Fig. 23.1
Diagnosis of PM on computed tomography. View of an omental involvement such as enhancing nodules or omental cake
Nevertheless, all of these imaging modalities strongly underestimate the real extent of the peritoneal disease [24]. In addition, because radiologic tests lack sensitivity for PM, when peritoneal extension is discovered during surgery, it is mandatory to precisely describe the locations, number, and sizes of the peritoneal implants, to estimate the possibility of complete resection.
Patients at Risk
Numerous studies have retrospectively reported on factors linked to the primary CRC that exert an influence on the onset of recurrences in general, but only very few have focused on peritoneal recurrences [4, 25–29]. Nevertheless, multiple factors have been identified that give rise to a high risk of developing PM. A predictive score of metachronous PM has been established, after follow up of 8044 patients, with a maximal incidence of 60.7% when all the risks factors are present [7]. In a recent review of the literature including studies published between 1940 and 2011, Honoré et al. [30] selected 16 clinical studies, three prospective and 13 retrospective, which analyzed the risk of PM after resection of CRC. The low quality of the methodology of these studies has to be underlined. Nevertheless, risk factors of developing PM were: synchronous PM resected with the primary tumor, history of ovarian metastases, perforated tumor, serosal and/or adjacent organ invasion, histological mucinous subtype, positive peritoneal cytology, with a reported incidence of peritoneal relapse ranging from 8 to 75%. In these patients identified at high risk of developing PM (localized PM resected, ovarian metastasis, perforated tumor), new treatment protocols have been evaluated and will discuss below.
Complete Cytoreductive Surgery Plus HIPEC—Objectives and Results
For the last two decades, prognosis of PM arising from CRC has nevertheless been widely improved, and modern systemic chemotherapies actually enable a median survival of 12.7 to 24 months [31, 32]. However, prognosis of stage IV patients unable to undergo surgery and treated with systemic chemotherapy (5-FU plus oxaliplatin or plus irinotecan) was worst in case of PM associated to other metastatic sites, with a median survival 12.7 months, compared to 17.6 months when patients had no PM [21]. The worst prognosis of the patients with PM from CRC, and their lower benefit from recent improvement in contemporary systemic chemotherapy, leading to only limited survival benefit, were confirmed in a large cohort study of 2406 patients [26].
Beside the improvements in these drugs, the development of a new therapeutic concept which combines a complete cytoreductive surgery (CCRS) of the visible peritoneal tumorous deposits followed by hyperthermic intraperitoneal chemotherapy (HIPEC) was able to improve the median survival up to 63 months [32–34]. This major survival benefit could only be achieved in a selected population of patients.
Principles and Objectives
The combination of maximal cytoreductive surgery with HIPEC to treat peritoneal cancer was first described by Spratt in 1980 [35], but the main initiator of this combined treatment for peritoneal disease was Sugarbaker [36, 37]. The purpose of surgery is to treat all the macroscopic, i.e., visible disease, and immediately after resection, the purpose of HIPEC is to treat the remaining microscopic i.e., non-visible residual disease. It is essential that surgery resects all the tumor implants exceeding 1 mm, as the drug penetration in the tissue and in the tumoral deposits is small, less than 1 to 2 mm [38, 39]. HIPEC must be performed immediately after surgery, to avoid peritoneal adhesions in which cancer cells may be trapped and which could constitute a tumor sanctuary [40, 41]. In fact, the exact effect of HIPEC alone in this package is currently unknown in human beings. In an experimental study, animals treated with HIPEC survived longer than those treated with intraperitoneal chemotherapy alone or exclusively with intraperitoneal hyperthermia [42]. This was confirmed in another experimental study, with a reduced tumor load in rats which received intraperitoneal chemotherapy combined to hyperthermia, compared to those which had either chemotherapy or hyperthermia alone [43]. With regard to the potential beneficial effect on survival of HIPEC, until now, only one randomized study has been conducted, a multicentric French trial (NCT00769405), which compared CCRS plus HIPEC to CCRS without HIPEC. This trial has just closed for inclusion, and final results on overall survival should be available in 2017. Two retrospective [44, 45] and one prospective [46] studies have reported survivals of patients who had a complete resection of the PM without intraperitoneal treatment; the 5-year overall survival ranged from 24 to 36%, but their non-randomized manner and their small effect make conclusions difficult to do.
