Ann Surg Oncol DOI 10.1245/s10434-014-4297-y
ORIGINAL ARTICLE – COLORECTAL CANCER
Serious Postoperative Complications Affect Early Recurrence After Cytoreductive Surgery and HIPEC for Colorectal Peritoneal Carcinomatosis Geert A. Simkens, BSc (Med), Thijs R. van Oudheusden, MD, Misha D. Luyer, MD, PhD, Simon W. Nienhuijs, MD, PhD, Grard A. Nieuwenhuijzen, MD, PhD, Harm J. Rutten, MD, PhD, and Ignace H. de Hingh, MD, PhD Department of Surgical Oncology, Catharina Hospital, Eindhoven, The Netherlands
ABSTRACT Background. The prognosis of patients with peritoneally metastasized colorectal cancer has improved significantly with the introduction of cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS ? HIPEC). Although a macroscopically complete resection is achieved in nearly every patient, recurrence rates are high. This study aims to identify risk factors for early recurrence, thereby offering ways to reduce its occurrence. Methods. All patients with colorectal peritoneal carcinomatosis treated with CRS ? HIPEC and a minimum follow-up of 12 months, in April 2014, were analyzed. Patient data were compared between patients with or without recurrence within 12 months after CRS ? HIPEC. Risk factors were determined using logistic regression analysis. Postoperative complications were graded according to the serious adverse events (SAEs) score, with grade 3 or higher indicating complications requiring intervention. Results. A complete macroscopic cytoreduction was achieved in 96 % of all patients treated with CRS ? HIPEC. Forty-six of 133 patients (35 %) developed recurrence within 12 months. An SAE C3 after CRS ? HIPEC was the only significant risk factor found for early recurrence (odds ratio 2.3; p = 0.046). Median survival in the early recurrence group was 19.3 months compared with 43.2 months in the group without early recurrence (p \ 0.001). Patients with an SAE C3 showed a reduced
Ó Society of Surgical Oncology 2014 First Received: 19 September 2014 I. H. de Hingh, MD, PhD e-mail:
[email protected]
survival compared with patients without such complications (22.1 vs. 31.0 months, respectively; p = 0.02). Conclusions. Early recurrence after CRS ? HIPEC is associated with a significant reduction in overall survival. This study identifies postoperative complications requiring intervention as the only significant risk factor for early recurrence, independent of the extent of peritoneal disease, highlighting the importance of minimizing the risk of postoperative complications.
At least 10 % of patients with colorectal cancer (CRC) develop peritoneal metastases during the course of their disease.1,2 In these patients, treatment with systemic chemotherapy alone does not result in long-term survival.3,4 During the last decades, cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS ? HIPEC) has acquired a prominent role in the treatment of peritoneal carcinomatosis (PC) of CRC. Its reported survival rates now typically range from 24 to 40 months.5,6 CRS ? HIPEC often includes major surgery and is associated with acceptable morbidity in relation to the improved oncological prognosis.7 However, patient selection is of utmost importance in order to combine good results with an acceptable treatment-related morbidity and mortality. In fact, optimizing patient selection may nowadays be regarded as one of the biggest challenges in the treatment of patients with PC. The aim of CRS ? HIPEC is surgical removal of all visible tumors combined with destruction of the remaining microscopic disease with heated chemotherapy. Despite radical removal of all tumor tissue in the vast majority of patients, recurrence rates are high.8–10 The current study focuses on identifying important factors in patients who develop recurrence within 1 year after CRS ? HIPEC. While these patients are exposed to CRS ? HIPEC, they are less likely to benefit from this major intervention. By
