Outcome of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is stated as the third most frequent cancer in people around the world. In patients, its recurrence occurs most commonly in the peritoneum, accounting for 25% to 35% of all recurrences, making it the second most common site for CRC. Although new and more effective chemotherapeutic agents and combinations were developed, the results of systemic chemotherapy showed only a limited impact on survival, which is disappointing. It is known that cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) lead to survival improvement in comparison to the sole treatment consisting in intravenous chemotherapy. This combined procedure showed encouraging results in terms of overall survival, lower complication rates and better patient outcomes in many reported findings. The objective of this article was to review published data for evaluating the outcome of CRS and HIPEC versus standard of care.

Keywords:colorectal cancer, CRS, HIPEC, peritoneal metastasis.

INTRODUCTION

Colorectal carcinoma (CRC) has become a crucial issue towards public health. In Europe, CRC is ranked as the second highest cause responsible for death (1). The strategy for treating patients suffering from colon cancer depends on tumor characteristics such as location, TNM stage and histological subtype; patient’s physical condition is also considered. A complex interaction between patient, tumor and treatment-related characteristics leads to the desired treatment outcome (2, 3). Systemic chemotherapy (SC) involved in conventional treatment of patients with colorectal cancer peritoneal metastasis (CPM), with or without palliative surgery, showed a poor outlook, with a median survival of 5–7 months (4-6). However, a treatment option involving a radical multimodality locoregional approach that uses combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) procedures has been advocated in more recent times and is offered in a growing number of specialist units (7-9). This review primarily aims to present the available outcome data of CRS and HIPEC procedures.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

The combined procedures of maximal CRS with HIPEC were firstly described by Spratt, in 1980, in order to treat a recurring peritoneal pseudomyxoma. But in the early 1990s, Paul Sugarbaker became the main apostle of this method (10, 11). Generally, this multimodality treatment consists of two steps. In the first one, both peritoneal and visceral resections are performed to remove all macroscopically visible tumor tissue from the peritoneal surface; this part is called cytoreductive surgery. In the second step, the remaining microscopic tumor cells are eliminated by HIPEC. Chemotherapy bath cannot penetrate tumor seeding beyond the depth of 1 to 2 mm; therefore, it is crucial that surgery resects all tumor seeding greater than 1 mm (12, 13). Hyperthermia along with intraperitoneal chemotherapy clearly demonstrated its ability to potentiate the penetration and activity of local chemotherapy in cancer cells in vitro, and this role was confirmed by in vivo method too in several studies (14, 15).

Hyperthermic intraperitoneal chemotherapy techniques are heterogeneous and are highly complex for elaboration. The combination of drugs, their concentration, composition and volume of the perfusion, duration and temperature can be modified. Of these six parameters, a high number of combinations are possible but tests cannot be done on all of them (16). A new pharmacokinetic study can be conducted by modifying one of these parameters (17). Schematically, HIPEC procedure has two main trends around the world: in one, mitomycin C is used at 41¢ªC over 60 to 90 min, with a closed-abdomen technique, and in the other one, oxaliplatin (irinotecan) is used at 43¢ªC over 30 to 40 min, with an opened-abdomen technique (18).

Patient selection

Cytoreductive surgery together with hyperthermic intraperitoneal chemotherapy is considered as a major procedure in surgery with significant morbidity. Studies have reported operative mortality rates ranging from 0% to 8% and overall complication rates >30% (19, 20). Like any major operative procedure, appropriate patient selection is necessary to achieve optimal outcomes. Principles of patient selection for CRS plus HIPEC procedures are similar to those used for the resection of metastatic disease to the liver. Patient’s fitness for surgery and ability to achieve complete resection are the two chief factors which are mostly considered. The overall burden of disease can be assessed by the developed scoring systems that help to select patients and predict the relative benefit of the CRS plus HIPEC procedures.

Prognostic factors

The PCI score and CC score is an essential caveat to the good outcomes linked with CRS/ HIPEC for colorectal cancer.

