Ann Surg Oncol DOI 10.1245/s10434-015-5081-3

ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY

Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is Cure a Possibility? C. S. Chia, MBBS, MMed, FRCS1, B. You, MD, PhD2,11, E. Decullier, PhD3,4,5, D. Vaudoyer, MD1, G. Lorimier, MD6, K. Abboud, MD7,11, J.-M. Bereder, MD8, C. Arvieux, MD, PhD9,11, G. Boschetti, MD10, O. Glehen, MD, PhD1,11,12 and the BIG RENAPE Group 1

Hospices Civils de Lyon, Department of General and Oncologic Surgery, Cancer Institute, Pierre Be´nite, France; Hospices Civils de Lyon, Department of Oncology, Cancer Institute of HCL, Pierre Be´nite, France; 3Hospices Civils de Lyon, Poˆle Information Me´dicale Evaluation Recherche, Unite´ de Recherche Clinique, Lyon, France; 4Universite´ de Lyon, RECIF, EA Sante´ Individu Socie´te´ 4129, Lyon, France; 5Universite´ Lyon 1, Lyon, France; 6Service de Chirurgie Digestive et Cance´rologique, Centre P. Papin, Angers, France; 7Service de Chirurgie Ge´ne´rale, Hopital Nord, St Etienne, France; 8 Service de Chirurgie Ge´ne´rale et Cance´rologie Digestive, CHU L’Archet II, Nice, France; 9Service de Chirurgie Digestive, CHU A. Michallon, Grenoble, France; 10Department of Hepatogastroenterology, Cancer Institute of HCL, Lyon Sud, Pierre Be´nite, France; 11Universite´ Lyon 1, Research Unit EMR 3738, Lyon, France; 12Surgical Oncology Department, CHRU Lyon Sud, Pierre Be´nite, Cedex, France 2

ABSTRACT Background. Peritoneal carcinomatosis is an increasingly common finding in gastric carcinoma. Previously, patients were treated as terminal, and median survival was poor. The use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in this context is still highly debatable. Objective. The aim of this study was to evaluate the longterm outcomes associated with CRS and HIPEC, and define prognostic factors for cure, if possible. Patients and Methods. All patients with gastric carcinomatosis from five French institutions who underwent combined complete CRS and HIPEC and had a minimum follow-up of 5 years were included in this study. Cure was defined as a disease-free interval of more than 5 years from the last treatment until the last follow-up. Results. Of the 81 patients who underwent CRS and HIPEC from 1989 to 2009, 59 had a completeness of cytoreduction score (CCS) of 0 (complete macroscopic resection), and the median Peritoneal Cancer Index (PCI) score was 6. Mitomycin C was the most commonly used drug during HIPEC

Ó Society of Surgical Oncology 2016 First Received: 19 October 2015 C. S. Chia, MBBS, MMed, FRCS e-mail: [email protected]

(88 %). The 5-year overall survival (OS) rate was 18 %, with nine patients still disease-free at 5 years, for a cure rate of 11 %. All ‘cured’ patients had a PCI score below 7 and a CCS of 0. Factors associated with improved OS on multivariate analysis were synchronous resection (p = 0.02), a lower PCI score (p = 0.12), and the CCS (p = 0.09). Conclusion. The cure rate of 11 % for patients with gastric carcinomatosis who are deemed terminal emphasizes that CRS and HIPEC should be considered in highly selected patients (low disease extent and complete CRS).

Despite a decrease in the incidence of gastric cancer, it is the second leading cause of cancer-related death worldwide.1 Even for advanced cases without metastasis, prognosis is poor and the mortality rate high.2 Dissemination to the peritoneal cavity is increasingly common.3 Patients diagnosed with peritoneal disease from gastric adenocarcinoma have a poor prognosis, with a median survival of 1–3 months. Many are treated with palliative chemotherapy, which is associated with an overall survival (OS) of 8–12 months.2,4–8 Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are emerging as the standard of treatment in various pathologies, and are still being evaluated for peritoneal carcinomatosis (PC) from gastric carcinoma.9 Previous studies assessing the use of CRS and HIPEC in PC from

