Keywords
cytoreductive surgery - multimodality - curative approach - chemotherapy - colorectal cancer
Introduction
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the world accounting for 8.7% of all cancer deaths.[1] Cytoreduction surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC) is part of one of the multimodal approaches toward the management of CRCs. Since peritoneum is the second most common metastatic site and is involved in about 10% of cases at initial presentation, its prognostic and predictive role is well recognized.[2] The peritoneum is a serous membrane that covers abdominal and pelvic organs, with limited vascularization. It forms a plasma peritoneum barrier that reduces efficacy of cancer-directed systemic therapy. CRS involves surgical removal of all macroscopic disease, whereas HIPEC targets residual microscopic disease using heated chemotherapy. CRS with HIPEC appears to slow oncological progression without affecting long-term survival though the operation is still experimental and should be reserved for younger patients under the age of 60.[3] HIPEC as a novel addition to the multimodality armamentarium has also been used with benefit in other cancers like ovarian cancer and gastric cancer, where its impact on overall survival (OS) is significant.[4]
[5] In fact, one of the earliest randomized controlled trials (RCTs) investigating the role of HIPEC was performed in patients of CRC with peritoneal carcinomatosis (PC) by Verwaal et al demonstrating significant improvement in the prognosis.[6] In properly selected patients, CRS + HIPEC is associated with a median OS of 51 months and can give a potential cure or long-term remission in a significant number of patients.[7]
[8]
Value of HIPEC depends on the efficacy of the chemotherapy agent at high temperatures. Various perioperative intraperitoneal (IP) chemotherapy studied include “Sugarbaker regimen,” “triple dosing regimen,” and the “low dose mitomycin C regimen: concentration-based regimen.”[9] Factors that affect outcome include, but are not limited to, the extent of disease, completeness of surgery, type of primary tumor (organ of origin), histological subtype, and age. For instance, PC with appendiceal origin have a much longer OS as compared to that of gastric origin.[10] Since there have been a lot of publications on the subject, conflicting data is often difficult to interpret, and the process of administering HIPEC is benefiting from technological advances, we bring to you the current status of HIPEC in CRC.
HIPEC in CRC: Early Trials and Applications
HIPEC is a procedure that involves the direct administration of heated chemotherapy drugs for a short time into the abdominal cavity after surgical removal of the primary tumor.[11] This approach allows for the direct targeting of residual tumor cells and micrometastases within the peritoneal cavity and has the potential to improve local control as well as survival. Multiple phase 2 studies conducted in the 1990s laid the foundation for larger retrospective and prospective studies.[12]
[13]
[14] One study conducted by Verwaal et al included a total of 105 patients who underwent surgical cytoreduction followed by HIPEC. The results showed significant improvement in OS compared to surgery alone.[6] Another study by Glehen et al reported similar findings.[15] These studies sparked increasing interest in using HIPEC as adjuvant treatment for CRC. Several questions still remained unanswered. Who are the patients most likely to benefit from HIPEC? Does it really improve the OS and to what extent? Will preliminary results be verified in larger prospective studies? Are there technological parameters that could be optimized? Verwaal et al's pioneering work with a period of 6 years has still left us perplexed in identifying patients that would have the best chance of improvement in OS.[16]
HIPEC Procedure
Preoperative evaluation must include patients' age, body mass index, comorbidities, performance status, organ reserves, prior therapies (and its tolerability), and fitness to undergo the rigorous procedures.[2]
[17] Once a suitable patient is identified, the procedure can be carried out via the open abdomen or closed abdomen technique.
