Peritoneal malignancy is an ominous finding with few treatment options and an almost inevitable fatal outcome. A proportion of cases have peritoneal ‘surface’ malignancy which lends itself to localized treatments involving a combination of macroscopic tumour excision and intraperitoneal chemotherapy. Such radical approaches are particularly suitable for low grade tumours, especially pseudomyxoma peritonei of appendiceal origin¹² and some cases of peritoneal mesothelioma.³#

Pseudomyxoma peritonei, also known as “Jelly Belly,” is a rare clinical entity, with an incidence estimated to be one per million per year, characterised by diffuse intra-abdominal gelatinous fluid collections and mucinous implants on peritoneal surfaces and the omentum. Though it has generally been considered a benign condition, its behaviour over time, suggests that it should, at best, be considered a borderline malignant condition with inevitable disease progression and a final terminal outcome. In reality, the clinicopathological entity of “pseudomyxoma peritonei syndrome” probably represents a spectrum of disease ranging from adenomucinosis, which gives rise to true pseudomyxoma peritonei, to invasive and rapidly progressive mucinous adenocarcinoma.#

Long-term survival of patients with pseudomyxoma peritonei, without definitive treatment, remains poor with 5-year and 10-year survival rates of 50 and 10–30% respectively.⁴ Sugarbaker has developed and popularised the complex approach of cytoreduction and intra operative, hyperthermic, intraperitoneal chemotherapy (HIPEC) since the 1980s.⁴ In favourable cases a 5-year survival rate of 86% has been reported.⁴ The combination of surgery and intraperitoneal chemotherapy is time consuming and expensive with associated high morbidity and mortality rates.²⁴⁵ The extensive nature of the peritoneal disease, and the surgical interventions required, crosses the boundaries of subspecialized abdominal surgery. Indeed the treatments used cross whole specialties including gynecology, hepatobiliary and gastrointestinal tract surgery. These factors, together with the few numbers of suitable cases treated in any single institution have resulted in a slow acceptance of this new treatment modality.#

The subspecialty of Surgical Oncology in North America theoretically allows a single surgical unit to address all the requirements for combined treatment of pseudomyxoma peritonei. In Europe surgery is evolving from gastro-intestinal tract surgery to organ specific such as colorectal, upper gastrointestinal, pancreatico-hepatobiliary, with such subspecialization at an advanced stage in the UK. This subspecialization may be a major barrier in the development of a peritoneal malignancy unit.#

The experience of a colorectal unit in developing a national centre is reviewed in an attempt to document some of the issues involved. In particular, the development, funding and resources required to initiate and maintain a unit, the surgical skills with its associated learning curve and some early results are presented with the hope that such an experience may be of help to others.#

The initial index case was a young man from Scotland with pseudomyxoma peritonei (PMP) diagnosed at emergency laparotomy and omental biopsy. CT scans suggested the classical features of PMP with favourable features.⁶ The patient self-referred to our colorectal unit. With no prior experience it was decided to invite Paul Sugarbaker from the Washington Hospital Centre to perform this operation in Basingstoke. In March 1994, in a 12-h laparotomy, complete tumour removal of a disseminated mucinous tumour originating from a cystadenoma of the appendix together with early postoperative intraperitoneal chemotherapy was achieved. After a prolonged ileus he was discharged home and remained fit and well until he developed inoperable recurrence 7years later. Despite systemic chemotherapy he died from disease 8years from the initial surgery. At that time the surgery was funded by a process entitled Extra Contractual Referral (ECR) with £40,000 secured by our financial department from the Scottish Health Service.#

Some time later a self-referral was received via the internet of a young woman who had been found to be inoperable at two previous laparotomies and had failed to respond to systemic chemotherapy for a disseminated appendiceal tumour. The patient had self-referred to Washington but the cost of treatment in Washington was estimated as being at least $100,000 and she was advised to contact our unit. As a UK resident entitled to free National Health Service (NHS) care, she requested ECR referral to Basingstoke. At that point the estimated cost had been recalculated at £25,000. She underwent a 14-h complete cytoreduction, combined with intraperitoneal chemotherapy in 1995. With the exception of a severe chest infection, her recovery was uncomplicated and she is currently alive and well and disease free over 9years later.#

The next cytoreduction was on a local patient, with disease confined to the lower abdomen, completed in 8h, but a prolonged hospital stay of 6weeks due to an anastomotic leak which resolved with conservative treatment.#

The fourth case was a landmark in the service development. After a 16h complete cytoreduction, the patient developed post-operative uncontrollable haemorrhage, predominantly from a liver laceration and required four further laparotomies (three at night) together with 164 units of blood. After 66days in Intensive Care he was finally discharged home 78days later. He remained well until he developed recurrent, progressive, disease at 5years and died a year later. The pre-surgical agreed ECR tariff of £25,000 fell far short of the estimated costs of £120,000.#

