Langenbecks Arch Surg (2014) 399:41–53 DOI 10.1007/s00423-013-1144-8
REVIEW ARTICLE
Surgical treatment of peritoneal carcinomatosis: current treatment modalities Yakup Kulu & Beat Müller-Stich & Markus W. Büchler & Alexis Ulrich
Received: 31 October 2013 / Accepted: 7 November 2013 / Published online: 19 November 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Background Selected patients with peritoneal surface malignancies (PSM) have been treated effectively by the combination of cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Purpose The purpose of this study is to summarize the treatment outcomes and general considerations regarding definitions and staging systems of current CRS and HIPEC modalities in malignant peritoneal mesothelioma and in secondary peritoneal malignancies such as peritoneal metastasis from appendiceal, colorectal, gastric, and epithelial ovarian cancers. Conclusion Disease progression within the peritoneal cavity has in the past been regarded as a terminal event. Accumulating evidence underlines the therapeutic potential and the acceptable morbidity and mortality rates of CRS and HIPEC in selected patients. Keywords Cytoreductive surgery . HIPEC . Peritoneal carcinomatosis . Peritoneal surface malignancies
Introduction The prognosis of patients with peritoneal surface malignancies (PSM) is poor. However, in appropriately selected patients, long-term survival is achievable using the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The feasibility of such a combined approach was first demonstrated more than 30 years ago by Spratt and colleagues in 1980 [1]. In 1987 and 1993, Y. Kulu : B. Müller-Stich : M. W. Büchler : A. Ulrich (*) Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany e-mail: [email protected]
Sugarbaker was the first to repeatedly report beneficial results in patients with pseudomyxoma peritonei (PMP) following treatment with CRS and HIPEC [2,3]. To date, CRS and HIPEC has been investigated in multiple clinical studies as a possible treatment option for peritoneal carcinomatosis of appendiceal, colorectal, gastric, and ovarian cancers, as well as for the treatment of malignant peritoneal mesothelioma (MPM). However, randomized controlled studies are scarce, and the chemotherapeutic agents used vary widely in terms of combinations and concentrations.
Definitions Pharmacokinetic rationale for intraperitoneal drug administration Sugarbaker et al. demonstrated that the blood capillary wall and the surrounding interstitial matrix are the principal barriers for clearance of molecules from the abdominopelvic space, not the mesothelial lining [4]. Animal experiments in rats evaluating the significance of the peritoneum as a transport barrier were along the same lines. Manual drying of the peritoneum or removal of the entire peritoneum did not result in significant alterations in transport [5]. Pharmacological studies in patients with PSM revealed that the extent of parietal peritoneal resection only minimally affects the pharmacokinetics of intraoperative intraperitoneal chemotherapy [6]. Consequently, in contrast to intravenous application where dosing is limited to systemic toxicity, intraperitoneal tumor cells may be exposed to much higher concentrations of chemotherapeutic drugs. In a pharmacological analysis of intraperitoneal administered doxorubicin, drug concentrations in plasma, peritoneal fluid, tumor nodules, and normal tissue were evaluated [7]. Intraperitoneal drug administration resulted in a significantly greater concentration in the peritoneal
42
cavity, as compared with plasma. The differences are expressed by Area Under the Curve (AUC) ratios. The AUC ratio of peritoneal fluid to plasma was 73, of tumor to plasma was 128, and of tumor tissue to peritoneal fluid was 1.8. Cell-cycle specific drugs such as taxanes or 5-fluorouracil are more suitable for repeated treatments such as early postoperative intraperitoneal chemotherapy (EPIC) or perioperative intravenous administration. Drugs commonly used for HIPEC to treat PSM from appendiceal, colorectal, gastric, ovarian cancer, as well as from malignant peritoneal mesothelioma include mitomycin C (MMC) and doxorubicin. Oxaliplatin-based HIPEC regimens have been used to treat colorectal and appendiceal malignancies. Intraperitoneal cisplatin and carboplatin have been used in metastasized ovarian cancer [8–10]. Care has to be taken to use the appropriate carrier solution for the given chemotherapeutic drug. Oxaliplatin, for example, is not stable in chloride-containing solutions and is used in a glucose- or dextrose-based solution [11]. Tables 2 to 5 include the published carrier solutions for reported HIPEC and EPIC regimens. Surgical aspects A parietal peritonectomy represents the first part of CRS and HIPEC. To achieve good long-term results, it is absolutely essential to remove all visible tumor. Visceral resections and intraoperative HIPEC are performed afterwards. Tumor implants can be located virtually anywhere in the peritoneum. However, there are locations that are particularly predisposed to peritoneal implants. Large amounts of peritoneal fluid resorption occurs especially subphrenically and at the undersurface of the omentum. Furthermore, intraperitoneal hydrodynamics may direct peritoneal fluid up to the subphrenic space [12]. The other anatomic sites, such as the right retrohepatic space, paracolic sulcus, and the pelvis are frequently involved due to gravitational reasons [13]. The surface of the umbilical cord may also incorporate tumor nodules. In these cases, the resection of the umbilical ligament must occur at its entrance into the liver parenchyma. If the umbilical ligament is covered by liver parenchyma, it has to be divided, to enable inspection of the peritoneal surface within this part [14]. Regarding the optimal timing of bowel anastomosis following CRS and HIPEC, surgeons adopting the open abdominal technique delay the anastomoses until after HIPEC. It is believed that a better distribution of heat and drugs throughout the abdomen is thereby possible. When the abdomen is closed during HIPEC, there remains a choice as to whether to anastomose before or after perfusion. However, there are insufficient data in the literature to favor one time point over the other [15]. In our institution, we use the closed abdomen technique and perform all anastomoses after perfusion. There