G. A. Simkens et al.
identifying risk factors for such early recurrence, patient selection may be further improved and patients at risk for early recurrence may receive more intense follow-up in order to detect and possibly treat recurrence at an early stage. METHODS Patients This study protocol was approved by the local Medical Ethics Committee of the Catharina Hospital. All patients with PC of CRC treated in our hospital with CRS ? HIPEC between June 2007 and April 2013 were included in the current study. Relevant patient-, tumor-, and treatmentrelated characteristics were collected in a prospective database, which contained 133 patients. Minimal follow-up was 12 months but patients who died within this period were also included in the analysis, resulting in a shorter follow-up for these patients. Postoperative complications were staged according to the serious adverse events (SAEs) score, with an SAE C3 indicating a complication requiring an intervention, either surgical or radiological.11 Patients with early recurrence were defined as those who developed local and/or systemic recurrent disease within 12 months after CRS ? HIPEC. Recurrence was diagnosed by either radiological assessment or laparotomy/laparoscopy with histological confirmation. Intraperitoneal, intra-abdominal or abdominal wall recurrence was defined as ‘local recurrence’. Liver, lung, or other systemic metastases were defined as ‘systemic recurrence’. In case of recurrence, a multidisciplinary team assessed the treatment strategy of choice, being resection, systemic treatment, radiotherapy, or optimal supportive/palliative care. CRS ? HIPEC All procedures were performed by a specialized surgical team with expertise in CRS ? HIPEC, as described extensively elsewhere.12 The extent of peritoneal disease was assessed using the peritoneal cancer index (PCI) score.13 The success of cytoreduction was scored using the R-score (R1 = no macroscopic disease, R2a = macroscopic residual disease B2.5 mm, and R2b = macroscopic residual disease between 2.5 mm and 2.5 cm). Only patients with an R1 or R2a cytoreduction status were included in this study. Statistics Statistical analyses were performed using the Statistical Package for Social Sciences, Version 21.0 (IBM Corporation, Armonk, NY, USA). All relevant parameters were compared between those with recurrent disease within
12 months after CRS ? HIPEC and those without recurrence within 12 months using a v2 or Fisher’s exact test according to sample size. In case of continuous variables, Student’s t test or Mann–Whitney U-test were used, depending on distribution. All tests were performed twosided and a p value \0.05 was considered statistically significant. Risk factors were determined by analyzing all non-correlating variables with p B 0.05 in a binary logistic regression analysis. Multicollinearity and correlation were assessed using the variance inflation factor and Pearson’s v2 test. The Kaplan–Meier test, with comparison using the log-rank test, was used to analyse survival. RESULTS Altogether, CRS ? HIPEC was performed in 133 patients (57 % female) with a median age of 62.0 years. Median follow-up time was 22.9 (0.4–75.3) months. During follow-up, recurrence was diagnosed in 82 patients (62 %). Mean time to recurrence was 12.4 ± 8.0 months. Early recurrence within 1 year was diagnosed in 46 patients (35 %)—locoregional in 17 patients, systemic in 15 patients, and both locoregional