Reprinted from: [Interpretation] Perioperative Hyperthermic Intraperitoneal Chemotherapy for Stage T4 Colorectal Cancer: Can It Improve Patient Prognosis? Propensity Score Matching

[Abstract]: In this study, prophylactic HIPEC reduced the risk of PM in patients with cT4N0-1M0 disease and significantly improved DFS. Postoperative prophylactic HIPEC did not significantly increase the incidence of surgery-related complications. Meanwhile, performing HIPEC after laparoscopic surgery in T4-stage CRC patients is relatively safe and does not increase the risk of peritoneal implantation or metastasis. Prophylactic hyperthermic intraperitoneal chemotherapy for T4-stage colorectal cancer has been shown to be effective [strong] and is worthy of clinical adoption!

Perioperative Hyperthermic Intraperitoneal Chemotherapy for Stage T4 Colorectal Cancer: Can It Improve Patient Prognosis?—A Propensity Score Matching Study

1. Background

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system. Currently, approximately 7% of CRC patients have synchronous peritoneal metastasis (PM), and more than 4% of patients develop PM alone. Based on large-scale population studies, the 5-year cumulative risk of developing metachronous PM in patients with recurrent colorectal cancer reaches as high as 6%. Even when patients with PM receive optimal systemic chemotherapy, their overall survival (OS) remains only 16.3 months [95% CI, 13.5–18.8]. In recent years, studies have shown that cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can improve OS and may become a treatment option for certain colorectal cancer patients with localized peritoneal metastasis. Some studies indicate that CRS combined with HIPEC has increased the median survival of PM patients to over 41 months. However, for high-risk populations with peritoneal metastasis from T4-stage or perforated colon cancer, the survival benefits of CRS combined with HIPEC compared to systemic chemotherapy alone or CRS surgery remain unclear. The recently conducted HIPEC-T4 trial is the first randomized controlled trial (RCT) to evaluate prophylactic HIPEC using mitomycin C. The results suggest that HIPEC combined with mitomycin C and complete surgical resection significantly improves local regional control rates in T4 (cT4) colon cancer, consistent with our own study findings. This study aims to clarify whether prophylactic HIPEC can improve the survival prognosis or reduce the risk of PM in T4-stage CRC patients, and whether it might increase the risk of anastomotic leakage (AL) or other postoperative complications. The findings of this study could potentially extend disease-free survival (DFS) in T4-stage patients, which is crucial for clinicians in developing appropriate treatment strategies for T4-stage CRC patients.

2. Methods

① Study population

Patients were screened from prospective randomized controlled trials registered on clinicaltrials.gov (NCT02179489) and the National Key Research Project “Specialized Cohort Study on Colorectal Cancer” (2017YFC0908200), from November 2014 to November 2018. The experimental group/HIPEC group included patients who received mitomycin C treatment from the NCT study, while those who received oxaliplatin treatment were recruited from the Specialized Cohort Study on Colorectal Cancer. The control group/non-HIPEC group comprised patients from both the NCT study and the Specialized Cohort Study on Colorectal Cancer. All patients included in the analysis met the following inclusion and exclusion criteria: Inclusion criteria: clinically T4 (cT4) N0-2M0 CRC patients who underwent intention-to-treat analysis; Exclusion criteria: patients who received neoadjuvant therapy prior to surgery; patients who underwent emergency surgery due to urgent conditions; patients with high-risk factors for peritoneal metastasis, such as tumor perforation, ovarian metastasis, or locally resectable peritoneal metastasis; patients with postoperative follow-up periods shorter than six months; and patients lacking complete information on disease treatment. Based on whether HIPEC was administered, the total cohort, after propensity score matching (PSM), was divided into two groups: the HIPEC group (n=45) and the non-HIPEC group (n=135).

