Iterative Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Peritoneal Metastases

Discussion

CRS–HIPEC has become a valuable treatment option in patients affected by primary or secondary PSM. Over 20 years of experience at several specialized centers worldwide have perfected this procedure, achieving an acceptable morbidity profile and a mortality rate comparable to those of other major surgical operations (15). Cancer outcomes are continuously improving, mainly due to a better knowledge of prognostic factors, which leads to more appropriate patient selection (16). However, peritoneal recurrence after CRS–HIPEC still represents a major challenge for several reasons. Peritoneal recurrence is often characterized by a short life expectancy and poor quality of life. Frequently, the peritoneal cavity remains the only site of relapse and any disease progression implies complications difficult to palliate (i.e. intestinal obstruction, fistulas and pain). Moreover, any surgical approach to peritoneal recurrence, especially after CRS–HIPEC, is feared by surgeons, as the abdomen contains scars and adhesions from previous extensive surgeries. In addition, when considering surgical exploration in patients previously treated with CRS–HIPEC, the effects of hyperthermia and intraperitoneal drugs are largely unknown and, at the same time, the benefit of an iterative procedure in terms of oncological outcome is difficult to balance against the potential risk of complications and death.

In our study, we confirmed that iCRS–HIPEC is safe and that the number of complications is very similar to that reported in our series after primary treatment (data not shown). Previous experience showed that iCRS–HIPEC is associated with an acceptable morbidity profile. The grade III-IV morbidity rate after iCRS–HIPEC ranged between 20-40%, which is in line with the complication rate reported after primary CRS–HIPEC. Mortality is around 3%, similar to that reported after first CRS–HIPEC (15). The morbidity and mortality profile similar to that reported after primary CRS–HIPEC is in part the result of a more accurate selection process, which includes age, performance status and tumor extension. The relationship between tumor extension and postoperative morbidity after CRS–HIPEC is well known (17). In our experience, the median PCI is relatively low (14.5) and, in other studies, it rarely exceeded 16 (11). This means that iCRS–HIPEC can generally be proposed for younger patients with a good performance status and a relatively lower tumor load.

The long-term effects of intraperitoneal drugs after HIPEC on normal tissues and the peritoneum are unknown. The hypothesis is that HIPEC might have a potential detrimental effect on the peritoneal layers and small bowel wall, through a direct cytotoxic effect of the drugs. The subsequent long-term damage and weakness of bowel layers and the presence of more scar tissue make surgery after HIPEC even more dangerous. Clinical data on the onset of abdominal adhesions after HIPEC show that intraperitoneal mitomycin C, cisplatin, and doxorubicin induce local toxicity through an irritator effect on the peritoneal layer (18). The final effect is a higher incidence of postoperative adhesions whose severity is dependent on the type of drug infused. Adhesion after intraoperative intraperitoneal cisplatin can produce intestinal obstruction requiring surgery in 6% of cases (19). Doxorubicin, which is an alkylating agent exerting its antineoplastic activity through DNA intercalation, inhibition of topoisomerase II, and formation of oxygen free radicals (oxidative stress), causes a severe inflammatory reaction in the peritoneum and significant fibrosis when used for intraperitoneal therapy. A dose–escalation study demonstrated that intraperitoneal administration of doxorubicin at total dose of 15 mg/m² resulted in a thin layering of fibrosis on peritoneal layers (20). This sclerosing effect of doxorubicin is useful for the treatment of debilitating malignant ascites and is considered the best drug for palliative laparoscopic HIPEC (21). Similarly, the effect of heat in the intraperitoneal area during HIPEC on normal tissues is poorly understood. In in vitro studies, the thermal dose (derived from exposure time and given temperature) required to induce hyperthermic cell death varies according to cell type. Hyperthermia can induce irreversible changes to tissue microcirculation, with a breakdown of circulation even after termination of heat exposure (22). Further studies are needed for clarify if regional hyperthermia can induce more intraperitoneal scar adhesion and small bowel weakness. In our study, two out of the three reported III/IV complications were related to small bowel fistulas (all unrelated to anastomosis). In one case, we observed perforation in two different loops, interestingly after the third CRS–HIPEC. This finding support the hypothesis that previous HIPEC could have weakened intestinal layers, leaving them at a higher risk for perforation. This hypothesis should be further explored.

From the oncological point of view, histological type should probably be the main selection criterion for iCRS–HIPEC. We selected, in most cases, only patients with PMP with low-grade features (5/8) and the two patients who underwent a third iCRS–HIPEC both had low-grade mucinous tumor. Of the remaining three patients, two had low-grade histology (uterine sarcomatosis and epithelial mesothelioma) and one had a high-grade colorectal peritoneal recurrence. It is well known that some PSM tumors are characterized by intraperitoneal spread throughout the entire disease history and systemic chemotherapy is rarely effective and not routinely used. The lack of valuable therapeutic alternatives and low-grade histology were the most determinant selection factors for iCRS–HIPEC in our series. This ‘selection effect’ has been confirmed in several studies, where PMP and mesothelioma represent the most frequent indications for iCRS–HIPEC (11).

The cancer outcome after iCRS–HIPEC is satisfactory, with most patients being alive, and about half without evidence of disease at study end. However, even considering previous experience with iCRS–HIPEC, data are scarce and difficult to compare as indications vary and HIPEC protocols differ among centers. Although some benefit is expected in patients treated for PMP and mesothelioma, the long-term results of iCRS–HIPEC remain uncertain and should be further evaluated.