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Treatment of peritoneal surface malignancies

Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy as multimodal treatment strategy for peritoneal surface malignancies is discussed

Beate Rau MD PhD
Mathilde Feist MD
Andreas Brandl MD
Eva Pachmayr
Wieland Raue MD
Department of General, Visceral and Transplantation Surgery and Department of General, Visceral, Vascular and Thoracic Surgery, Campus Virchow and Mitte, Charité, Universitätsmedizin Berlin, Germany
In the case of peritoneal surface malignancy (PSM) in patients with a solid tumour in their history, such as colorectal cancer, appendiceal cancer, ovarian cancer, gastric cancer, gynaecological malignancies or peritoneal mesothelioma, has long been considered as a palliative situation with a median survival time for patients with PSM of six months. 
During the last 20 years a therapeutic approach was developed to surgically attack PSM and reduce the peritoneal disseminated disease. Sugarbaker developed this procedure with cytoreductive surgery extended to complete peritonectomy in selected patients with additional hyperthermic intraperitoneal chemotherapy (HIPEC).1,2 Some of the underlying reasons for the surgical approach are the difficulties for chemotherapy to get into the tumour cells, the poor blood supply of the peritoneum, reduction of the tumour mass and topical intraperitoneal chemotherapy for some residual tumour cells. 
Surgery is not the right treatment option in every patient with peritoneal disseminated disease. A careful selection of patients is necessary because the surgically-induced complication rate is high and additional treatment with intraperitoneal chemotherapy adds toxicity (Figure 1). 
Fig. 1: Selection process.
Role of cytoreduction 
The role of cytoreductive surgery (CRS) has become a new role in surgical oncology. It is undoubtedly accepted that incomplete tumour resection in primary cancer has a negative impact on long-term survival. Surgery indicated for distant metastases is underlying the same rules. This is easily possible if the metastases are diagnosed as solitary tumour nodules and the localisation is peripherally located. However, in peritoneal surface malignancy this is not the case. Usually the PSM has spread everywhere in the peritoneum and is often combined with malignant ascites. The range of tumour burden is great and indication for surgical cytoreductive treatment has to be indicated very carefully (Figure 2). 
Fig. 2: Multiple types of peritoneal surface malignancies (PSM).
We have learned that CRS should achieve a maximal tumour reduction. But even in the optimal surgical procedure the long-term results are not impressive. The peritoneal carcinomatosis index (PCI) has been developed to categorise the tumour burden of PSM. It is an important prognostic factor. The lowest number is zero and the highest 39.3 PCI influences the prognosis of the patient; the higher the PCI, the worse the outcome of the patients.3 Another important issue is the localisation of the primary tumour. Upper gastrointestinal tumours such as oesophageal, gastric, pancreatic or hepatobiliary cancer are associated with a poor prognosis. 
Usually the tumour spread is not of mucinous quality and the PCI is mostly over ten. These patients, unless in emergency, do not profit from multivisceral resection and CRS. In lower gastrointestinal tumours, including appendix cancer, colon and rectal cancer, CRS can be beneficial if the PCI is low and the morphology of the PSM is mucinous. Especially in mucinous PSM, even high PCI is accepted for CRS. 
These patients usually have a higher morbidity because of the procedure itself, but this is widely accepted because of the increased rate on long-term survival in these patients. Therefore, taking into account clinical as well as oncological patient outcomes, preoperative selection is of major importance for the success of CRS. Thus, preoperative diagnostics should include physical examination, laboratory parameters (renal function, tumour markers), and computed tomography of chest, abdomen and pelvis. 
The cytoreductive surgery procedure
Complete cytoreductive surgery can achieve curation or long-term survival in selected patients with peritoneal malignancy. The procedure aims for complete tumour removal. That means in the case of synchronous disease, the primary tumour has to be oncologically resected according to the existing guidelines for the primary tumour combined with CRS. Complete macroscopic CRS includes the removal of peritoneal lesions in the abdomen and can be achieved by parietal and visceral peritonectomy. The completeness of the procedure depends on the extent and the kind of the peritoneal tumour manifestation. 
