In our cohort of patients with CRC-PM who underwent extensive CRS and perioperative chemotherapy including systemic and intraperitoneal chemotherapy, 14.0% (33/236) survived beyond 5 years. Sixteen of 33 patients remained recurrence-free more than 5 years after the last surgery for metastases and were considered “cured”. Additionally, 5 patients in this cohort survived more than 10 years. Our study proves that long-term survival and cured status are possible in an appropriately selected sub-set of patients with PM from CRC.
Despite the adoption of CRS and HIPEC in many centers worldwide, this approach is still met with criticism. One of the arguments against CRS and HIPEC is high morbidity and mortality risk of these procedures (30-32). However, whether patients with PM from CRC can attain equivalent long-term survival with systemic therapy alone is doubtful (8-10). A comprehensive approach with a combination of neoadjuvant systemic chemotherapy, CRS/HIPEC, and adjuvant systemic therapy may provide long-term survival in CRC-PM patients.
OS in CRC-PM patients treated with CRS is strongly associated with achieving complete cytoreduction. Several studies showed that patients with complete cytoreduction (CCR-0 or CCR-1) have a better survival outcome than patients with incomplete cytoreduction (CCR-2 or CCR-3) (33-35). Others reported survival differences between CCR-0 and CCR-1 in CRC-PM patients (36). In our study, all 33 patients received CCR-0 resection, which reaffirms that complete cytoreduction with no macroscopic disease is important to achieve long-term survival.
PCI, which describes the extent and distribution of peritoneal disease, is one of the most important prognostic indices. Several investigators have suggested that better outcomes are obtained after CRS and HIPEC with a PCI < 10 (37, 38), and worse survival with a PCI >17 (39, 40). The median PCI in our cohort was 4, and 87.9% (29/33) of the long-term survivors had a PCI ≤ 10. Moreover, all patients in the cured group had a PCI ≤ 8. These facts suggest that higher PCI is a negative prognostic factor for long-term survival.
It has been assumed that PMs from rectal origin behave differently from colonic origin PMs regarding survival. Previous studies demonstrated that PMs from primary rectal cancer were associated with a poor prognosis compared with primary colonic origin (41-44). In our cohort, none of the 33 long-term survivors had a primary tumor in the rectum, and our findings are similar to those in previous studies. The indications for CRS and HIPEC for rectal cancer PM might have to be more restrictive than for colonic PM.
Other important findings in our study were, first, that well to moderately differentiated tubular adenocarcinoma was the most frequently diagnosed histology of CRC followed by MC and SRCC. In our cohort, 7 patients had MC, and 2 had SRCC. Histological differences between mucinous and non-mucinous regarding prognosis are controversial. Some investigators suggested that mucinous carcinoma patients had a worse prognosis (45-47) while others did not (48, 49). Of the 7 MC patients in our cohort, 3 were cured of disease, and 4 were not, indicating that CRC-PM patients with MC histology can obtain long-term survival and cure. The negative impact of SRCC in CRC-PM has been described in multiple studies, with the median OS in these patients ranging from 7 to 13 months even if patients are treated with CRS and HIPEC (35, 44, 50-52). It is rare to witness 5-year survival in SRCC. The 2 SRCC patients in our cohort experienced 62- and 71-month survival, respectively. The proportion of SRCC patients who are eligible for CRS and consequently experience long-term survival is currently low. More detailed reporting and further research are required to identify potential long-term survivors.
Second, in our cohort, patients who had lymph node metastases constituted more than one-half of long-term survivors and the subgroup of cured patients. It has been proposed that regional lymph node metastasis has a negative prognostic impact on survival (36, 53-55). The recently-developed COMPASS (colorectal peritoneal metastases prognostic surgical score) reported by Simkens et al. includes nodal status among the four clinical factors (PCI, nodal status, histology, and age) used to predict outcomes after CRS and HIPEC in CRC-PM (56). However, lymph node meatastases in isolation cannot be considered an exclusion criterion (38). With standardization of techniques for total mesorectal excision and complete mesocolic excision, which removes tumors en bloc with lymphatics, local recurrence has decreased (57, 58). In our patient population, the majority (21/33, 63.6%) of patients presented with lymph node metastases, and 10 of 20 patients were categorized into the cured group. It is reasonable to support that CRC-PM patients with lymph node metastasis can achieve long-term survival and cure.
Third, 84.8% (28/33) of our patients received preoperative systemic therapy, and 93.9% (31/33) received systemic chemotherapy during the course of their management. Kujipers et al. noted that OS and progression-free survival were better in subjects receiving systemic therapy irrespective of the timing of its administration (pre-/post-CRS and HIPEC) (59). The fact that 93.9% of our cohort received systemic therapy underscores the importance of multimodal treatment in CRC-PM. One of the criticisms of the recent PRODIGE-7 trial, which questioned the role of HIPEC in the clinical management of PM from CRC, was the use of oxaliplatin in both neoadjuvant chemotherapy and HIPEC (60). Previous chemotherapy regimens with oxaliplatin could cause alterations in the cancer cell genome and in oxaliplatin sensitivity (61). These findings suggest that HIPEC with oxaliplatin may be ineffective. Therefore, our practice is to consider different drug regimens (cisplatin + mitomycin C) if neoadjuvant chemotherapy with oxaliplatin exceeds 4–6 cycles.
Readers may question the frequency of low PCI in our study group, and question whether HIPEC was required in such cases. First, because our hospitals are tertiary referral centers, our waiting period for surgery is approximately 6–12 weeks, and systemic therapy is initiated during this period. This potentially reduces the size and extent of PM, and there is a consequent reduction in PCI. However, the decision to perform CRS and HIPEC is based on the initial PCI calculation from imaging or laparoscopy. Second, patients responding favorably to preoperative chemotherapy could have had a favorable tumor biology that benefitted from this extensive procedure. While complete cytoreduction for optimal outcomes is vital, the role of systemic therapy in achieving tumor shrinkage and providing maintenance after CRS cannot be underestimated.
This study had several major limitations. First, because our study was retrospective in design, selection biases were introduced, due to the exclusion of patients with unresectable PM. Second, as a descriptive study, this current research lacked any comparison of control groups for statistical analysis of effectiveness of CRS/HIPEC and prognostic factors. Finally, the definition of long-term survival and cure is not officially defined and was based only on survival times. However, the data in this study allowed a detailed assessment of the clinical features among long-term survivors in CRC-PM patients.