Open abdomen technique: The “coliseum technique” (described elsewhere in details) uses a silastic sheet to suspend the abdominal wall, forming a “coliseum” receptacle for the instillation of the peritoneal perfusate. An incision in the center of this sheet allows manipulation of the intra-abdominal contents and prevents statis of the heated perfusate. A smoke evacuator is utilized to remove aerosolized chemotherapy.[18]
Closed abdomen technique: This is the more popular method of HIPEC ([Fig. 1]). The colonic anastomoses can be performed before or after the HIPEC perfusion. Its main advantage is being a sterile closed circuit. This abdominal wall may be physically massaged during the perfusion in order to enhance uniform heat distribution.[18]
Fig. 1 Sterile closed abdominal technique for hyperthermic intraperitoneal chemotherapy (HIPEC).
A prospective phase II trial evaluating seven different procedures in 32 participants conducted by Elias et al documented the limitations of completely closing the abdominal wall before perfusion—limited the amount of the perfusion, decreased spatial diffusion of the instillate, and led to a lack of thermal uniformity. Elias et al concluded that the coliseum technique was recognized as the best technique for heat uniformity and spatial diffusion.[19]
Laparoscopic method: Laparoscopic HIPEC in lithotomy position combines advantages of open and closed techniques. Laparoscopy allows stirring of abdominal contents during closed-abdomen HIPEC. Balloon trocars provide wide exposure of the parietal surface and alternating laparoscopic stirring achieves optimal drug distribution. Thermal probes, drains, palpators, and the use of pneumoperitoneum allows the closed perfusion HIPEC to be done over 90 minutes.[20]
The Advent of Liquid Biopsy and Its Integration with HIPEC
Liquid biopsy can identify patients most likely to benefit from HIPEC as circulating tumor deoxyribonucleic acid (ctDNA) levels can assess tumor burden and predict response to therapy.[21]
[22] Serial ctDNA testing can identify early signs of recurrence, allowing for timely adjustments to the treatment regimen, thereby personalizing management.[23]
[24] Mutations identified through liquid biopsy also guide targeted therapy decisions as well as the choice of the chemotherapy drug(s) used during HIPEC.[25] If ctDNA testing indicates low tumor burden postsurgery, it might also help avoid unnecessary adjuvant systemic chemotherapy.[24] Integrating liquid biopsy results into clinical decision-making algorithms for CRC treatment plans holds significant promise.[26] However, it cannot be considered as standard of care at this time.
HIPEC in Colorectal Cancer: Current Scenario
Several published RCTs, systematic reviews, and meta-analyses have been published on the use of HIPEC in CRC.[27]
[28]
[29] In a recent study, Cohen et al commented that, while the procedure is feasible, oncological safety and criteria for appropriate patient selection are still being evaluated.[30] Oxaliplatin and mitomycin C are the two most common drugs used for HIPEC. Zhang et al's meta-analysis comparing the survival efficacy of oxaliplatin against mitomycin C in patients having CRC with PC, concluded that mitomycin C is the safer option. On the other hand, Hompes et al had not reported any significant difference between the two.[31]
[32] While oxaliplatin can provide the advantage of a shorter exposure time (as reported by Wisselink et al), it did not translate into differences in OS and disease-free survival (DFS) as compared to mitomycin.[33] The more recent PRODIGE 7 is crucial in today's decision making.[34]
In this trial 265 patients were randomly assigned to either CRS + HIPEC with oxaliplatin-based chemotherapy or CRS alone. After a median follow-up of 63.8 months, there was no significant difference in OS between the two groups. Fortunately, HIPEC did not increase the rate of early postoperative complications or mortality at 30 days in this trial. Nor was there a difference in the frequency of grade 3 or worse digestive fistulae. However, the addition of oxaliplatin-based HIPEC to CRS did increase the frequency of grade 3 or worse complications at 60 days. The authors concluded that the treatment for peritoneal metastases should prioritize complete surgical removal of visible tumors (macroscopic complete cytoreductive surgery).[35]