Langenbecks Arch Surg (2014) 399:41–53
is also no consensus on whether to protect colorectal anastomoses after CRS and HIPEC [15]. However, our policy is to protect low rectal anastomoses by a deviation ileostomy. HIPEC administration HIPEC is delivered in the operating room after the cytoreductive surgical procedure is finalized and all visible cancer has been resected. The treatment is initiated prior to the construction of suture lines. Different methods have been reported: open abdominal technique, closed abdomen technique, and semi-opened abdominal technique using a peritoneal cavity expander [16,17]. The method of open abdominal technique is performed by securing the skin edges of the abdominal incision up to a self-retaining retractor, whose frame has previously been elevated over the patient. A plastic sheet is incorporated into these sutures to create a reservoir of the abdominal cavity. An incision is made in the plastic cover to allow the surgeon's double-gloved hand access to the abdomen and pelvis [16,18]. In the closed method, laparotomy skin edges are sutured watertight and perfusion is done in a closed circuit. The abdominal wall is externally agitated in order to promote uniform heat and drug distribution. In order to optimize the delivery of perfusate, a semi-opened abdominal technique has been developed. This method can be considered as a further development of the open abdomen technique. The open method construction is covered by a disposable drape with a hole placed centrally to allow manual access to the abdominal cavity [19]. The peritoneal cavity expander is an acrylic cylinder that is secured over the laparotomy wound. When filled with heated perfusate, it can accommodate the small intestine, allowing it to float freely and be manipulated within the perfusate [16]. The advantages and disadvantages of each method are summarized in Table 1. EPIC administration Both inflow and outflow tubes necessary to perform the EPIC as well as drainages in all four abdominal quadrants are inserted at the time of CRS. The transabdominal inserted tubes and drains are secured watertight at the skin. To prevent tumor cell entrapment within fibrin deposits, treatment is initiated before wound healing occurs. Therefore, most EPIC regimens are administered postoperatively starting on day 1. The intraperitoneally administered chemotherapy is left within the abdominal cavity for 23 h. Usually, the treatment is continued for 4 or 5 days [20]. Staging systems Previous works by Elias et al. and da Silva et al. have demonstrated that patient selection is crucial to identify the individuals that benefit from combined CRS and HIPEC [21,22].
Langenbecks Arch Surg (2014) 399:41–53
43
Table 1 Comparison of different methods to deliver HIPEC Method
Advantages
• Uniform heat and drug distribution • Possibility of pharmakokinetic monitoring of tumor and normal tissue Closed • Minimizes exposure of staff to chemotherapy • Increased intra-abdominal pressure may increase drug penetration and tissue uptake • Simple to assemble Peritoneal cavity • Uniform heat and drug expander distribution Open
Semi-opened
Disadvantages • Heat dissipation • Complex to assemble • Uneven heat and drug distribution
• Increased exposure of staff to chemotherapy • Possibility of pharmakokinetic • Complex to monitoring of tumor and assemble normal tissue • Uniform heat and drug • Complex to distribution assemble • Minimizes exposure of staff to chemotherapy • Possibility of pharmakokinetic monitoring of tumor and normal tissue
Depending on the extent of carcinomatosis, the outcome differs considerably. To serve as prognostic indicators, several staging systems were proposed by different investigators. Whereas the Gilly peritoneal carcinomatosis staging system [23,24] takes into account the size of the lesions found at operation, the Peritoneal Cancer Index (PCI) proposed by Sugarbaker [18,25] combines distribution and lesion size. In order to calculate the PCI score, the peritoneal cavity is divided into nine regions and the small bowel into four more parts. For each of the 13 regions, a lesion-size score (LS) is assigned. Depending on the size of the peritoneal nodules, the lesion size score (LS) equals to 0 (if no macroscopic disease is evident), 1 (if the maximum diameter of the lesion is up to 5 mm), 2 (if the maximum diameter of the lesion is between 5 mm and 5 cm), or 3 (if the maximum diameter of the lesion is larger than 5 cm or in the case of confluent lesions) [26]. Following CRS, the completeness of cytoreduction score (CC) can be determined. CC-0 corresponds to no visible residual tumor within the peritoneal cavity. In the case of tumor nodules persisting after CRS, depending on their size, they are termed CC-1 (less than 2.5 mm), CC-2 (between 2.5 mm and 2.5 cm), and CC-3 (greater as 2.5 cm). A complete cytoreduction indicates that all visible tumor was cleared (CC-0) or minimal residual nodules smaller than 2.5 mm in size (CC-1) have been left behind that are expected to be cleared by HIPEC. The prognostic relevance of the CC score and the PCI was evaluated by Elias et al. in 523 patients [22]. In multivariate