Surgical Technique
A complete exploration of the entire abdominal cavity has to be done, with a meticulous exploration and palpation of all the peritoneal surfaces, and all the previous dissected planes have to be reopened, as tumor cells could be trapped inside these cicatricle planes. Searching extraperitoneal metastases (liver, retroperitoneal lymph nodes) has also to be performed during the exploration. At the end of the exploration, the extent of the PM is scored using the peritoneal cancer index (PCI) described by Jacquet et Sugarbaker [47] (Fig. 23.2). Succinctly, the abdomen is divided into 13 areas (nine abdominal regions and four small-bowel sections), and a score is attributed for each region according to the size of the peritoneal implants (score from 0 to 3). At this time, the surgeon has to decide if the complete resection of all the peritoneal disease can be performed, taking into account the value of the PCI, the amount of the visceral resections, the risk of postoperative complications, and the expected quality of life after surgery. With regard to the surgical technique, all the visible peritoneal deposits have to be resected, even if they look like granulomatous nodules; indeed, macroscopic differentiation between benign inflammatory nodules and tumoral nodules might be difficult to do. Digestive anastomoses are usually performed after HIPEC in the open technique (see below), and before HIPEC in the closed technique. Ostomies are usually done to protect colorectal anastomosis.
Fig. 23.2
Peritoneal cancer index (PCI). The abdomen is divided in 13 areas (9 abdominal regions and 4 small bowel sections), and a score is attributed for each region according to the size of the peritoneal implants (score from 0 to 3)
Hyperthermic Intraperitoneal Chemotherapy
HIPEC techniques are heterogeneous but their elaboration is highly complex. The combination of drugs can be modified, as can their concentration, but also the composition as well as the volume of the perfusion, the duration, and the temperature. A high number of combinations of these six parameters are possible, and it is not possible to test all of them [48]. Each modification of one of these parameters implies conducting a new pharmacokinetic study. In a recent experimental study which compared the open to the closed technique, using intraperitoneal oxaliplatin at a temperature of 42 °C, the open technique had far higher systemic absorption and abdominal tissue penetration of oxaliplatin than the closed technique; the closed technique achieved a higher temperature in the diaphragmatic regions, while the open technique was more effective in the other areas. Nevertheless, intraperitoneal hyperthermia could be achieved with both techniques [49]. After all, it is very important for the surgeon to obtain a high and homogeneous temperature throughout the abdominal cavity, to choose “his” technique and to routinely perform this technique, leading to an analysis of homogenous data, as no prospective comparison of open and closed techniques of HIPEC in terms of survival, morbidity, or pharmacokinetics as ever been reported [50].
Schematically, there are two main trends worldwide for HIPEC: one uses mitomycin C over 60–90 min at 41 °C with a closed-abdomen technique, and the other uses oxaliplatin (460 mg/m2 of oxaliplatin in 2 L/m2 of iso-osmotic 5% dextrose) over 30 min (strictly 30 min as soon as the minimal temperature of 42 °C had been reached throughout the abdominal cavity, plus 5 to 8 min before to heat the infusate from 38° to 42 °C), at a homogeneous temperature of 43 °C (range: 42–44 °C) with an opened-abdomen technique [51] (Fig. 23.3). A bidirectional (intraperitoneal + systemic) intraoperative chemotherapy which combines intraperitoneal oxaliplatin preceded by an intravenous infusion of 5-FU (400 mg/m2) with leucovorin (20 mg/m2) is now mostly used for PM from CRC [52, 53].
Fig. 23.3
HIPEC: Open technique. Pictures corresponding to operative view of the opened-abdomen technique over 30 min at a homogeneous temperature of 43 °C (range: 42–44 °C)
Short-Term Results
Specialized centers have now reached technical maturity, leading to an incidence of adverse events comparable with those for other established surgical procedures. Reported mortality is now below 5%, and severe morbidity (grade 3–4) is approximately 30%. These acceptable operative results can be obtained in experienced centers, and in selected patients [54–65].
Many predictors of postoperative complications have been described, including the operation length [53, 60], the age [61], the number of visceral resections [53], the stoma formation [62], the dose of chemotherapeutic agent [63], and recurrent cancer [59]. But the most widely known factor is the extent of the peritoneal disease measured with the PCI, with an increased risk of grade IV morbidity when the PCI is greater than 12 [58–60]. In the study reported by Saxena et al. [58], an extensive disease involvement in the left hemidiaphragm was the only significant predictor of severe morbidity on multivariate analysis, probably because this procedure results in respiratory complications, and in a higher risk of pancreatic leak, bleeding, intra-abdominal abscess, due to the dissection of the hilum of the spleen.
