Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer (pmCRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standardization of oncologic treatment regimens for pmCRC. The addition of further therapeutic options such as neoadjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investigated to optimize therapeutic regimens and further improve the oncological outcome.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide[1]. Peritoneal metastasis (PM) is common in patients with advanced stage primary and recurrent colorectal cancer[2,3]. The natural course of this disease is associated with poor prognosis and led to a mean overall survival of 5.2 mo in the prospective European multicenter EVOCAPE I study (n = 118)[4]. A retrospective analysis of 3000 patients with pmCRC reported a median survival of 7 mo without specific treatment[5]. Although peritoneal metastases develop avascular tumor nodules within the abdominal cavity that often cannot be efficiently addressed by systemic chemotherapy[6], advances in the development of cytostatic agents, targeted therapy and combined treatment regimens has led to significant improvement in survival rates. Moreover, additive treatment options such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) might be performed with curative intent in selected patients[7]. Thus, pmCRC currently requires a multidisciplinary treatment approach that considers the available treatment options and modalities (Figure 1).

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Figure 1 Proposed algorithm for treating peritoneal metastatic colorectal cancer. CC: Completeness of cytoreduction; CC-0/1: Complete macroscopic cytoreduction; IPC: Intraperitoneal chemotherapy; NIPS: Neoadjuvant intraperitoneal/systemic chemotherapy; PIPAC: Pressurized intraperitoneal aerosol chemotherapy; sCTx: Systemic chemotherapy; scattered lines indicate additional therapeutic options; HIPEC: Hyperthermic intraperitoneal chemotherapy.

The estimation of the extent of peritoneal tumor dissemination plays an important role in choosing therapeutic options for patients with pmCRC. Different staging systems allow for the standardization of PM classification and facilitate prognosis estimation. The most commonly used classification system for peritoneal tumor dissemination is the peritoneal cancer index (PCI). This numerical score combines the lesion size (LS) and tumor localization in 13 abdomino-pelvic regions including four small bowel regions (region 0-12) and ranges from 0 to 39[8]. The PCI was initially introduced for intraoperative determination of the extent of peritoneal carcinomatosis but the extent can also be determined by staging laparoscopy or diagnostic imaging. Elias et al[9] showed that the PCI is easy to use and reproducible with high inter-surgeon concordance. Although the PCI is underestimated by computed tomography compared to intraoperative findings, the clinical impact of the inaccuracies of CT-PCI is modest[10]. Thus, the (CT-)PCI is a helpful tool to determine and communicate the extent of peritoneal disease and to select patients for different therapeutic options. Moreover, the PCI correlates with overall and progression-free survival in patients with pm CRC[11-14]. Nevertheless, the predictive value is limited with respect to PM and does not include other prognostic factors. Therefore, prognostic scores for patients with pm CRC have been developed. The Peritoneal Surface Disease Severity Score (PSDSS) is based on the following three important prognostic indicators: (1) clinical symptoms; (2) PCI; and (3) tumor histopathology. The PSDSS ranges from 2 to 22 and divides patients into four prognostic groups (stage I = PSDSS 2-4, stage II = PSDSS 4-7, stage III = PSDSS 8-10 and stage IV = PSDSS > 10)[15]. Several retrospective analyses show a high correlation between PSDSS and the survival of patients with pmCRC. The score might be helpful for determining survival probability and resectability of peritoneal disease in the context of therapeutic decision-making[16-18]. Another recently developed prognostic score for patients with pmCRC is the Colorectal Peritoneal Score (COREP). COREP includes signet cell histology, hemoglobin, white blood cell count and the value and status of serum tumor markers and ranges from 0 to 18. The cut-off value for the poor-prognosis group is COREP > 6. In the first published evaluation of 77 patients the predictive value of COREP for open/close-procedure, R1 resection and one-year survival was superior to that of PSDSS[19]. Based on the Japanese classification of pmCRC, which divides peritoneal tumor dissemination into four groups (P0: no PM, P1: local PM, P2: limited distant, PM and P3: extended distant PM)[20,21] Noura et al[22] proposed a new simple classification system that includes the colorectal liver metastases (CLM) status. Patients without CLM and local (P1) or limited distant PM (P2) are classified as Grade A and Grade B, respectively. Patients with extended distant PM and all patients with CLM have been defined as Grade C. Initial data shows significant stratification of the survival and R0 resection rates[22]. However, new scores considering different histological and clinical factors might be helpful for decision-making and allow for further improvement of the selection of appropriate therapeutic options within a multidisciplinary treatment approach.