Peritoneal carcinomatosis index: The extent of carcinomatosis is quantified using a scoring system, i.e., peritoneal carcinomatosis index (PCI), which has been recognized as one of the most essential predictive indicators for enduring outcomes of CPM patients (21-24). Either computed tomography or MRI radiographic techniques can be used to determine PCI before surgery, but the accuracy of its report is highest in intraoperatively. The abdomen is separated into 13 sections: central region [0], right upper region [1], epigastrium region [2], left upper region [3], left blank region [4], left lower region [5], pelvis region [6], right lower region [7], and right blank region [8], and the small bowel is separated into four: upper jejunum region [9], lower jejunum region [10], upper ileum region [11], and lower ileum region [12] (25, 26). Lesion size (LS) score of 0-3 assigned to each one is the representative visualization of the largest implant lesion. A LS with score 0 indicates no tumor seen, LS score 1 is assigned for <0.25 cm implants, LS score 2 for implants ranging between 0.25 cm and 5 cm, and LS score 3 in confluence of disease or >5 cm size implants (25, 26).

Peritoneal carcinomatosis index is scored from 0 to 39 and is a final numerical score (25, 27). The PCI score is identified as a chief prognostic factor through several large cohort studies (10, 28-31). Goe.re. et al. stated that no survival benefit was seen in patients with a PCI score .17.43 from CRS and HIPEC procedures. As per the above-mentioned studies results, the performance of CRS and HIPEC should be refused by surgeons in patients with a PCI score >20. Furthermore, the extent of small bowel involvement is a closely related factor (32). If the disease affects a large portion of the small bowel, performance of the CRS and HIPEC should be denied as that resection would consequently lead to short bowel syndrome.

Completeness of cytoreduction score: The completeness of cytoreduction (CC) score is a scoring system for patients with peritoneal metastasis (PM) developed by Sugarbaker, which reflects the thoroughness in degree of peritoneal CRS (10). The score of CC is calculated with respect to the maximum diameter of the residual tumor after surgery: CC with score 0 (CC-0) indicates that no residual tumor is seen, CC with score 1 (CC-1) shows a maximum diameter <2.5 mm of the residual tumor, CC with score 2 (CC-2) indicates that the maximum diameter of the residual tumor ranges between 0.25 cm and 2.5 cm, and CC with score 3 (CC-3) shows a maximum diameter > 2.5 cm of the residual tumor (33). Both CC-0 and CC-1 are included in a CC score for colorectal cancer: CC with score 0 indicates that all visible tumors are completely removed, while CC with score 1 shows that only a very small amount of residual tumors that are expected to be eradicated by the HIPEC remain not resected (34). Complete cytoreductive surgery (CRS) is an essential prognostic influence factor and a necessary requirement for managing PM for long term benefit. A study conducted in a French multicenter trial that enrolled 523 subjects who underwent surgery in 23 centers from four French-speaking countries between 1990 and 2007 showed that patients with complete cytoreductive surgery had a remarkably better survival than those with incomplete cytoreductive surgery as per the study results (35). According to Huang et al., it was possible to safely perform CRS plus perioperative intraperitoneal chemotherapy for patients with CPM in order to provide encouraging benefits for survival. Hence, most researches have reported that CC-0 and CC-1 were the standard for cytoreductive surgery. In contrast, the recommendation of CC-2 and CC-3 surgery is not currently advisable (36).

Treatment strategies and outcome of CRS plus HIPEC

As per the guideline of the National Comprehensive Cancer Network (NCCN), no routine recommendation of combined peritoneal CRS and HIPEC has been made for patients suffering from CPM. Nonetheless, more well-designed clinical trials have been also recommended to be carried out by the NCCN guidelines. Conversely, guidelines issued by the European Society for Medical Oncology (ESMO) hold a more positive attitude towards it; thus, patients with colorectal cancer peritoneal metastasis and low peritoneal carcinomatosis index should be treated with surgery plus HIPEC only when a complete CRS could be reached. A complete CRS for patients with P1 phase CPM as well as P2 phase CPM has been recommended in Japan if technically possible (37). Experts in China have also recommended combined peritoneal CRS and HIPEC for patients suffering from CPM with PCI <20.