Another study was published to determine whether HIPEC is better if the chemotherapy drug is not oxaliplatin. Kitaguchi et al conducted a retrospective collaborative cohort study in Korea and Japan comparing CRS + HIPEC with R0 (CC – completeness of cytoreduction) resection for patients with cancer and peritoneal metastasis (CPM) having a low PC index (PCI) scores (less than or equal to 6). Patients in the CRS arm did not undergo peritoneal stripping. The study results showed that CRS + HIPEC significantly prolonged relapse-free survival (RFS) (35.9% vs. 6.9%, p < 0.001) and peritoneal RFS (PRFS) (44.5% vs. 27.6%, p = 0.017) but no benefit in OS (59.4% vs. 74.1%, p = 0.087). The postoperative complications remained similar between the two groups. Propensity score matching analysis also confirmed that OS was significantly longer in the R0 resection group (59.4% vs. 80.5%, p = 0.031). The study concluded that in patients with low PCI scores, CRS + HIPEC provides only the benefit of longer local control of CPM (as evidenced by longer RFS and PRFS). The importance of complete cytoreduction for improving OS cannot be overemphasized. Future research with prospective studies and longer follow-up will add value to the emerging data on the place of HIPEC in CRC.[36]
There are additional factors that have been shown to have important clinical implications for specific subgroups of patients. Di Giorgio et al's meta-analysis showed that low skeletal muscle mass before surgery is an important adverse prognostic factor.[37] Conflicting rates of postoperative bleeding as well as venous thromboembolism (postsurgery) was discussed thoroughly by Lundbech et al in their meta-analysis. Their manuscript indicates that CRS + HIPEC pose only a low risk of bleeding in the 30-day postoperative period and low risk of venous thromboembolism in the 90-day postoperative period.[38] Addressing cancer-associated anemia has the potential to improve tolerance of patients to HIPEC.[39]
[40] Incorporation of neoadjuvant chemotherapy alongside HIPEC + CRS remains controversial in the absence of prospective studies.[41] The review by de Cuba et al suggests that curative resection + HIPEC shows a lower OS in comparison with CRS and HIPEC combination.[42] Other prognostic factors to keep in mind are site of primary, adjuvant chemotherapy use, intestinal obstruction or perforation, PCI score, and morbidity grade as reported by Narasimhan et al and Hallam et al.[43]
[44]
[45] Systemic chemotherapy post-CRS-HIPEC can provide survival advantage to carefully selected patients.[46] So also does excision of liver metastasis.[47]
No wonder the recent systematic review by Parikh et al failed to find clear evidence of OS benefit.[48] We could extrapolate from HIPEC use in patients with locally advanced gastric cancer,[49] but only to encourage CRC patients to enter RCTs involving HIPEC.[50] Alternatives to HIPEC, such as early postoperative intraperitoneal chemotherapy (EPIC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC), are under investigation and we eagerly await their mature data.[28]
There is scepticism among oncologists regarding CRC with PC, after the three recently published RCTs that investigated the role of HIPEC. The PRODIGE 7 trial examined the role of oxaliplatin-based HIPEC in patients treated with curative intent.[35] Conversely, the PROPHYLOCHIP and the COLOPEC were designed to investigate the prophylactic role of HIPEC in high-risk patients (T4aN01-2, synchronous lesions).[51]
[52] Although all three trials demonstrated the relative ineffectiveness of HIPEC in treating or preventing peritoneal metastases, these results are not sufficient to abandon HIPEC.
The common point of these trials is the use of oxaliplatin-based HIPEC regimen. Based on the results of these papers, the experts are of the opinion that oxaliplatin-based HIPEC is ineffective in improving surgery results in patients with CRC with PC and should be abandoned for several reasons. First, most of the patients in these received oxaliplatin-based neoadjuvant chemotherapy (FOLFOX), which raised the question of whether systemic oxaliplatin might induce chemoresistance and reduce the efficacy of oxaliplatin-based HIPEC. In a recent study, oxaliplatin chemoresistance was demonstrated in the preoperative setting, potentially making the HIPEC regimen ineffective.[53] Second, oxaliplatin-based HIPEC has higher rate of postoperative complications (grade 3 morbidity in the HIPEC arm was 26% vs. 15%, p = 0.035).[35] Another issue with these trails investigating the effectiveness of HIPEC is the difficulties in conducting randomized trials in this subset of patients (isolated peritoneal metastasis [PM] with PCI less than 20). Moreover, the choice of OS as the primary endpoint does not adequately prove the role of CRS-HIPEC, which is primarily a locoregional treatment directed to control metastatic disease inside the peritoneal cavity.
