Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for colorectal cancer: choosing the right candidates

Keywords:

• colorectal cancer
• completeness of cytoreduction score
• cytoreductive surgery
• hyperthermic intraperitoneal chemotherapy
• peritoneal cancer index

Despite advances in systemic chemotherapy, the survival of patients with peritoneal metastases from colon cancer remains poor. In contrast, the median overall survival rate after complete cytoreduction, hyperthermic intaperitoneal chemotherapy (HIPEC) and systemic chemotherapy is about 30–50 months, and the 5-year survival rate is about 30–50%. Treatment with cytoreductive surgery (CRS) plus HIPEC is associated with significant morbidity and potential mortality, so careful patient selection is critical to maximize the potential success of this treatment. The best candidates have the following characteristics: few co-morbidities, excellent performance status, no extra-abdominal disease, low peritoneal cancer index (PCI) score (<20), limited small bowel involvement, prolonged disease-free interval between primary cancer treatment and peritoneal metastasis and completely resectable disease (CC-0/1). For patients with high-grade colorectal cancers (including signet ring) or extensive peritoneal disease on imaging studies, preoperative systemic chemotherapy is recommended and may increase the proportion of patients who can receive complete cytoreduction. Diagnostic laparoscopy is also useful in selecting appropriate patients and avoiding non-therapeutic laparotomy in patients with borderline characteristics. Finally, depending upon the outcomes of ongoing randomized trials, prophylactic HIPEC may be useful for patients with high-risk cancers who do not have established metastases.

Incidence of peritoneal metastases

Approximately 10–15% of patients with colorectal cancer will develop peritoneal metastases at some point during the course of their disease [1,2]. The peritoneal surface is the only site of metastasis in about 50% of these patients [1,3]. Multiple risk factors have been identified for the development of peritoneal metastases and include advanced tumor stage, advanced lymph node stage, venous invasion, mucinous adenocarcinoma, emergency surgery and non-radical resection [1,2].

Systemic chemotherapy only

Historically, patients with peritoneal metastases who were treated with palliative chemotherapy (5-flurouracil [5-FU], leucovorin [LV]) had poor survival outcomes. The median survival of these patients was approximately 6 months, and few lived more than 5 years after diagnosis [1,4]. As newer chemotherapeutic agents were incorporated into practice, the survival rates of patients with peritoneal metastases have improved. A pooled analysis of two Phase III North Central Cancer Treatment Group studies determined survival outcomes of patients with colorectal cancer and peritoneal metastases treated primarily with irinotecan or oxaliplatin [5]. The median overall survival rate was 12.7 months, and the 5-year overall survival rate was 4.2%. Another study (CAIRO1/CAIRO2) analyzed the outcomes of patients with peritoneal metastases treated with modern chemotherapy or without targeted agents and reported that the overall median survival ranged from 10.4 to 15.2 months [6].

CRS plus HIPEC

Modern chemotherapy has had only limited success in improving the survival of patients with peritoneal metastases from colorectal cancer. Consequently, CRS plus HIPEC has been increasingly used in recent years to improve patient outcomes. The combination treatment aims to removal all visible tumor nodules and deliver high local concentrations of chemotherapeutic agents under hyperthermic conditions to treat any remaining microscopic residual disease.

An accurate appraisal of the survival benefit from CRS plus HIPEC on survival outcomes is limited by the lack of high quality of data. Data from prospective randomized trials comparing outcomes after CRS plus HIPEC to those after systemic chemotherapy only for colorectal peritoneal metastases are limited. In a single-center trial from the Netherlands Cancer Institute, 105 patients with peritoneal metastases from either colorectal or appendiceal cancer were randomized to palliative surgery plus 5-FU/LV (control arm) or to CRS plus HIPEC plus postoperative 5-FU/LV (experimental arm) [7,8]. Overall, CRS plus HIPEC was associated with a significant improvement in median survival (control arm, 12.6 months; experimental arm, 22.3 months, p = 0.032). The major limitation of this study is that the chemotherapy (5-FU/LV) used in the control arm is not modern chemotherapy.

To date, there is no comparable randomized clinical trial comparing CRS plus HIPEC to modern chemotherapeutic regimens. However, retrospective studies suggest a survival advantage for CRS plus HIPEC. Elias et al. evaluated the outcomes of 96 patients with peritoneal metastases from colorectal cancer treated either with modern chemotherapy (primarily irinotecan or oxaliplatin) or with CRS plus HIPEC [9]. The patients in the chemotherapy-only arm had potentially resectable peritoneal metastases and no extraperitoneal disease. The median survival (23.9 vs 62.7 months) and 5-year survival (13 vs 51%) rates were significantly improved in the CRS plus HIPEC group compared to chemotherapy alone group.

