Surgical Management of PANCREATIC CANCER
INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) carries one of the poorest overall prognosis of all human malignancies. The 5-year survival in patients with PDAC, for all stages, remains as low as 6–7%. The low survival rate is attributed to several factors, of which the two most important are aggressive tumor biology and late stage at which most patients are diagnosed. Only 10–20% of patients are eligible for resection at presentation, 30–40% are unresectable/locally advanced, and 50–60% are metastatic. Pancreatic cancer without distant metastasis can be divided into three categories: resectable, borderline resectable, and locally advanced. In absence of metastatic disease, the most important factor for improving survival and possibly offer cure is to achieve a margin-negative resection. Even after potential curative resection, most patients develop recurrences eventually, and 5-year survival of completely resected patients is only up to 25%. The aggressive tumor biology and its inherent resistance to chemotherapy and radiotherapy contributes to early recurrence and metastasis.
SURGICAL ADVANCES
Pancreatic cancer surgery has evolved over the past few decades and remains the cornerstone of treatment of resectable and borderline resectable tumors. Advances in modern imaging give precise information on disease extension and vascular involvement that aids in surgical planning in order to achieve a margin-negative resection.
SURGICAL TECHNIQUES
Surgical techniques for pancreatic cancer include pancreaticoduodenectomy, distal pancreatectomy with splenectomy, and total pancreatectomy. Standard lymphadenectomy for pancreatoduodenectomy should include removal of lymph node stations 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. Involvement of superior mesenteric vein (SMV)/portal vein(PV) was previously considered as a contraindication for resection. However, curative resection along with SMV/PV with vascular reconstruction has now become a standard practice in specialized high-volume centers. To improve margin-negative resections, specially in borderline resectable tumors with proximity to vascular structures, SMA first approach was proposed as a new modification of standard pancreatico-duodenectomy. In a systematic review, SMA first approach was shown to be associated with better perioperative outcomes, such as blood loss, transfusion requirements, pancreatic fistula, delayed gastric emptying, and reduced local and metastatic recurrence rates. In case of arterial involvement, there is no good evidence at present to justify arterial resections for right-sided pancreatic tumors. However, the modified Appleby procedure, which includes en bloc removal of celiac axis with or without arterial reconstruction, when used in appropriately selected patients, offers margin negative resection with survival benefit for locally advanced pancreatic body and tail tumors and should be performed in high-volume centers. Most evidence does not support advantage of more extended resections such as removal of the para-aortic lymph nodes and nerve plexus and multivisceral resections routinely. Such extended resections are associated with compromised quality of life because of associated higher perioperative morbidity and intractable diarrhea. However, in highly selected patients, with preserved performance status and stable or nonprogressive disease on neoadjuvant treatment, such extended resections can provide survival advantage over palliative treatments. Radical surgery in the presence of oligometastatic disease has also been reported to prolong survival in highly selected patients.
Adverse events in SURGERY
The surgical domain can be seen as more complex and high risk in its delivery of care than other non-interventional specialities. It is therefore not surprising that in the majority of studies of adverse events in healthcare, at least 50% occurred within the surgical domain and the majority of these in the operating theatre. Furthermore, at least half of these adverse events were also deemed preventable. Just as the multiple studies in the developed world have similar figures for adverse events in hospitalised patients across all specialities, there appears to be a similar rate of harm in surgery. A review of 14 studies, incorporating more than 16000 surgical patients, quoted an adverse event occurring in 14.4% of surgical patients. This was not simply minor harm; a full 3.6% of these adverse events were fatal, 10% severe and 34% moderately harmful. Gawande, a surgeon from Boston, made one of the first attempts to clarify the source of these adverse events.
This paper pioneered the concept that the majority of these adverse events were not due to lack of technical expertise or surgical skill on the part of the surgeon, finding instead that ‘systems factors’ were the main contributing factor in 86% of adverse events. The most common system factors quoted were related to the people involved and how they were functioning in their environment. Communication breakdown was a factor in 43% of incidents, individual cognitive factors (such as decision-making) were cited in 86%, with excessive workload, fatigue and the design or ergonomics of the environment also contributing.
