本文由武汉大学中南医院腹部肿瘤外科李雁主任提供

Journal of Surgical Oncology

2008;98:277-282

Consensus Statement on the Loco-Regional Treatment of Appendiceal Mucinous Neoplasms

 with Peritoneal Dissemination (Pseudomyxoma Peritonei)

BRENDAN MORAN, md,¹ DARIO BARATTI, md,² TRISTAN D. YAN, BSc(Med), mbbs, PhD,³ SHIGEKI KUSAMURA, md, PhD,² and MARCELLO DERACO, md²*

^Colorectal Research Unit, North Hampshire Hospital, Basingstoke, Hampshire, UK ²Department of Surgery, National Cancer Institute of Milan, Italy ³University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia

Pseudomyxoma peritonei (PMP) is a rare condition mostly originating from low malignant potential mucinous tumours of the appendix. Although this disease process is minimally invasive and rarely causes haematogenous or lymphatic metastases, expectation of long-term survival are limited with no prospect of cure. Recently, the combined approach of cytoreductive surgery (CRS) and perioperative loco-regional chemotherapy (PLC) has been proposed as the standard of treatment for the disease. The present paper summarizes the available literature data and the main features of the comprehensive loco-regional treatment of PMP. The controversial issues concerning the indications and technical methodology in PMP management were discussed through a web-based voting system by internationally known experts. Results were presented for further evaluation during a dedicated session of "The Fifth International Workshop on Peritoneal Surface Malignancy (Milan,Italy, December 4-6, 2006)''. The experts agreed that multiple prospective trials support a benefit of the procedure in terms of improved survival, as compared with historical controls. Concerning the main controversial methodological questions, there was an high grade of consistency among the experts and agreement with the findings of the literature.

J. Surg. Oncol. 2008;98:277-282. © 2008 Wiley-Liss, Inc.

Key Words: pseudomyxoma peritonei; appendiceal tumours; cytoreductive surgery;

hyperthermic intraperitoneal

chemotherapy; HIPEC

Pseudomyxoma peritonei (PMP) is a rare condition characterized by copious mucinous ascites and peritoneal mucinous implants [1-2]. The earliest description of the condition was by Rokitansky in1842 ina patient with a benign mucocele of the appendix [3].

Traditionally patients with PMP have been treated with repeated interval debulking procedures for relief of symptoms, but with limited expectation of long-term survival and no prospect of cure [1-2]. However, accurate historical controls of uniformly treated patients are scarce, partly due to the rarity of the disease. In 1994, Gough reported a 10-year survival of 32% in 56 PMP patients who underwent serial debulking procedures and selectively treated with intra-peritoneal radiotherapy or chemotherapy between 1957 and 1983 [4]. In 2005, Miner reported a 10-year survival of 21% in 97 PMP patients treated with serial debulking, systemic chemotherapy and/or delayed inter­mittent intra-peritoneal 5-fluorouracil over a 22-year period [5]. Misdraji reported on 107 patients with a median survival of about 7.5 years, and a 20-year survival of 25% after serial debulking and intra-peritoneal chemotherapy. The number of patients in this group who received aggressive locoregional treatment is unknown [6].

Although a subset of patients may remain asymptomatic for many years, the disease almost always recurs and patients often re­present with gastrointestinal obstructive symptoms. Over time each repeated debulking procedure becomes more ineffective and sometimes more dangerous due to the risk of bowel injury [1]. In addition, in some patients the disease may not remain indolent throughout its clinical course. Yan and colleagues showed that some patients underwent transitions from a less aggressive to a more aggressive histopathologic type over time and with repeated surgical interventions [7].

The structured approach of cytoreductive surgery (CRS) and perioperative loco-regional chemotherapy (PLC) regimens has shown in multiple studies improved survival, as compared with historical controls [8-18]. Sugarbaker published a large series of 385 patients in 1999 [8]. Of these, 205 received hyperthermic intra-peritoneal chemotherapy (HIPEC). He showed survival advantages in those who had complete versus incomplete cytoreduction (80% vs. 20%) and in those with low-grade versus high-grade tumours (80% vs. 28%) but did not

comment on whether the introduction of HIPEC made any difference to survival. Most recent updates by Sugarbaker demon­strated a median survival of 156 months and 5- and 10-year survival of 72% and 55% in 501 patients [11]. Taken together these data suggest that treatment of PMP by means of CRS and PLC is supported by a "type 3 evidence'', coming from non-randomised studies with external controls allowing comparisons [19].