The treatment programme for pseudomyxoma peritonei was halted for a year while we undertook an application to the National Specialist Commissioning Advisory Group (NSCAG). NSCAG is a subdivision of the NHS in England which provides central, top-sliced, funding to support specialist centres to undertake assessment and management of rare disease entities. The bid to become a peritoneal malignancy unit was rejected initially due to the broad spectrum and high incidence of diseases such as ovarian cancer. A refinement of the bid to be an approved centre for the treatment of “Pseudomyxoma Peritonei of Appendiceal Origin,” estimated to be approximately 1 case per million per year, was successful in 2000. The initial contract for an annual caseload of 12 cases has increased to 33 and is funded at approximately £60,000 per case, with any cases in excess of this funded at a lower marginal rate. This funding covers all activities including outpatient assessment, surgical treatment and post-operative care, follow up audit, research, etc. and includes the provision of a national advisory centre.#

The logistics of undertaking a case per month initially (though currently in excess of one per week) has major capital and manpower resource implications in a hospital, and workforce, already working at capacity. Our current structure encompasses two dedicated surgeons: one is routinely performing rectal cancer surgery and the other laparoscopic colorectal surgery in addition to peritoneal malignancy surgery. The team also utilizes two dedicated anaesthetists, a clinical nurse specialist, a clinical fellow, two administrators, and data managers, in an attempt to ensure optimal service delivery, continuity of care and accurate data collection and analysis. With the exception of some additional payments for out of hours work, no incentives, above the normal NHS salary scales, are paid to any of the staff including the consultant surgeons.#

The main costs are theatre time and intensive care. The need to prevent cancellations of surgery, which takes on average 10h, with major risks of cardiorespiratory morbidity, illustrated the need to completely fund a dedicated intensive care unit (ITU) bed at a cost in excess of £1000 per day. While the median ITU stay is now 3days, the range is considerable with some patients requiring prolonged ventilation and, in some cases, readmission to ITU. For these reasons, with a current annual surgical workload of approximately 60 new cases, and with flexibility required for overlap when complications occur, a fully funded ITU bed has been invaluable to minimize disruption, and indeed to preserve local hospital services.#

Complete cytoreduction in extensive cases requires major surgery with multivisceral resection and has significant morbidity and mortality. The surgical technique is novel and usually involves extensive use of diathermy in a prolonged procedure with one, or more, intra-abdominal gastro-intestinal tract anastomoses, often in oedematous bowel. Such surgery is likely to have a learning curve and analysis of our experience may elucidate some of the issues. In my opinion there are two main aspects to the learning curve, namely, technical skills and decision making. Surgical technical skills can often be gained in similar type operative experiences and most of the skills required are broadly covered in a general surgical training programme, but not to the level of expertise required. A safe pelvic dissection with rectal resection, a gastric resection and reconstruction of continuity of the gastro-intestinal tract are skills that undoubtedly are best performed by experts with a large case load and a subspecialty interest. However such skills and experience extending across the whole range of intra-abdominal organs are rare. Indeed skill and experience of the whole procedure have to be acquired and generally can only be gained either in an established unit or during development of the service.#

The skills also reflect a knowledge of the likely morbidity, instituting techniques to minimize complications and early recognition, and management, should complications occur. While the technical skills are obviously important, decision making may be as important and involves fundamental innate surgical “common-sense” and acquired knowledge. Decision making involves case selection, intra-operative strategic plans and alterations required when encountering the unexpected, and strategic decisions in the management of complications.#

Unfortunately, we probably learn best by our own mistakes but it is possible to learn by the mishaps and management errors of others, though, as one would expect publication of such reports are infrequent.#

As the lead surgeon in our unit I have analysed my initial outcomes in three numerically similar groups of patients in the first 100 laparotomies between 1994 and 2002. Due to an expanding service the time scales involved vary with the first 33 cases over 6years, the next 33 over 18months and the last 34 over 12months.#

The details of all cases referred since January 1994 have been recorded prospectively. Between January 1994 and October 2002, there were 241 consecutive referrals to the unit and 176/241 (73%) were assessed regarding suitability for surgical intervention. Of the remainder, 42/241 (17.4%) were not seen but advice given following CT evaluation and clinical discussion with the referring unit and at the cut-off time in October 2002, when 100 patients had undergone surgery, 23/241 (9.6%) were awaiting assessment.#

Of the 176 seen 100 (57%) underwent laparotomy.#

There were 45 males and 55 females with a mean age of 52years. The primary tumour was an appendiceal neoplasm in 87, 6 were from a colonic adenocarcinoma, 5 were abdominal mesothelioma and 1 each of leiomyoma and ovarian cystadenoma. Complete macroscopic tumour excision was achieved in 65 patients with a mean operating time of 10.2h. Twenty-eight patients had major palliative debulking with a mean operating time of 6h. In 7 patients the disease was so advanced and extensive that no worthwhile debulking was feasible and apart from biopsy essentially an “open and close” laparotomy was performed.#

