Role of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Colorectal Peritoneal Metastases

Abstract

Peritoneal metastases from colon cancer are a particularly challenging disease process given the limited response to systemic chemotherapy. In patients with isolated peritoneal metastases, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy offers a potential treatment option to these patients with limited peritoneal metastases as long as a complete cytoreduction is achieved. Decision about a patient's candidacy for this treatment modality should be undertaken by a multidisciplinary group at expert centers.

Keywords

peritoneal carcinomatosis - cytoreductive surgery - HIPEC

Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality.[1] Typically, when diagnosed early, patients have favorable prognosis with over 80% being eligible for curative intent surgery with 5-year overall survival (OS) rates of 70 to 93% for stages I to III.[2] At the time of diagnosis, up to a third of patients may present with distant metastatic disease with approximately 8 to 10% having peritoneal disease and 50% having metastatic disease to the liver.[3] Peritoneal metastases are thought to be most prevalent after lung and liver metastases for colon cancer, but given limitations of diagnosis on traditional imaging, true rates are difficult to ascertain and may be higher than reported in literature.[4]

Implants are thought to result from primary tumor cell detachment, dissemination into the peritoneal cavity, and attachment to the peritoneal mesothelial cells or lymphatic channels with subsequent attachment and vascular neogenesis.[5] Additionally, studies show that expression of specific binding proteins and oncogenes that may allow for detachment of tumor cells from primary sites with potential for proliferation in the peritoneum portends a worse prognosis.[4] For example, data suggests that patients with BRAF V600E mutations, which are observed in approximately 10% of CRCs, have a higher likelihood of peritoneal dissemination and also worse prognosis.[6] Similarly, presence of KRAS mutations, which are found in approximately 40% of CRCs, also portend worse prognosis when associated with PM.[7] Clinical studies have shown that there are likely also patient and tumor-related risk factors that increase the likelihood of metachronous peritoneal carcinomatosis from CRCs. These include right-sided cancers, infiltrative or ulceroinfiltrative tumors, mucinous tumors, T4a or greater tumors, and lymph node metastases.[8] [9] Given these high-risk features, prophylactic and early detection strategies have been evaluated and are discussed later in this article.

The concept of peritoneal cytoreduction was established by Sugarbaker in the 80s and to a degree, peritoneal carcinomatosis from CRC was considered to be a systemic problem as opposed to a terminal condition.[10] As such there has been ongoing debate regarding management of peritoneal carcinomatosis from CRC with consideration for stand-alone systemic therapy versus systemic therapy in combination with surgical cytoreduction and intraperitoneal chemotherapy.

Rationale for a Regional Therapy Over Systemic Chemotherapy

Historically, peritoneal metastases have had limited response to systemic therapy alone. Systemic therapy, though efficacious, may be less effective in providing disease control in small disease given limited systemic delivery to small metastatic deposits.[11] Typically, the size of individual peritoneal nodules may also be below the level of detection on conventional computed tomography (CT) or positron emission tomography (PET). In the era of 5-fluorouracil (5-FU) treatment alone, most studies suggested that peritoneal metastases were less responsive than other metastatic sites to systemic therapy.[12] [13] [14] With the advent of modern systemic therapies (oxaliplatin and irinotecan), though significant improvements were seen in patients who had CRC liver metastases, there did not appear to be significant improvement in disease response in patients with peritoneal metastases.[15] [16] As such consideration for cytoreductive surgery in addition to systemic therapy became part of the treatment protocol in select patients with peritoneal disease.

For patients in whom surgery was a consideration, the discussion now turned to the utility of systemic therapy neoadjuvantly or adjuvantly (perioperatively). A systematic review by Waite and Youssef suggested no strong evidence for the efficacy of neoadjuvant therapy in patients who are candidates for cytoreductive surgery.[17] Two studies that reported on overlapping data from large multicenter case series (n = 506) found on univariate analysis that preoperative systemic chemotherapy did not achieve statistical significance, while multivariable analysis suggested a significant association between neoadjuvant chemotherapy and decreased median survival (p = 0.01).[18] [19] Additional studies found on univariate analysis that the use of neoadjuvant chemotherapy demonstrated a significant improvement in OS.[20] [21] In a study by Ceelen et al, this benefit was only present when neoadjuvant chemotherapy included treatment with bevacizumab and on multivariable analysis, there was a significant improvement in median OS with neoadjuvant bevacizumab versus no neoadjuvant bevacizumab (p = 0.02). Despite significance of bevacizumab in this study, the same significance was not demonstrated when comparing neoadjuvant therapy versus no therapy.[20]