and systemic in 14 patients. This group of 46 patients has been systematically compared with the group of 87 patients showing either recurrence after 1 year or no recurrence at all. The mean PCI score was higher in the early recurrence group (9.8 ± 5.5 vs. 8.0 ± 4.7), reaching borderline significance (p = 0.051). Tumor characteristics such as location of the primary tumor, histological differentiation, T status, and lymph node involvement did not differ between both groups. Also, the percentage of patients with synchronous PC was similar in both groups. Chemotherapy, either neoadjuvant or adjuvant, was given with equal frequency. There were no significant differences between both groups in the time interval between CRS ? HIPEC and the start of adjuvant chemotherapy or the number of provided cycles. Patient- and tumor-related characteristics are compared in Table 1. Complete macroscopic cytoreduction (R1) was achieved in 96 % of all patients (94 % in the early recurrence group vs. 98 % in the no early recurrence group; p = 0.34). Mean procedure time, including HIPEC, was the same as well. While the median amount of blood loss was higher in the early recurrence group [1,000 (250–4,000) vs. 700 (100–6,600) ml], this difference remained not statistically significant. The number of postoperative complications requiring intervention (SAEs C3) was significantly higher in the early recurrence group (37 vs. 18 %; p = 0.02). This difference between groups was also reflected in the frequency of intraabdominal complications (28 vs. 13 %; p = 0.03) and median hospital stay (13 vs. 10 days; p = 0.003). The number of re-
Complications Affect Recurrence After HIPEC TABLE 1 Patient and tumor characteristics and recurrence rates of patients undergoing cytoreduction and HIPEC All patients Recurrence \1 year [n = 133 (100 %)] [n = 46 (34.6 %)]
Recurrence [1 year, or no recurrence [n = 87 (65.4 %)]
p value
Male
57 (42.9)
19 (41.3)
38 (43.7)
0.79
Female
76 (57.1)
27 (58.7)
49 (56.3)
62.0 (24.3–77.9)
63.0 (24.3–77.9)
61.1 (37.7–77.1)
0.20
1
17 (12.8)
3 (6.5)
14 (16.1)
0.26
2 3
107 (80.5) 9 (6.8)
39 (84.8) 4 (8.7)
68 (78.2) 5 (5.7)
Synchronous
80 (60.2)
24 (52.2)
56 (64.4)
Metachronous
53 (39.8)
22 (47.8)
31 (35.6)
8.6 ± 5.0
9.8 ± 5.5
8.0 ± 4.7
Right colon
47 (35.3)
21 (45.7)
26 (29.9)
Transverse
11 (8.3)
1 (2.2)
10 (11.5)
Left colon
8 (6.0)
4 (8.7)
4 (4.6)
Sigmoid
46 (34.6)
12 (26.1)
34 (39.1)
Rectum
21 (15.8)
8 (17.4)
13 (14.9)
Good
12 (9.0)
6 (13.0)
6 (6.9)
Moderate
66 (49.6)
20 (43.5)
46 (52.9)
Poor Signet cell
24 (18.0) 8 (6.0)
5 (10.9) 5 (10.9)
19 (21.8) 3 (3.4)
Unknown
23 (17.3)
10 (21.7)
13 (14.9)
22 (16.5)
7 (15.2)
15 (17.2)
0.77
B3
65 (48.9)
23 (50.0)
42 (48.3)
0.93
4
66 (49.6)
22 (47.8)
44 (50.6)
Unknown
2 (1.5)
1 (2.2)
1 (1.1)
0
45 (33.8)
15 (32.6)
30 (34.5)
1
31 (23.3)
12 (26.1)
19 (21.8)
2
54 (40.6)
19 (41.3)
35 (40.2)
Variable Gender
Age at CRS ? HIPEC [years; median (range)] ASA score
Diagnosis of initial peritoneal metastasis
PCI score (mean ± SD)
0.17 0.051
Tumor location 0.10
Tumor differentiation
Mucinous
0.12
T status
N status
Unknown
0.75
3 (2.3)
0
3 (3.4)
Neoadjuvant chemotherapy
21 (15.8)
7 (15.2)
14 (16.1)
0.90
Adjuvant chemotherapy
104 (78.2)
38 (82.6)
66 (75.9)
0.37
Interval between CRS ? HIPEC and adjuvant chemotherapy [months; median (range)]
1.9 (0.2–7.5)
2.0 (0.2–7.5)
1.9 (0.5–7.0)
0.68
No. of cycles of adjuvant chemotherapy [mean ± SD]
6.6 ± 2.2
6.2 ± 2.6
6.9 ± 1.9
0.21
0.58
