Advances in the Management of Peritoneal Surface Malignancies

Dear Colleagues,

Peritoneal surface malignancies, whether primary or secondary, continue to be difficult to manage. Despite the fact that there have been significant successes in the treatment of hematologic-based metastases, the peritoneum surface remains relatively elusive due to a blood–peritoneal barrier. However, in combination with effective systemic therapies, progress has been made with the addition of cytoreductive surgery and hyperthermic intraperitoneal therapy (CRS-HIPEC). In the case of colorectal cancer, patients with isolated metastatic peritoneal carcinomatosis can now achieve a survival rate of 40–50% in select patients who receive systemic therapy combined with CRS-HIPEC; this is similar to the survival of patients with isolated liver metastases.

The utilization of CRS-HIPEC remains controversial in some cases due to a lack of level one evidence showing a survival benefit for some primary disease sites. Cytoreductive surgery alone, especially when all gross disease is removed, consistently shows a survival advantage in the multimodality treatment of peritoneal carcinomatosis for many disease sites. However, the addition of hyperthermic intraperitoneal chemotherapy has been questioned as providing a survival advantage. Interestingly, in peritoneal carcinomatosis from ovarian cancer, the addition of hyperthermic intraperitoneal chemotherapy to cytoreductive surgery has consistently shown an inherent survival value in several large randomized prospective surgery studies despite this disease having only recently been studied for this approach.

The multimodality management of peritoneal surface malignancies remains in its infancy. Multiple variables require further research, and more clinical trials are needed. The use of CRS-HIPEC needs to become more standardized before it is universally accepted as an integral component in managing peritoneal surface malignancies from specific primary sites of origin. Important topics need to be addressed such as appropriate patient selection, including patient and tumor molecular correlates, that can lead to individualized care. Furthermore, the standardization of CRS-HPEC techniques needs to be fine-tuned, including delivery systems, agents, dosages, length of HIPEC administration, and temperatures. Importantly, ideal sequencing of CRS-HIPEC with systemic therapy needs to be established.

This Special Issue of Cancers aims to include original studies and reviews of the important topics in peritoneal surface malignancies and their treatment, including CRS-HIPEC and systemic therapy. The integration of surgery, systemic therapy, and other modalities will require cooperation between the various types of providers. Many in the field have strong opinions about the management of peritoneal surface malignancies, which could hinder progress. Providers in several fields need to remain open-minded. Finally, several studies have shown that only institutions with the appropriate resources and volume of cases should take on the more complex cases of peritoneal surface malignancies.

Prof. Dr. Mazin Al-Kasspooles
Guest Editor

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• peritoneal surface malignancies
• cytoreductive surgery
• hyperthermic intraperitoneal therapy
• systemic therapy
• multimodality management

Title: A theory to achieve cure for peritoneal metastases from low grade appendiceal mucinous carcinoma peritonei
Authors: Yutaka Yonemura; Haruaki Ishibashi; Akiyoshi Mizumoto; Takuji Fujita; Yang Liu; Satoshi Wakama; Shouzou Sako; Nobuyuki Takao; Yasuo Hirono; Gorou Tukiyama; Keizou Taniguchi; Daisuke Fujimoto; Toru Imagami; Satoshi Ikeda
Affiliation: Asian School of Peritoneal Surface Malignancy Treatment, Kyoto City, Kyoto Prefecture, Japan, 600-8189.
Abstract: : Patients with peritoneal metastasis (PM) can not be cured by surgery nor chemotherapy alone. A comprehensive treatment (COMPT) composed of macroscopic complete removal of PM and perioperative chemotherapy was proved to cure patients with PM. The present article shows the theoretical basis to cure patients with PM by CPMPT. When the micrometastasis（MM）does not exist outside te surgical field, complete cytoreduction (CCR-0) alone can cure the patients (Scenario A). In contrast. When MM burden after CCR-0 (Scenario B) or neoadjuvant chemotherapy (neoadjuvant intraperitoneal chemotherapy: NIPC or neoadjuvant systemic chemotherapy: NASC) plus CCR-0 (Scenario E) exceeds the threshold that can be completely eradicate by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC), patients will always die of regrowth of residual MM. If the MM burden left after CRS (Scenario C) or NAC plus CCR-0 (Scenario D) is less than the threshold level that could be completely eliminated by intraoperative HIPEC, patients will be cured by CRS plus HIPEC. Scenario F shows the status where MM can be completely eliminated by NAC, resulting in cure by NAC+CRS without HIPEC. In trying to cure patients with PM, our aim is to induce patients to follow Scenarios A, C, D or F. Between 2009 and 2023, patients with 467 appendiceal PMP received complete cytoreduction, and had peritoneal disease that was histologically diagnosed as low-grade mucinous carcinoma peritonei. Of these patients, 142 patients were treated with HIPEC by laparoscopy (LHIPEC) and/or NIPC, and 101 patients were treated with NASC. One hundred and twenty patients underwent LHIPEC. At laparoscopy, an IP port system was introduced into the peritoneal cavity. One month after LHIPEC, second laparoscopy was performed. After one cycle of LHIPEC, PCIs was significantly reduced by 4.1, from 16.1± 9.57 to 12.0± 8.55. PCIs before LHIPEC was 17.3±10.50 and following LHIPEC+NIPC 10.6±9.45 (N=131) (P<0.0001). The mean reduction in PCI was 6.7 (P < 0.0001). Five-year, and 10-year overall survival rates of these patients after CCR0 resection were 88.7%, and 77.6%, respectively. Recurrence was found in 158 patients, and peritoneal, pleural, and lung recurrence were found in 143, 6 and 3 patients. Treatment options related to the cure were inspected. To calculate cure rates, patients who survived without recurrence within five years were excluded (N=144), and 43.2% (19/44) of patients were cured after CCR-0 alone (Scenario A). Patients treated with CRS + intraoperative HIPEC were cured in 54.3% (132/243), and those treated by NIPC+ CCR-0 were cured in 53.5% (38/71). Cured rates after treatment by NIPC and NASC were 53.5% (38/71), and 38.4% (35/91) (p=0.056,X2=3.65). The rate after CCR-0 + HIPEC + NASC (Scenario D) or CCR-0+ HIPEC + NIPC and CRS without intraoperative HIPEC were 51.0% (64/126), and 35.0% (28/80), respectively (P=0.026, X2=4.94). Cure rate after non NIPC plus intraoperative HIPEC (68/117; 58.1%), and NIPC plus intraoperative HIPEC (34/54; 62.9%) were significantly higher than those after CRS alone (19/44; 43.2%), or NIPC plus no intraoperative HIPEC (4/17; 23.5%) or NASC + no intraoperative HIPEC (5/19; 26.3%), or NASC plus intraoperative HIPEC (30/72; 46.7%), (p=0.0023, X2=10.967). The PCI scores of patients treated with intraoperative HIPEC and non HIPEC were 15.1±10.4 and 13.7±9.7 (NS). In contrast, scores for patients treated with NIPC and with NASC were 10.7±8.2 and 16.8±10.6 (P<0.0001). After NIPC, PCIs were significantly smaller than after NASC. Grade 3, 4 and 5 postoperative complications after CRS were enbuntered in 43 (9.2%), 43 (9.2%) and 5 (0.9%) patients, respectively. Grade 5 mortalities occurred in five (1.1%) patients, respectively. Conclusions: CCR-0 with intraoperative HIPEC and NIPC may improve the cure rate of patients with PMP. According to our theory, this improvement is due to the elimination of MM by intraoperative HIPEC. We await more effective options for the elimination of MM.

