In the setting of CCa with metastatic disease, best supportive care offers a median survival of 2.5 months(18). Though the addition of gemcitabine/capecitabine-based palliative chemotherapeutic regimens has improved survival to 9.3-14 months(19, 20), it still remains poor. To the best of our knowledge, to date, there are only two case reports in the literature of metastatic CCa managed with CRS/HIPEC. Golse et al. reported on a retrospective series of iterative CRS/HIPEC procedures(13). One patient with CCa was treated twice with CRS/HIPEC for tumor recurrence limited to the peritoneal cavity. Though the specific PCI for this patient was not reported, they required limited debulking (omentectomy and peritonectomy) and complete cytoreduction was achieved. The HIPEC agents used were mitomycin C and cisplatin. Neither the specific morbidity nor the survival data was available. The second case, reported by Brandl et al.(14), underwent a single CRS/HIPEC procedure with a PCI of 16 and achieved CC-0. The HIPEC agent was not stated. PFS was 12.1 months and OS was 12.7 months. Neither study reported if the malignancies originated from the intra- or extrahepatic biliary tree. In our study, all four patients with CCa (three intrahepatic, one hilar) underwent a single CRS/HIPEC procedure; 50% were for metachronous PC. The median PCI was 7, all patients achieved complete cytoreduction (requiring 1-6 organ resections) and mitomycin C was used as the HIPEC agent in all procedures. Two patients underwent neoadjuvant chemotherapy and all underwent adjuvant chemotherapy with gemcitabine or FOLFIRINOX. No patients experienced major perioperative morbidity. Median PFS was 10 months and median OS was 19 months. Hilar CCa had a shorter OS (11 months) and PFS (3 months) compared to intrahepatic origin.
ii. Gallbladder adenocarcinoma
Advanced GBC has a 5-year survival rate of less than 5%(21). Phase II trials with gemcitabine-based chemotherapeutic regimens have demonstrated survival benefits; PFS 6-9 months and OS 9.8-14 months(22). The ABC-02 phase III trial by Valle et al. reported significant superiority of gemcitabine/cisplatin over gemcitabine alone with improved median PFS (8 versus 5 months) and median OS (11.7 versus 8.1 months); thus gemcitabine-cisplatin is now the standard of care for advanced biliary tract cancers(23). However, there is limited data regarding the role of CRS/HIPEC in GBC. Most reports of debulking only include patients with locally advanced, non-metastatic GBC(24, 25), and there are only very few discussing outcomes of metastasectomy(26, 27). A 2017 study by Park et al. reviewed 19 patients with metastatic biliary tract cancers; 7 had GBC with PC (3 were metachronous disease)(28). After metastasectomy, only two achieved R0 and three achieved R1. Median PFS and OS were 8.5 and 16.6 months, respectively; longer in patients with metachronous metastases and fewer organs resected. There is only one study in the literature examining CRS/HIPEC for GBC. Randle et al. reviewed 5 patients undergoing 6 procedures for GBC with PC(12). All patients had low PCI scores and achieved complete cytoreduction. Major perioperative morbidity was reported in 17% of patients. Median OS was 22.4 months and 3-year OS was 30%. In our study, there were three patients with GBC who underwent CRS/HIPEC for metachronous metastases. The median PCI was 21 and only 1 patient achieved complete cytoreduction, the remaining two had a CC-2 score. All patients underwent neoadjuvant and adjuvant chemotherapy with gemcitabine-based regimens. 1 patient experienced major morbidity with wound complications requiring reoperation. PFS was 13 months for the patient who achieved CC-0 and median OS was 7.5 months (13 months for the CC-0 patient).