② Research Steps

1. Study Design: Patients in the control group (non-HIPEC group) underwent conventional open surgery or laparoscopic radical surgery followed by standard adjuvant chemotherapy (FOLFOX4, mFOLFOX6, CapeOx, or capecitabine). Similar to the control group, patients in the experimental group (HIPEC group) first received radical surgery; postoperatively, depending on the surgical findings and the patients’ baseline conditions, HIPEC was performed either concurrently with closure of the abdominal cavity or within three days following surgery. Subsequently, these patients completed standard adjuvant chemotherapy.

2. HIPEC Procedure: (1) Four infusion catheters are inserted through punctures in both abdominal walls—two for inflow and two for outflow—and are placed within the upper abdominal liver-kidney recesses on both sides of the腹腔, at the splenic hilum and venous plexus, and in the pelvic floor. (2) The flow rate is set at 400 (±100) ml/min. (3) A solution containing mitomycin C (30–40 mg/m²) or oxaliplatin (300 mg/m²) is continuously infused into the腹腔 at a constant temperature of 43°C for 60 minutes. Immediately after completion of HIPEC, the perfusion fluid is drained out.

③ Data Collection

The primary endpoint is DFS, defined as the time interval between the initial resection and the first recurrence or death from any cause. Secondary endpoints include the 3-year PM rate, distant metastasis, OS, and safety. OS is defined as the time interval from the initial resection to death from any cause or the last follow-up visit. The analysis cut-off date was November 30, 2021.

3. Results

Demographics of the study population and the PSM cohort

1. As shown in Figure 1, from November 2014 to November 2018, a total of 220 patients were enrolled, excluding those lost to follow-up; the median follow-up duration was 52 months (IQR, 42.0–64.0).

2. As shown in Figure 2A, the 3-year DFS in the HIPEC group was 83.9%, compared to 67.2% in the control group. The difference in cumulative DFS between the two groups was statistically significant (p = 0.014).

3. After 1:3 PSM, we compared the 45 patients in the HIPEC group with the 135 patients in the non-HIPEC group. As shown in Table 1, there was sufficient balance in the propensity score matching between the two groups, and the differences in clinical and pathological characteristics were minimal. Among the unmatched variables, there were no significant differences between the unmatched groups.

The outcome of survival

1. As shown in Figure 2B, the 3-year DFS was 83.9% in the HIPEC group and 70.1% in the non-HIPEC group (p = 0.034).

2. As shown in Figures 3A and 3B, in the subgroup analysis based on lymph node metastasis status, N2 patients accounted for 22.2% of the HIPEC group and 20.7% of the non-HIPEC group (p = 0.833). In the non-HIPEC group, the cumulative incidence of PM was 17.9%, and the incidence of distant metastases to the liver, lungs, bones, and brain was 39.1% (p = 0.026 and p = 0.035, respectively). Disease-free survival (DFS) and overall survival (OS) were significantly lower in N2 patients than in N0-1 patients.

3. As shown in Figures 3C and 3D, after prophylactic HIPEC, the disease-free survival (DFS) of T4N0-1 patients improved significantly (p=0.045), whereas no difference was observed in N2 patients between those who underwent HIPEC and those who did not (p=0.370).

4. As shown in Figure 3E, in the subgroup analysis of T4 patients who underwent laparoscopic surgery—patients accounting for approximately 81.1% of the total in both groups—the 3-year PM rate was 13.8% in the control group and 2.6% in the HIPEC group (p = 0.070). The 3-year DFS was 83.6% in the HIPEC group and 70.1% in the control group (p = 0.063). There was no significant difference in outcomes between T4 patients who underwent laparoscopic surgery, regardless of whether they received HIPEC or not.

Prophylactic HIPEC surgery is an independent predictor of DFS.

