Outcome and Safety of Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) +/-Intraoperative Radiation Therapy (IORT) in the Management of Peritoneal Sarcomatosis: A Real-World Experience

Background: Peritoneal sarcomatosis (PS) is an aggressive disease; cytoreductive surgery (CRS) could be curative. Can the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) +/- intraoperative radiation therapy (IORT) overcome treatment failure with an overall survival benefit. Methods: Retrospective review of the medical records of patients with PS treated by CRS, HIPEC and IORT at a comprehensive cancer center in the period between 2011-2016. Results: Twenty-four patients were identified. Fifteen were men and their median age was 58 years. Liposarcoma was the most frequent diagnosis (50%). Cytoreduction completeness (CC) score 0/1 was achieved in 19 patients, with a median pathological peritoneal cancer index (pPCI) of 12. Intraoperative radiation therapy was given in 16 patients. Eight patients developed grade III-IV Clavien-Dindo post-operative complications and 1 patient died 5 days post operative. Adjuvant chemotherapy was received in 9 patients. After a median follow-up of 28.5 months, the median PFS was 20.7 months, while the estimated 2- and 4-year PFS were 37.1% and 19.1%, respectively. The median OS was 176.5 months and the estimated 2- and 4-year OS were 95.8% and 79.8%, respectively. In the univariate analysis, the PFS differed significantly according to the CC score only. The median PFS for patients with CC 0-1 was 23.8 vs. 8.8 months for those with CC 2-3 (p = 0.027). Conclusions: The addition of HIPEC and IORT to CRS in the management of PS is feasible and safe. Comparing our results to several studies, this multimodality approach seems to improve local and regional control rates. A larger cohort of patients is needed for further evaluation and to give a concrete conclusion.


Introduction
Soft tissue sarcomas represent about 1% of all adult malignancies, a third of them originate from the abdominal viscera or retroperitoneum 1 . They are characterized by the high ability for hematogenous spread, typically to the lungs, liver, and direct spread to involve other peritoneal surfaces and adjacent organs 2 . They had also; a high post-surgical locoregional failure rate ranged from 35 to 82 % 3,4 .
Peritoneal sarcomatosis (PS) presents a diffuse form of intra-abdominal dissemination; either due to recurrence or spread by seeding to the nearby peritoneal surface. It could be the initial diagnosis, but more frequently occurs at recurrence, most probably as a result of tumor spillage during the initial resection 5-7 . The prognosis of patients with PS is poor, therefore the ultimate need for research to find the best treatment options increased 7 .
Intraoperative radiation therapy (IORT) is a highly conformal radiation therapy modality that is administered in the operating theater. It has been used in a variety of malignancies, including retroperitoneal sarcoma, in order to increase the tumor radiation dose without exceeding normal tissue tolerance doses for better tumor local control [19][20][21][22][23] . Many studies have addressed the prognostic value of many factors such as: KI-67 index, pretreatment inflammatory markers such as neutrophil-lymphocyte ratio (NLR) and plateletlymphocyte ratio (PLR) in soft tissue sarcoma patients reporting that patients with high levels of these markers have poor prognosis and survival [24][25][26][27] .
In this study, we reviewed the outcome of PS patients who had been treated with CRS-HIPEC +/-IORT, including postoperative morbidity and mortality, local control rate, progression-free survival (PFS), overall survival (OS) and the significant correlation of multiple variables including the KI-67 index, NLR and PLR with survival.