Only a minority of patients will be cured after CRS-HIPEC, and survival results are mainly related to response to systemic chemotherapy. For this reason, peritoneal recurrence/progression-free survival would have been more appropriate endpoint. Although the PRODIGE 7 trial did not support the use of oxaliplatin-based HIPEC, there are two positives in the trial. First, the trial unequivocally proves the role of CRS in the multimodal treatment of patients with CRC with PC. The gain of 42 months in median OS is a remarkable result and 15% of patients can be considered cured at 5 years. Second, significant benefit on the survival of HIPEC was seen in patients with PCI score between 11 and 15.[35] Even though oncologists have reservations about the role of CRS + HIPEC.[54]
The debate on the role of HIPEC in CRC PM treatment is constantly evolving. It is premature to completely dismiss the role of HIPEC. One of the major issues requiring further investigation after the PRODIGE 7 trial publication (and COLOPEC and PROPHYLOCHIP as well) is the choice of intraperitoneal or combination of drugs for HIPEC. Several trials are ongoing investigating mitomycin-based HIPEC after CRS. HIPEC could still prove to be useful with new protocols/new drug combinations. In future trials, apart from trails for Mytomicin C (MMC), a change in the oxaliplatin regimen is needed. Only one-half of oxaliplatin is systemically absorbed over 30 minutes of HIPEC, thus limiting its exposure to the peritoneal layers, extending the HIPEC time up to 120 minutes with a lower drug dose could improve the oxaliplatin-based HIPEC efficacy. The addition of a second drug to oxaliplatin (i.e., irinotecan) is another option. In a survey of expert surgeons of the Peritoneal Surface Oncology Group International (PSOGI), the panelists consider CRS + HIPEC still an indication for CRC with PC and the change of HIPEC regimen in most of the panelists, with a shift toward MMC-based HIPEC as mentioned in the meta-analysis where several studies are ongoing investigating other HIPEC drugs and regimens both for therapeutic and prophylactic setting.[55]
The results of the Spanish trial HIPECT4 (ClinicalTrials.gov NCT02614534) have been recently presented at the European Society for Medical Oncology 2022 (abstract n 314O).[56] Proactive cytoreductive surgery associated with mitomycin C-based HIPEC at the time of primary cT4 CRC curative resection leads to a significant improvement in the 3-year locoregional control rate (97% in the HIPEC group vs. 87%). However, the DFS was not statistically different between groups.
Conclusion
IP therapies like HIPEC, EPIC, and PIPAC are potentially useful locoregional treatments in CRC with PC patients. Despite being widely used in several cancer centers around the world for other pathologies, its role had never been conclusively proved in CRC with PC as the HIPEC regimen has not been standardized. HIPEC continues to remain an option in the management of CRC with peritoneal metastases. As of today, it has failed to conclusively prove its OS benefit. The studies conducted by Cao et al, Narasimhan et al, and Hallam et al show that success rates vary based on patient selection, chemotherapy regimens, and several other factors of prognostic importance. Further research will determine the exact benefit and criteria of patient selection for HIPEC, especially in comparison to CRS alone or with EPIC and PIPAC. Their role in conjunction with neoadjuvant chemotherapy is also to be teased out. HIPEC should still be considered a therapeutic option for selected patients and offered by dedicated, experienced centers and surgical teams.
In the meantime, we encourage the participation of eligible CRC patients in HIPEC clinical trials till such time as its definitive role in patient care is proven conclusively.