These findings were confirmed in the systematic review of surgical adverse events, where it was found that errors in what were described as ‘nonoperative management’ were implicated in 8.32% of the study population versus only 2.5% contributed to by technical surgical error. In accordance with other high-risk industries, such as commercial aviation, the majority of these adverse events are therefore not caused by failures of technical skill on the part of the individual surgeon, but rather lie within the wider healthcare team, environment and system. Lapses and errors in communication, teamworking, leadership, situational awareness or decision-making all feature highly in post-hoc analysis of surgical adverse events. This knowledge of error causation has been prominent and acknowledged in most other high-risk industries for many years, but it is only recently that healthcare has appreciated this.
Hepatocellular ADENOMA
Benign liver tumours are common and are frequently found coincidentally. Most benign liver lesions are asymptomatic, although larger lesions can cause non-specific complaints such as vague abdominal pain. Although rare, some of the benign lesions, e.g. large hepatic adenomas, can cause complications such as rupture or bleeding. Asymptomatic lesions are often managed conservatively by observation. Surgical resection can be performed for symptomatic lesions or when there is a risk of malignant transformation. The type of resection is variable, from small, simple, peripheral resections or enucleations, to large resections or even liver transplantation for severe polycystic liver disease.
General Considerations
Hepatocellular adenomas (HCA) are rare benign hepatic neoplasms in otherwise normal livers with a prevalence of around 0.04% on abdominal imaging. HCAs are predominantly found in women of child-bearing age (2nd to 4th decade) with a history of oral contraceptive use; they occur less frequently in men. The association between oral contraceptive usage and HCA is strong and the risk for a HCA increases if an oral contraceptive with high hormonal potency is used, and if it is used for over 20 months. Long-term users of oral contraceptives have an estimated annual incidence of HCA of 3–4 per 100000. More recently, an increase in incidence in men has been reported, probably related to the increase in obesity, which is reported as another risk factor for developing HCA. In addition, anabolic steroid usage by body builders and metabolic disorders such as diabetes mellitus or glycogen storage disease type I are associated with HCAs. HCAs in men are generally smaller but have a higher risk of developing into a malignancy. In the majority of patients, only one HCA is found, but in a minority of patients more than 10 lesions have been described (also referred to as liver adenomatosis).
Clinical presentation
Small HCAs are often asymptomatic and found on abdominal imaging being undertaken for other purposes, during abdominal surgery or at autopsy. Some patients present with abdominal discomfort, fullness or (right upper quadrant) pain due to an abdominal mass. It is not uncommon that the initial symptoms of a HCA are acute onset of abdominal pain and hypovolaemic shock due to intraperitoneal rupture. In a series of patients who underwent resection, bleeding was reported in up to 25%. The risk of rupture is related to the size of the adenoma. Exophytic lesions (protruding from the liver) have a higher chance of bleeding compared to intrahepatic or subcapsular lesions (67% vs 11% and 19%, respectively, P<0.001). Lesions in segments II and III are also at higher risk of bleeding compared to lesions in the right liver (35% vs 19%, P = 0.049).
Management
There is no guideline for the treatment of HCAs, although there are general agreements. In men, all lesions should be considered for surgical resection independent of size, given the high risk of malignant transformation, while taking into account comorbidity and location of the lesion. Resection should also be considered in patients with HCAs due to a metabolic disorder. In women, lesions <5 cm can be observed with sequential imaging after cessation of oral contraceptive treatment. In larger tumours, treatment strategies vary. Some clinicians have proposed non-surgical management if hormone therapy is stopped and patients are followed up with serial radiological examinations. The time period of waiting is still under debate, however recent studies indicate that a waiting period of longer than 6 months could be justified.
