TO THE EDITOR
The term “peritoneal carcinomatosis” has contributed to maintaining the nihilistic approach of the medical oncology community and general surgeons toward surgical resection as part in the treatment of colorectal cancer (CRC) peritoneal metastases. Until recently, surgery for these patients has only been considered as palliative treatment[1]. Nevertheless, the medical oncology community has always considered surgery as the standard treatment approach for patients with resectable oligometastatic disease of CRC origin, “even in the absence of randomized trials comparing surgical with non-surgical disease management”, as written by the authors of ESMO consensus guidelines for the management of patients with metastatic CRC in 2016[2]. Consequently, when surgical treatment of liver metastases from CRC began, the strategy was easily embraced by the oncologic community, even before any dedicated randomized trial was complete. Peritoneal surgery, unlike liver surgery, has never received the same recognition.
The conventional therapy for patients with CRC peritoneal metastases is based on systemic chemotherapy that aims to obtain prolongation of survival and symptomatic relief. Keeping in mind that isolated modern chemotherapy regimens have poorer efficacy in patients with CRC peritoneal metastases than in patients with other metastatic sites[3,4], it would be desirable to make available a more aggressive locoregional therapy to address the peritoneal involvement.
DEVELOPMENT OF PERITONEAL SURGERY
In the 1980s and 1990s, surgical pioneers in peritoneal surface malignancies: Paul Sugarbaker[5], François Gilly[6], Dominique Elias[7], and Franz Zoetmulder[8], developed surgical techniques to address malignant involvement of the peritoneal cavity, naming those procedures cytoreductive surgery (CRS). Surgeons worldwide trained in this surgical expertise, and an international group (Peritoneal Surface Oncology Group International (PSOGI), 1998) and other national groups (for example the Grupo Español de Cirugía Oncológica Peritoneal (GECOP) 2007, in Spain) were founded. Within these surgical groups, the combination of hyperthermic intraperitoneal chemotherapy (HIPEC) with CRS has always been considered.
The rational for the association of CRS and HIPEC is to achieve a complete surgical resection of all macroscopic disease within the peritoneal cavity, and to treat the residual microscopic disease (or residual nodules less than 2.5 mm in diameter) with intraperitoneal chemotherapy[9].
Other surgical groups also perform peritoneal metastatic resection without the use of HIPEC[10-12]. The reason for not using HIPEC is mostly due to its presumed high morbidity. In 2016, Baratti et al[13] conducted a systematic review on CRC peritoneal metastases treatment, based on retrospectives studies, and showed the benefits of comprehensive treatment with CRS and HIPEC. For comparison purposes, only retrospective studies have ever been required for the acceptance of surgical treatment of CRC liver metastases. For CRS/HIPEC, there is a greater demand required to prove its benefits, and the lack of randomized trials has been underscored.
CONTROVERSIAL STUDIES ON CYTOREDUCTIVE SURGERY AND HIPEC
A phase III randomized trial was conducted by Verwaal et al[14] comparing CRS/HIPEC to the standard treatment at the time, i.e. systemic chemotherapy with 5-fluorouracil (5-FU) and leucovorin. The results revealed a median survival of 12.6 months in the standard therapy arm, and 22.3 months in the HIPEC group (P = 0.032), but the median follow-up was only 21.6 months. This study generated a great deal of criticism. It was mainly criticized as cases of peritoneal disease from mucinous appendicular neoplasia were present within the included patients in the HIPEC group, and the study was performed in the era of 5-FU. Subsequently, chemotherapy and target therapy for CRC have evolved since then with increased overall survival (OS).
The results of PRODIGE 7, a multicenter French randomized phase III trial comparing CRS/HIPEC with CRS alone for CRC peritoneal metastases, were presented at the ASCO meeting and published as an abstract in 2018[15]. Curiously, the manuscript was not published until 2021[16].
The study included 133 patients in the CRS/HIPEC arm, and 132 patients in the CRS alone group. After a median follow-up of 63.8 months, the median OS was 41.7 months in the CRS/HIPEC group and 41.2 months in the CRS alone group (P = 0.99). The negative result for HIPEC in this study made us recall Thomas Henry Huxley at The Address at the Meeting of the British Association at Liverpool (1870), when he said: “But the great tragedy of Science-the slaying of a beautiful hypothesis by an ugly fact … was played, almost immediately, for the benefit of Buffon and Needham”[17]. In this case, the results of PRODIGE 7 were promptly “played for the benefit of” the anti-HIPEC adversaries[18].
In the PRODIGE 7 study, systemic 5-FU and folinic acid were delivered intravenously 20 minutes before intraperitoneal infusion of oxaliplatin at 43 ºC over 30 minutes[16]. From their results it appears that “the beautiful hypothesis” of the benefit of oxaliplatin as locoregional treatment for microscopic disease for 30 minutes was rejected because this HIPEC did not prolong survival (which became “the ugly fact”). Nevertheless, the hypothesis of HIPEC as adjuvant locoregional treatment in CRC with peritoneal involvement was not falsified by this trial. What the trial leads us to conclude is that HIPEC with oxaliplatin at that specific dose and perfusion time did not influence OS. Furthermore, the trial results show that a potential benefit of the regimen cannot be excluded. There was a trend towards better locoregional control of the disease in the first 18 months after surgery, as shown by the Kaplan Meier curves, corresponding to a decrease in peritoneal recurrence observed in the CRS/HIPEC group compared with CRS alone[19]. Additionally, the authors found in a post-hoc subgroup analysis that median overall and relapse-free survival were longer in patients with a peritoneal cancer index (PCI) of 11-15 in the CRS plus HIPEC group than in those in the CRS group. This result may encourage future research into the role of HIPEC in patients with a PCI of 11-15 and in whom complete or near-complete surgical resection is achieved.