Methods
The medical records of 24 PS patients treated with the multimodal approach including (CRS and HIPEC +/-IORT) at the King Faisal Specialized Hospital and Research Center, Riyadh, Saudi Arabia, in the period between January 2011 and December 2016 were retrospectively reviewed. The  and chemotherapeutic agent used in HIPEC), the dose of IORT, postoperative complications according to the Clavien-Dindo classification system, postoperative treatment received, pattern of disease recurrence (locoregional, distant or combined) and current status of patient (alive with a disease or alive without disease or dead).
The HIPEC technique is used in our center in addition to CRS in the management of PS patients with the following inclusion criteria: (1) ECOG performance status ≤2, (2) satisfactory laboratory work, (3) proven diagnosis of PS confirmed by preoperative biopsy, (4) no evidence of distant extra abdominopelvic metastases to the liver, lungs, brain or bones. The details of the operative and HIPEC technique were published earlier in our previous studies 17, 28 .
After completion of the surgical procedure, residual tumor assessment was performed intraoperatively using the standard CC scores, as documented by Sugarbaker, CC-0 (no gross residual disease) was regarded as complete cytoreduction, whereas CC-1 (up to 2.5 mm gross residual disease) was regarded as near-complete cytoreduction 29 . Intraoperative radiation therapy is usually used in our center for patients with PS using Mobetron ® in a dose range of 10-20 Gy. The total dose of IORT received depended on the extent of the residual tumor after resection. IORT was used in patients with CC-0 and CC-1 only. In patients with CC-0, a dose of 10-12 Gy is used. For the patients CC-1(with residual tumors less than 1mm), a dose of 12-15 Gy is used. For those with CC-1(residual tumor 1-2.5 mm), a dose of 15 to 20 Gy. A dose between 10 and 20 Gy was considered a safe dose with minimal postoperative side effects 30, 31 , taking in consideration other factors as the location of nearby risk structures and the dose of previous radiation therapy if present.
Many therapeutic agents for HIPEC were used as a combination of cisplatin (50 mg/m 2 ) plus doxorubicin (15 mg/m 2 ) infused over 90 minutes or single agent melphalan (60 mg/m 2 ) infused over 60 minutes. The choice of HIPEC therapeutic agent depends on the case as agreed by the multidisciplinary medical oncology and surgical oncology team treating.
During the HIPEC procedure, all hemodynamic and cardiopulmonary parameters were strictly monitored. After completion of the entire procedure, including CRS, HIPEC +/-IORT, all patients were transferred to the intensive care unit (ICU) for 1 to 3 days (median:1 day) and then transferred to the surgical ward for recovery.
In some cases, adjuvant treatment (chemotherapy, radiation therapy, or both) was planned if deemed indicated based on the postoperative pathological and radiological data.
All patients were kept at regular follow-up, every 3 months during the first 2 years after HIPEC, every 6 months for another 2 years, then annually. Followup investigations included complete blood work, chest, abdomen, and pelvis CT, abdominal magnetic resonance imaging + / -PET-CT (when indicated).

Statistical analysis
Statistical analysis was performed using IBM SPSS® Statistics version 26 (IBM® Corp., Armonk, NY, USA). Quantitative variables were described as median and range. Qualitative variables were described as numbers and percentages. The study's primary endpoints were toxicity profile (assessed according to the Clavien-Dindo [CD] grading system) and PFS. The secondary endpoint was OS. Progression-free survival was calculated from the date of surgery to the date of documented progression, death, or the last follow up; and OS from the date of diagnosis to the date of death or the last follow-up. Survival analysis was performed using the Kaplan-Meier method and survival curves were compared using the log-rank test. A p value <0.05 was considered statistically significant.

Results
Fifteen males and nine females were reviewed, the median age at the time of CRS was 58 (31-77) years. Seventeen (71%) patients had stage III disease according to AJCC staging system. KI-67 were detected in 14 (58%) patients with a variable range of 6-370/10 high power field (HPF), with a median value of 56/10 HPF. Different neoadjuvant chemotherapy protocols were used in 5 (20.8%) patients; (imatinib, doxorubicin and combined ifosfamide-etoposide). Three patients received neoadjuvant radiation therapy with a dose of 45Gy/25 fractions using intensity modulated radiation therapy technique. Detailed patients and treatment characteristics are listed in Table 2. All patients underwent CRS and HIPEC to achieve cure. The CC score (0/1) was achieved in 19 (79.17%) patients with a median pPCI of 12 (range: 3 to 28). Melphalan was the most used chemotherapeutic agent in HIPEC, it was used in 16 (66.67%) patients. IORT was given in 16 (66.67%) patients (dose range 10-15 Gy), Table 3.
Different adjuvant chemotherapy protocols were used in 9 (37.5%) patients including (imatinib, Grade I CD complications occurred in 6 (25%) patients and grade II in 9 (37.5%). Nine (37.5%) patients developed ≥ grade III Clavien-Dindo (CD) complications, and 1 (4.2%) patient died (grade V CD) 5 days after operation in the ICU due to massive pulmonary embolism despite full coverage of prophylactic anticoagulants. The details of grade III and IV CD complications are illustrated in Table 4.
After a median follow up of 28.5 (2-70) months, the median overall (locoregional and systemic) PFS was 20.7 months, while the estimated 2 and 4 years overall PFS were 37.1% and 19.1%, respectively ( The median OS was 176.5 months, with estimated 2-and 4-year OS were 95.8% and 79.8% respectively ( Figure 2).
For PFS, in the univariate analysis, the CC score was significantly correlated with PFS as the median PFS for patients with CC 0-1 was 23.8 months vs 8.8 months for those with CC 2-3 (p = 0.027). Progressionfree survival did not differ significantly according to the other variables studied (Table 5). Similarly, none of the studied variables was associated with a significant difference in OS in the univariate analysis.