Usually following a midline laparotomy, the amount of disease located within the peritoneal cavity is quantified using the peritoneal cancer index, which provides a numerical indication of abdominal tumour burden according to the distribution and size of metastatic deposits.2,4
The mucinous type of PSM including pseudomyxoma peritonei (PMP), low grade adenomucinosis neoplasia (LAMN), peritoneal mucinous carcinomatosis (PMCA), and mesothelioma usually need a total peritonectomy and infragastric omentectomy and lesser omentectomy, whereas in non-mucinous type of PSM, partial peritonectomy and infragastric omentectomy, removing the tumour-baring part of peritoneum, is recommended. 
In the case of infiltrating tumour lesions on the visceral peritoneum, surgery may include organ resections such as: splenectomy, cholecystectomy, resection of the liver capsule, small bowel resection, subtotal colectomy and extraperitoneal anterior rectal resection (and, if female, combined with hysterectomy and ovariectomy), (subtotal) gastrectomy, hysterectomy, ovariectomy and urine bladder resection. The extended resection of the organs should only be considered if a total tumour resection is achievable. 
In extraperitoneal disseminated disease, the indication for CRS is debatable. If distant metastases in the liver or in the lung are easily removable, the results are promising.5
The operation should be performed in a standardised manner. Due to possible tumour manifestation in all four quadrants of the abdomen and extensive extraperitoneal dissection, extensive surgical and oncological expertise is a prerequisite. Treatment in specialised surgical oncology centres is recommended to minimise morbidity and mortality.6
The standard surgical procedures for CRS integrate systemic exploration, infragastric omentectomy, peritonectomy with stripping the bilateral diaphragm, subhepatic space, often Glisson capsula, paracolic gutter, cul-de-sac. Small and scattered localisations on the visceral surface were resected by local excision or electrocoagulation. In the case of massive and infiltrating disease, visceral resections might be necessary, including cholecystectomy, splenectomy, sigmoid, right or total colectomy, extraperitoneal anterior resection and, in women, hysterectomy with bilateral salpingo-oophorectomy. Resection of the ovary or gallbladder per principle is not described. Clinically suspicious regional lymph nodes are recommended to be removed.7
Definition of the completeness of cytoreduction
Cytoreduction is the strongest prognostic factor. The aim of CRS is to obtain complete macroscopic cytoreduction (CCR-0/1). The residual disease is classified intraoperatively using the completeness of cytoreduction (CCR) score. CCR-0 indicates no visible residual tumour and CCR-1 residual tumour nodules ≤2.5mm. CCR-2 and CCR-3 indicate residual tumour nodules between 2.5mm and 2.5cm and >2.5cm, respectively (Figure 3).8
Fig. 3: Disseminated appendiceal cancer pre-CRS and post-CRS.
Tumour entities
The diffuse malignant mesothelioma develops from cells of the mesothelium, the protective lining that covers many of the internal organs of the body. The most common anatomical site for mesothelioma is the pleura, but it can also arise in the peritoneum. 
Histological subtypes are epithelioid, sarcomatoid and biphasic mesothelioma. Together, these three variants account for the majority of mesothelioma. Epithelioid comprise about 50–60% of malignant mesothelioma cases and generally holds a better prognosis than the sarcomatoid or biphasic subtypes.9 The multicystic mesothelioma is very rare and usually localised in the abdomen.
The diffuse malignant peritoneal mesothelioma (DMPM) was associated with an incurable disease. During the last 20 years aggressive surgical cytoreduction in combination with HIPEC to treat microscopic residual disease developed locoregional surgery aiming eradication of the visible tumour nodules.
Pseudomyxoma peritonei
PMP is a rare disease, and the majority of PMP cases are reported to originate from the ovaries and appendix. The disease is poorly understood and characterised by disseminated mucinous tumour mass and mucus ascites. Females present three times more frequently with PMP then males. The patient often presents with increased abdominal circumference. The PMP is separated in disseminated peritoneal adenomucinosis (DPAM) and PMCA. 