Long-Term Results
The benefit of the cytoreductive surgery combined with HIPEC above systemic chemotherapy (5-FU leucovorin) has been confirmed in a phase 3 randomized study [33, 34], with a significant improvement of the median overall survival from 12.6 to 22.2 months (p = 0.028). Moreover, these results were obtained despite the fact that half of the patients in the experimental arm were ultimately not good candidates for HIPEC because their PM could not be completely surgically resected. A more recent retrospective study compared similar patients with resectable PM treated either with CCRS and HIPEC or with standard systemic chemotherapy (FOLFOX, or FOLFIRI). Again, the median survival was significantly increased in patients who underwent CCRS plus HIPEC, from 24 to 63 months (p < 0.05) (Fig. 23.4) [32]. Thus, the results of experienced centers concerning patients who underwent CCRS plus HIPEC are consistent with an overall 5-year survival rate close to 40% [34, 55, 66]. In a large review of the literature [67], the median overall survival after CCRS (R0/R1) plus HIPEC varied between 28 and 62.7 months. Finally, definitive cure of PM with HIPEC is possible. The authors recently followed up those of their patients who had had no recurrence more than 5 years after their last treatment. Among 107 patients treated between 1995 and 2005, 16% were definitely cured [68]. This rate of cure was comparable to that reported after resection of colorectal liver metastases [69, 70], suggesting that prognosis of selected patients who underwent CCRS plus HIPEC could benefit from this aggressive treatment, as well as patients operating on liver metastases. This was confirmed in a recent study, with a 5-year overall survival rate not statistically different between patients operated on liver metastases from CRC and those who had CCRS plus HIPEC (respectively, 38.5% and 36.5%) [71].
Fig. 23.4
Overall survivals: comparison between patients treated with curative intent (CCRS plus HIPEC) and those treated with modern systemic chemotherapy. Survivals reported in a retrospective study which compared similar patients with resectable PM treated either with CCRS and HIPEC or with standard systemic chemotherapy (Folfox, or Folfiri). The median survival was significantly increased in patients who underwent CCRS plus HIPEC, from 24 to 63 months (p < 0.05) [32]
Prognostic Factors
Completeness of Resection
As mentioned above, one key prognostic factor is the completeness of cytoreduction. Indeed, the median survival is about 12 months for patients in whom macroscopically complete resection of PC is not possible [33, 72, 73]. This survival is comparable to that obtained with palliative systemic chemotherapy alone [6, 31], while systemic chemotherapy bears significantly lower morbidity and mortality risks. Resection is scored according to the completeness of cytoreductive surgery (CCS score ranging from 0 to 3). All the studies have the same conclusions: an incomplete resection, leaving tumor deposits greater than 2 mm, does not provide prolonged survival even if HIPEC is performed [33, 54, 74]. In the French registry, there was no 5-year survivor in cases of remnant tumor deposits greater than 2 mm.
Extent of Peritoneal Disease
Another major prognostic factor is the extent of PM, which is intimately associated with the completeness of resection. Different scores evaluate peritoneal extension, the most common being the PCI (see above), which can only be accurately determined at laparotomy. Among 523 patients reported in the French registry [54], 5-year overall survival was directly correlated with the PCI, ranging from 44% with a very low PCI (less than 6) to 7% with the highest PCI (more than 19); and a PCI exceeding 20 appeared as one of the main prognostic factors for survival in the multivariate analysis. The main impact of the PCI has been underlined in many studies, and some tried to define a cut-off above which CCRS and HIPEC could not be effective. Thus, a PCI above 16 [75] or 20 [66] has been demonstrated to have a negative prognostic impact. Recently, a group of patients judged amenable to CCRS, but in whom CCRS plus HIPEC could not be performed during laparotomy (they received palliative systemic chemotherapy), was compared to a group of patients who underwent CCRS and HIPEC, with the aim of determining a threshold value beyond which CCRS plus HIPEC may not offer survival benefit compared to systemic chemotherapy. After a median follow-up of 60 months (47–74), 3-year overall survival was 52% [95% CI 43–61] in the curative group compared to 7% [95% CI 2–25] in the palliative group. Comparison of survivals for each PCI (comprised between 5 and 36) showed that OS did not differ significantly between the two groups of patients when the PCI was greater than 17 (HR = 0.64 [0.38–1.09]) (Fig. 23.5) [76].