Discussion
The theoretical advantage of using HIPEC after major CRS in patients with PS may come from the ability to achieve high regional concentrations of chemotherapeutic agents while keeping systemic drug levels low. This is mostly due to the slow movement of drugs from the peritoneal cavity into the plasma (peritoneal clearance) as an effect of the peritoneal-plasma barrier 33, 34 . The other advantage is the beneficial exposure of potential hepatic micrometastases to chemotherapeutic agents as the blood drainage of the peritoneal surface reaches the liver via the portal vein 35 .
The benefit of using HIPEC with CRS has been thoroughly studied in many patients with peritoneal surface involvement from many cancers of epithelial origin resulting in improvement of the locoregional control 36-42 , however, these benefits of using HIPEC in addition to CRS in PS have not been documented in many studies 4,5,[12][13][14][15][16][17][18] 18 , where the median PFS and OS were 9 and 55 months, respectively. That survival improvement may come from the improved locoregional control (will be discussed in a separate section below) in our study compared to these studies. Despite improved survival in our study compared to other studies, strong recommendations cannot be concluded due to the great difference in histopathology, pPCI, and degree of cytoreduction between these studies.
The debate of using HIPEC in addition to CRS in PS could be related to the high ability of sarcomas for hematogenous spread as, in one series, 11% of PS patients had distant dissemination at presentation increased to 28 % during the treatment course 6 . Another series reported that distant metastasis could involve multiple organs, most commonly lung in 16% of cases followed by liver in 11% of cases 43 . This was also evident in our study where 15 (62.5%) patients developed systemic recurrence and two (8.3%) patients developed only isolated local recurrence.
In trials to reduce the incidence of distant metastasis post-CRS and HIPEC, many investigators have used a bidirectional intraoperative intravenous chemotherapy in combination with HIPEC in patients with peritoneal metastasis from a variety of neoplasms including gastric and colorectal malignancies with promising results 44, 45 , however, no published data about its efficacy in PS. A recently published study conducted at our center by Hakeam et al 46 was assessing the safety and reported side effects of bidirectional intraoperative intravenous chemotherapy using iphosphamide in combination with HIPEC in 18 patients with peritoneal metastasis from different primaries (50% of the patients had PS).
They concluded that bidirectional intraoperative intravenous chemotherapy in combination with HIPEC was generally tolerable with low rates of mild leukopenia and frequent mild thrombocytopenia, but severe suppression of platelets was uncommon. They reported nephrotoxicity in one-third of the patients. Survival data for the patients included in this study are still pending.
When comparing the locoregional recurrence rate in our study (16.6%) with other studies, Karamveri et al. 18 showed locoregional recurrences in 65.5% of patients, Lim et al. 5 study, the locoregional recurrence rates were 79% in patients treated with cisplatin and 68% in the group of patients treated with combination cisplatin/mitoxantrone in HIPEC regimens. In Baratti et al 43 study, the isolated local recurrence rate was 57.1% and in Rossi et al 4 study, the local recurrence rate was 67%. The improved locoregional control rate in our study in comparison to the above-mentioned studies came despite that our patients had advanced disease. This is evidenced in our study by the mean pPCI of 13.6 and pPCI>10 in 14 (58.3%) patients in comparison to patients enrolled in Karamveri et al 18 study where 31% had PCI>6 and in Rossi et al 4 study where the mean PCI was 7. The improved local regional control rate in our study could be explained by using IORT (used in 16 patients), the different agents used in HIPEC (melphalan was used in most of our patients (66.6%), in addition to highly experienced surgeons with highly efficient skills.