analysis, they found that CC and PCI strongly correlate with the overall survival. The authors reported that, while the 5year survival rate of patients with a complete CRS (CC-0/1) was 29 %, none of the patients with incomplete CRS (CC-2 and CC-3) survived 5 years. Concerning the prognostic significance of PCI, only 7 % of patients with a PCI greater than 19 are alive after 5 years, whereas 44 % survival at 5 years was reported in the group of patients with a PCI of 6 or less. Treatment of pseudomyxoma peritonei of appendiceal origin PMP is a clinical syndrome that is characterized by large collections of intraperitoneal mucin, caused most frequently by advanced mucinous appendiceal neoplasms that perforate into the peritoneal cavity. Before the introduction of CRS and HIPEC as the treatment modality of choice for patients with PMP, they were treated by repeated debulking surgery. According to a single-center study by Gough et al., median survival for patients with limited low-grade PMP after surgical management was reported to be 72 months [27]. As mentioned earlier, in the early 1990s Sugarbaker and colleagues were first to demonstrate the beneficial effects of CRS and HIPEC in PMP patients [2,3]. In the mid-1990s, histologic subtypes of PMP were defined following the clinicopathological analysis of 109 patients [28]. Following careful histopathological examination, three PMP subtypes were established: if the primary tumor was an appendiceal adenoma and the peritoneal lesions were characterized by proliferative epithelium with minimal to moderate cytologic atypia, they were termed disseminated peritoneal adenomucinosis (DPAM); and if the primary tumor was an appendiceal tumor of intestinal mucinous carcinoma and the peritoneal lesions were characterized by cells consistent with carcinoma displaying marked cytologic atypia, they were termed peritoneal mucinous carcinomatosis (PMCA). Tumors in the intermediate and discordant category were termed intermediate type. Several studies in which the patients' outcome was stratified to the corresponding histology revealed the histopathologic subtype as an independent prognostic indicator. In a recently published retrospective multicenter study evaluating the outcome of 2,298 patients with PMP following CRS and HIPEC, an overall survival of 196 months was reported. Patients with DPAM had a better prognosis compared with patients with PCMA or intermediate-type tumors. Ten-year survival has been reported to be 70, 63, and 49 %, respectively [29]. A systematic review analyzing the results after CRS and HIPEC in ten expert institutions in 863 patients showed a 5year survival ranging between 52 and 96 % [30]. Another recently published systematic review and metaanalysis summarized the reported data on 1,624 patients after CRS and IPEC for the treatment of PMP of appendiceal origin. Mean 3-, 5-, and 10-year survival rates were 77, 77,
[33] 72.6 NR Elias, D 2010
NR not reported, MMC mitomycin C, OXA oxaliplatin, FU fluorouracil, IP intraperitoneal, EPIC early postoperative intraperitoneal chemotherapy
Chua, TC 2011
a
1 L dextrose 1.5 % NR NR
Austin, F 2012
Six hundred eighty eight patients received additional early postoperative intraperitoneal chemotherapy (EPIC) on postoperative days 1–5 with 5-FU 650 mg/m2.
89.4 >100 73 Open NR 60–120 30
3 l dextrose 1.5 %
41–42 43
[74] 45 NR NR 56.4 22.5 38 NR
Closed
34 255
[73]
82 78 52.7 NR NR NR NR NR NR 196 196 81 36 36 24 258 1,784 282
30 90 60 40 90
OXA 460 mg/m2 IP MMC 10–12.5 mg/m2 IP 1. Dose: MMC 30 mg IP 2. Dose: MMC 30 mg IP MMC 10–12.5 mg/m2 IP EPIC: 5-FU 650 mg/m2 MMC, dosing NR OXA, dosing NR Chua, TCa 2012
NR NR >800 mL saline
(°C) (min) solution
40–42 40–42 42 42 42
Open/closed
(n)
Follow-up
Survival
1-Y
2-Y
5-Y
Ref. Survival (%) Median (months) Pat. Technique Temp. Duration Carrier HIPEC Regimen Investigator
The median survival of patients with peritoneal carcinomatosis (PC) from colorectal carcinoma (CRC) is poor and is reported to be about 5 months following best supportive care [36]. Modern chemotherapeutic regimens such as FOLFOX improve the survival of patients with PC from CRC to a median of 15.7 months [37]. To answer the question of what impact targeted therapy may have on this patient collective, Klaver and colleagues recently reported their outcome analysis of CRC patients with PC treated with chemotherapy, with and without targeted therapy. The median survival of patients with PC after treatment with a combination therapy containing capecitabine, oxaliplatin, and bevacizumab was 15.2 months. The further addition of cetuximab to the combination resulted in a median survival of 13.9 months, a 5-year survival rate was not reported [38]. In contrast to the limited benefit of systemic therapy, multiple reports to date demonstrate that in selected patients with PC of CRC, complete CRS followed by HIPEC may enable long-term survival and even cure. According to a systematic review by Chua and colleagues, CRS with HIPEC has been reported to obtain median survival lasting from 20 to 63 (median 33) months and 5-year survival rates from 17 to 51 % (median 40 %) [39]. The most common HIPEC regimen consisted of 40 mg MMC for 90 to 120 min at 42 °C, followed
Year
Treatment of peritoneal carcinomatosis from colorectal carcinoma
Table 2 Chemotherapy regimens and survival rates of patients with pseudomyxoma peritonei of appendiceal origin after CRS and HIPEC
and 57 %, respectively [31]. Even in patients with low-grade appendiceal tumors in which debulking procedures may provide long-term survival, local recurrence of microscopic disease is inevitable [32]. The combined approach of complete CRS and HIPEC is the standard of care in many centers. The extent of the disease has been described as a prognostic indicator that was associated with survival independent of the pathological grade in univariate and multivariate analyses. In a recently published study of 206 patients with PMP (across all pathological grades) following CRS and HIPEC, 5-year survival for patients with a PCI less or greater than 19 was 83 and 57 %, respectively (P =0.004) [33]. Not surprisingly, the CC is also associated with improved outcome. In patients with an incomplete cytoreduction (CC2 or CC3), the outcome is significantly poorer with a 5-year survival rate of 24 %, compared with 85 % in CC0 patients and 80 % in CC1 patients [29]. Furthermore, nodal positivity in high-grade tumors [34], poor patient performance status (Eastern Cooperative Oncology Group [ECOG] score 2 or 3) [35], and prior debulking surgery without HIPEC [29] are associated with poor outcome. In most studies, either MMC at a dose of 10–12.5 mg/m2 was delivered at 40–42 °C for 90 min, or 460 mg/m2 oxaliplatin was administered at 43 °C for 30 min. A more detailed overview of recently published reports is given in Table 2.