The present paper addresses the available scientific evidence and the results of a group of health-care providers trying to achieve a consensus statement in the management of PMP by means of CRS and PLC regimens, including intra-operative HIPEC and/or early post­operative intra-peritoneal chemotherapy (EPIC) within 7 days from surgery.

Disclosures: The authors have no financial interest related to the contents of this article to disclose.

Correspondence to: Dr. Marcello Deraco, MD, Istituto Nazionale Tumori

Milano, Via Venezian, 1 20133Milano,Italy. Fax: +39-02-23902404.

E-mail: marcello.deraco@istitutotumori.mi.it

Received 19 March 2008; Accepted 21 March 2008

DOI 10.1002/jso.21054

Published online in Wiley InterScience

(www.interscience.wiley.com).

TERMINOLOGY AND PATHOLOGICAL CLASSIFICATION

There has been considerable confusion in the literature about the site of origin and pathological classification of PMP [1,6]. High-grade colonic mucinous neoplasms, adenocarcinomas of the appendix and mucinous adenocarcinomas originating from any other intra- abdominal organ can simulate the clinical, radiological and patho­logical features of PMP. Additionally, there appears to be a histological spectrum of disease from low to high-grade [1]. Recent pathological, molecular genetic and immunohistochemical evidence supports the theory that the majority of classical PMP originate from ruptured low- grade appendiceal tumours [20-22]. Undoubtedly a small proportion of cases arise from other organs and it is possible that an ovarian primary mucinous tumour may be the commonest in this diverse group arising from the stomach, colon, pancreas, gallbladder, urachus and other intra-abdominal organs [23 -26].

These difficulties in pathological classification of the clinical entity of PMP have led to ongoing confusion as to the outcomes following intervention. Thus, many series include all cases of PMP, of whatever origin, and include patients with mucinous adenocarcinoma of the appendix whereas others have reported only on classical pseudo- myxoma from appendiceal cystadenomas. Ronnett, in a retrospective review of a series of patients undergoing complete cytoreduction reported a pathological system commonly quoted in the literature [20]. They classified low-grade tumours as disseminated peritoneal adenomucinosis (DPAM) and high-grade tumours as peritoneal mucinous carcinomatosis (PMCA), with an intermediate group (IG). Survival was significantly higher in DPAM group as compared with the IG and PMCA, with actuarial 5-year survivals of 84%, 37.6% and 6.7%, respectively. They were unable to show a statistically significant difference between the IG and PMCA groups and in subsequent articles have grouped these together [27].

In a recent study by Misdraji, a different histopathologic classifica­tion of appendiceal neoplasm was proposed [6]. They classified the appendiceal mucinous tumours into low-grade appendiceal mucinous neoplasms (LAMN) and high-grade mucinous adenocarcinomas (MACA). The former diagnosis corresponds to mucinous cysto- adenoma and the latter to mucinous cysto-adenocarcinoma in the conventional classification system [28]. However, in this study, follow- up data were available only in 66 of 107 patients and patients underwent a variety of treatments by different surgeons over a 50-year period. More recently, based on the clinically malignant behaviour of all PMP varieties, Bradley has proposed that mucinous carcinoma peritonei, either low-grade or high-grade, is best applied to all cases of PMP [29].

PREOPERATIVE EVALUATION

The clinical presentation of PMP has been poorly defined due to few reports with large patient populations. The recent publication by Esquivel and Sugarbaker is the most enlightening [30]. In a series of 410 patients with appendiceal tumours, 27% presented with suspected appendicitis, 23% with increasing abdominal distension and 14% with a new onset hernia. In women, a diagnosis of PMP was most commonly made while being evaluated for ovarian mass (39%). Nevertheless, the majority of patients are diagnosed at a laparotomy performed for either suspected appendicitis, peritonitis or gynaeco­logical cancer.

More recently, the diagnosis of PMP is suspected in an increasing number of patients at imaging studies, particularly based on radio­logical features at CT-scan [31,32]. Appropriate radiologic techniques and a combination of oral, rectal and venous contrast are needed. On CT-scan PMP appears of low attenuation but areas of high attenuation, due to solid elements within the mucinous material or compressed mesentery, can be seen [32]. The circulation of peritoneal fluid in the abdominal cavity is dictated by gravity, pressure changes associated with respiration and physical boundaries of the peritoneal reflections. The mucin-producing cells in PMP are poorly adherent and freely circulate with peritoneal fluid. This process has been termed as redistribution phenomenon [33]. Accordingly, the predictable pattern of accumulation of mucinous ascites instead of the individual deposits can suggest the diagnosis of early-stage PMP. When the peritoneal cavity is completely, or almost completely filled with PMP, CT-scan findings become less specific. In most cases, the striking feature is the relative sparing of the small bowel and its mesentery and their compartimentalization in the central abdomen by a large omental cake and massive mucinous ascites.