Major technical complications, in particular anastomotic leakage and intra-abdominal bleeding were a source of major morbidity. These theoretically preventable complications were more common in the early part of the series. In total 6% had anastomotic leakage diagnosed clinically and radiologically and major post-operative intra-abdominal bleeding was diagnosed in 11% of patients in the series. Of these, 5/11 required re-laparotomy, with one requiring four further laparotomies to evacuate haematoma and control hepatic bleeding.#

The postoperative mortality in the three groups was 4/65 (6%) in the complete cytoreduction group, 1/28 (3%) in the major palliative cytoreduction group and 3/7 (43%) for patients having laparotomy alone for advanced disease.#

A total of four patients died of multiple organ failure, two had fatal pulmonary embolism, one died of disseminated intravascular coagulopathy and one had post-operative myocardial infarction.#

Looking at the three similarly sized numerical groups, the mortality, anastomotic leakage and major post-operative haemorrhage requiring re-operation are outlined in Fig. 1. The striking features are the major mortality and morbidity in the first 33 cases. Major haemorrhage and anastomotic leakage are to my mind technical failures and errors, and perhaps represent a technical learning curve. Meticulous attention to haemostasis has reduced the latter and a universal policy of defunctioning any colorectal anastomosis has reduced clinical leakage. The mortality rates in the first group partly represent poor case selection, a high serious morbidity rate and probably delayed and inadequate management of complications.#

All patients are reviewed annually by clinical assessment, CT scanning and measurement of tumour markers. The overall Kaplan–Meier 5-year predicted survival rate in 65/100 patients who had complete cytoreduction is 79.3%, with the best results in those with appendiceal tumours (Table 1). Most patients returned to an excellent quality of life with resumption of their normal activities.#

The treatment of PMP and PMP like conditions is controversial and is lacking in hard scientific evidence. Such evidence is unlikely ever to be available due to the rarity and heterogeneity of the disease.¹⁰ Furthermore, the definition of PMP has been a subject of much confusion with different reports including patients with ovarian, colonic and other primary tumours, in addition to appendiceal tumours.^4–9 The experience gained in developing a centre which has focused predominantly on appendiceal tumours has resulted in several observations. Early experience demonstrated the potentially major and costly complications requiring a focused approach to seeking appropriate funding. Central government funding, as we have obtained from NSCAG, is optimal and requires generous funding to allow service development and outcome assessment. The initiation and development of a service is probably best approached by focusing on a condition that is rare, with a reasonable number of cases and good outcomes. In our case this involved focusing on “pseudomyxoma peritonei of appendiceal origin” with an estimated annual incidence of one per million per year.#

Ongoing experience with pseudomyxoma peritonei syndrome suggests that there is undoubtedly a spectrum varying from a borderline malignant and progressive disease previously considered benign, right through to aggressive mucinous adenocarcinoma. In addition there may well be an adenoma-carcinoma sequence, akin to that in colorectal cancer. Clearly, a great variation in the suitability of patients for the advanced local-regional treatments exists.#

The current recommended treatment modality of PMP involving complex multivisceral resection and reconstruction of the gastrointestinal tract, is associated with considerable postoperative morbidity and mortality. Sugarbaker reported a mortality rate of 2.7% and morbidity rate of 27% (grade III/IV) in 155 consecutive patients with PMP.¹¹ There have also been reports of an increase in post-operative fistula complications and of anastomotic leakage, especially after colorectal anastomosis which may be partly attributable to the heated chemotherapy.¹²¹³#

The learning curve is a complex issue but undoubtedly is real. The technical and decision making aspects of the learning curve probably apply to the whole team, but the main component is undoubtedly a surgical responsibility. The overall mortality rate in our series was 8%. This included three patients who in retrospect should probably not have had surgery. This, in conjunction with the high incidence of technical complications, probably reflects a “learning curve” with this extensive surgery. Improved outcomes in respect of operability, mortality and morbidity in the later stages in this series probably reflect improved technical expertise, better patient selection and a more focused postoperative management.#

In conclusion, cytoreductive surgery combined with heated introperative, intraperitoneal chemotherapy appears promising in the management of peritoneal malignancy. In the absence of an animal model or a randomised controlled trial, efforts should continue to further fine tune such a surgical strategy with a view to improving treatment outcome in this challenging, though rare tumour. Similar techniques may have applications in other more common malignancies such as colorectal cancer, both to prevent and treat isolated peritoneal carcinomatosis. The surgery is costly, has major morbidity but provides good disease control and the only possibility of cure.#