C. S. Chia et al.

gastric cancer have shown promising results but this approach is still not accepted as standard therapy.10 For this reason, we sought to assess the actual cure rate among patients with PC from gastric cancer at five French institutions of the BIG RENAPE (Base clinic-biologique des carcinoses peritoneales d’origine Digestive du Reseau National de Prise en charge des Tumeurs du Peritoine) group, and attempted to identify factors that predict longterm survival. Other authors evaluating poor prognostic conditions such as non-resectable colorectal liver or peritoneal metastasis previously defined ‘cure rate’ as a disease-free interval of at least 5 years after the last treatment, a definition we also use here.11,12 PATIENTS AND METHODS Consecutive patients from five French institutions who underwent CRS and HIPEC for carcinomatosis from gastric cancer, from 1989 to 2009, were included in this study. Data were collected retrospectively from the five institutions and entered into a central database. Patient Selection Patients diagnosed with PC from gastric cancer were considered for CRS and HIPEC. PC was confirmed histopathologically, and patients had to be fit for surgery, therefore only those with a performance status of 2 or less were considered. The presence of extra-abdominal disease, a contraindication for surgery, was excluded on preoperative imaging. In the majority of patients (76.1 %), a primary tumor resection was performed concurrently with CRS and HIPEC, while the remaining patients underwent CRS and HIPEC for recurrent disease in the peritoneum after initial curative surgery for their primaries. The feasibility of adequate cytoreduction was discussed at multidisciplinary tumor board meetings. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy CRS was performed as described by Jacquet and Sugarbaker with the aim of removing all macroscopic peritoneal disease.13 The extent of CRS performed (i.e. number of organ resections, extent of peritonectomy) was variable. Mitomycin C, cisplatin, or oxaliplatin was used as the intraperitoneal chemotherapy agent, and the duration of HIPEC was 90 min, administered at 42 °C. The institutions used different methods to perform the HIPEC procedure; three used the closed abdomen technique with the CavithermTM hyperthermic machine, and two used the open abdomen (coliseum) technique with the Clerad device and Gamidatech SunChipTM system.

Peritoneal Cancer Index and Completeness of Cytoreduction Score Institutions used the Peritoneal Cancer Index (PCI) score, as described by Jacquet and Sugarbaker, to characterize the extent of the disease intraoperatively.13 The completeness of resection was measured using the completeness of cytoreduction score (CCS).13 A CCS of 0 corresponds to macroscopic complete resection, while a CCS of 1 corresponds to resection leaving small deposits of 2.5 mm or less. In patients with a CCS of 2 or 3, residual deposits are more than 2.5 mm. CCS is one of the most important prognostic factors for CRS and HIPEC.14,15 For this reason, only patients who had a complete cytoreduction (CCS 0 or 1) were included in the current study. Postoperative Care and Course All intraoperative and 30-day postoperative complications were recorded. Morbidity was evaluated using the Common Terminology Criteria for Adverse Events, version 3.0, of the National Institutes of Health criteria. All patients were followed up with an outpatient computed tomography (CT) scan at the outpatient clinics approximately 4 weeks after surgery. Subsequently, follow-up was every 4 months for the first year and every 6 months thereafter. CT scans of the thorax, abdomen, and pelvis, together with tumor markers, were performed at each follow-up visit. Patients received adjuvant systemic chemotherapy depending on a subsequent multidisciplinary discussion, and events of recurrent disease were recorded. Endpoints and Analysis Our primary endpoint was cure rate, while secondary endpoints were OS and disease-free survival (DFS). OS was calculated as the time from CRS and HIPEC to death (death from other causes were censored), or censored at last follow-up if the patient was still alive. DFS was calculated as the time from CRS and HIPEC surgery to relapse, or censored at death or last follow-up if the patient had not relapsed. Patients were considered cured if they were disease-free 5 years or more after CRS and HIPEC. Baseline factors and intraoperative details were recorded. Postoperative details recorded were the length of hospital stay, complications, postoperative mortality, tumor histology, presence of signet ring cells, and adjuvant therapy. Cured and non-cured patients were compared using the Chi square test or Fishers exact test. Median survival rates were computed using the Kaplan– Meier method, and the influence of baseline risk factors on survival was assessed using univariate and multivariate Cox proportional hazards models. PCI cuts were chosen