The role of magnetic resonance imaging (MRI) in this clinical setting is presently under investigation. According to a preliminary report, the use of MRI seems promising in disease staging and patient selection for cytoreductive surgery [34]. PET is of very limited value for low-grade mucinous lesions, such as pseudomyxoma [35]. CT-scan or US-guided biopsy may be useful, although the relatively acellular material is often difficult to diagnose with certainty.

Most patients are referred from other surgical or gynaecological units and have usually had variable degrees of surgery prior to formal attempts at complete cytoreduction. Extensive previous attempts to reduce tumour load were shown by one large study to have a negative impact on survival [8]. It advisable, therefore, that the referring teams perform the minimal amount of surgery required to establish a histological diagnosis prior to referral to a specialist centre.

In total 78% of the panel agreed that PMP should always be considered a cancer and

therefore malignant. However, even when the pathology was stated as ''Malignant PMP syndrome-mucinous Appendix Carcinoma and Mucinous Carcinoma from any origin'' surprisingly 11% of the panel still considered this not to be a cancer.

Regarding pathological classification, no consensus was reached with 44% favouring Ronnetts three-category classification. A further 44% voted for a two-category system of Low-Grade Adenocarcinoma and High-Grade Adenocarcinoma. The novel recent terminology of Mucinous Carcinomatosis Pertitonei (MCP) low-grade and MCP high- grade, which is in reality new terminology similar to the two grade system, was favoured by 12%.

These discrepancies in terminology and pathological classification are important and really require universal agreement due to the difficulties in comparing series, credibility in justifying major surgical intervention, utilization of chemotherapy and difficulty in establishing treatment programmes for what even experts consider a "benign disease''. Based on the terminology of uncontrolled growth of abnormal cells it is the authors opinion that PMP is at best a "borderline malignancy" with optimal treatment being that of a cancer entailing complete macroscopic tumour removal combined with intraperitoneal chemotherapy. An interesting comment to one of us at the consensus meeting was "Based on this statement on PMP do you equally consider endometriosis a malignancy?''.

There was general agreement concerning pre-operative work-up with 100% considering abdominal and pelvic CT-scan very important, 66% considering clinical examination very important with very little role for PET-scan, CT-PET, MRI or US. The panel felt that colonoscopy and laparoscopy and biopsy might help on occasion but were not essential. Important laboratory work-up was considered to be basic metabolic panel urea, creatinine and electrolytes, CEA, complete blood count and coagulation studies by 75% of the panel with little importance attached to pulmonary function, urinalysis or CA125 measurement.

ELIGIBILITY FOR SURGICAL TREATMENT

Careful selection for this expensive, time consuming and high-risk surgery is essential. However, the potential surgical morbidity, along

with the spectrum of disease aggressiveness, makes preoperative selection of patients for CRS and PLC critical. Current selection criteria predominantly revolves around clinical assessment andCT-scan imaging [32].

Patients affected by peritoneal carcinomatosis with performance score = 2/3 according to the Eastern Cooperative Oncology Group (ECOG) have shown significantly poorer overall survival, compared to those with ECOG score = 1 [35].

In an effort to correlate the role of previous surgery in the establishment of peritoneal implants, Sugarbaker introduced the Prior Surgical Score (PSS). In patients with a PSS = 0, diagnosis of peritoneal carcinomatosis was obtained through biopsy or laparoscopy only. PSS = 1 indicates only a previous exploratory laparotomy. PSS = 2 indicates exploratory laparotomy with some resections. Usually this was a greater omentectomy and/or right colectomy. PSS = 3 indicates patients had an attempt at a complete cytoreduction. Patients with PSS = 0-2 had a significantly improved survival compared with those with a PSS = 3 [8].

The current best method to assess operability is contrast-enhanced CT-scan. Radiological features predicting the likelihood to adequate remove all the peritoneal tumour deposits have been described by Jacquet and validated by Sulkin [31,32]. In the study by Jacquet two radiologic findings predicted complete versus suboptimal cytoreduc- tion: the segmental obstruction of the small bowel and tumour masses >5 cmon small bowel and its mesentery exclusive of distal ileum. A statistical approach using a tree-structured diagram showed that patients with both these features on preoperative CT-scan, had an 88% probability of incomplete resection. Patients without these two findings had a 92% probability of complete resection [31].