More recently, the subtypes of the Bordeaux classification of HCA have been studied related to their risk of complications. Some groups report that percutaneous core needle biopsy is of limited value because the therapeutic strategy is based primarily on patient sex and tumour size. Others report a different therapeutic approach based on subtype. Thomeer et al. concluded that there was no evidence to support the use of subtype classification in the stratification and management of individual patients related to risk of bleeding. Size still remains the most important feature to predict those at risk of bleeding during follow-up. However, malignant transformation does seem to be related to differences in subtypes. β-catenin-mutated HCAs trigger a potent mitogenic signalling pathway that is prominent in HCC. Cases of inflammatory HCAs can also show activation of the β-catenin pathway with a risk of developing malignancy. Therefore, β-catenin-mutated and inflammatory HCAs are prone to malignant degeneration, and particularly if >5cm. In these circumstances, invasive treatment should be considered.
Liver Uptake on Cadaveric Donors for Transplant
Since the initial descriptions of orthotopic liver transplantation (OLT) in the 1960s, both the number of patients receiving transplants and the indications for the procedure have increased significantly. OLT represents the only treatment modality for many patients with a diverse spectrum of disease, with the predominant common factor end-stage liver failure. Advances in perioperative care of the donor and recipient, organ preservation methods, and surgical techniques have resulted in a 5 year overall survival of 78% for all recipients (Kim et al, 2015).
OPERATIVE TECHNIQUES
The first published description of human liver transplantation was by Starzl and colleagues in 1963 at the University of Colorado. In this seminal paper, the dismal outcomes of three OLT recipients were described, including one intraoperative death from uncorrectable coagulopathy and two survivors of 7 and 22 days. In addition to the pioneering conceptual framework and implementation of LT, the advanced techniques included grafts from non–heart-beating donors, venovenous bypass in the recipients, choledochocholedochostomy, and coagulation monitoring by using thromboelastography (TEG). Many of these concepts remain or have reentered the realm of LT more than 40 years after their initial description. Based largely on the initial body of work by Starzl and colleagues, this section describes the surgical procedures commonly used worlwide.
The typical deceased donor has had a catastrophic head injury or an intracerebral bleed, with brain death but without multisystem organ failure. Electrolyte imbalance and hepatic steatosis in the donor are predictors of graft nonfunction. A “donor risk index” has been derived to assess the likelihood of good graft function. Key adverse factors include older donor age (especially >60 years of age), use of a split or partial graft, and a non–heart-beating donor, from which the organs are harvested after the donor’s cardiac output ceases, in contrast to the more typical deceased donation in which the organs are harvested prior to cardiovascular collapse. Use of non–heart-beating donors is associated with reduced rates of long-term graft survival and increased risk of biliary complications, which correlate with the duration of “warm ischemia” after cardiovascular collapse and before retrieval of the organ. With the critical shortage of deceased organ donors, expansion of the donor pool has included acceptance of donors 70 years of age and older for selected recipients. Prior to hepatectomy, the harvesting team makes a visual and, if necessary, histologic assessment of the donor organ. Particular attention is paid to anatomic variants in the hepatic artery that may complicate the graft arterial anastomosis in the recipient. Once donor circulation is interrupted, the organ is rapidly infused with a cold preservation solution (e.g., University of Wisconsin, histidine-tryptophan-ketoglutarate, or Institut Georges Lopez solution). Donor iliac arteries and veins are also retrieved in case vascular grafting is required. After its arrival at the recipient institution, further vascular dissection, with arterial reconstruction if necessary, is performed before implantation.
Future Perspectives
Major challenges remain in LT, including the shortage of donor organs, threat of recurrent disease, and morbidity associated with lifelong therapeutic immunosuppression. Nevertheless, the availability of LT has transformed the lives of patients with advancing liver disease and their health care providers from an ultimately futile effort to manage the complications of cirrhosis into a life-prolonging and life-enhancing intervention.