Title: Hyperthermic Intraperitoneal Chemotherapy (HIPEC) and Cytoreductive Surgery (CRS): Age-related Outcomes and a look into the future.
Authors: Salvador Aguirre; Jill K. Haley; Julie A. Broski; Jordan Baker; Luke V. Selby; Shahid Umar; Mazin F. Al-Kasspooles
Affiliation: Department of Surgery, The University of Kansas Medical Center, Kansas City, Kansas 66103, USA
Abstract: Introduction: Peritoneal carcinomatosis presents significant treatment challenges. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) offers a promising ther-apeutic approach. Patient selection remains critical, and the role of age as an exclusion criterion requires further investigation. This study evaluates whether age influences post-operative out-comes in CRS-HIPEC patients. Methods: A retrospective review of a prospective comprehensive database of 271 CRS-HIPEC procedures performed between 2018 and 2023 was conducted. Logistic regression assessed the relationship between age and postoperative outcomes. Age groups (18–44, 45–69, ≥70 years) were compared based on demographic data, primary tumor site, peritoneal cancer index scores, and key outcome measures. Results: Across the different age groups, there were no significant differences in PCI scores, re-currence, disease-free survival, 30-day morbidity, or mortality. Length of stay was longer in older patients (p=0.009). Patients aged ≥70 had higher readmission rates (p=0.041) and were more often discharged to transitional care facilities (p=0.001). Older patients were also more likely to experi-ence Clavien-Dindo grade III or higher complications (p=0.008). Logistic regression confirmed these findings. Continuous age analysis yielded similar results and revealed significant differences in race and primary organ involvement. Conclusion: Age is not a significant predictor of 30-day morbidity, mortality, or survival out-comes in patients undergoing CRS-HIPEC. However, older patients require closer attention to discharge planning and readmission risk management. This study highlights the importance of comprehensive patient assessment beyond age and underscores the need for further research to better understand factors influencing outcomes in this population.

Title: Pre-operative Prediction of Incomplete Cytoreduction in Peritoneal Carcinomatosis Using a Prognostic Nomogram
Authors: Grace McCrea; Mackenzie L Coffin; Lauren Puig; John Kidwell; Edwin Onkendi; Tyler J Mouw
Affiliation: Texas Tech University Health Sciences Center
Abstract: Background and Objectives: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been utilized across many malignancies. Its efficacy is often inferred from low-grade appendiceal neoplasms and is unclear regarding other cancer types. It may be possible to predict failed cytoreduction using pre-operative computed tomography estimates of the peritoneal carcinomatosis index (CT-PCI). Methods: A single center review was conducted, including patients undergoing completed and attempted HIPEC. Pre-operative imaging was reviewed by attending radiologists with body subspecialty to estimate the CT-PCI score. Regression analysis was used to determine predictors of failed CRS. Results: There were 329 patients in the study. Of these, 220 patients underwent HIPEC. Malignancies treated included appendiceal mucinous neoplasm, colon, and rectal adenocarcinoma, ovarian cancer, primary peritoneal mesothelioma, and gastric cancer. The CT-PCI score differed between completed and incomplete CRS groups (9.59 vs. 16.34 p