Continuous demonstration of an improved overall survival with CRS/HIPEC compared with systemic chemotherapy alone has been done in more recent studies. The investigation was carried out to study the CRS and HIPEC effect in colorectal PM patients in two randomized controlled trials. In the first study conducted by Verwaal et al. among patients who underwent CRS and HIPEC procedures followed by adjuvant systemic 5-fluorouracil with leucovorin, a significant survival benefit was seen comparatively to patients who received systemic 5-fluorouracil with leucovorin. However, several questions have remained unanswered regarding the CRS and HIPEC procedure’s true benefit owing to this outdated systemic chemotherapy regimen study and the lack of a cytoreductive surgery only in the control group (21). Cashin et al have also conducted a randomized controlled trial, but it was ended prematurely because of recruitment complications; nevertheless, with twenty-four subjects in each arm, those subjected to the CRS and HIPEC procedure showed a significant survival benefit comparatively to patients who received oxaliplatin-based chemotherapy (38). The analysis carried out by several multicenter studies revealed that highly selected patients who had been efficaciously subjected to the CRS and HIPEC procedures showed median overall rates of survival of up to sixty-three months (8, 25, 35, 39, 40). Even cure was achieved in a small percentage of subjects who were given this treatment (41). Hence, globally many guidelines have presently incorporated CRS and HIPEC techniques on the basis of these randomized trials and cohort studies (42).

Another clinical trial, which was conducted in nine Dutch HIPEC centers, included subjects who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. In total, 176 subjects were randomly selected to either adjuvant HIPEC followed by the experimental arm’s routine adjuvant systemic chemotherapy or systemic chemotherapy only in the control arm after primary tumour resection. Before HIPEC, 5-fluorouracil and leucovorin were intravenously administered. Adjuvant HIPEC was performed using oxaliplatin for 30 minutes at 42-43°C as a chemotherapeutic agent instantaneously or as soon as the primary resection was performed. The trial found that, in subjects with T4 or perforated colon cancer, the anticipated 25% absolute risk of peritoneal carcinomatosis (PC) was reduced to 10%, enhancing the probability of prolonged overall survival (43). In another study, conducted in Singapore, 35 consecutive patients who underwent the CRS and HIPEC procedures in the investigators’ institute were selected to evaluate prognostic factors for disease-free survival (DFS), overall survival (OS), and perioperative morbidity and mortality. Optimal cytoreduction was found in 94% patients (n=33). Thirty-day mortality was reported as nil, but postoperative complications were seen among 14 subjects. Median DFS was reported as 9.4 months. Disease-free survival was reported to be 43.8% at one year, 22.3% at three years and 22.3% five years. The median overall survival was calculated to be 27.1 months and OS was 83.7% at one year, 38.2% at three years and 19.1% at five years (44). Thirteen institutions (Australia, Saudi Arabia, Washington DC, Japan, France, Netherland, Denmark, Italy, Germany, UK, North Carolina) retrospectively analyzed the feasibility of iCRS (iterative cytoreductive surgery) and HIPEC procedures in CRPC (colorectal peritoneal carcinomatosis), survival, recurrence, mortality and morbidity outcomes, and prognostic factors for OS by enrolling 231 subjects, of which 126 were females (54.5%) with a mean age of 51.3 years at iCRS. The rate of iterative high-grade (3/4) morbidity was 23.4% and the rate of mortality 1.7%. The median recurrencefree survival was 15.0 months and 10.1 months after initial and iCRS, respectively. The median and five-year survival from the initials was 49.1 months and 43%, respectively, while the median and five-year survival from iCRS was 26.4 months and 26%, respectively. The peritoneal carcinomatosis index (PCI) >20 (P=0.02) and lymph node positivity (P=0.04) are included as an independent negative survival from the initial CRS, and PCI >10 (P=0.03 for PCI 11-20; P <0.001 for PCI >20), high-grade complications (P=0.012), and incomplete cytoreduction (P <0.001) are included as an independent negative survival from iCRS. This study reported that CRS and HIPEC provided long-term benefits for survival to highly selected subjects with colorectal peritoneal carcinomatosis, with comparable rates of mortality and morbidity to the initial procedure of CRS (45).