Langenbecks Arch Surg (2014) 399:41–53 [29]
44
Langenbecks Arch Surg (2014) 399:41–53
by EPIC with 5-fluorouracil (5-FU) (650 mg/m2) on postoperative days (PODs) 1 to 5 with or without MMC [40]. However, more recently, different investigators have used intraperitoneal oxaliplatin with intravenous 5-FU and leucovorin (LV) and obtained 5-year median survival rates of up to 42 % (Table 3). In the early postoperative period, before wound healing occurs, the treatment of CRS and HIPEC may be continued with EPIC. Therapy regimens usually include 5-fluorouracil and continue from PODs 1 to 5, utilizing inflow and outflow tubes that are placed intraoperatively within the abdomen and pelvis. Dwell time is usually 23 h, and there is drainage of the fluid before subsequent instillations [41]. The conceptual advantage of this approach may be that chemotherapy is administered before significant tumor cell entrapment occurs in postoperative fibrin deposits. However, randomized controlled studies have not been conducted to assess which modality of intraperitoneal chemotherapy is more advantageous. Elias et al. compared the perioperative and oncological outcome of 23 patients with PC of CRC after CRS and HIPEC with oxaliplatin, with retrospectively selected and matched 23 patients after EPIC with MMC and 5-FU. The rate of digestive fistulas was statistically significantly higher (P =0.02) in the EPIC group (26 %) than in the HIPEC group (0 %). There was a trend towards longer overall survival in the HIPEC group, (54 % at 5 years vs. 28 % for EPIC, P =0.22). Peritoneal carcinomatosis recurred (P =0.03) much more frequently in the EPIC group (57 %) than in the HIPEC group (26 %) [42]. A 2012 published case control study by Cashin and colleagues included 32 patients and compared treatment outcomes in 16 patients after HIPEC and 16 after EPIC [43]. The authors concluded that HIPEC was associated with an improved survival at similar morbidity and mortality compared with EPIC. The most recent study on the comparison of HIPEC and EPIC was published by McConnell et al. in 2013 [44]. The outcomes of 85 patients after CRS+HIPEC+EPIC were compared with 113 patients after CRS+HIPEC alone. Because of the increased rate of Grades III and IV complications after CRS + HIPEC + EPIC, the authors suggest that surgeons should consider using HIPEC only in combination with CRS. The aforementioned completeness of the cytoreduction (CC) score and PCI is an important prognostic indicator enabling the surgeon to predict whether a patient is going to benefit from CRS and HIPEC [26]. For CRC, a complete cytoreduction (CC-0 and CC-1) results in 5-year survival rates of 30–40 % [18,22,45]. In contrast, the oncological outcome after an incomplete cytoreduction (CC-2 and CC-3) is no better than after systemic chemotherapy [22]. PCI is useful as a prognostic indicator and predicts the likelihood of an incomplete cytoreduction [26]. Whereas survival at 5 years for patients with PCI greater than 19 has been reported to be less than 10 %; it is 27 % with PCI between 7 and 19 and 50 % with PCI less than 6 [22].