Although there are multiple prospective randomized trials and retrospective analyses about systemic chemotherapy in patients with advanced stage and metastatic CRC, data regarding the subgroup of patients with pmCRC are limited. Franko et al[23] analyzed 364 patients with PM out of 2095 patients enrolled in the two prospective randomized NCCTG phase III trials N9741 and N9841 and showed a 30% relative reduction in overall survival in this subgroup. The 5-year OS rates were 4.1% and 6% and the median survival was 12.7 mo and 17.6 mo in the pmCRC and the non-pmCRC group, respectively. In this analysis infusional oxaliplatin-based chemotherapy was superior to irinotecan-based regimens irrespective of the PM status[23]. The subgroup analysis of patients with pmCRC enrolled in the prospective randomized CAIRO and CAIRO2 trials showed a significant impairment in the overall survival of these patients. Klaver et al[24] published a median OS of 10.4 and 17.3 mo in the CAIRO trial and 15.2 and 20.7 mo in the CAIRO2 trial. An Asian prospective single-arm phase II study investigating FOLFOX-4 in patients with pmCRC reported median overall survival of 21.5 mo. The median time to progression was 4.4 mo[25]. Consistent with these reported survival rates, Elias et al[26] reported a median OS of 23.9 mo under modern multidrug systemic chemotherapy in 48 patients with pmCRC from the French registry.

Considering the promising results of the first line treatment of patients with metastatic colorectal cancer using systemic polychemotherapy plus targeted therapy with median OS ranging from 25 mo to 41.3 mo[27-30] these regimens have also been used for treating pmCRC. In a retrospective analysis of 65 consecutive patients with pmCRC, Adachi et al[31] reported an improvement in the survival rate in response to systemic chemotherapy after incomplete cytoreduction. The oxaliplatin-based regimen and addition of targeted therapy was superior to irinotecan-based chemotherapy[31]. Razenberg et al[32] analyzed 1235 patients treated with palliative systemic chemotherapy for pmCRC. In 436 patients (35%) bevacizumab has been added to the treatment regimen. The median OS was 7.5 mo vs 11 mo in the bevacizumab group[32]. In a population-based study patients with metachronous colorectal PM were analyzed with respect to their treatment as follows: 94 patients received palliative systemic chemotherapy, 36 patients had the addition of bevacizumab and 92 did not receive therapy and the median survival was 13 mo, 20.3 mo and 3.4 mo, respectively[33]. Comparable results are reported by van Oudheusden in 82 patients who underwent open/close procedures for unresectable colorectal PM. The median OS was 11.2 mo with palliative systemic chemotherapy and 2.7 mo with best supportive care[34].

These data demonstrate the efficacy of modern systemic chemotherapy regimens with or without targeted therapy in improving the survival of patients with unresectable pmCRC. Based on these findings systemic chemotherapy should be considered the standard of care in patients with unresectable pmCRC and should be the backbone of a multimodal treatment regimen in patients who qualify for a multidisciplinary therapeutic approach. In the absence of contraindications, infusional oxaliplatinbased regimens, such as FOLFOX with or without monoclonal antibodies like bevacizumab, cetuximab or panitumumab, might be preferred as first-line therapies for these patients. Moreover, based on the results of the RAISE trial, ramucirumab might also be considered for the second-line treatment of patients with pmCRC[35]. Nevertheless, reliable data for this subgroup are not available.

The importance of systemic chemotherapy in the context of CRS and HIPEC has been demonstrated. Postoperative systemic chemotherapy has been shown to be an independent positive prognostic marker in all registries and retrospective analyses[13,70]. In a recently published database analysis of 5516 patients with PM arising from colorectal adenocarcinoma, mucinous adenocarcinoma and signet ring cell carcinoma, Simkens et al[71] showed that systemic chemotherapy improved survival independent of the histological subtype. In contrast to these findings, a multicenter study, including 221 patients with pmCRC reported no significant difference in the OS after CRS and HIPEC between postoperative systemic chemotherapy and surveillance. The median OS was 43.3 mo. Nevertheless, during the first year the rates of progression and recurrence were significantly lower in the chemotherapy group[72]. However, the optimal sequence of the therapeutic modalities remains a matter of investigation. Elias et al[13] reported no significant impact on the prognosis of neoadjuvant systemic chemotherapy in patients undergoing CRS and HIPEC for pmCRC. Passot et al[73] showed an overall response rate of 36% and a disease progression rate of 21% in patients who received different regimens of modern neoadjuvant systemic chemotherapy before CRS and HIPEC. Interestingly, the response to neoadjuvant treatment was not a significant prognostic factor, therefore, it might not be considered a contraindication for CRS and HIPEC. The median survival of patients with disease progression was 31.4 mo[73]. Further analysis of different preoperative chemotherapy regimens consisting of 5-FU, oxaliplatin, irinotecan and/or monoclonal antibodies showed a 9.7% complete response rate, 20.2% major response and 70.1% rate of minor or no response. In the multivariate analysis the pathohistological response was an independent predictor of survival (P = 0.01)[74]. Devilee et al[75] compared patients with pmCRC who received neoadjuvant systemic chemotherapy before CRS and HIPEC with patients who were treated with adjuvant systemic chemotherapy after CRS and HIPEC. All patients underwent complete or nearly complete macroscopic cytoreduction. The 3-year survival rates were 89% and 50% for the neoadjuvant and adjuvant groups. Although the PCI was lower and operation time was shorter for patients who received preoperative chemotherapy, neoadjuvant treatment was still independently associated with improved survival after correcting for other significant prognostic factors[75]. Kuijpers et al[76] analyzed a prospective database regarding the effect of systemic chemotherapy on survival of patients with lymph-node positive pm CRC undergoing CRS and HIPEC. There was a statistically significant increase in the median PFS (15 mo vs 4 mo, P = 0.024) and median OS (30 mo vs 14 mo, P = 0.015) in patients who received perioperative systemic chemotherapy. Interestingly, the timing of systemic chemotherapy had no influence on survival[76]. The prospective multicenter phase II COMBATAC study evaluates CRS and bidirectional oxaliplatin-based HIPEC plus perioperative cetuximab-containing polychemotherapy[77]. The first safety data showed no increase in the morbidity or mortality when using the perioperative treatment approach[78]. There is another ongoing prospective phase II study (BEV-IP) evaluating perioperative systemic chemotherapy plus bevacizumab in combination with CRS and oxaliplatin-based HIPEC[79]. However, survival data from both studies are not yet available.

