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: Theoretical basis of comprehensive treatment to cure patients with peritoneal metastasis
Authors: Yutaka Yonemura
Affiliation: Asian/Japanese School of Peritoneal Surface Malignancy Treatment. Regional Cancer Therapies. Department of Peritoneal Surface Malignancy Treatment. Kishiwada Tokushukai Hospital
Abstract: The aim of this article is to describe the theory underlying comprehensive treatment (COMPT) designed to cure patients with peritoneal metastasis (PM). There are four curative scenarios following COMPT. Scenario A involves cases without MM, where patients can potentially be cured by complete cytoreductive surgery (CCRS) alone. Similarly, if the residual number of MM is below the threshold level that can be completely eliminated by intraoperative hyperthermic intraperitoneal chemoperfusion (IOHIPEC), patients will be cured by CCRS plus IOHIPEC (Scenario C). If neoadjuvant chemotherapy (NAC) reduces the MM burden below the threshold level that can be completely eradicated by IOHIPEC, patients may then be cured by CCRS combined with IOHIPEC (Scenario D). If NAC completely eliminates MM, patients will then be cured by CCRS alone (Scenario F). Cure is defined as survival without recurrence for longer than 5 years after following COMPT. The number of patients cured of gastric cancer, colorectal cancer and PMP was 25 /320 (7.8%) , 25/278 (9.0%), and 146/257 (56.8%) patients. Among patients with gastric cancer patients who had PM, all 21 treated with CRS alone died of recurrence, and no patients folloed Senario A (figure 2). However, 8 (7.5%, in Scenerio F) of 107 patients treated with NAC plus CRS without HIPEC were cured. Additionally, 3 (8.3%, in Scenario C) of 36 patients treated with CRS plus HIPEC without NAC were cured, and 14 (9%, in Scenario D) of 156 patients treated with CRS plus HIPEC after NAC were cured. In colorectal cancer with PM, 1 (11.1%, in ScenarioA) of 9 patients treated with CRS alone was cured, and 2 (3.3%, in Scenario F) of 60 patients treated with NAC plus CRS without HIPEC were cured. Three (21.4%, in Scenario C) of 14 patients treated with CRS plus HIPEC without NAC were cured. Additionally, 19 (9.7%, in Course Scenario D) of 195 patients treated with CRS plus HIPEC after NAC were cured. In PMP patients, 17 (40.5%, in Scenario A) of 42 patients treated with CRS alone were cured. Six (28.5%, in Scenario F) of 21 patients treated with CRS without HIPEC after NAC were cured. In contrast, 75 (71.4%, in Scenario C) of 105 patients treated with CRS plus HIPEC without NAC, and 48 (52.9%, in Scenario D) of 89 patients treated with CRS plus HIPEC after NAC were cured, respectively. In gastric cancer, Scenario A, B, C, D, E and F comprised 0 (0%), 33 (10.3%), 3 (0.9%), 3 (0.9%), 14 (4.4%), 142 (44.4%) and 8 (2.5%) of cases, respectively, for colorectal cancer with PM the resective numbers were 1 (0.4%), 11 (4.0%), 3 (1.1%), 19 (6.8%), 176 (63.3%) and 2 (0.7%). For PMP, the corresponding numbers were 17 (6.6%), 30 (11.7%), 75 (29.2%,) 48 (18.7%), 41 (16.0%), and 6 (2.3%). After CRS alone, the cure rate (17/42; 40.4%) in PMP patients was significantly higher than that for gastric and colorectal cancer patients with PM (1/30; 3.3%) (P=0.0002). Five-year survival rates after CRS alone, NAC+CRS without HIPEC, NAC+CRS +HIPEC, and CRS +HIPEC without NAC in gastric cancer were 4.8%,11.2%, 13.5%, and 17.2%, respectively, and the survival after CRS alone was significantly poorer than that inpatients treated with CRS plus/minus NAC or HIPEC. In colorectal cancer with PM, five-year survival rates with CRS alone, NAC plus CRS without HIPEC, NAC plus CRS with HIPEC, and CRS plus HIPEC without NAC were 13.3%, 31.9%, 22.9%, and 25.0%, respectively. There was no survival difference between each group. The corresponding values for PMP were 84.8%, 81.5%, 92.1%, and 90.6%, respectively. Conclusions: Patients with less than the threshold level of micrometastases burden after CCRS with or without neoadjuvant chemotherapy could be cured by IOHIPEC.