Compared with the control group (62.4 months, 95% CI 57.1–67.7), the study group receiving prophylactic HIPEC had a longer disease-free survival (DFS) (74.1 months, 95% CI 67.3–80.9; Figure 2B, p=0.034). In univariate survival analysis, two additional factors significantly affecting DFS were lymph node staging (Table 2, p=0.026) and postoperative chemotherapy (Table 2, p=0.046). Meanwhile, multivariate analysis identified two independent predictors of DFS: prophylactic HIPEC (HR 0.43, 95% CI 0.19–0.95; p=0.037) and lymph node N2 staging (HR 1.97, 95% CI 1.09–3.56; p=0.025) (Table 2).

Sensitivity analysis to validate the PSM analysis results.

Table 3 summarizes the sensitivity analysis for the HIPEC group and the non-HIPEC group, including Kaplan-Meier analyses and Cox regression model analyses of DFS. We still identified two variables—prophylactic HIPEC (HR 0.39, 95% CI 0.18–0.86; p=0.020) and lymph node N2 stage (HR 1.96, 95% CI 1.08–3.57; p=0.028)—as independent predictors of DFS (Table 3).

Surgical outcome

There was no statistically significant difference in surgery-related complications and reoperation rates between patients with a Clavien-Dindo score ≥ Grade II (p = 1.000). Anastomotic leakage (AL) was the primary concern for surgeons, but the difference between the two groups was not statistically significant (p = 0.439). In the non-HIPEC group, 2.2% of patients experienced postoperative complications; among these, 1.5% (2/135) developed incisional hernias, and 0.7% (1/135) of patients with AL (CD4) exhibited symptoms of septic shock, which ultimately improved following surgical intervention. Among patients who underwent prophylactic HIPEC, we recorded only 2.2% (1/45) developing AL (CD2) without requiring active therapeutic intervention. No surgical deaths attributable to operative complications were documented in the electronic medical records.

4. Discussion

In patients with colorectal cancer complicated by peritoneal metastasis (PM), the progression-free survival (PFS) and overall survival (OS) are typically shorter than in patients with colorectal cancer not involving the peritoneum. Peritoneal metastasis is considered an end-stage disease with a very poor prognosis; the OS in these patients (16.3 months [95% CI 18.3–18.8]) is significantly lower than that in patients with liver metastasis (19.1 months [95% CI 18.3–19.8]) or lung metastasis (24.6 months [95% CI 22.7–26.4]). Given that the symptoms of colorectal cancer complicated by PM are non-specific, current diagnostic tools have limited sensitivity and accuracy, making it difficult to detect PM at an early stage. To address these challenges, the preventive HIPEC approach can help prevent local recurrence of CRC and PM in high-risk patients. When used without combined extensive CRS, preventive HIPEC has a low complication rate and a short hospital stay.

In this study, we found that recurrence and metastasis in stage T4 CRC were significantly associated with whether patients received prophylactic HIPEC. Multivariate analysis confirmed that prophylactic HIPEC is an independent predictor of disease-free survival (DFS) in stage T4 colorectal cancer. The data lead to the conclusion that prophylactic HIPEC in patients with stage T4 CRC can improve DFS and reduce the risk of distant metastasis. Moreover, the HIPEC-T4 trial is consistent with the findings of this study in one aspect: the combination of HIPEC based on mitomycin C with complete surgical resection improved local regional control rates in cT4 colon cancer. At the same time, the researchers found that only 2.2% of patients in the HIPEC group experienced anastomotic leakage, while no other adverse complications occurred in the remaining patients. In this regard, the results of this trial differ from those of the PROPHYLOCHIP trial, in which 41% of patients in the second-stage surgery group experienced severe postoperative complications (grade 3 or 4), significantly impacting their quality of life. Although no difference in efficacy was observed, severe postoperative complications associated with mitomycin C were less frequent than those associated with oxaliplatin (21% vs. 30%). Therefore, this study confirms that HIPEC is feasible and relatively safe for reducing the risk of distant metastasis in patients with stage T4 colorectal cancer.