When assessing the utility of adjuvant therapy, multiple studies have evaluated the benefit of therapy with variable results. The overarching challenge is that the populations being studied, outside of having colorectal and sometimes appendiceal peritoneal metastases, are not uniform in terms of disease burden or treatment regimens and most studies are observational. Additionally, timing of cytoreductive surgery, agents used for intraperitoneal chemotherapy, and quality of cytoreduction may have some variability, making these results difficult to interpret. Nonetheless, in a majority of studies, use of adjuvant systemic therapy appears to have a significant impact in improving OS.[15] [22] [23] Verwaal et al performed a randomized control trial (RCT) in patients with colorectal and appendiceal peritoneal metastases (median follow-up period of 21.6 months), and a significant improvement in OS with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) was observed. This trial along with other studies evaluating survival outcomes is further discussed in detail later in this review.

Diagnosis

In selecting patients who are appropriate candidates for CRS HIPEC, multiple factors are critical. The overall health of the patient is an important consideration given the potential magnitude of surgical debulking. Typically, Eastern Cooperative Oncology Group (ECOG) should be 0/1 and patients are selected if complete cytoreduction is thought to be feasible. In addition to the patient's functional status, other considerations are discussed below.

Patients should undergo evaluation with colonoscopy to assess for primary tumor and rule out multiple synchronous lesions that could define the extent of colectomy. Additionally, patients should have a complete staging with CT of the chest, abdomen, and pelvis. Given that conventional scans can frequently underestimate the degree of disease, workup can include MRI or diffusion weighted MRI. Typically, the size of peritoneal metastases can be below the detection level of conventional PET or CT imaging, which likely leads to higher than predicted peritoneal cancer index (PCI) scores at time of surgical evaluation.[24] Recent studies have demonstrated that diffusion-weighted MRI seems to better predict presence and degree of peritoneal metastases than other imaging modalities.[25] [26] [27] Some studies have reviewed specific preoperative imaging criteria that could portend worse prognosis and decreased likelihood of an optimal cytoreduction. Among these are presence of extra-abdominal disease, presence of more than three liver lesions, high volume of disease in the gastrohepatic ligament, presence of ureteral and/or biliary obstruction, and presence of multifocal bowel obstruction and mesenteric disease.[28]

Role of Diagnostic Laparoscopy

In addition to imaging, diagnostic laparoscopy is considered to be feasible and safe in the evaluation of patients with peritoneal metastatic disease. Given that current imaging modalities may underestimate the degree of disease, direct visualization of the abdominal cavity may provide valuable information and in many instances is considered to be the only truly reliable method to assess tumor resectability or ability to perform a complete/optimal cytoreduction.[29] [30] [31] Many institutions performing CRS + HIPEC currently ascribe to performance of diagnostic laparoscopy to assess resectability to spare patients the potential morbidity of an aborted laparotomy. Studies show that with thorough assessment, adequate visualization of the abdominal cavity is feasible to accurately assess the disease burden.[32]

PCI and Completeness of Cytoreduction Score

The extent of the peritoneal disease represents one of the major prognostic factors for survival and, thus, is a critical criterion for patient selection. To quantify it, several indices have been proposed, but presently, the most widely used is the PCI described by Sugarbaker.[33] It is a score that considers both the peritoneal implant size and its distribution in 13 abdominopelvic regions. In relation to this index, some authors have contended that a PCI higher than 10 leads to a worse prognosis and a score greater than 20 as a possible contraindication to CRS and HIPEC, as the 5-year survival rate in patients with PCI more than 19 is 7%.[34] [35]

To standardize the method of quantifying residual disease after CRS, Sugarbaker proposed the completeness of cytoreduction (CC) score.[33] This score ranges from 0 to 3, with a score of 0 to 1 suggesting residual tumors smaller than 2.5 mm and a score of 2 or 3 suggesting residual tumor nodules larger than 2.5 mm. A CC score of 0 or 1 suggests a complete cytoreduction, whereas a score of 2 or 3 suggests an incomplete cytoreduction.[36] Patients with an incomplete cytoreduction have a shorter PFS and worse OS than patients with CC scores of 0 or 1.[37] [38]

Disease-Specific Outcomes

CRS with HIPEC has been shown to improve OS in patients who undergo a complete cytoreduction (CC-0) along with HIPEC. This was initially evaluated in single-institution studies with encouraging survival results, leading to subsequent RCTs that are discussed in detail here.[39] [40] [41]