In one study, 101 consecutive patients were selected from two high-volume peritoneal malignancy management centers of Italy with the chief outcomes of overall survival and disease-specific survival. All macroscopic tumors were removed through peritonectomy procedures and multi-visceral resections, and mitomycin-C plus cisplatin-based HIPEC was used for controlling microscopic residual disease. The rate of mortality was reported to be 3.0% and the major morbidity rate 23.8%. The median follow-up was 44.9 months (95% CI, 24.1–65.7). The five-year disease-specific survival was 14.3% in patients who had major complications and 52.3% in those without such complications. Likewise, five-year OS was 11.7% in patients with major complications and 58.8% in those without them (46). Another study in Italy evaluated patients subjected to surgical treatment for PC from colorectal cancer in which no other organs were involved. In 38 subjects who received CRS-HIPEC treatment, the CC score was 0. Clavien-Dindo grade >2 postoperative complications were seen among five subjects (13.1%). The median OS was 60 months, PCI >6 and significant nodal involvement (N2) prognostic factors were found to be independent. The median DFS was reported to be 16 months. The only significant negative prognostic factor was N2 for DFS. As per the authors’ reports, survival can be substantially improved by CRS-HIPEC. But this procedure may not benefit subjects with N2 and high PCI >6 (47).

Thirty-three patients suffering from colorectal and appendiceal cancer with peritoneal metastasis, who were planned for CRS and HIPEC, were analyzed for morbidity, mortality, and survival. Of these, 14 had disease of appendiceal origin and 19 disease of colorectal origin. Cytoreductive surgery was performed 29 times in 27 patients and was abandoned in six patients. Overall morbidity was 55.17%, with hematological toxicity being the most common (46.1%), and mortality was 3.4%. Four-year actuarial survival was 58.39% for subjects undergoing CRS and HIPEC and 33.33% for those who received CRS alone. From the findings it was concluded that CRS and HIPEC could be conducted with tolerable mortality and morbidity in selected patients of colorectal and appendiceal malignancies with peritoneal carcinomatosis. In addition, its association with a better OS and morbidity profile in subjects from the Indian subcontinent is different from that of Western population, hematological toxicity being the most commonly encountered (48). In China, phase II investigation was conducted to study the effectiveness and adverse events of CRS+HIPEC procedure by including 60 successive CRC PC subjects who had already undergone 63 procedures involving CRS+HIPEC and postoperative chemotherapy, with disease-specific overall survival and perioperative safety profiles being the primary and secondary end points, respectively. In 47.0% subjects, PCI was . 20, and the remaining 53.0% subjects underwent complete cytoreductive surgery (CC0-1). The median OS was reported to be 16.0 months. The rate of survival was 70.5% at one year, 34.2% at two years, 22.0% at three years and 22.0% at five years. During the 30-day postoperative period, the rate of mortality was 0.0% and grades 3 to 5 morbidity rate was reported to be 30.2%. Three parameters were identified by univariate analysis which had significant effects on OS: PCI .20, CC0-1 and adjuvant chemotherapy over six cycles. However, in multivariate analysis the only independent factors for OS benefit were CC0-1 and adjuvant chemotherapy over six cycles. This study reported that the combined CRS+HIPEC procedure in a specialized center could lead to OS improvement for carefully chosen CRC PC subjects with satisfactory perioperative safety (49).

Clinical outcomes of CRS and HIPEC treatment for colorectal cancer with peritoneal carcinomatosis were explored in Taipei Medical University, Wanfang Hospital, Taiwan, in a study which enrolled 31 patients subjected to a total of 33 procedures. On two of all included patients, the HIPEC procedure was performed twice. Hyperthermic intraperitoneal chemotherapy was done subsequently to CRS performance. For subjects who underwent CRS and HIPEC, OS rates were reported to be 57% at two years and 38% at five years. In 18 (54.5%) subjects, the CC score was 0 (CC-0), in three (9%) it was 1 (CC -1), in seven (21.2%) 2 (CC-2), and in five (15.2%) patients 3 (CC-3). The mean PCI was 16.20, and the mean PPCI (postoperative peritoneal cancer index) 4.6. In these subjects, the chief risk factors for death were when the scores of total peritoneal cancer index was >20, the total PPCI was > 0, and CC .2. Through multivariate analysis, the total PPCI score was revealed as the strongest interpreter of death following CRS and HIPEC in these subjects. According to their results, authors believe that long-term survival can be achieved by CRS performance and HIPEC administration, which are feasible for treating subjects suffering from colorectal cancer with peritoneal metastasis (PM) (50).