Type of recurrence Locoregional
32 (39.0)
17 (37.0)
15 (41.7)
Systemic
23 (28.0)
15 (32.6)
8 (22.2)
Both
27 (32.9)
14 (30.4)
13 (36.1)
Data are expressed as n (%) unless otherwise specified CRS ? HIPEC cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, ASA American Society of Anesthesiologists, PCI peritoneal cancer index, SD standard deviation
G. A. Simkens et al. TABLE 2 Operative data and postoperative complications of patients undergoing cytoreduction and HIPEC All patients [n = 133 (100 %)]
Recurrence \1 year [n = 46 (34.6 %)]
1
128 (96.2)
2a
5 (3.8)
Variable
Recurrence [1 year, or no recurrence [n = 87 (65.4 %)]
p value
43 (93.5)
85 (97.7)
0.34
3 (6.5)
2 (2.3)
R-score
Procedure timea [min; mean ± SD]
374 ± 75
386 ± 71
367 ± 76
0.15
Blood loss [ml; median (range)]
750 (100–6,600)
1,000 (250–4,000)
700 (100–6,600)
0.09
No. of bowel anastomoses C1
100 (75.2)
33 (71.7)
67 (77.0)
0.50
Enterostomy Complications
52 (39.1)
22 (47.8)
30 (34.5)
0.13
SAEs grade C3
33 (24.8)
17 (37.0)
16 (18.4)
0.02
Intra-abdominal complication
24 (18.0)
13 (28.3)
11 (12.6)
0.03
Abscess
14 (10.5)
7 (15.2)
7 (8.0)
0.24
Fistula
8 (6.0)
3 (6.5)
5 (5.7)
1.00
Gastrointestinal leakage
6 (4.5)
2 (4.3)
4 (4.6)
1.00
Bleeding
2 (1.5)
2 (4.3)
0
0.12
Urinoma
1 (0.8)
0
1 (1.1)
1.00
Infected intra-abdominal hematoma
1 (0.8)
0
1 (1.1)
1.00
Peritonitis with unknown cause
1 (0.8)
1 (2.2)
0
0.31
Ileus
23 (17.3)
6 (13.0)
17 (19.5)
0.35
Wound infection
20 (15.0)
8 (17.4)
12 (13.8)
0.58
Pneumonia
10 (7.5)
5 (10.9)
5 (5.7)
0.31
Urinary tract infection
12 (9.0)
4 (8.7)
8 (9.2)
1.00
Wound dehiscence Line sepsis
5 (3.8) 3 (2.3)
3 (6.5) 2 (4.3)
2 (2.3) 1 (1.1)
0.34 0.28
Pulmonary embolism
1 (0.8)
1 (2.2)
0
0.35
Re-operation to treat complication
19 (14.3)
8 (17.4)
11 (12.6)
0.46
30-day/in-hospital mortality
1 (0.8)
0
1 (1.1)
1.00
Hospital stay [days; median (range)]
11 (4–84)
13 (7–84)
10 (4–79)
0.003
Bold values indicate difference between groups being significant Data are expressed as n (%) unless otherwise specified HIPEC hyperthermic intraperitoneal chemotherapy, R-score resection score, SAEs serious adverse events, SD standard deviation a
Both cytoreductive surgery and HIPEC
operations was higher in the early recurrence group but the difference was not statistically significant. One patient (0.8 %) died during the initial admission. Additionally, three patients (2.3 %) died after 30 days during re-admission due to complications directly related to CRS ? HIPEC. Patients with SAEs C3 were treated with adjuvant chemotherapy less frequently than those remaining free of such complications (61 vs. 84 %; p = 0.005). The time interval between CRS ? HIPEC and the administration of adjuvant chemotherapy was longer in the group with SAEs C3 (4.0 ± 1.7 vs. 2.0 ± 1.0 months; p = 0.001). Operation details and complications from treatment are listed in Table 2. In a multivariate analysis (Table 3), only the occurrence of postoperative complications requiring an intervention (SAEs C3) was associated with early recurrence [odds ratio
(OR) 2.3; 95 % confidence interval (CI) 1.02–5.30; p = 0.046]. There was no statistical significant influence of PCI on the risk of developing early recurrence (OR 1.1; 95 % CI 0.98–1.14; p = 0.13). Overall median survival was 27.0 months (95 % CI 18.8– 35.3). Median survival in the early recurrence group was 19.3 (95 % CI 14.2–24.5) months compared to 43.2 (95 % CI 28.1– 58.2) months in the group without early recurrence (p \ 0.001; Fig. 1). The overall 3-year survival rate was 42 % (20 % in the early recurrence group vs. 55 % in the other group; p \ 0.001). Patients with complications graded as SAEs C3 showed a reduced survival compared to patients who did not experience such complications [median survival 22.1 (95 % CI 17.0–27.2) vs. 31.0 (95 % CI 17.7–44.4) months, respectively; p = 0.02; Fig. 2]. In a subanalysis in which