Apart from OS results, the issue of morbidity and mortality is of importance when discussing the role of HIPEC. The morbidity at 30 days reported by the PRODIGE 7 study was not different between the groups, with 42% in the CRS/HIPEC group vs 32% in the CRS alone group (P = 0.083). The intra-abdominal complications were not different at 30 days (27% vs 18%, P = 0.084) and 60 days (6% vs 3%, P = 0.38) between the CRS/HIPEC and CRS alone groups, respectively. Four patients died within 30 days of CRS with or without HIPEC, two (2%) due to cardiac failure and massive pneumonia in the CR/HIPEC group, and 2 (2%) due to intraperitoneal hemorrhage and septic shock in the CRS alone group. The difference in morbidity was statistically significant for: neutropenia (17% vs 8%, P = 0.025), thrombocytopenia (9% vs 2%, P = 0.011), and late severe complications (day 31-60) (26% vs 15%, P = 0.035) in the CRS/HIPEC group and CRS alone group, respectively. It is striking that the higher complication rate in the HIPEC/CRS group was rapidly associated with the oxaliplatin intraperitoneal infusion, and was not considered to be related to 5-FU intravenous bolus administered to the anesthetized patient, as this was performed following the bidirectional chemotherapy protocol[20] used in the trial. It is well known that bolus administration of 5-FU is associated with hematological toxicities (anemia, neutropenia, and thrombocytopenia)[21-23]. Therefore, the effect of endovenous administration of 5-FU on postoperative complications should be studied before ascribing the higher morbidity shown in the CRS/HIPEC group to the sole administration of intraperitoneal chemotherapy agent.
The Group of Professor Bruno Camps from Valencia, Spain, one of the pioneers of CRS/HIPEC in this country, used mitomycin C for 60 minutes at 40 ºC, without the administration of systemic chemotherapy. No treatment-associated myelosuppression was observed in our patients.
Despite the negative results for HIPEC in the PRODIGE 7 trial, worldwide CRS/HIPEC surgical groups have not been discouraged and persevere using several HIPEC protocols in patients with CRC peritoneal metastases. These patients, mainly if metastases are metachronous, may require very complex surgical management, due to the disease itself and to previous surgical adhesions. Therefore, identifying patients who will benefit from CRS with or without HIPEC would be of great interest.
PROGNOSTIC MARKERS AND SURGICAL INDICATIONS FOR CRS/HIPEC
In the recent issue of World Journal of Gastrointestinal Oncology, Wu et al[24] published their work on markers related to the prognosis of patients with peritoneal metastasis of CRC. The authors performed a study aiming to investigate the association of preoperative inflammatory neutrophil-to-lymphocyte ratio (NLR) and nutritional markers (hemoglobin) with prognosis in patients with CRC peritoneal metastases. They undertook a retrospective study including a series of 133 patients with peritoneal metastases from CRC who underwent CRS and HIPEC. The protocol used in their institution was a mixture of 5-FU, oxaliplatin, and platinum, at 42ºC, for 60 minutes for patients with a completeness of cytoreduction (CC) score of CC 0 or CC 1 (non-macroscopic disease after resection, or residual tumor nodules of less 2.5 mm as the maximum diameter, respectively). They determined an optimal NLR cutoff value of 3.1 for predicting OS (high NLR group: NLR ≥ 3.1; low NLR group: NLR < 3.1). The authors observed a median OS for patients with high NLR of 7.9 months compared with 25.4 months for those with low NLR (P = 0.002). As revealed by the authors, there are currently no standardized NLR values for all patient cohorts and this could limit the conclusion of the study concerning the influence of NLR on OS.
Another finding in the study was that albumin level, unlike hemoglobin (Hb) level, was not an independent prognostic factor in their multivariate analysis, and therefore they proposed that Hb was a better indicator of nutritional status and prognosis than albumin. In their series, patients with normal Hb had a significantly longer median OS (18.5 months) than those with low Hb (6.3 months; P < 0.001)[24].
The study also provided a nomogram, which included the factors Hb, age, NLR, serum cancer antigen 19.9, and PCI[24], that translated the importance of these factors for assessment of surgical risk, as well as prognostic factors. The consideration of these factors, mainly the PCI, will be necessary when the decision to proceed with CRS with or without HIPEC is taken.
CONCLUSION
In conclusion, CRS must be included in the treatment of selected patients with stage IV CRC with peritoneal metastases, in association with systemic chemotherapy. Thus, surgery should not be viewed only as palliative treatment, and therapeutic resection surgery must always be considered. The administration of HIPEC should be left to the discretion of the surgical group. Provided that there are no postoperative complications directly related to HIPEC, the administration of HIPEC should be encouraged mainly when CC 0 and CC 1 resections are obtained, and preferably in clinical trials.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: Spain
Peer-review report’s classification
Scientific Quality: Grade A
Novelty: Grade A
Creativity or Innovation: Grade A
Scientific Significance: Grade A
P-Reviewer: Li S S-Editor: Qu XL L-Editor: Webster JR P-Editor: Zhao S