The PMP is a low grade malignant tumour and the progression of the disease is slow with five-year survival rates of about 86%.10,11 Postoperative recurrence occurs in 60–76% of patients and the patients may have to undergo secondary surgical resections. Even after extensive and complete resection of the tumour nodules completeness of cytoreductive surgery of CCR-0 is mainly not achievable. 
Ovarian cancer 
Ovarian cancer is known as the gynaecological cancer with the poorest results. For early ovarian cancer, in FIGO Stage IAG1 to IBG2, surgery is the optimal treatment; in higher stages, additional treatment (preferably platinum taxane-based chemotherapy) is recommended. Comprehensive surgical staging is advised to rule out higher occult disease in presumed ovarian cancer. 
The standard surgical procedures, such as systemic exploration, hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsy, and lymphadenectomy are considered as part of the surgical management of patients with ovarian cancer apparently confined to the pelvis. Because of the spread of exfoliated tumour cells along the surface of the peritoneal cavity, it is an ongoing discussion whether aggressive CRS (such as omentectomy, diaphragm stripping, paracolic gutter) is important for surgical treatment in ovarian cancer. 
Aggressive surgery might result in a higher morbidity and mortality, but completeness of cytoreduction significantly gains survival time. Unfortunately, definition of tumour burden on the peritoneal surface (such as PCI) as well as definition of completeness of cytoreduction (such as CCR) in ovarian cancer is not always available, which makes comparison very difficult. 
For recurrent ovarian cancer there is still an ongoing debate whether chemotherapy before surgery or residual disease has an impact on long-term survival. The interval between primary surgery and recurrent disease is important for the indication. Currently for platinum-resistant tumours surgery is not recommended. However, in a multicentre French study including 474 recurrent ovarian cancer patients, patients with platinum-resistant and platinum-sensitive disease treated with optimal cytoreduction had a similar survival with 51.6 and 47.2 months, respectively.12 Similar results were demonstrated by Spiliotis and colleagues.13
In their randomised trial, 60 patients were treated with CRS and 60 patients with CRS and HIPEC. The platinum sensitivity had no impact on survival. In platinum-sensitive patients the median survival time was 26.6 months, whereas in platinum-resistant disease survival time was 26.8 months.14
In a risk analysis of recurrent ovarian cancer, an impact of PCI and CCR on survival was demonstrated. In a Cochrane analysis, it was clearly stated that residual disease should be avoided and CRS should achieve a complete cytoreduction to gain the best results.15
Appendiceal cancer
Peritoneal metastases originating from mucinous appendiceal neoplasm spread throughout the peritoneal cavity. Usually the tumour nodules do not infiltrate the peritoneum layer and therefore even in high tumour burden complete cytoreductive surgery with total peritonectomy (cul-de-sac, bilateral diaphragm, subhepatic peritoneum, Glisson capsula, omentectomy, paracolic gutter, interenteric space of mesenteric route) is indicated. An aggressive loco-regional approach is associated with a higher severe morbidity of up to 40%, and patients need time to recover. 
A quality of life assessment found that patients with a maximal approach of surgery need nearly six months of rehabilitation. Without surgery, patients experience progressive disease leading to bowel obstruction, pressure on the organs and ultimately death. However, extensive CRS is associated with greater surgery time, blood loss, and length of stay, but is not associated with higher morbidity, mortality, or inferior oncologic outcomes in patients with appendiceal carcinomatosis.18
Non-mucinous tumours of the gastrointestinal tract
The peritoneal spread of non-mucinous gastrointestinal tract cancer is mostly undifferentiated or poorly differentiated adenocarcinoma. These peritoneal metastases usually develop infiltrating peritoneal metastases and total resection is difficult to achieve. Therefore, indication for surgery has to be indicated very carefully. Both the tumour burden and the completeness of the cytoreduction is of major importance in this type of tumour.
Gastric cancer 
Gastric cancer is one of the very aggressive epithelial cancer types. Patients who develop peritoneal metastases have a poor prognosis with a median survival of less than six months. 