The study further analyzed the prognosis of T4 patients who underwent laparoscopic surgery—these patients constituted the majority of the cohort. Among these patients, the incidence of peritoneal metastasis (PM) after HIPEC treatment was 2.6%; however, in the non-HIPEC group, the PM incidence was as high as 13.8%. This suggests that laparoscopic surgery combined with prophylactic HIPEC treatment is feasible for T4-stage colorectal cancer patients and does not increase the risk of peritoneal implantation spread due to intra-abdominal gas flow. A retrospective study conducted by Professor Sugarbaker showed that among all patients who underwent laparoscopic or robotic colectomy, 13 eventually developed port-site metastasis, with 85% of these patients having advanced T-stage disease (T3 or T4). Hiroshi Nagata et al. found that compared to patients undergoing open colectomy (OC), those undergoing laparoscopic colectomy (LC) had a higher risk of PM in pT4a colon cancer patients; however, they also studied cT4a patients and found no significant difference in PM risk between the LC and OC groups. Nevertheless, several studies have demonstrated that both laparoscopic and robot-assisted surgeries are safe when compared to open resection for T4 cancers and can lead to better tumor outcomes and survival rates. The role of minimally invasive surgery in p/cT4 CRC still requires further investigation.

In the T4N2 subgroup analysis, the incidence of PM without prophylactic HIPEC intervention was 17.9%, and the incidence of distant metastasis was 39.1%. This suggests that patients with stage T4N2 colorectal cancer are prone to distant metastasis, and patients in stage N2 exhibit significantly lower DFS and OS compared to those in stages N0-1. Lymph node metastasis is an important prognostic factor associated with local tumor recurrence, distant metastasis, and cancer-specific survival. Another study found that among 796 CRC patients, 68% of T4N2M0 cases had distant metastasis. In this regard, the patients enrolled in the current trial differ from those in the COLOPEC trial: both the experimental and control groups had an N2 patient proportion close to 40%. However, the COLOPEC study showed that in T4 or colon cancer patients with perforation who received 30-minute adjuvant HIPEC treatment with oxaliplatin, there was no significant improvement in peritoneal metastasis-free survival at 18 months. Therefore, conventional radical surgery combined with standard adjuvant chemotherapy—even when supplemented by prophylactic HIPEC—may not substantially improve the prognosis of T4N2M0 CRC patients.

Limitations of this study: This is not a randomized controlled trial, and the selection of patients may influence the study results. However, the researchers attempted to mitigate the impact of non-randomization through propensity score matching (PSM). A potential limitation of this study is the timing of prophylactic HIPEC—whether administered intraoperatively or within 3 days postoperatively—and the choice of drugs (mitomycin C or oxaliplatin). Nevertheless, in this study, there was no significant difference in survival outcomes between the two groups of patients. Moreover, PM remains challenging to diagnose at an early stage. Currently, it is not yet feasible to perform diagnostic laparoscopy at a specific point in time; instead, diagnosis relies solely on imaging techniques. Larger-scale, prospective, randomized controlled trials are needed to verify whether prophylactic HIPEC treatment can achieve the expected therapeutic effects in high-risk CRC patients.

5. Conclusion

In summary, both clinically and pathologically, patients with stage T4 CRC have a significantly higher probability of developing peritoneal metastasis (PM) compared to those with stages T1–3. In this study, prophylactic HIPEC reduced the risk of PM in cT4N0-1M0 patients and significantly improved disease-free survival (DFS). Moreover, postoperative prophylactic HIPEC did not significantly increase the incidence of surgery-related complications. At the same time, performing HIPEC after laparoscopic surgery for stage T4 CRC patients is relatively safe and does not increase the risk of peritoneal implantation or metastasis. In the future, further research should be conducted to identify the optimal indications for prophylactic HIPEC.

Proofreading: Ma Yuan, Chen Haiwei

Editor: Zhao Hongxia

Reviewed by: Zhao Wei

Statement

The content published on this official account represents only my personal views. Due to my limited expertise, errors are inevitable. If you spot any mistakes, I would greatly appreciate your constructive criticism and corrections.