CRS and HIPEC: Curing Gastric Peritoneal Disease?

according to a Mayo Clinic macro (FINDCUT), and multivariate OS was adjusted for age. SAS statistical software version 9.2 (SAS Institute Inc., Cary, NC, USA) was used for all analyses. RESULTS A total of 81 patients from the five institutions, with a median age of 51 years (range 24–73), fulfilled the inclusion criteria (Fig. 1). One single institution included 52 patients (64 %) and the others had fewer than 10 patients each. Patient characteristics are presented in Table 1. The majority of patients had involvement of the whole stomach (23.3 %), and 36 patients (46.8 %) underwent neoadjuvant chemotherapy. Intraoperatively, the median PCI was 6, and 34 patients had a score of 7 or more (47 %). The CCS was 0 for 59 patients (73 %) and 1 for 22 patients (27 %), and the median duration of surgery was 107.5 min (range 60–420). Mitomycin C was the intraperitoneal chemotherapeutic agent used in 71 patients (88 %), cisplatin in 8 patients, and oxaliplatin in the remaining 2 patients. The 30- and 90-day postoperative mortality rates were 2.5 and 6.2 %, respectively. Thirty-five patients (44 %) had grade III–IV postoperative complications, and the median

length of hospitalization was 18.5 days (range 8–117). For the final pathological analysis, 43 patients (56 %) had lymph node involvement; 30 patients (41 %) had signet ring cells, and 9 patients (12.5 %) had linitis plastica. A flowchart of the patient outcomes are detailed in Fig. 1; 6 of the 81 patients were lost to follow-up. The 5year OS was 18 %, median OS was 17.3 months, and median DFS was 12 months. Of 81 patients, 9 were alive and free of disease at 5 years after CRS and HIPEC, giving our study a cure rate of 11 %. Factors that differed significantly between cured and non-cured patients were the PCI values, with no patient having a PCI score above 7 in the cured group, and the presence of neoadjuvant chemotherapy and/or adjuvant treatment (Table 2), with fewer patients in the cured group undergoing neoadjuvant and/or adjuvant therapy. All patients in the cured group had a CCS of 0, compared with 68 % of patients in the non-cured group; this difference was not statistically significant (p = 0.0545). Fewer patients in the cured group (28.6 vs. 41.9 %) had signet ring cells identified on histology, but this difference was also not statistically significant (p = 0.6925). On Cox univariate analysis for OS, we found that synchronous resection, absence of signet ring cells, a low PCI

n = 145

Surgery before 2010 n = 114

CCS 0 or 1 n = 81

Cured n =9

Non-cured n = 66

Death within 5 years

With recurrence, n = 53 46 related deaths 1 unrelated death 6 un specified deaths

Alive at 5 years

Alive at 5 years

With recurrence <5 y, n = 3 1 related death >5 y 1 unspecified death >5 y

Without recurrence at 5 y, n=9 1 unrelated death >5 y 1 un specified death >5 y 7 alive at latest follow -up

FIG. 1 Patient selection and outcomes. CCS completeness of cytoreduction score

Lost to follow up n =6

Without recurrence at 5 y, unrelated death, n=3

C. S. Chia et al. TABLE 1 Patient modalities

and

tumor

characteristics,

and

treatment

of 0 (p = 0.09), and a low PCI (p = 0.12) were still in the model as predicting for improved survival.

N (%)

DISCUSSION Sex Female

44 (54.3)

Male

37 (45.7)

Age [median (range)]

51 (24–73)

Location of tumor Whole

19 (40.4)

Distal third Middle third

11 (23.4) 7 (14.9)

Proximal third

10 (21.3)

Missing

34

Tumor differentiation Well-differentiated

7 (12.5)

Moderately differentiated

13 (23.2)

Poorly differentiated

36 (64.3)

Missing

25

Histology Adenocarcinoma

62 (86.1)

Linitis plastic

9 (12.5)

Others

1 (1.4)

Missing

9

Synchronous resection of primary and peritoneal disease Yes No

54 (76.1) 17 (23.9)

Missing

10

Neoadjuvant treatment Yes

39 (48.1)