Palliative gastrectomy for patients with advanced gastric cancer remains controversial. Guidelines suggest (NCCN German) that gastric resections should only be reserved for the palliation of symptoms in patients with incurable disease (for example, obstruction or uncontrollable bleeding).19
In a systematic review by Di Vita et al.,20 all reported studies agreed that surgery in gastric cancer with peritoneal metastases should be performed carefully, including resection of the primary tumour with acceptable margins, any adjacent structures involved, lymphadenectomy, and every peritoneal surface involved by tumour, according to the peritonectomy procedure developed by Sugarbaker.1 This statement is underlined by the results of a meta-analysis by Yang et al.21
From the results of the meta-analysis, palliative gastrectomy for patients with incurable advanced gastric cancer may be associated with longer survival, especially for patients with stage M1 gastric cancer. Patients with liver metastases had a better outcome than patients with metastases in other organs, such as in the peritoneum. However, even in selected cases with peritoneal metastases, chemotherapy is an important tool in the treatment of patients with disseminated disease in gastric cancer.22
Chemotherapy can also be delivered intraperitoneally. HIPEC has been shown to be an effective treatment whenever a complete or an almost complete resection of the peritoneal implants can be performed. For this procedure, the patient has to be in a good condition, which is not always the case in gastric cancer patients, and complete resection should be possible to undergo a major surgical intervention. 
To fill the gap of treatment options in this special situation, a randomised trial (GASTRIPEC) for patients with histological proven primary tumour and peritoneal metastases is ongoing. Patients undergo preoperative chemotherapy in both arms and receive oncological tumour resection as well as cytoreductive surgery for complete resection. Additionally, HIPEC is delivered in one arm. Postoperatively, both groups again receive chemotherapy.23
Colorectal cancer 
Peritoneal metastases arising from colorectal cancer (CRC) are generally considered to have a poor prognosis and treatment options are limited. Removal of the primary asymptomatic tumour in incurable CRC disease is debatable. However, there is a lot of evidence that palliative tumour resection in stage IV CRC patients is associated with improved overall and cancer-specific survival. 
Additionally, novel treatment strategies have emerged: a maximal tumour reduction, including aggressive peritonectomy of parietal and visceral peritoneum – with organ resection if necessary – and additional intraperitoneal chemotherapy. However, the main prognostic factors after complete cytoreductive surgery of colorectal peritoneal metastases are completeness of the resection and extent of the disease, which can be assessed by the peritoneal cancer index, and the completeness of cytoreduction. When the PCI exceeds 17 in peritoneal metastases of colorectal origin, CRC, even with intraperitoneal chemotherapy, does not seem to offer any survival benefit.24
Morbidity and mortality
Extensive surgery such as complete cytoreductive surgery in huge tumour masses is associated with a higher morbidity; a number of factors could be responsible. Non-CRS-related factors are associated with preoperative chemotherapy, poor condition expressed by the ECOG or Karnowsky status, renal dysfunction, extent of tumour burden, and others. 
CRS-related factors are evaluated as surgery time, blood loss, extend of organ resection, and others. The reasons for morbidity have to be separated into surgical related and non-surgical related complications. Surgery-related complications are associated with anastomotic leakage, pancreatic fistula, postoperative bleeding, surgical site infections, compartment syndrome and pleural effusion. 
Non-surgery related complications have a wider diversification with neurological, haematological (neutropenia, thrombocytopenia), urinary (infections), cardiovascular (rhythmic disorder, infarction, thrombosis), pulmonary (pneumonia, embolism), and renal complications (dysfunction, dialysis). 
Briefly, the goal of complete cytoreductive surgery in peritoneal surface malignancy is to remove all visible tumours. The extent of the surgical procedure depends on the kind of PSM and the original primary tumour. Mucinous tumours can be removed more easily even if the PCI is high. In non-mucinous disease, unfortunately, this is not the case. It is recommended that the PCI should not exceed a PCI of >20. 
CRS significantly increases hospital stay and delays the initiation of chemotherapy. However, there is no evidence to suggest that this delay is associated with reduced response rates leading to reduced survival.
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