Complications Affect Recurrence After HIPEC TABLE 3 Multivariate analysis of risk factors for developing early recurrence in patients undergoing cytoreduction and HIPEC Variable
Recurrence \1 year [n = 46 (34.6 %)]
Recurrence [1 year, or no recurrence [n = 87 (65.4 %)]
p value
Odds ratio
95 % CI
SAEs C3 [n (%)]
17 (37.0)
16 (18.4)
0.046
2.3
1.02–5.30
PCI score [mean ± SD]
9.8 ± 5.5
8.0 ± 4.7
0.13
1.1
0.98–1.14
Bold value indicates difference between groups being significant HIPEC hyperthermic intraperitoneal chemotherapy, SAEs serious adverse events, PCI peritoneal cancer index, CI confidence interval, SD standard deviation
100
100
With SAE ≥3
Early Recurrence
Without SAE ≥3
No Early Recurrence 80
Cumulative Survival (%)
Cumulative Survival (%)
80
60
40
20
60
40
20
0
0 0
20
40
60
Months after CRS + HIPEC
0
20
40
60
Months after CRS + HIPEC
FIG. 1 Kaplan–Meier survival curves for patients with early recurrence and those without early recurrence. CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy
FIG. 2 Kaplan–Meier survival curves for patients with or without SAEs C3. SAEs serious adverse events, CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy
fatal treatment-related deaths were omitted, a similar difference was still present although statistically nonsignificant [median survival 23.3 (95 % CI 19.2–27.4) vs. 31.0 (95 % CI 17.3–44.7) months, respectively; p = 0.11].
early recurrence. This study reports on the largest singlecenter cohort identifying risk factors for early recurrence after CRS ? HIPEC published in literature today. In this cohort, postoperative complications requiring intervention were significantly associated with an increased risk of early recurrence (OR 2.3) and decreased survival. A recent two-center study with 101 patients also identified postoperative morbidity as an independent prognostic factor for disease-free survival.14 In addition, patients who were disease-free 5 years after CRS ? HIPEC had experienced less postoperative complications than those with recurrent disease.15 A similar phenomenon has also been observed after surgery for colorectal liver metastases where postoperative morbidity was associated with early recurrence (OR 4.7).16 Reported recurrence rates in patients with postoperative complications after radical resection for CRC were also increased.17 Finally, anastomotic leakage has been described as a risk factor for both local and
DISCUSSION As patients who experience early recurrence after CRS ? HIPEC are unlikely to experience significant benefit from this drastic treatment, it is imperative to determine the factors that may affect its development. The current study shows that approximately 35 % of patients develop recurrent disease within 1 year after an intensive multimodality treatment combining CRS and HIPEC. Early recurrence was not related to PCI, completeness of cytoreduction, or other tumor-related factors. However, patients with postoperative complications requiring an intervention (SAE C3) had a significantly increased risk of developing