Additionally, a systematic review that included 19 studies and 2492 patients by Chua et al. compared survival outcomes after CRS plus HIPEC to those after palliative surgery and/or systemic chemotherapy [10]. The overall median survival after CRS plus HIPEC was 33 months (range: 20–63 months) compared with only 12.5 months (range: 5–24 months) for patients having palliative surgery and/or systemic chemotherapy. The respective median 5-year survival rates were 40% (range: 17–50%) and 13% (range: 13–22%).

Prognostic factors after CRS plus HIPEC

Multiple factors are predictive of survival outcomes following CRS plus HIPEC. The completeness of cytoreduction (CC) score is an important prognostic factor and is based on the size of any residual tumor nodules after maximum cytoreduction: CC-0, no nodules; CC-1, <2.5 mm; CC-2: 2.5 mm–2.5 cm; and CC-3, >2.5 cm. In a multicenter study, the median survival rates were significantly associated with CC scores: CC-0, 33 months; CC-1, 20 months; and CC-2/3: 7 months [11]. The PCI is another important predictor of survival and is based upon the size and distribution of tumor nodules in 13 different regions of the peritoneal cavity. In one multicenter study, the 5-year survival rates according to PCI scores were: 1–6, 44%; 7–12, 22%; 13–19, 29%; and >19, 7% [11]. Other predictors of survival include tumor grade, signet ring cell histology, patient age, lymph node metastases and small bowel involvement.

Patient selection

CRS plus HIPEC is a major surgical procedure with considerable morbidity. Studies have reported operative mortality rates ranging from 0 to 8% and overall complication rates of greater than 30% [12,13]. Like any major operative procedure, appropriate patient selection is necessary to achieve optimal outcomes. Clear contraindications to CRS plus HIPEC include poor general health and/or performance status, the presence of extraperitoneal metastases and diffuse unresectable metastases not amenable to complete cytoreduction. Small bowel involvement is one of the most common reasons for incomplete cytoreduction. In a single-center prospective study, Elias et al. reported that involvement of area 12 of the PCI index (distal ileum) was an independent negative prognostic factor [14]. So, small bowel involvement requiring extensive resection is another contraindication to CRS and HIPEC. Some patients have both liver and peritoneal metastases. For these patients, hepatic resection and/or ablation can be performed with CRS and HIPEC for highly selected patients with limited hepatic disease. Other relative contraindications include disease in the porta hepatis or around major vascular structures, PCI index of >20, multiple levels of bowel obstruction, bilateral ureteral obstruction and biliary obstruction. Since preoperative imaging often underestimates the extent of peritoneal metastases, diagnostic laparoscopy may be used to identify patients who are poor candidates for CRS plus HIPEC. Although there is no universally accepted upper age limit, the authors rarely perform CRS plus HIPEC in patients over 75 years.

Prophylactic HIPEC

Since early peritoneal metastases are often asymptomatic and difficult to detect on imaging studies, there is increasing interest in ‘prophylactic’ HIPEC for those patients who are at high risk for developing peritoneal metastases. Elias and colleagues evaluated the outcomes of three high-risk groups: patients who had a small burden of peritoneal nodules resected along with the primary tumor; patients with ovarian metastases and patients who had perforated tumors. During second-look operations, asymptomatic peritoneal nodules were found in 62, 60 and 37% of these respective subgroups [15]. These findings prompted a now-ongoing French multicenter randomized trial (Prodige 15) that includes patients at high risk for peritoneal metastases. All patients receive standard adjuvant systemic chemotherapy and are then randomized to undergo either surveillance or a second-look laparotomy with HIPEC. To date, the data assessing the effectiveness of prophylactic HIPEC are quite limited. One case–control study suggested that HIPEC significantly decreased the recurrence rates and improved overall survival rates in patients at high risk of developing colorectal peritoneal metastases [16].

HIPEC centers seem to be sprouting up all across the USA in both academic and community medical centers. These trends are concerning because several studies have demonstrated that operative and oncologic outcomes after CRS plus HIPEC are correlated with institutional experience [17,18]. Authors from one high-volume academic center concluded that approximately 180 procedures were required to achieve the lowest risk of incomplete cytoreduction and severe morbidity, and approximately 90 cases were required to improve oncologic outcomes [17]. Perhaps, centers of excellence should be established and accredited to maximize patient outcomes. Although surgeons must carefully choose the right patients for HIPEC, it is equally important that patients choose the right surgeons for HIPEC.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.