No

42 (51.9)

Adjuvant treatment Yes

37 (54.4)

No

31 (45.6)

Missing

13

score, and a CCS of 0 predicted for better OS at 5 years. When we analyzed the PCI score as a continuous variable, we found that each unit increase in PCI score increased the risk of death at 5 years by 10 % (p \ 0.001). When scores were analyzed by category (Fig. 2), a PCI score of 0–6 was associated with a median survival of 26.4 months, and a score of more than 7 was associated with a median survival of 10.9 months (hazard ratio [HR] 2.67 [1.54–4.64]; p \ 0.001). Those patients with a CCS of 1 had a median survival of 8.4 months (Fig. 3) compared with 22.1 months for those with a CCS score of 0 (HR 2.96 [1.69–5.20]; p \ 0.001). Patients without signet ring cells also showed a better OS of 21.8 months compared with 13.2 months for those who had signet ring cells (p = 0.0214). In the multivariate analysis, synchronous resection (p = 0.02), a CCS

PC is an increasingly common finding in patients with gastric carcinoma. Diagnostic laparoscopy and washings for peritoneal cytology are cited as appropriate in the National Comprehensive Cancer Network guidelines, and are performed by many centers as a staging tool. Reviewing patients undergoing diagnostic laparoscopy for staging of gastric adenocarcinoma, Sarela et al. found metastatic disease in 32 % of patients at presentation, 72 % of which were metastasis to the peritoneum only.16 CRS and HIPEC form the gold standard for treating diseases such as pseudomyxoma peritonei and peritoneal mesothelioma.17–19 The combination is also being accepted as possible therapy for PC from colorectal cancers and, in certain cases, ovarian cancer, especially in the recurrent setting.20–23 However, despite multiple published series of encouraging results for CRS and HIPEC in gastric cancer, the approach is still not accepted as standard treatment, likely because gastric cancer is still associated with a poor prognosis,even without peritoneal disease.9,14,15,24–26 With regard to morbidity, a 30-day mortality rate of 2.5 % was observed, which is comparable to the mortality rates in other series, which vary from 0 to 6.5 %.14,15,24–27 The 90-day mortality was 6.2 %, and the morbidity rate for grade III–IV complications was 43.8 %. These high rates underline the necessity of being highly selective with respect to the general status of the patient when combining CRS including gastrectomy with HIPEC. The 5-year OS rate was 18 %, while the median OS was 17.3 months. The literature shows 5-year OS rates of 13– 29 % and a median OS of 15–43.4 months.14,15,24–27 In their review, Gill et al. identified a median OS of 15 months for patients with a CCS of 0 or 1.10 However, a direct comparison of these studies is difficult because of changes in approaches over time and variability in factors such as adjuvant and neoadjuvant therapy, intraperitoneal chemotherapy agent (mitomycin C, cisplatin, oxaliplatin, etoposide, fluorouracil), duration of intraperitoneal chemotherapy (range 30–120 min), surgical techniques, extent of surgery, and perioperative care. A recent metaanalysis showed that the use of intraperitoneal chemotherapy improved OS at 1, 2, and 3 years for patients with gastric PC, but the data were not sufficient to demonstrate a benefit at 5 years.28 In many pathologies, including gastric cancer, one of the most important prognostic factors for CRS and HIPEC is the CCS.14,15 As such, we included only patients with a CCS of 0 or 1 in our study, and found that patients with a CCS of 0 did better than those with a CCS of 1. Yang et al.

CRS and HIPEC: Curing Gastric Peritoneal Disease? TABLE 2 Comparison of cured and non-cured patients Cured (n = 9)

Non-cured (n = 66)

p value

50 ± 11

52 ± 13

0.6077

Female

5 (55.6)

36 (54.5)

1.0000

Male

4 (44.4)

30 (45.5)

1

1 (16.7)

0 (0)

2

1 (16.7)

7 (18.9)

3

4 (66.7)

18 (48.6)

4

0 (0)

12 (32.4)

Missing

3 (.)

29 (.)

Age, mean ± SD Sex

T stage

N stage ?

