free survival (Kaplan–Meier) of 20 patients who underwent repeat complete cytoreductive surgery (CCS) ? intraperitoneal chemotherapy (IPC) for isolated peritoneal recurrence from peritoneal carcinomatosis, after a median follow-up of 63.2 months (range 12–145 months) from the repeat CCRS?IPC. Five-year overall survival: 72.5%, 10-year overall survival: 58%. Five-year disease-free survival: 19%

TABLE 4 Postoperative course of 20 patients who underwent 25 repeat CCRS ? IPC for recurrent peritoneal carcinomatosis n = 25 Postoperative mortality at 90 days

1

Postoperative complications

12

Abdominal complications

5

Extra-abdominal complications

9

Reoperation

4

Complications, Dindo grade C3

6

Hospital stay (in days)a

15 [7–120]

a

Median [range]

TABLE 5 Comparison of the series of repeat CCRS ? IPC reported in the literature

a

Miscellaneous included peritoneal carcinomatosis from gastric, ovarian, and endocrine cancers NR not reported

a colpohysterectomy with lymphadenectomy. Although we systematically attempted to reopen all the previous dissection planes used in the first CCRS ? IPC, we most probably did not detect and thus did not treat tiny residual tumor deposits that were still present after the very first surgical procedure. This is a strong argument not to treat pseudomyxoma peritonei like ovarian cancer, even if the main tumor burden is located in the ovaries. Peritoneal carcinomatosis from pseudomyxoma peritonei can be misdiagnosed at the time of laparotomy and treated as a primary ovarian tumor. In other words, in case of pseudomyxoma, resection including colpohysterectomy and pelvic dissection should be performed only if complete cytoreduction can be achieved and ideally associated with intraperitoneal chemotherapy. Recurrence can also be due to inadequacy of the IPC used during the first procedure. It appears logical to use a different IPC regimen during the second procedure by analogy with systemic chemotherapy regimens, which are replaced by another regimen when disease progresses during first-line treatment. We therefore decided to change the type of IPC and/or the type of chemotherapy regimen in the repeat procedure. The choice between HIPEC and EPIC was based on the type of disease and the type of intraperitoneal chemotherapy used for previous procedures combining complete cytoreductive surgery and intraperitoneal chemotherapy. For the first procedure, HIPEC was performed as much as possible, since it is the reference treatment of PC and supposed to be more efficient than EPIC.4 However, in two cases, the discovery of peritoneal carcinomatosis during the first procedure was fortuitous, therefore, HIPEC was not immediately available and the patient had not signed the informed consent before HIPEC as recommended. These two patients had an EPIC for the first-line treatment. For the second procedure and other additional procedures combining CCRS ? IPC, a change was done either in the drug used or the type of IPC (HIPEC or EPIC).

Reference

Study population

Repeat procedure number (%)

CC-0 procedure number (%)

Median survival (months)

15

106 colon-rectum

15 (14%)

NR

10.3

23

43 colon-rectum

11 (26%)

NR

NR

16

70 colon-rectum

26 (37%)

16 (61%)

39

402 appendix

98 (24%)

26 (26%)

[60

Present series

109 colon-rectum

4 (4%)

4 (100%)

32

112 appendix

12 (11%)

12 (100%)

29 mesothelioma

3 (10%)

3 (100%)

143 miscellaneousa

1 (\1%)

1 (100%)

