Ann Surg Oncol DOI 10.1245/s10434-015-4387-5
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Extent of Colorectal Peritoneal Carcinomatosis: Attempt to Define a Threshold Above Which HIPEC Does Not Offer Survival Benefit: A Comparative Study Diane Goe´re´, MD, PhD1, Amine Souadka, MD1, Matthieu Faron, MD1,2, Alexis S. Cloutier, MD1, Benjamin Viana, MD1, Charles Honore´, MD1, Fre´de´ric Dumont, MD1, and Dominique Elias, MD, PhD1 Department of Surgical Oncology, Gustave Roussy, Cancer Center, Villejuif Cedex, France; 2Departement of Biostatistics, Gustave Roussy, Cancer Center, Villejuif Cedex, France
ABSTRACT Background. The main prognostic factors after complete cytoreductive surgery (CCRS) of colorectal peritoneal carcinomatosis (PC) followed by intraperitoneal chemotherapy (IPC) are completeness of the resection and extent of the disease. This study aimed to determine a threshold value above which CCRS plus IPC may not offer survival benefit compared with systemic chemotherapy. Methods. Between March 2000 and May 2010, 180 patients underwent surgery for PC from colorectal cancer with intended performance of CCRS plus IPC. Results. Among the 180 patients, CCRS plus IPC could be performed for 139 patients (curative group, 77 %), whereas it could not be performed for 41 patients (palliative group, 23 %). The two groups were comparable in terms of age, gender, primary tumor characteristics, and pre- and postoperative systemic chemotherapy. The mean peritoneal cancer index (PCI) was lower in the curative group (11 ± 7) than in the palliative group (23 ± 7) (p \ 0.0001). After a median follow-up period of 60 months (range 47–74 months), the 3year overall survival (OS) rate was 52 % [95 % confidence interval (CI) 43–61 %] in the curative group compared with 7 % (95 % CI 2–25 %) in the palliative group. Comparison of the survivals for each PCI (ranging from 5 to 36) shows that OS did not differ significantly between the two groups of
Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4387-5) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2015 First Received: 1 October 2014 D. Goe´re´, MD, PhD e-mail: [email protected]
patients when the PCI was higher than 17 (hazard ratio 0.64; range 0.38–1.09). Conclusion. This study confirmed the major prognostic impact of PC extent. When the PCI exceeds 17 in PC of colorectal origin, CCRS plus IPC does not seem to offer any survival benefit.
Peritoneal extension of colorectal cancer is common. It is synchronous in 5 to 10 % of patients and metachronous in 25 % of patients.1 The presence of peritoneal carcinomatosis (PC) confers a poor prognosis. However, the survival of patients with PC has improved during recent years through complete cytoreductive surgery (CCRS) of the disease followed by intraperitoneal chemotherapy (IPC).2–10 Such treatment has led to a 5-year overall survival rate of 30–49 %.4,6,8–10 Among many prognostic factors identified for selection of patients who could benefit from this treatment,4,5,9,11,12 a key prognostic factor is completeness of cytoreduction. Indeed, the median survival period is about 12 months among patients for whom macroscopically complete resection of PC is not possible.3,13,14 This survival time is comparable with that obtained using palliative systemic chemotherapy alone,15,16 which is associated with significantly lower morbidity and mortality risks. Another major prognostic factor is the extent of PC, which is intimately associated with completeness of resection. Peritoneal extension is evaluated by different scores, the most common of which is that established by Sugarbaker: the peritoneal cancer index (PCI) ranging from 0 to 39.17 A PCI higher than 1618 or 2019 has been demonstrated to have a negative prognostic impact. But in fact, when complete resection of the lesions is possible, a high PCI is not considered a contraindication to surgery. Indeed,
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67 % of the voters attending the Milan Peritoneal Oncology Consensus Meeting did not regard a PCI higher than 20 to be an absolute exclusion criterion for the combined treatment. Furthermore, these threshold values were identified by statistically determining a significant difference in overall survival among a single group of patients. This study aimed to determine a threshold value above which CCRS plus IPC offers no survival benefit compared with systemic chemotherapy alone. PATIENTS AND METHODS Selection Criteria Patients were selected from a prospective database. All patients presenting with PC of colorectal origin whose treatment was intended to be CCRS plus IPC were included in this study. Preoperative Workup The diagnosis of colorectal PC was histologically confirmed. The preoperative evaluation included clinical examination, biologic assessment of serum tumor markers (carcino embryonic antigen and carbohydrate antigen 199), and contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis. In this study, 18-fluorodesoxyglucose (18-FDG)-positron emission tomography (PET) was not systematically performed. The decision to perform an exploratory laparotomy followed by CCRS plus IPC was made at a multidisciplinary meeting. The contraindications for CCRS plus IPC were World Health Organization (WHO) performance status greater than 2, age exceeding 70 years, disease progression under chemotherapy, extraperitoneal extension (except for two or three liver metastases amenable to complete resection), and bulky peritoneal nodules with diffuse invasion of the mesentery shown on a CT scan.