In a single-institution phase 3 RCT that took place from 1998 to 2001 at the Netherlands Cancer Institute, 105 patients were randomized to receive either systemic chemotherapy (n = 51) with 5-FU/leucovorin or cytoreductive surgery with HIPEC (n = 54) with mitomycin C (35 mg/m² at 41–42 C for 90 minutes). At a median follow-up of 21.6 months, the OS in the standard therapy (systemic chemotherapy) arm was 12.6 months compared with 22.3 months in the CRS + HIPEC arm (p = 0.032) ([Fig. 1]). CRS + HIPEC significantly reduced the risk of death (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.32–0.95: p = 0.032). Further analysis of the data in patients who underwent CRS + HIPEC demonstrated that patients with disease in multiple peritoneal regions (6–7) had worse survival than those with limited involvement (0–5 regions). If the cytoreduction was macroscopically complete (R-1), the median OS was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, p < 0.0001; [Fig. 2]).[42]

Fig. 1 Kaplan–Meier survival curve, comparing standard treatment to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).

Fig. 2 Kaplan–Meier survival curve of 49 patients treated with cytoreductive surgery with hyperthermic intraperitoneal chemotherapy and the impact of complete cytoreduction on survival.

In an 8-year follow-up analysis, the median disease-specific survival was 12.6 months in the control arm and 22.2 months in the HIPEC arm (p = 0.028) and the 5-year survival was 45% for patients in whom a complete macroscopic cytoreduction (R-1) was achieved.[43] This trial established the role of CRS+ HIPEC for the management of colorectal peritoneal metastases. However, these findings did not lead to widespread rapid adaptation of CRS + HIPEC as a treatment modality as one of the major criticisms of the study was the lack of “modern” systemic chemotherapy utilized in this trial.

However, a meta-analysis of this study, in additional to three case–control trials, demonstrated significant increases in both 2- and 5-year survival with CRS and HIPEC compared with systemic chemotherapy alone (both p = 0.001).[44]

PRODIGE7 Trial

In a subsequent RCT performed at 17 centers in France evaluating the role of HIPEC (PRODIGE7) using high-dose oxaliplatin in patients with CRC peritoneal metastases who underwent a complete cytoreductive surgery (complete macroscopic resection), patients were randomized to the CRS + HIPEC (n = 133) and CRS alone (n = 132). In the HIPEC cohort, systemic chemotherapy (400 mg/m² fluorouracil and 20 mg/m² folinic acid) was delivered intravenously 20 minutes before intraperitoneal infusion of oxaliplatin (460 mg/m² if the open technique was used and 360 mg/m² if the closed technique was used) in 2 L/m² of dextrose at 43°C over 30 minutes. Of note, all patients received systemic chemotherapy with or without targeted therapy perioperatively.

At a median follow-up of 63.8 months, the median OS was 41.7 months (95% CI: 36.2–53.80) in the CRS with HIPEC group and 41.2 months (95% CI: 35.1–49.7) in the CRS only group (p = 0.99). However, in a posthoc subgroup analysis, median OS and relapse-free survival were longer in patients with a PCI of 11 to 15 in the CRS + HIPEC group [Fig. 3].[45]

Fig. 3 Kaplan–Meier estimated of overall survival (OS) (A) and recurrence-free survival (RFS) (B) according to treatment arm in the medium peritoneal cancer index (PCI) (11–15) subgroup of patients. CI, confidence interval; HIPEC, hyperthermic intraperitoneal chemotherapy; HR, hazard ratio.

Role of “Adjuvant/Prophylactic” HIPEC in Patients with Locally Advanced Colon Cancer—The COLOPEC and PROPHYLOCHIP Trials

Patients with locally advanced colon cancer (T4 tumors) and perforated tumors are at an increased risk of peritoneal metastases. As discussed earlier, peritoneal metastases especially when the volume of disease in the peritoneal cavity is small are difficult to diagnose radiologically. Recently, two RCTs evaluated the role of CRS/HIPEC in the subset of patients known to have an increased risk of development of peritoneal metastases with the rationale that early detection and treatment may impact survival.