2750

Therefore, the policy for the chemotherapy regimen for the second procedure combining complete cytoreductive surgery and intraperitoneal chemotherapy was to systematically change. Although benefits of this attitude were not demonstrated, we hypothesized that isolated peritoneal recurrence could be due to failure of intraperitoneal chemotherapy and in particular because of resistance of the tumor to drugs used for intraperitoneal chemotherapy. The 5-year progression-free survival rate of 19% observed in patients whose disease was supposedly resistant to the first IPC was close to the progression-free survival observed in treatment-naive patients following CCRS ? IPC and this may be an argument for systematically switching the IPC procedure and/or regimen when repeated. Furthermore, a similar analogy in long-term outcome was previously reported for patients who underwent rehepatectomy for colorectal liver metastases.25,26 Even if the recurrence rate remains elevated, a survival benefit can be observed following repeat CCRS ? IPC even in patients who developed re-recurrence. Indeed, the 5-year overall survival rate was 72.5%. A third or a fourth procedure can be also indicated for highly selected patients. Peritoneal recurrence occurring in patients who underwent CCRS ? IPC could also be explained by the advanced stage of the disease at the time of diagnosis. Indeed, in the present study, the mean peritoneal index was 17 at the time of the first procedure. These patients could potentially benefit from adjuvant chemotherapy following CCRS ? IPC, but the advantage of such a strategy, if any, has not been demonstrated to date. Selection criteria in the present study were based on: (1) the supposedly limited extent of peritoneal recurrence on the preoperative imaging work-up (even though imaging is not very accurate in assessing the extent of the disease in the peritoneum, we consider that more than two areas invaded was a contraindication for iterative procedures), (2) general status and age, and (3) the interval between the first procedure and the recurrence. The patient population mainly had a colorectal tumor, with grade 3 peritoneal pseudomyxoma, or with malignant epithelial mesothelioma. Survival and recurrence rates following repeat CCRS ? IPC were not significantly different whatever the origin of the disease; this is certainly related to the small sample size and to the high degree of selection for each patient whatever the origin of the disease. Given the outcome of patients in the present study, the main question is whether this strategy could be indicated in other patients, with different selection criteria. In the present study, the two main selection criteria were the limited extent of peritoneal recurrence on preoperative imaging investigations and the time interval between the first procedure and peritoneal recurrence. On the one hand, the accuracy of imaging for the diagnosis of peritoneal

A. Brouquet et al.

dissemination remains poor and laparoscopy is not feasible in patients who have already undergone extensive surgery with large peritonectomies. On the other hand, re-recurrences rates in the present study were 17% in patients with an interval exceeding 24 months versus 78.5% in patients with a shorter interval. Even though these results cannot reach significance probably due to the small sample size, this is a strong argument to only propose repeat CCRS ? IPC alone in patients with late peritoneal recurrence ([24 months) following a first procedure. It can be hypothesized that preoperative chemotherapy could help the selection of good candidates, improve the resectability rate of PC, and decrease the recurrence rate after CCRS ? IPC. However, there are currently no data to support this hypothesis and, in the present series, the sample size was too small to draw any conclusion. Maybe in the future, response to preoperative systemic chemotherapy will be a relevant selection criterion in these patients, as is already observed for colorectal liver metastases.27 Morbidity and mortality of repeat CCRS ? IPC were 48% and 4%, respectively, similar to reported following the first CCRS ? IPC. To our knowledge, this is the first study to focus on the postoperative course of patients who underwent repeat CCRS ? IPC. In recent studies, we reported that after CCRS ? IPC, mortality and morbidity rates were 7.6% and 67.6%, respectively, in a series of 106 patients treated for peritoneal pseudomyxoma, 9.1% and 54.6% for 64 patients treated for colorectal PC, and 4% and 54% for 24 patients treated for malignant peritoneal mesothelioma.3,9,11 These data are in accordance with those reported in the literature, where mortality and morbidity rates range from 0% to 12% and from 12% to 55%, respectively.28,29 Nevertheless, the low complication rate observed in the present study can be explained by the fact that most patients had limited peritoneal disease (mean peritoneal index = 7), and consequently, the surgical procedure was not particularly extensive. Indeed, in this series, 11/25 procedures (44%) included only peritonectomies, without visceral resection. In conclusion, repeat CCRS ? IPC, switching to another type of IPC or regimen, in highly selected patients with limited and isolated peritoneal recurrence following CCRS ? IPC, can result in prolonged survival. Selection of good candidates for repeat CCRS ? IPC should be based on the general status of patients, i.e., ASA status and no severe comorbidities, on the extent of peritoneal recurrence, i.e., one or two peritoneal area involved on imaging, and on the interval between the first procedure and recurrence exceeding 24 months. ACKNOWLEDGMENT Saint Ange for editing.