then were assigned to the curative group or the palliative group based on the possibility of CCRS performance. Only patients who underwent CCRS (no remaining tumor nodules [1 mm) received IPC. These patients formed the curative group. For a minority of patients, chemotherapy was administered mainly as hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin ± irinotecan or as early postoperative intraperitoneal chemotherapy (EPIC). For patients in whom CCRS could not be achieved (palliative group), the reasons for unresectability were reported, and palliative surgery was performed according to symptoms. These patients then were offered palliative chemotherapy. Follow-up Evaluation The patients were followed up every 3 months during the first 2 years, then every 6 months to 3 years thereafter. Each follow-up visit included clinical examination, serum tumor marker determination, and an abdominopelvic CT scan. When recurrence was suspected, imaging was analyzed by two radiologists and could be supplemented by 18-FDG-PET. Statistical Analysis
The majority of the patients received preoperative systemic chemotherapy. The regimens were selected according to current recommendations and primary tumor response. Treatment was adjusted according to toxicity and based on the patient’s general condition.
Quantitative data are expressed as means ± standard deviations unless otherwise stated. Qualitative data are expressed as number (%). A p value of lower than 0.05 was considered significant. Categorical variables were compared within groups using v2 and Fisher exact tests when appropriate. The survival analysis was performed using the Kaplan–Meier method and compared using the log-rank test. In the multivariate analysis, a Cox proportional hazard model was used to identify the set of independent predictors of survival. In the search to determine the threshold PCI value for which CCRS plus IPC is debatable, patients with a very low PCI (i.e., patients certain to be treated with CCRS plus IPC) and patients with a very high PCI (i.e., patients for whom CCRS plus IPC could not be considered) were excluded from our analysis. The statistical analysis was restricted to patients within the PCI brackets in which the PCI scores of patients from both groups overlapped.
Surgery and IPC
Every patient in this study underwent explorative laparotomy aimed at intended performance of curative CCRS and IPC. At laparotomy, meticulous exploration of the abdominal cavity was performed, and the PCI was calculated. Patients
Between March 2000 and May 2010, 180 patients presenting with PC of colorectal origin underwent treatment intended to be CCRS plus IPC. Complete cytoreductive surgery followed by IPC was performed for 139 of the
Colorectal Carcinomatosis: HIPEC or Not? TABLE 1 Patients and tumor characteristics
Curative group (CCRS plus IPC) n (%)
Palliative group (ineligible for CCRS plus IPC) n (%)
49 ± 10
51 ± 12
Site of primary cancer
pT stage of primary colorectal cancer
T1 or T2
T3 or T4
Therapy 16(11.6) pN staging of primary colorectal cancer
Mean peritoneal cancer index
11 ± 7
23 ± 7
Extraperitoneal metastases (ovaries excluded)
Intraperitoneal chemotherapy EPIC alone
23 ± 10
10 ± 7
HIPEC alone Median hospital stay (days) Postoperative complications
Preoperative chemotherapy CCRS complete cytoreductive surgery, IPC intraperitoneal chemotherapy, PC peritoneal carcinomatosis, EPIC early postoperative intraperitoneal chemotherapy, HIPEC hyperthermic intraperitoneal chemotherapy
Postoperative chemotherapy Yes No Unknown
patients (curative group, 77.2 %), whereas CCRS could not be achieved for 41 of the patients (palliative group, 22.8 %). The group consisted of 108 women (60 %) and 75 men (40 %) with a median age of 51 years (range 19– 70 years). The primary tumor was located in the colon in 81 % of the cases. Lymph node invasion was present at the diagnosis in 83 % of the patients. Details concerning the demographics of the patients and the characteristics of the primary tumor are reported in Table 1.