A study conducted in the USA showed the safety and outcome of CRS and HIPEC in elderly subjects. Overall, 170 successive subjects who had already undergone CRS-HIPEC for peritoneal carcinomatosis were enrolled. Intraperitoneal administration of Mitomycin C (88.8%) at 42¢ªC was carried out for ninety minutes. Subjects were divided in two groups with according to their age at the time of surgery: group 1 included subjects aged 65 and group 2 subjects aged over 65. The differences between these groups were investigated. Thirty-five subjects were older than 65 years of age out of all 170 enrolled subjects. Colorectal and appendiceal cancer were the two most common sites of tumor. In the elderly, the perioperative rates of mortality and morbidity were 8.6% and 18.8%, respectively. The rate of recurrence at one year for colorectal/appendiceal PC was 48.0% in group 1 and 44.3% in group 2 at a median follow- up of 15.7 months. The median survival for subjects with colorectal/appendiceal carcinomatosis was 29.79 months in group 1 and 21.2 months in group 2. It was reported that in the elderly, treatment of peritoneal carcinomatosis by the CRS-HIPEC procedures resulted in comparable outcome in well-chosen subjects perioperatively. In the majority of cases, optimal cytoreduction was achieved with no significant survival difference in comparison to the younger group (51). Retrospectively, in a population-based cohort study, the benefit of CRS and HIPEC procedures in comparison to other treatment options, with respect to long-term OS in subjects with isolated synchronous and metachronous PM of colorectal origin, was investigated at the Regensburg Tumor Center in Bavaria, Germany. The data of 370 subjects from the cancer registry were collected and results showed that those who underwent CRS and HIPEC had an overall median survival of 41.6 months comparatively to surgery and chemotherapy (24.0 months), chemotherapy only (14.1 months), surgery only (11.4 months), and best supportive care (7.9 months). The findings highlighted that CRS and HIPEC procedures were significantly more effective than all other therapeutic options (52).

Cost effectiveness

In Singapore, the cost effectiveness of the CRS and HIPEC procedures was compared to that of palliative chemotherapy for patients with colorectal peritoneal carcinomatosis from colorectal cancer by a retrospective review of patients treated at the NCCS (National Cancer Centre Singapore). It was reported that prolonged survival and lower cost per life year was attained through CRS and HIPEC treatment in selected subjects suffering from colorectal peritoneal carcinomatosis in comparison to the traditionally used palliative chemotherapy. So, it was suggested that, for selected subjects suffering from colorectal peritoneal metastasis, this should reasonably be the preferred treatment choice (53).

CONCLUSION

Our comprehensive review of the clinical outcomes and cost effectiveness of CRS plus HIPEC demonstrated that acceptable mortality and morbidity could be achieved by these two feasible procedures for selected subjects with peritoneal carcinomatosis even though it is a complex procedure. The outcome of treatment results in prolonged survival, with fewer readmissions after surgery and better quality of life. In patients with colorectal cancer peritoneal metastasis, peritoneal cancer index and completeness of cytoreductive score are the chief prognostic indicators. The treatment of colorectal peritoneal metastasis using CRS and HIPEC procedures in selected subjects should reasonably be the preferred choice of treatment based on the indicator score. Even better oncologic and surgical results may be seen in its future evolution. With all these advances, there is a huge need in more well-designed multicentric clinical trials in figuring the best multidisciplinary treatment modality for colorectal peritoneal metastasis.

Conflict of interests: none declared

Financial support: none declared.

Acknowledgements: The authors would like to thank ResearchNeeds for helping medical writing.