iii. Pancreatic adenocarcinoma
Over the last few decades, the approach to managing PCa has undergone a paradigm shift. It has largely become a non-operative disease treated with chemotherapy owing to the morbidity of the procedures as well as the frequent occurrence of occult metastases at diagnosis. Postoperative recurrence is common and 5-year survival is estimated at 8.2%(1). Multiple chemotherapeutic regimens have been shown to extend survival in advanced PCa(29, 30); in particular the 2011 ACCORD-11 trial which reported improved survival with FOLFIRINOX compared to gemcitabine (11.1 versus 6.8 months). Metastasectomy has been well established in pancreatic neuroendocrine tumors, and in recent years there have been a few small studies examining its utility in adenocarcinoma. Though literature has shown that pancreatectomy with synchronous hepatic metastasectomy can be performed safely(31-33), the long-term survival benefit is unclear. A 2017 systematic review and meta-analysis of 11 studies with 1147 patients concluded that there was a significant improvement in medium-term (<3 year) survival compared to non-surgical approaches with median 1-year, 3-year and OS of 40.9%, 13.3% and 9.9 months, p<0.0001(34). Pulmonary metastasectomy for PCa has also been described(35). Arnaoutakis et al.(36) reported a significantly improved median OS (52 versus 22 months, p=0.04) and survival after relapse (18.6 versus 7.5 months) for PCa undergoing resection for isolated pulmonary metastases. However, all of these individual studies were small and the patients highly selected. Authors recommended metastasectomy be considered only when an R0 resection can be achieved after pancreatectomy, the PCa has good tumor biology (seen by a favorable response to neoadjuvant chemotherapy) and the oligometastases are resectable(35). To the best of our knowledge, there are, however, no studies in the literature examining the utility of surgical intervention in PC, even if R0 could be achieved. We report on the first case of CRS/HIPEC in PCa. Our one patient underwent a single CRS/HIPEC procedure for synchronous metastases. The PCI was 10 and CC-0 was achieved necessitating hepatectomy, colectomy and diaphragmatic resection. The HIPEC agent used was mitomycin C. The patient received both neoadjuvant and adjuvant chemotherapy with gemcitabine. The patient did not experience perioperative morbidity. PFS and OS were 15 months.
Compared to pancreaticobiliary malignancies, relatively fewer patients with HCC (13-42%) have evidence of metastatic disease at diagnosis(37). In unresectable HCC, the only effective systemic therapy is sorafenib, which offers significant OS benefits of up to 10.7 months; 2-3 months longer than with best supportive care(38). However, the role of sorafenib in isolated PC without distant metastases is unclear. As such, there have been many studies examining the role of aggressive surgical therapy in patients with PC, with some promising results. Ding et al. conducted a literature review of 24 patients with PC from HCC treated with CRS and found 1-year and 2-year OS of 83% and 71%, respectively(39). These findings were echoed by Lin et al. who reviewed 53 patients with HCC and PC and demonstrated significantly improved OS for CRS compared to best supportive care (12.5 versus 2.1 months, p=0.0013)(40). As an extension of this concept, CRS and HIPEC has been evaluated by a few authors(7, 10, 41). Spiliotis et al.(41) reviewed 4 patients with localized PC who underwent CRS and HIPEC, with a mean PCI of 10.2. All patients received adjuvant sorafenib. The median PFS and OS were 13.5 and 30 months, respectively. In 2018, Mehta et al. published results from a multicenter study of 21 patients with HCC (11). At the time of surgery, the median PCI was 14 and complete cytoreduction was achieved in 16 patients. The most frequent HIPEC agent used was cisplatin, followed by doxorubicin and mitomycin C. They did not comment on concomitant use of sorafenib. The median PFS and OS were 26.3 months and 46.7 months. Those patients who achieved complete cytoreduction had a significantly longer median OS (not reached) than those with incomplete cytoreduction (5.9 months); considerably longer than with sorafenib alone. A previous report from our institution by Tabrizian et al. described 14 patients with HCC and PC who were considered for CRS, of whom 7 also underwent HIPEC(10). At the time of surgery, 6 were for metachronous disease and the median PCI was 12. Complete cytoreduction was possible in 6 patients and the HIPEC agent used was mitomycin C in all cases. The median OS for all patients was 35.6 months, and they noted that the cohort with HIPEC had a higher OS (42.1 months) despite having higher PCI scores. This study reports on nine patients who underwent both CRS and HIPEC; 8 were for metachronous lesions. The median PCI was 12 and complete cytoreduction was achieved in 78% of patients. Two patients experienced major perioperative morbidity; one developed sepsis from pneumonia and required ICU stay and the other died. 7 patients received adjuvant sorafenib. Median PFS and OS were 7 and 42 months, respectively.
When considering the role of CRS/HIPEC for HPB malignancies with PC, it is evident that these cancers behave very differently depending upon their primary tumor origin. However, current literature is very sparse. This study, similar to others, is underpowered due to the small sample size. The short follow-up period is also a limitation. Despite these drawbacks, there does appear to be evidence suggesting the utility of CRS in HCC with PC with an acceptable morbidity profile, provided complete cytoreduction can be achieved. Further survival benefit may be gained with the addition of HIPEC; more studies need to be conducted to better evaluate this. Perhaps the most likely subset of patients to benefit from CRS/HIPEC would be those with ruptured HCC and presumed peritoneal dissemination, in whom primary hepatic resection may be otherwise contraindicated. The role of CRS/HIPEC in pancreaticobiliary malignancies is still unclear, though it could be considered in patients with limited PCI, resectable disease and metachronous metastases with a longer disease-free interval. Future studies with longitudinal evaluation need to be conducted in order to better define its value in these settings.