0 (0)

2 (5.3)

0

1 (16.7)

2 (5.3)

1

1 (16.7)

6 (15.8)

2

4 (66.7)

16 (42.1)

3

0 (0)

12 (31.6)

Missing

3 (.)

28 (.)

Yes

7 (100.0)

43 (72.9)

No

0 (0)

16 (27.1)

Missing

2 (.)

7 (.)

0.0666

0.3631

Synchronous resection of primary and peritoneal disease 0.1815

Peritoneal Cancer Index 0–6

8 (100.0)

28 (46.7)

C7

0 (0)

32 (53.3)

0.0055

Missing

1 (.)

6 (.)

9 (100.0) 0 (0)

45 (68.2) 21 (31.8)

0.0545

1 (16.7)

6 (13.3)

0.117

CC score 0 1 Tumor differentiation Well-differentiated Moderately differentiated

3 (50.0)

8 (17.8)

Poorly differentiated

2 (33.3)

31 (68.9)

Missing

3 (.)

21 (.)

Yes

2 (25.0)

27 (44.3)

No

6 (75.0)

34 (55.7)

Missing

1 (.)

5 (.)

90 (65–180)

120 (60–420)

0.1829

Yes

0 (0)

20 (30.3)

0.1593

No

9 (100.0)

46 (69.7)

Presence of signet ring cells

Duration of surgery [min; median (range)]

0.4529

Duration of surgery C200 min

Complications Yes

3 (33.3)

30 (46.2)

No

6 (66.7)

35 (53.8)

0.7225

Missing

0 (.)

1 (.)

Length of hospital stay [days; median (range)]

20 (9–51)

18 (8–117)

0.9264

4 (44.4)

27 (40.9)

0.8400

Length of stay C21 days Yes

C. S. Chia et al. TABLE 2 continued Cured (n = 9)

Non-cured (n = 66)

5 (55.6)

39 (59.1)

Yes

3 (33.3)

34 (51.5)

No

6 (66.7)

32 (48.5)

Yes

2 (25.0)

34 (60.7)

No

6 (75.0)

22 (39.3)

Missing

1 (.)

10 (.)

Yes

4 (50.0)

54 (88.5)

No

4 (50.0)

7 (11.5)

Missing

1 (.)

5 (.)

No

p value

Neoadjuvant treatment 0.4799

Adjuvant treatment 0.1236

Neoadjuvant or adjuvant treatment 0.0185

Data are expressed as n (%) unless otherwise specified

FIG. 2 Overall survival by PCI group (PCI \ 7 and PCI C 7). PCI Peritoneal Cancer Index

1.00

PCI<7 PCI>=7

Survival probability

0.75

0.50

0.25

0.00 0

1

2

3

4

5

Time (in years)

PCI 7 Left Failed

PCI<7 Left Failed

0

1

2

3

4

5

33

13

5

2

2

1

0

19

26

29

29

30

39

27

18

15

11

10

0

9

17

20

23

24

CRS and HIPEC: Curing Gastric Peritoneal Disease? FIG. 3 Overall survival by CCS. CCS completeness of cytoreduction score

1.00

CCS0 CCS1

Survival probability

0.75

0.50

0.25

0.00 0

1

2

3

4

5

Time (in years)

CCS0

Left Failed

CCS1

Left Failed

also reported a significant difference in survival between patients with a CCS of 0 and 1.24 From our results, no patient with CCS 1 resection could be cured, and the median survival was 8 months, which is similar to that associated with systemic chemotherapy alone. Thus, CRS and HIPEC should not be considered when patients are not amenable to complete CRS. PCI score has demonstrated a prognostic impact.14,15 Our results showed that all ‘cured’ patients had a PCI less than 7, in keeping with the findings of Yonemura et al., who also showed that patients with a PCI of less than 7 had a significant survival advantage.29 Unfortunately, these cases with a low PCI are usually not detected on morphologic examinations. Laparoscopy is mandatory during pre-therapeutic work-up in order to detect this disease early and select the best candidates for CRS and HIPEC. Patients who have signet ring cells have a worse prognosis.30 Our results on univariate analysis for OS confirm this finding; however, this factor was no longer significant