The PC was synchronous with the primary tumor in 59.5 % of the patients, with no significant difference between the curative group (55 %) and the palliative group (73 %) (p = 0.06). Extraperitoneal metastases (ovarian metastases excluded) were present at diagnosis of the PC in 23 % of the patients, mostly located in the liver (19 % of the cases), with no significant difference between the two groups. Details of the PC characteristics are presented in Table 1.
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Chemotherapy Systemic chemotherapy was administered before surgical exploration for the great majority of the patients (92 %), with no significant difference between the two groups. This systemic chemotherapy was based on 5-fluorouracil (5-FU) plus oxaliplatin (n = 105) or irinotecan (n = 83) or on 5-FU alone (n = 1). Some patients received several lines of chemotherapy. Targeted therapies were added for 62 patients (bevacizumab for 49 patients and cetuximab for 13 patients). Postoperative systemic chemotherapy was administered to 117 patients (65 %), with no significant difference between the two groups (p = 0.09). Surgical Results and Postoperative Course Most of the 139 patients from the curative group were treated with HIPEC (87 %). Oxaliplatin plus irinotecan was used for 72 % of the patients, whereas oxaliplatin alone was used for 15 % of the patients. The remaining 13 % of the patients received mitomycin/5-FU-based EPIC. The mean PCI was significantly lower in the curative group (11 ± 7) than in the palliative group (23 ± 7) (p \ 0.0001). Moreover, the mean number of invaded abdominal regions was significantly lower in the curative group (6 ± 3 vs. 10 ± 3; p \ 0.0001). The reasons for unresectability and the types of surgery performed are presented in Table 2. The main reasons preventing CCRS were major peritoneal extension and involvement of the small bowel and mesentery (75.6 % of the 41 patients). Surgical exploration without resection was performed for more than half of the patients (56.1 %) in the palliative group. For the remaining patients of this group, internal derivation or palliative bowel resections were performed to avoid postoperative intestinal obstruction. Postoperatively, 10 (5.6 %) patients died, 8 (5.8 %) in the curative group and 2 (4.9 %) in the palliative group (p [ 0.999). For the latter two patients, more than 90 % of the disease had been resected. The death occurred from a hemorrhagic shock in the one case and from sepsis due to anastomotic leakage in the other case. Intraabdominal complications occurred for 21.7 % of the patients, without a significant difference between the two groups (p = 0.42). Extraabdominal complications occurred more frequently in the curative group (44.6 %) than in the palliative group (12.2 %) (p = 0.0003). The mean hospital stay was significantly longer for the patients in the curative group (23 ± 10 vs. 10 ± 7; p \ 0.0001). Survival and Prognostic Factors The median follow-up period was 60 months [95 % confidence interval (CI) 47–74 months] from the CCRS
TABLE 2 Reasons for unresectability and type of surgery performed in patients ineligible for complete cytoreductive surgery (CCRS) plus intraperitoneal chemotherapy (IPC) Reasons for unresectability Extent of PC
Mesentery/small bowel involvement
Extent of PC ? mesentery/small bowel involvement Retroperitoneal lymph nodes
Hepatic pedicle involvement
Extent of PC ? liver metastases
Liver metastases ? pleural extension
Liver metastases ? retroperitoneal lymph nodes
Organes ‘‘noble’’ involvementa
Surgery performed in patients ineligible for CCRS plus IPC Surgical exploration only
Small bowel resection
Small bowel resection ? large bowel resection
Large bowel resection
Small bowel resection ? liver resection
Small bowel resection ? retroperitoneal lymphadenectomy Small bowel resection ? large bowel resection ? splenopancreatectomy
PC peritoneal carcinomatosis a