Necrotizing Gallstone Pancreatitis
The AGA recently published a Clinical Practice Update reviewing the best available evidence on pancreatic necrosis, regardless of cause. The update provides 15 best practice advice points that include the need for multidisciplinary care coordination and referral to a tertiary-care center as appropriate. The update describes supportive care, avoidance of prophylactic antibiotics, and optimization of nutrition. In addition, there is an included algorithm for the management of pancreatic necrosis requiring debridement. Debridement within the early acute phase of pancreatitis (within the first 2–4 weeks) should be avoided if possible secondary to increased morbidity and mortality. Intervention in the late phase (> 2–4 weeks) is indicated for patients with infected necrosis or persistent organ dysfunction and failure to thrive. Multiple approaches are available for the management of infected necrosis, including but not limited to percutaneous, endoscopic, or laparoscopic transgastric, or open debridement. In addition, a combination approach using percutaneous drainage followed by videoscopic retroperitoneal debridement or step-up approach can also be used. Since the publication of a multicenter RCT (PANTER) in 2010, the step-up approach for necrotizing pancreatitis has been increasingly used.
The step-up approach or video-assisted retroperitoneal debridement (VARD) is a minimally invasive technique that begins with percutaneous drain placement for necrotizing pancreatitis followed by a minimally invasive retroperitoneal necrosectomy. Patients who underwent the step-up approach versus open necrosectomy had less multiple-organ failure, incisional hernias, and newonset diabetes, but no difference in mortality. The 2020 AGA Clinical Practice Update on the management of pancreatic necrosis suggests that best practice is that ‘‘minimally invasive operative approaches to the debridement of acute necrotizing pancreatitis are preferred to open surgical necrosectomy when possible, given lower morbidity’’. However, the update also notes that open necrosectomy still has a role in the modern management of acute necrotizing pancreatitis, particularly for cases whereby less invasive techniques are not feasible.
POPF after Distal Pancreatectomy
Minimally Invasive Versus Open Techniques
Despite advances in laparoscopic and robotic approaches, the vast majority of distal pancreatectomies continue to be performed via an open approach. Recent retrospective data have demonstrated that minimally invasive distal pancreatectomy is associated with decreased blood loss and shorter hospital stays than open pancreatectomy. A large recent study utilizing the Nationwide Inpatient Sample database suggested, first, that the minimally invasive approach is becoming more widely utilized, increasing from 2.4 to 7.3 % over a study period from 1998 to 2009. Second, that study reported that the minimally invasive approach was associated with decreased length of stay as well as decreased incidence of infectious complications, bleeding complications, and blood transfusions. This population-based study echoes conclusions drawn by a large multi-institutional study performed several years previously. Drawing on a combined patient sample of 667 patients, with 24 % initially attempted laparoscopically, the authors were able to demonstrate lower overall complication rate, decreased blood loss, and shorter hospital stays among patients undergoing laparoscopic approach via a multivariate analysis.
Notably, there was no significant difference in the pancreatic leak rate between the open and laparoscopic approaches, although there was a nonsignificant trend favoring the laparoscopic approach. More recently, the robotic approach has generated significant interest as a technique for performing distal pancreatectomy. Retrospective analysis has suggested that the robotic approach is well suited for pancreatectomy. Fistula rates, however, remain a concern. A retrospective review of patients undergoing robotic pancreatic operations included 83 patients who underwent distal pancreatectomy. About 27 % were identified as having a ISPGF type A pancreatic leak; 12 and 4.8 % were identified as having a grade B or C leak, respectively.
Identifying Risk Factors
For pancreaticoduodenectomy (PTD) , a fistula risk score has been recently developed that has been shown to be highly predictive of POPF. This score assigns points based on gland texture, gland pathology, duct diameter, and intraoperative blood loss. In general, high blood loss, soft gland texture, and smaller duct diameter confer increased risk of POPF, whereas pancreatic adenocarcinoma and pancreatitis as the indication for PTD confer protection for the development of pancreatic fistula versus other diagnoses. Also of note, higher fistula risk scores correlated with greater incidence of clinically relevant (ISGPF grade B or C) fistula. The adaptation of this risk score to patients undergoing distal pancreatectomy is yet to be validated; however, at least one published study indicates that this scoring system may have limitations in the setting of distal pancreatectomy. In that study, risk factors for pancreatic fistula after stapled gland transection in patients undergoing distal pancreatectomy were examined, and in a multivariate analysis, only the presence of diabetes and the use of a 4.1-mm staple cartridge were associated with increased risk of pancreatic fistula formation.
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The SURGEON 