0

1

2

3

4

5

58

38

25

18

14

12

0

16

27

34

37

39

22

9

3

0

0

0

0

12

18

21

21

21

on multivariate analysis. We suggest that if the patient has a PCI of less than 7 and a complete cytoreduction can be achieved, the presence of signet ring cells should not exclude the patient from having CRS and HIPEC. On univariate analysis to assess for predictive factors between the cured group and the non-cured group, a higher percentage of patients who did not have neoadjuvant therapy and/or adjuvant treatment was observed in the cured group. However, neoadjuvant treatment and adjuvant treatment separately were not statistically significant, although there were fewer patients with neoadjuvant or adjuvant treatment in the cured group. Patients receive neoadjuvant or adjuvant therapy as a result of the gastric tumor being of a higher stage, close or positive margins, or inadequate nodal clearance. However, our univariate analysis shows that the T and N stages are not strong prognostic factors; hence, positive or close margins, as well as inadequate lymph node clearance, may play a bigger role in influencing this factor. This shows that complete

C. S. Chia et al.

surgical clearance is still a very crucial point in the prognosis of a patient. With clear margins and adequate lymph node dissection, the chance of a patient requiring adjuvant radiotherapy is diminished and ultimately leads to a reduced risk of recurrence and better survival. The assumption is that patients who present with metastasis synchronously have a poorer survival than those who present with metastasis metachronously. Various studies conducted in liver metastasis from colorectal cancer observed no difference in survival between synchronous and metachronous presentation.31,32 However, our results show that patients who had synchronous resection of their primaries and PC had better OS. We postulate that during iterative surgery following gastrectomy, it is more difficult to perform an adequate and accurate carcinologic procedure than during the first laparotomy because of adhesions and the ‘cancer cell entrapment’ phenomenon. Improvement can be gained by treating carcinomatosis as early as possible, which can be achieved with the prophylactic use of HIPEC for patients at high risk of developing peritoneal disease (invasion of the serosa, lymph node involvement, and positive peritoneal cytology).33–35 We are currently conducting a trial to evaluate the role of HIPEC during surgery for the primary lesion in gastric cancer patients at high risk of developing PC (GASTRICHIP; ClinicalTrials.gov identifier NCT01882933).36 This study has several limitations, including the possible selection bias inherent in a retrospective study. To minimize this, we analyzed patients from a time period when all patients with peritoneal disease from gastric cancer were undergoing CRS and HIPEC, including those with a high PCI score and those who had CCS 2 disease after surgery. In addition, with a multi-institutional study, variations will be present in both the experience of the centers as well as in the HIPEC technique, although there is no evidence as yet to determine if these variations result in survival differences. We identified nine patients who were disease-free 5 years after CRS and HIPEC, giving our study a cure rate of 11 %, close to the 16 % reported by Goe´re´ et al., who performed a similar study on colorectal PC treated with CRS and HIPEC.12 Colorectal PC has a better prognosis compared with gastric PC. CRS and HIPEC constitute an accepted therapy for colorectal PC, and because the rates of cure are comparable, CRS and HIPEC should also be considered in selected patients with gastric PC. CONCLUSIONS Not only do patients with peritoneal metastasis from gastric carcinoma have a chance of long-term survival but they also have a chance of cure, defined as at least 5 years free of disease post-surgery. The key is the appropriate

selection of patients, which should involve considering the patient’s general status and age because of high rates of postoperative mortality and morbidity, and a PCI less than 7, which can often only be detected by preoperative laparoscopy. Most important, if cure is the goal, the aim should be complete clearance of the tumor with CCS 0. CRS and HIPEC form part of the armamentarium of tools available to physicians today to treat patients with PC from gastric adenocarcinoma, even if it requires further evaluation in randomized, prospective trials. ACKNOWLEDGMENT The authors thank Isabelle Bonnefoy for data collection, and Emilie Durand and Christelle Maurice for statistical analysis validation. DISCLOSURES Claramae S. Chia, Benoıˆt You, Evelyne Decullier, Delphine Vaudoyer, Ge´rard Lorimier, Karine Abboud, JeanMarc Bereder, Catherine Arvieux, Gilles Boschetti, and Olivier Glehen have no financial disclosures or conflict of interests.

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