attempt date. The 3-year overall survival (OS) rate was significantly higher in the curative group (52 %; 95 % CI 43–61 %) than in the palliative group (7 %; 95 % CI 2– 25 %) (Fig. 1) (p \ 0.0001). For the patients who underwent CCRS plus IPC, analysis of their survival according to the PCI confirmed that survival decreased when the PCI increased (Fig. S1). The median OS was significantly higher for the patients in the curative group than for those in the palliative group (Fig. S1). Comparison of survivals for each PCI (ranging from 5 to 36) showed that OS did not differ significantly between the curative and palliative patients when the PCI was higher than 17 [hazard ratio (HR) 0.64; range 0.38– 1.09] (Fig. 2). Comparison of the postoperative chemotherapy treatments showed that 81 of the 117 patients with a PCI lower than 17 were treated postoperatively, whereas 36 of the 63 patients with a PCI of 17 or higher were treated postoperatively. This difference was not statistically significant (p = 0.10). Univariate analysis showed that three factors significantly influenced overall survival: extent of the peritoneal disease (PCI) (p \ 0.0001), achievement of CCRS plus IPC (p \ 0.0001), and age (p = 0.03) (Table 3). The first
Log−rank : p < 0.0001
17 Curative treatment
3.0 2.5 2.0 1.5 1.0 0.5
HR for overall survival (95% CI)
Palliative treatment Curative treatment
Colorectal Carcinomatosis: HIPEC or Not?
Months At risk 41 112
FIG. 1 Comparison of overall survival curves for the two groups of patients with peritoneal carcinomatosis from colorectal cancer in terms of ability to perform complete cytoreductive surgery (CCRS) plus intraperitoneal chemotherapy (IPC) or not. The overall survival rate for the patients who underwent CCRS plus IPC was significantly higher
two factors were independently correlated with survival in the multivariate analysis (Table 3). DISCUSSION The main result of this study was the finding that CCRS followed by IPC does not seem to offer any survival benefit over palliative surgery for patients with colorectal PC when the PCI is strictly higher than 17. The treatment for PC of colorectal origin has changed considerably during the past decade due to cytoreductive surgery combined with IPC, which can achieve prolonged survival.20,21 In most recent series, the median survival period is about 30 months. The 5-year overall survival rate ranges from 30 to 40 % and can reach nearly 50 % when complete cytoreduction is performed.21,22 These promising results are obtained through stringent patient selection based on criteria related to the patient, to the disease extent, and to its aggressiveness.23,24 Currently, patients older than 65 years with a WHO performance status greater than 2 or a severe medical history (severe cardiopulmonary or renal failure) are excluded from CCRS plus IPC. The presence of extraperitoneal metastases also is considered an absolute exclusion criteria for CCRS plus HIPEC (except for fewer than 3 easily resectable liver metastases). Progression of disease under systemic preoperative chemotherapy also is considered a relative contraindication to CCRS plus IPC, but this criterion is subject to debate.25
FIG. 2 Evolution of the hazard ratio (HR) for overall survival between the patients in the curative group and those in the palliative group according to each value of peritoneal carcinomatosis (PCI: 10 to 25). The overall survival rates did not differ significantly between the curative and palliative patients when the PCI was higher than 17 (HR 0.64; range 0.38–1.09)
Regarding the extent of peritoneal disease and its aggressiveness, some aspects have been well defined by the available studies, whereas others still require more precision. Studies have demonstrated that the two main prognostics factors after CCRS plus HIPEC are completeness of the cytoreduction and extent of PC. It is well accepted that HIPEC should not be performed if resection is incomplete.3,22 Furthermore, incomplete resection carries high risk of postoperative complications while offering no survival benefit and should therefore be avoided for such patients. The threshold value of PCI at which CCRS plus HIPEC, even if feasible, offers no survival benefit has yet to be clarified. In this study, the distribution of PC in the abdomen constituted the principal limitation for the performance of complete resection and IPC. Despite meticulous selection of the patients and optimal treatment including complete cytoreduction plus IPC, the median survival rate for patients with a PCI higher than 17 was low and close to that obtained with current systemic chemotherapy alone.6,16 Moreover, all the patients with a PCI higher than 17 experienced recurrences very early after CCRS plus IPC, with an average disease-free survival time of 9 months. From a structural and clinical perspective, these results should be carefully weighed, considering first the human and financial resources required in offering such cumbersome treatment, and second the morbidity and mortality risks inherent to this procedure. Clinicians should