45
Considering the relevance of early diagnosis of peritoneal metastasis, further improvements in oncological outcome may be achieved if this treatment modality is applied timely in appropriately selected patients. A timely diagnosis of especially limited PC is associated with more favorable survival results [46] and decreased morbidity and mortality because of less extensive surgery [26]. In a study by Elias et al., 41 patients defined as being at “high risk” to develop PC but with no evidence of PC in clinical and radiological evaluation were subjected to second-look surgery and systematic HIPEC 1 year after initial surgery. If PC was diagnosed, CRS and HIPEC were performed. The other patients underwent HIPEC alone. Despite no evidence of PC in clinical and radiological examination, PC was diagnosed in 56 %. Grades III–IV morbidity was 9.7 %, one patient died on postoperative day 69 from multiple organ failure. After a median follow-up of 30 months, 5-year overall survival was 90 % in this selected group. A trial is currently recruiting patients to investigate this approach (NCT01226394) [47]. Reported experience in the literature on CRS and HIPEC combined with curative treatment of colorectal liver metastases (LM) is limited. However, available evidence indicates that the presence of synchronous LM in patients with PC of CRC is no longer an absolute contraindication for CRS and HIPEC. Elias and colleagues demonstrated that when the extent of PC is limited (PCI
REVIEW ARTICLE
Surgical treatment of peritoneal carcinomatosis: current treatment modalities Yakup Kulu & Beat Müller-Stich & Markus W. Büchler & Alexis Ulrich
Received: 31 October 2013 / Accepted: 7 November 2013 / Published online: 19 November 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Background Selected patients with peritoneal surface malignancies (PSM) have been treated effectively by the combination of cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Purpose The purpose of this study is to summarize the treatment outcomes and general considerations regarding definitions and staging systems of current CRS and HIPEC modalities in malignant peritoneal mesothelioma and in secondary peritoneal malignancies such as peritoneal metastasis from appendiceal, colorectal, gastric, and epithelial ovarian cancers. Conclusion Disease progression within the peritoneal cavity has in the past been regarded as a terminal event. Accumulating evidence underlines the therapeutic potential and the acceptable morbidity and mortality rates of CRS and HIPEC in selected patients. Keywords Cytoreductive surgery . HIPEC . Peritoneal carcinomatosis . Peritoneal surface malignancies
Introduction The prognosis of patients with peritoneal surface malignancies (PSM) is poor. However, in appropriately selected patients, long-term survival is achievable using the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The feasibility of such a combined approach was first demonstrated more than 30 years ago by Spratt and colleagues in 1980 [1]. In 1987 and 1993, Y. Kulu : B. Müller-Stich : M. W. Büchler : A. Ulrich (*) Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany e-mail: [email protected]
Sugarbaker was the first to repeatedly report beneficial results in patients with pseudomyxoma peritonei (PMP) following treatment with CRS and HIPEC [2,3]. To date, CRS and HIPEC has been investigated in multiple clinical studies as a possible treatment option for peritoneal carcinomatosis of appendiceal, colorectal, gastric, and ovarian cancers, as well as for the treatment of malignant peritoneal mesothelioma (MPM). However, randomized controlled studies are scarce, and the chemotherapeutic agents used vary widely in terms of combinations and concentrations.
Definitions Pharmacokinetic rationale for intraperitoneal drug administration Sugarbaker et al. demonstrated that the blood capillary wall and the surrounding interstitial matrix are the principal barriers for clearance of molecules from the abdominopelvic space, not the mesothelial lining [4]. Animal experiments in rats evaluating the significance of the peritoneum as a transport barrier were along the same lines. Manual drying of the peritoneum or removal of the entire peritoneum did not result in significant alterations in transport [5]. Pharmacological studies in patients with PSM revealed that the extent of parietal peritoneal resection only minimally affects the pharmacokinetics of intraoperative intraperitoneal chemotherapy [6]. Consequently, in contrast to intravenous application where dosing is limited to systemic toxicity, intraperitoneal tumor cells may be exposed to much higher concentrations of chemotherapeutic drugs. In a pharmacological analysis of intraperitoneal administered doxorubicin, drug concentrations in plasma, peritoneal fluid, tumor nodules, and normal tissue were evaluated [7]. Intraperitoneal drug administration resulted in a significantly greater concentration in the peritoneal
42
cavity, as compared with plasma. The differences are expressed by Area Under the Curve (AUC) ratios. The AUC ratio of peritoneal fluid to plasma was 73, of tumor to plasma was 128, and of tumor tissue to peritoneal fluid was 1.8. Cell-cycle specific drugs such as taxanes or 5-fluorouracil are more suitable for repeated treatments such as early postoperative intraperitoneal chemotherapy (EPIC) or perioperative intravenous administration. Drugs commonly used for HIPEC to treat PSM from appendiceal, colorectal, gastric, ovarian cancer, as well as from malignant peritoneal mesothelioma include mitomycin C (MMC) and doxorubicin. Oxaliplatin-based HIPEC regimens have been used to treat colorectal and appendiceal malignancies. Intraperitoneal cisplatin and carboplatin have been used in metastasized ovarian cancer [8–10]. Care has to be taken to use the appropriate carrier solution for the given chemotherapeutic drug. Oxaliplatin, for example, is not stable in chloride-containing solutions and is used in a glucose- or dextrose-based solution [11]. Tables 2 to 5 include the published carrier solutions for reported HIPEC and EPIC regimens. Surgical aspects A parietal peritonectomy represents the first part of CRS and HIPEC. To achieve good long-term results, it is absolutely essential to remove all visible tumor. Visceral resections and intraoperative HIPEC are performed afterwards. Tumor implants can be located virtually anywhere in the peritoneum. However, there are locations that are particularly predisposed to peritoneal implants. Large amounts of peritoneal fluid resorption occurs especially subphrenically and at the