In the univariate analysis, the CC score was significantly correlated with PFS (p = 0.027). Patients with pPCI>10 had a lower median PFS compared to those with pPCI <10 although it was statistically nonsignificant. These results were compatible with other studies conducted by Rossi et al 4  The extent of PS was evaluated intraoperatively using the peritoneal cancer index (PCI) score 48 . Because surgical PCI (sPCI) is calculated based on a subjective evaluation of the extent of peritoneal disease during surgery, which often results in an overestimation of the score, we started to use pathological PCI (pPCI), which may be a more accurate and objective method for determining PCI and evaluating the extent of peritoneal disease 49 . This may have a more prognostic significance 50 .
In our study, many other factors (including KI-67 index, tumor size, histopathological grade and stage) were associated with better either PFS or OS although none of them had statistically significant correlation with PFS or OS in spite of being significantly correlated with PFS and OS in many other studies 24, 51 , for example, in our study, patients with high initial level of NLR and PLR have a lower median OS compared to those patients with lower levels. However, the relation was statistically nonsignificant. These findings are comparable to results from other studies where a high level of NLR and PLR were significantly correlating with survival [25][26][27] . In our study, histological subtypes were not significantly correlated with survival. These findings are contradictory to the study conducted by Baratti et al. 43 where the histological subtype was significantly correlated with survival, as retroperitoneal liposarcoma had the best OS (median 34 months) but with 100% peritoneal relapse. This difference could be attributed to the small number of patients enrolled in our study or to a different cohort of patients.
Postoperative morbidity and mortality in our study were assessed using the Clavien-Dindo grading system 32 . The 30 days mortality rate was 4.1%, with 8 (33.3%) patients developed grade III-IV complications (only 3 patients developed grade IIIb complications requiring intervention under general anesthesia). Karamveri et al 18 reported a postoperative mortality and morbidity rate of 0% and 20.7% respectively, and grade III, IV complications occurred in 13.8% of patients. In Baratti et al. 43 study, the operative mortality and morbidity were 3.7% and 21.6% respectively, while in Rossi et al. 4 study, the morbidity rate was 33% and the moderate to severe locoregional toxicity rate was 15%.
Multiple studies have addressed the value of using IORT in retroperitoneal sarcoma because it is difficult to completely remove with negative margin (due to its usual large size and proximity to critical structures) in addition to challenging delivery of an adequate dose of external beam radiation therapy (EBRT) postoperatively 19-23 . A randomized trial conducted by Sindelar et al. 23 reported a better local control rate with IORT in addition to low-dose postoperative EBRT compared to high-dose postoperative EBRT alone in patients with retroperitoneal sarcoma (60% vs. 20%, p < 0.05) after a median follow-up of 8 years.
Although some previous studies had addressed the benefits of combining both HIPEC and IORT with CRS in many cancer types with proved peritoneal involvement with documented improvement in locoregional control 31, 52-55 , yet to our mind this is the first study constructed initially to assess the benefit of combining both HIPEC and IORT with CRS in locoregional control of PS. In our study, we used IORT in addition to HIPEC in 66.6% of the patients taking into account the factors mentioned above that make complete surgical excision with a negative margin difficult, resulting in local control impairment. The sites, doses, and parameters of applied IORT were chosen based on the clinical judgment and discussion between the treating surgeon and radiation oncologist according to the actual findings in the operative room.
The limitations in our study include the wide variation in histopathological subtypes, treatment protocol used (neoadjuvant/ adjuvant chemotherapy, neoadjuvant radiation therapy, in addition to the different chemotherapeutic agents used in HIPEC), this diversity might be due to the rarity of such disease with few patient numbers.

Conclusions
Addition of HIPEC and IORT to CRS in the management of PS is feasible and safe. Comparing our results with several recent studies, this multimodal approach appears to improve local and regional control rates. A larger cohort of patients is needed for further evaluation and to give a concrete conclusion.