D. Goe´re´ et al. TABLE 3 Uni- and multivariate analysis of factors associated with survival in two groups of patients with peritoneal carcinomatosis from colorectal cancer Variable
Univariate HR (95 % CI)
Multivariate p value
HR (95 % CI)
1 2.67 (1.22–5.85)
11.70 (5.22–26.22) \0.0001
CS ? HIPEC
HR hazard ratio, CI confidence interval, NS not significant, PCI peritoneal cancer index, HIPEC hyperthermic intraperitoneal chemotherapy, CS
be even more careful when offering this treatment for this subset of patients considering the substantial improvement of OS offered by new systemic agents. Recent data show figures approaching or even exceeding 24 months in cases of metastatic colorectal cancer.6,26 Other factors beside PCI could be involved in the prognosis, such as histologic type, preoperative response to chemotherapy, and postoperative exposure to chemotherapy. In our study, response to chemotherapy did not differ between the two groups because nearly all the patients received preoperative chemotherapy (almost 90 %), and because our policy was to offer laparotomy with a curative intent only to patients presenting with a stable or responding disease under chemotherapy. Patients with progressive disease under preoperative chemotherapy were not selected for surgery with a curative intent. As for the rate of patients who received postoperative chemotherapy, it did not differ between the patients who had a PCI lower than 17 and those with a PCI of 17 or higher. The PCI score is routinely used in our center,27 and survival was analyzed according to this score in both groups of patients considered suitable for CCRS plus IPC at preoperative staging. Clinicians at our institution are fully aware of the difficulty transposing results such as those reported in this study to clinical decision making. One major remaining problem is that accurate determination of the PCI in preoperative imaging studies still is impossible, with the extent of PC underestimated for at least one third of the patients.28,29 Also, a laparoscopic calculation of the PCI certainly is less reliable than during laparotomy because all the dissection planes cannot be reopened. Calculating the number of regions affected as described by the Netherlands score seems more adapted to laparoscopy, with regions numbering six or more (out of 7 regions in total) considered a contraindication to
resection.30 Although less refined, this type of approach offers the major advantage of identifying unresectable patients earlier in the therapeutic process, hopefully before putting them at risk for morbidity or mortality without offering substantial benefit. One criticism that can be leveled against this study is the small sample size. However, all patients were treated and evaluated in the same center with recognized expertise in the treatment of PC. This small number of optimally treated patients with a PCI higher than 20 confirms that resectability is correlated with the extent disease and that CCRS is feasible only for a few patients with a PCI higher than 20. However, in this study and others conducted previously, the PCI appeared to be a major prognostic factor, and according to our results, a PCI higher than 17 could be an exclusion criterion for CCRS plus HIPEC. The retrospective analysis of our data and our small sample size certainly prevents us from establishing this factor as an absolute contraindication. However, with a median survival period of 19 months, we consider that this aggressive treatment should be discussed only for patients presenting an otherwise ideal situation in every other clinical aspect (age, tumor differentiation, extraperitoneal metastasis, tumor chemosensitivity, clinical symptoms). Therefore, the search for a new prognostic factor and the refinement of existing ones are critical in helping to identify better the subpopulation of patients who could benefit from this highly specialized treatment. These factors should be regularly challenged and questioned to make sure that patients going through this procedure would not be better served by constant improvement of systemic treatments. In conclusion, CCRS followed by IPC achieves prolonged survival, but only for selected patients. This study confirmed the major prognostic impact of the extent of PC,
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