undersurface of the omentum. Furthermore, intraperitoneal hydrodynamics may direct peritoneal fluid up to the subphrenic space [12]. The other anatomic sites, such as the right retrohepatic space, paracolic sulcus, and the pelvis are frequently involved due to gravitational reasons [13]. The surface of the umbilical cord may also incorporate tumor nodules. In these cases, the resection of the umbilical ligament must occur at its entrance into the liver parenchyma. If the umbilical ligament is covered by liver parenchyma, it has to be divided, to enable inspection of the peritoneal surface within this part [14]. Regarding the optimal timing of bowel anastomosis following CRS and HIPEC, surgeons adopting the open abdominal technique delay the anastomoses until after HIPEC. It is believed that a better distribution of heat and drugs throughout the abdomen is thereby possible. When the abdomen is closed during HIPEC, there remains a choice as to whether to anastomose before or after perfusion. However, there are insufficient data in the literature to favor one time point over the other [15]. In our institution, we use the closed abdomen technique and perform all anastomoses after perfusion. There
Langenbecks Arch Surg (2014) 399:41–53
is also no consensus on whether to protect colorectal anastomoses after CRS and HIPEC [15]. However, our policy is to protect low rectal anastomoses by a deviation ileostomy. HIPEC administration HIPEC is delivered in the operating room after the cytoreductive surgical procedure is finalized and all visible cancer has been resected. The treatment is initiated prior to the construction of suture lines. Different methods have been reported: open abdominal technique, closed abdomen technique, and semi-opened abdominal technique using a peritoneal cavity expander [16,17]. The method of open abdominal technique is performed by securing the skin edges of the abdominal incision up to a self-retaining retractor, whose frame has previously been elevated over the patient. A plastic sheet is incorporated into these sutures to create a reservoir of the abdominal cavity. An incision is made in the plastic cover to allow the surgeon's double-gloved hand access to the abdomen and pelvis [16,18]. In the closed method, laparotomy skin edges are sutured watertight and perfusion is done in a closed circuit. The abdominal wall is externally agitated in order to promote uniform heat and drug distribution. In order to optimize the delivery of perfusate, a semi-opened abdominal technique has been developed. This method can be considered as a further development of the open abdomen technique. The open method construction is covered by a disposable drape with a hole placed centrally to allow manual access to the abdominal cavity [19]. The peritoneal cavity expander is an acrylic cylinder that is secured over the laparotomy wound. When filled with heated perfusate, it can accommodate the small intestine, allowing it to float freely and be manipulated within the perfusate [16]. The advantages and disadvantages of each method are summarized in Table 1. EPIC administration Both inflow and outflow tubes necessary to perform the EPIC as well as drainages in all four abdominal quadrants are inserted at the time of CRS. The transabdominal inserted tubes and drains are secured watertight at the skin. To prevent tumor cell entrapment within fibrin deposits, treatment is initiated before wound healing occurs. Therefore, most EPIC regimens are administered postoperatively starting on day 1. The intraperitoneally administered chemotherapy is left within the abdominal cavity for 23 h. Usually, the treatment is continued for 4 or 5 days [20]. Staging systems Previous works by Elias et al. and da Silva et al. have demonstrated that patient selection is crucial to identify the individuals that benefit from combined CRS and HIPEC [21,22].
Langenbecks Arch Surg (2014) 399:41–53
43
Table 1 Comparison of different methods to deliver HIPEC Method
Advantages
• Uniform heat and drug distribution • Possibility of pharmakokinetic monitoring of tumor and normal tissue Closed • Minimizes exposure of staff to chemotherapy • Increased intra-abdominal pressure may increase drug penetration and tissue uptake • Simple to assemble Peritoneal cavity • Uniform heat and drug expander distribution Open
Semi-opened
Disadvantages • Heat dissipation • Complex to assemble • Uneven heat and drug distribution
• Increased exposure of staff to chemotherapy • Possibility of pharmakokinetic • Complex to monitoring of tumor and assemble normal tissue • Uniform heat and drug • Complex to distribution assemble • Minimizes exposure of staff to chemotherapy • Possibility of pharmakokinetic monitoring of tumor and normal tissue
Depending on the extent of carcinomatosis, the outcome differs considerably. To serve as prognostic indicators, several staging systems were proposed by different investigators. Whereas the Gilly peritoneal carcinomatosis staging system [23,24] takes into account the size of the lesions found at operation, the Peritoneal Cancer Index (PCI) proposed by Sugarbaker [18,25] combines distribution and lesion size. In order to calculate the PCI score, the peritoneal cavity is divided into nine regions and the small bowel into four more parts. For each of the 13 regions, a lesion-size score (LS) is assigned. Depending on the size of the peritoneal nodules, the lesion size score (LS) equals to 0 (if no macroscopic disease is evident), 1 (if the maximum diameter of the lesion is up to 5 mm), 2 (if the maximum diameter of the lesion is between 5 mm and 5 cm), or 3 (if the maximum diameter of the lesion is larger than 5 cm or in the case of confluent lesions) [26]. Following CRS, the completeness of cytoreduction score (CC) can be determined. CC-0 corresponds to no visible residual tumor within the peritoneal cavity. In the case of tumor nodules persisting after CRS, depending on their size, they are termed CC-1 (less than 2.5 mm), CC-2 (between 2.5 mm and 2.5 cm), and CC-3 (greater as 2.5 cm). A complete cytoreduction indicates that all visible tumor was cleared (CC-0) or minimal residual nodules smaller than 2.5 mm in size (CC-1) have been left behind that are expected to be cleared by HIPEC. The prognostic relevance of the CC score and the PCI was evaluated by Elias et al. in 523 patients [22]. In multivariate