The role of early “adjuvant” HIPEC after curative resection of the primary tumor (< 10 days or 5–8 weeks after resection) was evaluated in a multicenter trial performed at nine hospitals in the Netherlands. Patients with clinical or pathological T4 N0-N2 M0 tumors or perforated colon cancer were randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). A bidirectional HIPEC protocol was used with 5-FU and leucovorin delivered intravenously followed by HIPEC using oxaliplatin (460 mg/m²) in a single dose for 30 minutes at a temperature of 42 to 43 °C. The primary end-point was peritoneal recurrence-free survival (RFS) at 18 months. In the intention-to-treat analysis (n = 202), there was no difference in peritoneal RFS at 18 months (80·9% [95% CI: 73.3–88.5] for the experimental group vs. 76·2% [68.0–84.4] for the control group, p = 0·28).[46] Based on the results of this trial, the use of oxaliplatin-based HIPEC in the adjuvant setting is not recommended. However, this cannot be extrapolated to the use of mitomycin for HIPEC and further studies are needed to evaluate this.

The PROPHYLOCHIP-PRODIGE15 trial[47] compared mandatory second-look surgery with oxaliplatin HIPEC to standard surveillance after completion of 6 months of systemic chemotherapy in patients with high risk of peritoneal carcinomatosis from colon cancer. This included patients with perforated primary tumor, synchronous ovarian metastases, and patients with synchronous limited peritoneal metastases completely resected at the time of primary surgery. Patients were randomly assigned to surveillance or second-look surgery plus HIPEC. Second-look surgery consisted of a complete exploration of the abdominal cavity via a laparotomy and resection of all peritoneal implants followed by HIPEC. The primary outcomes were 3-year disease-free survival (DFS).

One-hundred fifty patients were randomly assigned to a treatment group (75 in each cohort) and at a median follow-up of 50.8 months, the 3-year DFS was 53% (95% CI: 41–64) in the surveillance group versus 44% (95% CI: 33–56) in the second-look surgery group (HR: 0·97, 95% CI: 0.61–1.56). The authors of the study concluded that systematic second-look surgery with HIPEC (using oxaliplatin) did not improve DFS compared with standard surveillance. It is possible that the use of oxaliplatin may have led to the negative results of this trial and the HIPECT4 (NCT02614534) clinical trial is currently evaluating the role of mitomycin C as an adjuvant HIPEC agent in high-risk cases.[48]

Perioperative and Quality of Life Outcomes after Cytoreduction and HIPEC

Early studies evaluating the morbidity and mortality in patients undergoing CRS-HIPEC led to significant concerns about the feasibility of this procedure.[49] [50] However, with refinement of the procedure, appropriate patient selection, better understanding of the degree and duration of hyperthermia, and safer anesthetic techniques, CRS-HIPEC is now a procedure that has surgical safety outcomes comparable to similar-risk oncologic procedures. In a retrospective comparative cohort study of 34,114 patients who underwent CRS/HIPEC, right hepatectomy, hepatic trisegmentectomy, pancreaticoduodenectomy, and esophagectomy included in the National Surgical Quality Improvement Project, Foster et al revealed that CRS/HIPEC was a safe procedure when compared with similar-risk oncologic procedures. In this study, they compared perioperative morbidity and mortality and, in fact, overall 30-day mortality was lower in CRS/HIPEC (1.1%; 95% CI: 0.6–1.6%) compared with pancreaticoduodenectomy (2.5%; 95% CI: 2.3–2.7%), right hepatectomy (2.9%; 95% CI: 2.4–3.4%), esophagectomy (3.0%; 95% CI: 2.6–3.4%), and trisegmental hepatectomy (3.9%; 95% CI: 3.1–4.7%); p < 0.001).[51]

Further, numerous studies have evaluated the quality of life (QoL) after CRS/HIPEC and most have shown that the QoL drops after surgery and returns to baseline by 6 months.[52] [53] [54] [55] A prospective study that used three different methods to evaluate QoL/functional status (FACT- Functional Assessment of cancer Therapy, SF-36, and the Medical Outcomes Study Health Survey) showed an impairment in QoL up to 3 months after surgery, with recovery to near or above baseline by 12 months.[56] Additionally, a recent systematic review of 14 studies that used 12 different questionnaires evaluating QoL data for 1556 patients showed a diminished QoL within 3 months after surgery and a return to baseline by 12 months. The authors did note that QoL was negatively influenced by older age, female sex, prolonged operation time, extensive disease, residual disease, treatment with adjuvant chemotherapy, postoperative complications, stoma placement, and disease recurrence.[57]

Conclusion

Patients with CRC can present with or ultimately develop peritoneal metastases and CRS + HIPEC in conjunction with systemic chemotherapy offers a potential treatment option to these patients. The patients should be managed in a multidisciplinary fashion with the inclusion of all oncological subspecialists at expert centers.

Conflict of Interest

None declared.

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Publication History

Article published online:
13 March 2023