G. A. Simkens et al.
systemic recurrence after curative surgery in patients with rectal cancer.18,19 In line, these studies support a relation between the occurrence of serious postoperative complications and a decreased disease-free survival. The correlation between serious postoperative complications and early recurrence of CRC may be explained in several ways. Most postoperative complications are related to an increased systemic inflammatory response that stimulates tumor growth through activating pro-inflammatory cascades.20 Moreover, the innate immune system chronically inhibits cancer proliferation less effectively when a systemic infection has to be fought.21,22 Through these mechanisms, postoperative complications can lead to increased tumor proliferation and early recurrent disease, both locally and systemically.23 A second explanation may be that in patients with serious postoperative complications, adjuvant chemotherapy is often postponed or omitted.18 In the present study, adjuvant chemotherapy was indeed administered less frequently and postponed more often in patients with serious postoperative complications. Patients with complications requiring intervention had a reduced survival compared with those without complications, which can only partially be explained by the direct effect of fatal postoperative complications. As may be expected, the median survival of patients with early recurrence was significantly lower than those of patients without early recurrence, as previously described by Verwaal et al.24 Nevertheless, these patients still exhibit a better survival than PC patients receiving only systemic chemotherapy.25 A higher PCI as a risk factor for recurrence has been described repeatedly.10,15,26 The present study found a univariate borderline significant correlation between PCI and early recurrence, which was not significant in the multivariate analysis. Also, others have identified lymph-node status, tumor grade, and completeness of cytoreduction as independent risk factors for recurrence;9,26 however, no such correlations were found in the current cohort. Since the occurrence of postoperative complications requiring intervention is an apparent risk factor for early recurrence, minimizing the risk of postoperative morbidity should be a major aim of treatment. A large French multicenter study found the experience of an HIPEC center to be a strong prognostic factor for both the number of postoperative complications and disease-free survival.26 It should be emphasized that CRS ? HIPEC is a challenging and complicated procedure, which should be performed exclusively in specialized centers. Next to minimizing the risk of postoperative complications, one could elaborate on other measures to reduce the early recurrence rate. For example, the percentage of patients treated with neoadjuvant chemotherapy in this cohort was low. The additional effect of neoadjuvant therapy on early recurrence in colorectal PC is not yet clear, and even large
trials report no benefit regarding overall survival for patients receiving neoadjuvant chemotherapy.15,26 Nevertheless, since a good response to neoadjuvant chemotherapy could be used as a predictor for improved survival in patients with colorectal liver metastases, several studies suggest using such a strategy in selecting patients with PC as well.27,28 In order to determine if neoadjuvant chemotherapy itself can specifically reduce early recurrence, more research is warranted. Further improvement of treatment efficacy could possibly be found in the HIPEC component. The chemotherapeutic agent used for HIPEC in the present study is mitomycin C. Currently, there is no consensus for a single agent to be superior for use in HIPEC, although a recent multicenter study reports a better survival with mitomycin C than with oxaliplatin in patients with lower disease burden and favorable histology.29 Overall, none of the currently used HIPEC agents has been indisputably proven to be superior over the other.30 It seems conceivable that the choice for antineoplastic agents can be further optimized. As prevention of early recurrence will not always be possible, management of recurrence could be an option to gain benefit in terms of survival. In selected patients, surgical resection of liver and/or local recurrence gives an increase in overall survival.10,31 To assess the possibility of treatment in patients with early recurrence, further research is needed. Although baseline characteristics were comparable, some degree of selection bias between specific subgroups cannot be ruled out due to the retrospective interpretation of this prospective database. The occurrence of postoperative complications may be related to comorbidity (e.g. diabetes) or habits (e.g. smoking), and further research is warranted on the preoperative assessment of the risk of postoperative complications.
CONCLUSIONS Early recurrence after CRS and HIPEC is associated with a significant reduction in overall survival. This study identifies postoperative complications requiring intervention as the only significant risk factor for early recurrence, independent of the extent of peritoneal disease or other tumor- and patient-related variables. These results highlight the importance of minimizing the risk of postoperative complications, and lend support to recommendations to perform these procedures in experienced centers only. DISCLOSURES
No disclosures to report.
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