analysis, they found that CC and PCI strongly correlate with the overall survival. The authors reported that, while the 5year survival rate of patients with a complete CRS (CC-0/1) was 29 %, none of the patients with incomplete CRS (CC-2 and CC-3) survived 5 years. Concerning the prognostic significance of PCI, only 7 % of patients with a PCI greater than 19 are alive after 5 years, whereas 44 % survival at 5 years was reported in the group of patients with a PCI of 6 or less. Treatment of pseudomyxoma peritonei of appendiceal origin PMP is a clinical syndrome that is characterized by large collections of intraperitoneal mucin, caused most frequently by advanced mucinous appendiceal neoplasms that perforate into the peritoneal cavity. Before the introduction of CRS and HIPEC as the treatment modality of choice for patients with PMP, they were treated by repeated debulking surgery. According to a single-center study by Gough et al., median survival for patients with limited low-grade PMP after surgical management was reported to be 72 months [27]. As mentioned earlier, in the early 1990s Sugarbaker and colleagues were first to demonstrate the beneficial effects of CRS and HIPEC in PMP patients [2,3]. In the mid-1990s, histologic subtypes of PMP were defined following the clinicopathological analysis of 109 patients [28]. Following careful histopathological examination, three PMP subtypes were established: if the primary tumor was an appendiceal adenoma and the peritoneal lesions were characterized by proliferative epithelium with minimal to moderate cytologic atypia, they were termed disseminated peritoneal adenomucinosis (DPAM); and if the primary tumor was an appendiceal tumor of intestinal mucinous carcinoma and the peritoneal lesions were characterized by cells consistent with carcinoma displaying marked cytologic atypia, they were termed peritoneal mucinous carcinomatosis (PMCA). Tumors in the intermediate and discordant category were termed intermediate type. Several studies in which the patients' outcome was stratified to the corresponding histology revealed the histopathologic subtype as an independent prognostic indicator. In a recently published retrospective multicenter study evaluating the outcome of 2,298 patients with PMP following CRS and HIPEC, an overall survival of 196 months was reported. Patients with DPAM had a better prognosis compared with patients with PCMA or intermediate-type tumors. Ten-year survival has been reported to be 70, 63, and 49 %, respectively [29]. A systematic review analyzing the results after CRS and HIPEC in ten expert institutions in 863 patients showed a 5year survival ranging between 52 and 96 % [30]. Another recently published systematic review and metaanalysis summarized the reported data on 1,624 patients after CRS and IPEC for the treatment of PMP of appendiceal origin. Mean 3-, 5-, and 10-year survival rates were 77, 77,
[33] 72.6 NR Elias, D 2010
NR not reported, MMC mitomycin C, OXA oxaliplatin, FU fluorouracil, IP intraperitoneal, EPIC early postoperative intraperitoneal chemotherapy
Chua, TC 2011
a
1 L dextrose 1.5 % NR NR
Austin, F 2012
Six hundred eighty eight patients received additional early postoperative intraperitoneal chemotherapy (EPIC) on postoperative days 1–5 with 5-FU 650 mg/m2.
89.4 >100 73 Open NR 60–120 30
3 l dextrose 1.5 %
41–42 43
[74] 45 NR NR 56.4 22.5 38 NR
Closed
34 255
[73]
82 78 52.7 NR NR NR NR NR NR 196 196 81 36 36 24 258 1,784 282
30 90 60 40 90
OXA 460 mg/m2 IP MMC 10–12.5 mg/m2 IP 1. Dose: MMC 30 mg IP 2. Dose: MMC 30 mg IP MMC 10–12.5 mg/m2 IP EPIC: 5-FU 650 mg/m2 MMC, dosing NR OXA, dosing NR Chua, TCa 2012
NR NR >800 mL saline
(°C) (min) solution
40–42 40–42 42 42 42
Open/closed
(n)
Follow-up
Survival
1-Y
2-Y
5-Y
Ref. Survival (%) Median (months) Pat. Technique Temp. Duration Carrier HIPEC Regimen Investigator
The median survival of patients with peritoneal carcinomatosis (PC) from colorectal carcinoma (CRC) is poor and is reported to be about 5 months following best supportive care [36]. Modern chemotherapeutic regimens such as FOLFOX improve the survival of patients with PC from CRC to a median of 15.7 months [37]. To answer the question of what impact targeted therapy may have on this patient collective, Klaver and colleagues recently reported their outcome analysis of CRC patients with PC treated with chemotherapy, with and without targeted therapy. The median survival of patients with PC after treatment with a combination therapy containing capecitabine, oxaliplatin, and bevacizumab was 15.2 months. The further addition of cetuximab to the combination resulted in a median survival of 13.9 months, a 5-year survival rate was not reported [38]. In contrast to the limited benefit of systemic therapy, multiple reports to date demonstrate that in selected patients with PC of CRC, complete CRS followed by HIPEC may enable long-term survival and even cure. According to a systematic review by Chua and colleagues, CRS with HIPEC has been reported to obtain median survival lasting from 20 to 63 (median 33) months and 5-year survival rates from 17 to 51 % (median 40 %) [39]. The most common HIPEC regimen consisted of 40 mg MMC for 90 to 120 min at 42 °C, followed
Year
Treatment of peritoneal carcinomatosis from colorectal carcinoma
Table 2 Chemotherapy regimens and survival rates of patients with pseudomyxoma peritonei of appendiceal origin after CRS and HIPEC
and 57 %, respectively [31]. Even in patients with low-grade appendiceal tumors in which debulking procedures may provide long-term survival, local recurrence of microscopic disease is inevitable [32]. The combined approach of complete CRS and HIPEC is the standard of care in many centers. The extent of the disease has been described as a prognostic indicator that was associated with survival independent of the pathological grade in univariate and multivariate analyses. In a recently published study of 206 patients with PMP (across all pathological grades) following CRS and HIPEC, 5-year survival for patients with a PCI less or greater than 19 was 83 and 57 %, respectively (P =0.004) [33]. Not surprisingly, the CC is also associated with improved outcome. In patients with an incomplete cytoreduction (CC2 or CC3), the outcome is significantly poorer with a 5-year survival rate of 24 %, compared with 85 % in CC0 patients and 80 % in CC1 patients [29]. Furthermore, nodal positivity in high-grade tumors [34], poor patient performance status (Eastern Cooperative Oncology Group [ECOG] score 2 or 3) [35], and prior debulking surgery without HIPEC [29] are associated with poor outcome. In most studies, either MMC at a dose of 10–12.5 mg/m2 was delivered at 40–42 °C for 90 min, or 460 mg/m2 oxaliplatin was administered at 43 °C for 30 min. A more detailed overview of recently published reports is given in Table 2.