Fig. 23.5
Overall survivals: comparison between patients treated with curative intent (CCRS plus HIPEC) and those whom CCRS plus HIPEC could not be performed during laparotomy (they received palliative systemic chemotherapy), according to the peritoneal extension (PCI). After a median follow-up of 60 months [47–74], 3-year overall survival was 52% [95% CI 43–61] in the curative group compared to 7% [95% CI 2–25] in the palliative group [76]
Others Prognostic Factors
Through multivariate analysis by various studies, others prognostic factors have been identified: the presence of positive lymph nodes, the absence of delivery of adjuvant chemotherapy, the progression under chemotherapy and the presence of liver metastases [32, 54, 66, 77]. Also, the presence of synchronous liver metastases decreases survival in patients operated on PM; however, when the extent of peritoneal disease is limited and when the number of liver metastases is not greater than three, complete resection of both types of disease results in interesting prolonged survival [78].
Histological Findings and Response to Systemic Preoperative Chemotherapy
Response to systemic preoperative chemotherapy is still difficult to appreciate, mainly due to the lack of target lesions on imaging. Therefore, appraisal of histological findings to evaluate response to systemic chemotherapy appears to be attractive. In a recent retrospective study, a review was performed of 115 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy before complete CRS alone or combined with hyperthermic intraperitoneal chemotherapy (HIPEC) [79]. The pathological response was defined as the mean percentage of cancer cells remaining within all specimens. A complete pathological response (no residual cancer cells in all specimens) was observed in nearly 10% of the patients, and 20% of the patients had a major response (1–49% residual cancer cells); the remainder had minor or no responses. Pathological response was the only independent predictor of survival (p = 0.01; major response: hazard ratio [HR] = 4.91; minor response: HR = 13.46), using multivariate analysis. The authors did not identify any significant predictor of pathological response. This study confirms that pathological response can be obtained in PM, but rates of major and complete responses appear to be lower than those observed after systemic chemotherapy for liver metastases from CRC.
Indications
The selection of patients is made roughly on clinical parameters and intra-operative findings. Indications are based on absolute and relative contraindications. An absolute contraindication for CCRS plus HIPEC is a poor general status, the presence of extraperitoneal metastases (except for three easily resectable liver metastases) and huge and diffuse PC. Relative contraindications are: a subocclusive syndrome due to more than one digestive stenosis, peritoneal disease progressing under systemic chemotherapy, and the presence of more than three resectable liver metastases (LM are not contraindicated if there are <4 and they are easily resectable) [78, 80].
In summary, eligibility criteria for CCRS and HIPEC are as follows: a good general status and age below 65–70 years, no extra-abdominal disease, no occlusive disorders, and no bulky clinical or radiological PM.
Perspectives
Standardization of the Procedures
The HIPEC procedure will have to be gradually standardized in the future in terms of the drugs, their concentration, the temperature of the perfusate, the duration, and the use of open or closed procedures. In theory, a randomized trial would be required for each modified parameter, but 100 or so different combinations would need to be tested. It is clear that multiple trials will not be conducted.
New Drugs, New Combinations
In the future, optimizing the long-term results, and reducing the morbidity of the procedure could pass by the use of new drugs intraperitoneally, new combinations either intraperitoneally or bidirectionally (IP and IV). In addition, the concept of personalized approach for cancer treatment could also be applied in the future to the treatment of PM. Better knowledge of the tumor biology at the individual scale may help to refine indications or to select drug among patients treated for PM. It is also possible that targeted therapies which have led to great advances in the colorectal liver metastases field may be used in the local treatment of PM. Their efficiency on peritoneal lesions has to be evaluated in patients with initially unresectable disease.
To Treat earlier
As the extent of the disease (PCI) and the completeness of resection are the main linked prognostic factors, survivals are far better in patient with low PCI. Because the early diagnosis of PM are unusual with current imaging, a new policy consisting in a systematic second look surgery in patients at high risk of developing PM has been evaluated [81, 82]. In patients without evidence of recurrence (clinical, radiological, or biological), a PC was discovered and resected during the second-look surgery in 55 per cent of the patients. The mean peritoneal cancer index was low (8 ± 6), and peritoneal deposits were resectable in all of the patients. After a median follow up of 30 [9–109] months, overall survival and disease-free figures at 5 years were 90% and 44% (Fig. 23.6). Therefore, this strategy is currently being tested in a randomized phase 3 study (NCT01226394) which has just been closed for inclusion. In this study, after 6 months of adjuvant systemic chemotherapy following resection of the primary, patients at high risk of peritoneal recurrence without any sign of recurrence were randomized in two arms: the standard arm which consists in monitoring every 3 months the first 2 years and then every 6 months the 3 years later, and the experimental arm which consist in a systematic second-look surgery followed by HIPEC.
Fig. 23.6
Overall and disease-free survivals after systematic 2nd look surgery in patients at high risk of developing PM. After a median follow up of 30 [9–109] months, overall survival and disease free at 5 years were 90% and 44% [82]
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