Allowing direct inspection of peritoneal surfaces, laparoscopy may also facilitate disease staging and the selection of surgical candidates. The role of laparoscopy for PMP has never been specifically addressed. The experiences with patients affected by carcinomatosis from colorectal cancer has led to the conclusion that laparoscopy is accurate to score peritoneal involvement and to assess the complete resectability of carcinomatosis in patients for which there is inadequate or contradictory information [36].

Finally, in recent years the prognostic value of markers has been extensively addressed. In the paper by Baratti and colleagues: normal preoperative CA125 correlated to adequate CRS, but only at univariate analysis; in the same study, increased baseline CA19.9 was an independent predictor of worse progression-free survival at multi- variate analysis [37]. In 63 patients, van Ruth found only weak statistical association between baseline CA19.9 and disease-free interval, but elevated CA19.9 after the procedure or rising during follow-up was related to disease recurrence [38]. Survival correlated to preoperative CEA and CA19.9 among 532 patients studied by Carmignani. Both markers, measured at the time of disease recurrence, correlated to survival after a second cytoreduction [39]. In a recent paper, recurrence-free interval was statistically reduced for patients with increased CEA, but also for patients with at least one positive marker (among CEA, CA125 and CA19.9) [40].

CT imaging and CT-scan with tumour marker measurements were chosen by 71% and 83% as key eligibility criteria with only 50% support for laparoscopy or other investigations. With regards to disease extension 100% felt that all asymptomatic patients with PMP with resectable peritoneal dissemination should have CRS and PLC, as should patients with minimal small bowel involvement and node negative primary (100%). There was 100% agreement that peritoneal carcinomatosis index (PCI) >20 was not an absolute exclusion criterion in PMP, with a low

grade tumour (87%), young age (63%), absence of mesenteric invasion (88%) or liver metastases (75%) were important factors to consider in conjunction with PCI.

STATE OF THE ART OF THE METHODOLOGY

The aim of surgery in PMP is complete cytoreduction as described by Sugarbaker [2]. This involves up to six different peritonectomy procedures in combination with visceral resections as required, to remove all visible tumour, or if this was not possible, to leave tumour deposits less than2.5 mm(2.5 mmbeing the maximum direct penetration of locally applied chemotherapy). In brief, peritonectomy includes a greater omentectomy and splenectomy, left upper quadrant peritonectomy, right upper quadrant peritonectomy, lesser omen- tectomy and cholecystectomy, appendicectomy or right/total colec- tomy, partial or total gastrectomy, and pelvic peritonectomy with anterior resection of the recto-sigmoid colon. Females require hysterectomy and bilateral salpingo-oophorectomy.

No study has reported on the effect of hyperthermic compared to normothermic intra-peritoneal chemotherapy in patients in whom a complete cytoreduction was performed. The chemotherapy agents utilized, the dosage, the temperature or duration of intra-peritoneal chemotherapy have not been subject to randomised trials but have been chosen on knowledge of the agents' intra-peritoneal pharmacokinetics. The commonly used intra-operative agents are mitomycin, cisplatin, 5-fluorouracil or a combination of these and are usually administered for 30-120 min [41]. For EPIC, 5-fluorouracil, cyclophosphamide and mitomycin C are most frequently used for up to 6 days (see Table I).

To date, all the English language articles regarding PMP treated by CRS combined with locoregional chemotherapy are observational studies without control groups performed by tertiary referral centers. Most are serial publications reporting accumulating numbers of patients or increased follow-up. There are no randomized trials or comparative studies. Six studies included >100 patients [8,11,14­16,18] and the remaining series <100 patients. Five studies exclusively reported PMP originating from appendiceal mucinous neoplasms [8,11,14,15,17] and the remaining PMP originating mainly from appendiceal mucinous neoplasms, representing 86-97% of their

sample population. The rate of complete cytoreduction is 40-91%. This supports the benefits of centralising this aggressive surgical treatment at institutions with an interest in PMP. Effectiveness of CRS and PLC on survival and recurrence is demonstrated in Table II.