Langenbecks Arch Surg (2014) 399:41–53 [29]
44
Langenbecks Arch Surg (2014) 399:41–53
by EPIC with 5-fluorouracil (5-FU) (650 mg/m2) on postoperative days (PODs) 1 to 5 with or without MMC [40]. However, more recently, different investigators have used intraperitoneal oxaliplatin with intravenous 5-FU and leucovorin (LV) and obtained 5-year median survival rates of up to 42 % (Table 3). In the early postoperative period, before wound healing occurs, the treatment of CRS and HIPEC may be continued with EPIC. Therapy regimens usually include 5-fluorouracil and continue from PODs 1 to 5, utilizing inflow and outflow tubes that are placed intraoperatively within the abdomen and pelvis. Dwell time is usually 23 h, and there is drainage of the fluid before subsequent instillations [41]. The conceptual advantage of this approach may be that chemotherapy is administered before significant tumor cell entrapment occurs in postoperative fibrin deposits. However, randomized controlled studies have not been conducted to assess which modality of intraperitoneal chemotherapy is more advantageous. Elias et al. compared the perioperative and oncological outcome of 23 patients with PC of CRC after CRS and HIPEC with oxaliplatin, with retrospectively selected and matched 23 patients after EPIC with MMC and 5-FU. The rate of digestive fistulas was statistically significantly higher (P =0.02) in the EPIC group (26 %) than in the HIPEC group (0 %). There was a trend towards longer overall survival in the HIPEC group, (54 % at 5 years vs. 28 % for EPIC, P =0.22). Peritoneal carcinomatosis recurred (P =0.03) much more frequently in the EPIC group (57 %) than in the HIPEC group (26 %) [42]. A 2012 published case control study by Cashin and colleagues included 32 patients and compared treatment outcomes in 16 patients after HIPEC and 16 after EPIC [43]. The authors concluded that HIPEC was associated with an improved survival at similar morbidity and mortality compared with EPIC. The most recent study on the comparison of HIPEC and EPIC was published by McConnell et al. in 2013 [44]. The outcomes of 85 patients after CRS+HIPEC+EPIC were compared with 113 patients after CRS+HIPEC alone. Because of the increased rate of Grades III and IV complications after CRS + HIPEC + EPIC, the authors suggest that surgeons should consider using HIPEC only in combination with CRS. The aforementioned completeness of the cytoreduction (CC) score and PCI is an important prognostic indicator enabling the surgeon to predict whether a patient is going to benefit from CRS and HIPEC [26]. For CRC, a complete cytoreduction (CC-0 and CC-1) results in 5-year survival rates of 30–40 % [18,22,45]. In contrast, the oncological outcome after an incomplete cytoreduction (CC-2 and CC-3) is no better than after systemic chemotherapy [22]. PCI is useful as a prognostic indicator and predicts the likelihood of an incomplete cytoreduction [26]. Whereas survival at 5 years for patients with PCI greater than 19 has been reported to be less than 10 %; it is 27 % with PCI between 7 and 19 and 50 % with PCI less than 6 [22].
45
Considering the relevance of early diagnosis of peritoneal metastasis, further improvements in oncological outcome may be achieved if this treatment modality is applied timely in appropriately selected patients. A timely diagnosis of especially limited PC is associated with more favorable survival results [46] and decreased morbidity and mortality because of less extensive surgery [26]. In a study by Elias et al., 41 patients defined as being at “high risk” to develop PC but with no evidence of PC in clinical and radiological evaluation were subjected to second-look surgery and systematic HIPEC 1 year after initial surgery. If PC was diagnosed, CRS and HIPEC were performed. The other patients underwent HIPEC alone. Despite no evidence of PC in clinical and radiological examination, PC was diagnosed in 56 %. Grades III–IV morbidity was 9.7 %, one patient died on postoperative day 69 from multiple organ failure. After a median follow-up of 30 months, 5-year overall survival was 90 % in this selected group. A trial is currently recruiting patients to investigate this approach (NCT01226394) [47]. Reported experience in the literature on CRS and HIPEC combined with curative treatment of colorectal liver metastases (LM) is limited. However, available evidence indicates that the presence of synchronous LM in patients with PC of CRC is no longer an absolute contraindication for CRS and HIPEC. Elias and colleagues demonstrated that when the extent of PC is limited (PCI