The authors particularly thank Lorna

Treatment of Recurrent Peritoneal Carcinomatosis

REFERENCES 1. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88:358–63. 2. Jayne DG, Fook S, Loi C, Seow-Choen F. Peritoneal carcinomatosis from colorectal cancer. Br J Surg. 2002;89:1545–50. 3. Elias D, Blot F, El Otmany A, Antoun S, Lasser P, Boige V, et al. Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer. 2001;92:71–6. 4. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:3737– 43. 5. Glehen O, Kwiatkowski F, Sugarbaker PH, Elias D, Levine EA, De Simone M, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol. 2004;22:3284–92. 6. Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol. 2006;24:4011–19. 7. Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2009;27:681–5. 8. Yan TD, Links M, Xu ZY, Kam PC, Glenn D, Morris DL. Cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei from appendiceal mucinous neoplasms. Br J Surg. 2006;93:1270–6. 9. Elias D, Honore´ C, Ciuchende´a R, Billard V, Raynard B, Lo Dico R, et al. Peritoneal pseudomyxoma: results of a systematic policy of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Br J Surg. 2008;95:1164–71. 10. Yan TD, Welch L, Black D, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann Oncol. 2007;18:827–34. 11. Elias D, Bedard V, Bouzid T, Duvillard P, Kohneh-Sharhi N, Raynard B, et al. Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy. Gastroenterol Clin Biol. 2007;31:784–8. 12. Feldman AL, Libutti SK, Pingpank JF, Bartlett DL, Beresnev TH, Mavroukakis SM, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol. 2003;21:4560–67. 13. Sugarbaker PH, Graves T, DeBruijn EA, Cunliffe WJ, Mullins RE, Hull WE, et al. Early postoperative intraperitoneal chemotherapy as an adjuvant therapy to surgery for peritoneal carcinomatosis from gastrointestinal cancer: pharmacological studies. Cancer Res. 1990;50:5790–4. 14. Stephens AD, Alderman R, Chang D, Edwards GD, Esquivel J, Sebbag G, et al. Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol. 1999;6:790–6.

2751 15. Verwaal VJ, Boot H, Aleman BM, van Tinteren H, Zoetmulder FA. Recurrences after peritoneal carcinomatosis of colorectal origin treated by cytoreduction and hyperthermic intraperitoneal chemotherapy: location, treatment, and outcome. Ann Surg Oncol. 2004;11:375–9. 16. Bijelic L, Yan TD, Sugarbaker PH. Treatment failure following complete cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal dissemination from colorectal or appendiceal mucinous neoplasms. J Surg Oncol. 2008;98:295–9. 17. Deraco M, Nonaka D, Baratti D, Casali P, Rosai J, Younan R, et al. Prognostic analysis of clinicopathologic factors in 49 patients with diffuse malignant peritoneal mesothelioma treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Ann Surg Oncol. 2006;13:229–37. 18. Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FA. Survival analysis of pseudomyxoma peritonei patients treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg. 2007;245:104–9. 19. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. In: Sugarbaker PH, editor. Peritoneal carcinomatosis: principles of management. Boston MA: Kluwer Academic Publishers; 1996. p. 359–74. 20. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221: 29–42. 21. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol. 1999;6:727–31. 22. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13. 23. Kianmanesh R, Scaringi S, Sabate JM, Castel B, Pons-Kerjean N, Coffin B, et al. Iterative cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis of colorectal origin with or without liver metastases. Ann Surg. 2007;245:597–603. 24. Verwaal VJ, Bruin S, Boot H, van Slooten G, van Tinteren H. 8year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol. 2008;15:2426–32. 25. Elias D, Lasser P, Hoang JM, Leclere J, Debaene B, Bognel C, et al. Repeat hepatectomy for cancer. Br J Surg. 1993;80:1557–62. 26. Adam R, Bismuth H, Castaing D, Waechter F, Navarro F, Abascal A, et al. Repeat hepatectomy for colorectal liver metastases. Ann Surg. 1997;225:51–60. 27. Adam R, Pascal G, Castaing D, Azoulay D, Delvart V, Paule B, et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg. 2004;240:1052–61. 28. Sugarbaker PH, Alderman R, Edwards G, Marquardt CE, Gushchin V, Esquivel J, et al. Prospective morbidity and mortality assessment of cytoreductive surgery plus perioperative intraperitoneal chemotherapy to treat peritoneal dissemination of appendiceal mucinous malignancy. Ann Surg Oncol. 2006;13: 635–44. 29. Glehen O, Osinsky D, Cotte E, Kwiatkowski F, Freyer G, Isaac S, et al. Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures. Ann Surg Oncol. 2003;10:863–9.