A number of recent reports in the literature have addressed the morbidity and mortality in patients with PMP treated by CRS and PLC (see Table III). The overall morbidity rate varied from 33 to 56%, hematological toxicity from 4 to 9%, blood loss from 2100 to 8000 cm³, mean operation duration from 6.0 to 12.6 hr. Re-operation rates for postoperative adverse events were 11 -21%, as reported in two studies. Overall mortality rates ranged from 0 to 18%. The median and mean hospital stay ranged from 16 to 21 days and 26 to 29 days, respectively (see Table III).

One aspect that has not been fully addressed is a strategy for the many patients whose tumours were preoperatively considered unlikely to be completely removable, either due to tumour extent and distribution, or as a result of serious co-morbidity or age. There is increasing evidence that many of these may benefit from a major palliative resection with reasonable intermediate-term survival of 43% at 2 years and 15% at 5 years and improved quality of life [42]. In these situations an approach involving extended right hemicolectomy, greater omentectomy and splenectomy with an ileocolic anastomosis may be advisable [43]. Glehen recommended combination of comprehensive surgical debulking with HIPEC except for patients with signet ring histology or lymph node involvement in his experience of 174 patients with incomplete cytoreduction [42].

There remains confusion as to the definition of complete cytoreduction with 100% stating this should be CC0 but 100% also agreeing it should include CC1. Maximal palliative surgery for patients not amenable to complete cytoreduction was endorsed by 78% of the panel, but 89% felt not for all cases, and 67% agreement for appendiceal tumours. In limited disease, 65% felt a limited peritonectomy was not appropriate, though 63% felt a complete parietal peritonectomy was not necessary for patients with a limited affected area. In patients with palliative or inoperable disease, 56% felt PLC should not be used compared to 44% in favour suggesting that this aspect might be amenable to a randomized trial. There was ambiguity concerning the optimum drug and relative temperature though428Cwas considered optimal for irinotecan and gemcitabine by 100% and for mitomycin and doxorubicin by 63% and 67%, respectively. The optimal single agent was felt to be mitomycin-C by 100% but 66% felt that combination therapy was optimal. If combination therapy was used 83% favoured cisplatin and mitomycin-C.

A common dilemma is the aspect of systemic chemotherapy in PMP. There was unanimous consensus that systemic chemotherapy should not be used whilst awaiting surgery and HIPEC, but should be given in non-resectable cases and those with high tumour grade. High tumour markers were considered an indication to consider systemic chemotherapy by 71%.

There was 100% agreement that the preferred imaging modality for follow-up was CT-scan with no role for MRI, PET or CT PET. Tumour markers, CT imaging and clinical examination at intervals of 0-12 months were favoured by 89% with 11% suggesting an interval of 12-24 months. For asymptomatic recurrence, 66% felt should have early surgery and 33% voted for no surgery and systemic chemotherapy. There was 100% support for a clinical trial of cytoreductive surgery and HIPEC followed by best systemic chemotherapy in patients with high-grade disease if a complete

cytoreduction was achieved. There was a 50/50 split concerning systemic chemotherapy after complete cytoreduction in patients with high tumour markers suggesting an area that could be considered for a randomized trial.

CONCLUSION

Recent evidence suggests that optimal surgical resection (complete cytoreduction if possible) combined with HIPEC is the most fundamentally based strategy for PMP. A combined approach makes both common and scientific sense, in that surgery attempts to remove all macroscopic disease whilst HIPEC addresses residual microscopic disease. This treatment strategy is a complex procedure, associated with significant morbidity and mortality with a substantial institutional and individual ''learning curve'' phenomenon [44,45].

The clinical results for cytoreduction and HIPEC in PMP show good survival for those patients with low-grade histology amenable to complete cytoreduction. Poorly defined and often confusing terms in the literature have resulted in most series being a heterogeneous population. This has limited the quality of the evidence with a lack of randomised controlled trials [41]. This deficiency is not unique to PMP surgery as few, if any, major surgical techniques are amenable to randomisation. Recent publications in the last 15 years with increasing numbers of medium to large case-series in the literature reflect an improved awareness and understanding of the disease. This trend should continue with the development of centralised treatment centres throughout the world such that the quality of care and information available for patients with PMP should ultimately improve.

An emerging network of specialized centres may facilitate multi- centre studies on aspects of chemotherapy type, duration and temperature to help allay the criticisms of many surgical, and in particular, medical oncologists on the lack of hard scientific evidence in PMP management.

Meanwhile good evidence is rapidly accumulating and surgical nihilism is no longer acceptable in this inexorably progressive, universally fatal, but eminently treatable disease.

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