Except for the case of early postoperative IPC (EPIC) instead of or in addition to HIPEC after cytoreductive surgery there are no reliable published data for normothermic IPC without cytoreductive surgery for local treatment of pmCRC. The concept of sequential intraperitoneal treatment, which could be applied over a peritoneal port system, has been demostrated for ovarian cancer[80]. Yonemura et al[81] developed a protocol consisting of neoadjuvant systemic and intraperitoneal chemotherapy (NIPS) for gastric cancer. Clinical trials are needed to evaluate the potential role of IPC in patients with pmCRC, especially in the neoadjuvant setting. Preoperative IPC or NIPS may allow for higher rates of CC-0/1 resection and may further improve the outcome after CRS and HIPEC. Moreover, sequential IPC with or without palliative systemic chemotherapy might improve response rates and local tumor control in patients with unresectable PM arising from CRC.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new technique for the local application of cytostatics as aerosol under pressure that allows for improved drug distribution and tumor tissue penetration. The feasibility and safety of the procedure has been demosntrated[82,83]. Most data published for ovarian cancer show local anticancer activity after sequential application of PIPAC[84]. A recently published retrospective analysis of 48 applications of PIPAC given every six weeks in 17 patients with pretreated pmCRC reported a median OS of 15.7 mo. The overall response rate was 71%[85]. Quality of life analysis accessed by the EORTC-QLQ30 questionnaire in 48 patients with PM arising from different tumor entities (PCI: 16 ± 10) that received at least two PIPAC applications showed an impairment of the global physical score and pain score after the first treatment improved after the second PIPAC application. Gastrointestinal symptoms remained stable with PIPAC therapy[86]. Based on the promising preliminary data, PIPAC might become an additional therapeutic option for the palliative local treatment of pmCRC in the future. Moreover, it might be interesting as a neoadjuvant local treatment with or without the addition of systemic chemotherapy beyond CRS and HIPEC. Several prospective clinical trials evaluating this therapy approach are ongoing. The results may help to determine the role of PIPAC within a multidisciplinary treatment concept and allow for further improvement of patient selection.

The therapeutic approach to PM of colorectal cancer has changed in recent decades. There are multiple treatment options for patients with pmCRC that must be integrated in an individualized multidisciplinary treatment approach (Figure 1). Consistent diagnostics and patient selection are crucial to obtaining optimal oncologic outcome. Thus, the therapeutic approach should be discussed by an interdisciplinary tumor board, and, if necessary, patients should be referred to specialized treatment centers. In addition to multiple palliative treatment options, CRS and HIPEC provide an additive treatment modality with curative intent for selected patients with pmCRC. The integration of further treatment options such as repeated preoperative intraperitoneal chemotherapy or PIPAC in current treatment regimens should be discussed and evaluated in randomized controlled clinical trials. Prognostic factors, such as peritoneal tumor distribution, lymph node status, hematogenous metastasis, histology, tumor mutation status, tumor immunology, numerous patient-related factors and the resection status must be considered during patient selection and should be further investigated. The development and clinical use of the prognostic scores may help tailor individual treatment regimens that consider all available therapeutic options. Further prospective randomized trials focussed on patients with pmCRC are highly recommended to optimize and standardize the multimodal treatment regimens.