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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Pancreatic cancer

and .

Department of General Surgery, University of Ulm

Introduction

Evidence from research has contributed to clinical decision making for many years. The nature of clinical research evidence has, however drastically changed over the last 30 years. With higher standards and better tools for assembling and analyzing information there has been a shift towards decision making on this so called concept of “evidence based medicine”. Clinical concepts should be based on the strongest available evidence, even if opposite to so called “expert opinion”. In pancreatic cancer the available “-strong” data on treatment regimes is not abundant. This could be due to the fact that only very few randomized controlled trials are being performed. The lack of sufficient patient numbers and the lack of desire among surgeons contribute to this fact. The following chapter reviews current treatment concepts and focuses on the surgical technique which is still very much in controversy.

Epidemiology

Worldwide, the incidence of pancreatic carcinoma seems to increase, however, there are large variations. In the United States, every year, 112,000 Americans die of gastrointestinal cancer and the carcinoma of the pancreas accounts for 22% of these deaths (American cancer society, 1991). In Germany, the incidence ranges between 9 and 10 patients per 100,000 inhabitants and is the 6th leading cause of carcinoma-related death. In Japan, the incidence of pancreatic carcinoma has sharply risen from 1.8 per 100,000 inhabitants in the Sixties to 5.2 in the Mid-Eighties (Hirayama, 1989). In contrast, in India, Kuwait and Singapore, the rate is less than 2.2 per 100,000 inhabitants and has remained stable over the last 20 years.

The cause for the onset of pancreatic cancer remains unknown but several environmental factors have been found to be associated with it. This association, however, is only firmly established for the following: Occupational exposure to employees of manufacturing plants handling benzidine, gasoline derivatives or 2-naphtalamine have shown in retrospective studies to carry a 5-fold increased risk of acquiring pancreatic cancer (Bardin et al., 1997; Selenskas et al., 1995; Tomenson et al., 1997; Yassi et al., 1994). Another risk factor which has been discussed very controversial over the last years, is cigarette smoking. Multiple cohort and case control studies have found that the relative risk of pancreatic cancer in smokers is at least 1.5. This risk increases with the amount of cigarette consumption.

Large epidemiological studies also identified the presence of chronic pancreatitis what about a 4-fold increased risk of acquiring pancreatic cancer in the further course (Lynch et al., 1996; Lowenfels et al., 1997; Andren et al., 1997)

Symptomatology and tumor biology

Ductal adenocarcinoma is twice as frequent in the head of the organ as in the body or tail. Tumors in the head of the organ might originate either in the dorsal aspect (uncinate process) or in the ventral aspect of the gland.

Ductal adenocarcinoma show intrapancreatic, but also early extrapancreatic tumor extension. Within the pancreas, the tumor infiltrates the acinar tissue and may extend along the large ducts. Lymphogenic spread especially along the retroperitoneal channels usually precedes hematogenous metastasis.

At the time of diagnosis over 85% of tumors have extended beyond the organ (Cubilla et al., 1978) and perineural invasion within and beyond the gland is present. Lymphatic spread is also found in up to 50% of so-called early cancer of the pancreas with the presence of metastases to adjacent. or distant lymphnodes (Birk et al., 1998b; Satake et al., 1992; Nagakawa et al., 1991).

Tumors which develop in the ventral aspect of the pancreatic head frequently cause obstruction both to the intrapancreatic common bile duct as well as to the main pancreatic duct. Jaundice and pain as a result often lead to the diagnosis of the underlying disease. Tumors originating from the dorsal aspect, however, are distant to both ducts but in the direct vicinity of the mesenteric root. Due to the absence of these “early symptoms” the diagnosis is often made late with gross tumor involvement to the mesenteric root present (Birk et al., 1998a).

The most common site of extralymphatic involvement are the liver and the peritoneum, the lung is the most frequently effected extraabdominal organ American Cancer Society (1991) Cancer facts and figures.

In the absence of clearly defined risk groups and valid diagnostic screening methods, the management of pancreatic cancer is complicated. Patients usually present late when clinical symptoms become apparent. The classical triad of complaints are pain, jaundice and weight loss. The new onset of the diabetes mellitus might herald the presence of a pancreatic tumor and over all is present in 60 to 68% of patients (Everhart, Wright, 1995). These symptoms, however, are not specific neither to cancer nor to a particular type of cancer., but they are not helpful in screening large populations for this particular malignancy (Safi et al., 1996). As a result of this diagnostic difficulty, therapeutical options in pancreatic cancer patients are often limited at the time of diagnosis.

Diagnostic approach

The introduction of improved imaging modalities such as helical CT and multiplanar MRI contributed to a reduced diagnostic work up in pancreatic cancer patients. The digital data allows the three dimensional reconstruction of the arterial and venous system and in case of MRI also of the pancreatic duct and the biliary tree.

Therefore modalities such as angiography and upper GI-series are unnecessary in most patients unless the above mentioned imaging techniques are not available.

In general preoperative diagnostics should consist of conventional ultrasound and a high resolution CT or MRI. Endoscopic ultrasound may be helpful in local staging of the disease. Laparoscopy offers an exact staging and the possibility for palliation in patients with metastatic disease.

Serologic markers (CA19-9, CAM 17-1, CEA) have a sensitivity and specificity for ductal adenocarcinoma up to 90%. Nevertheless, they may support a clinical diagnosis or might monitor the course of an identified carcinoma of the pancreas. Indication for surgery can not be solely based on these markers.

Staging of pancreatic cancer

Over the last 15 years two different staging systems for pancreatic cancer patients have evolved.

Japanese patients are staged according to the general rules of the Japanese Pancreas Society (Japan Pancreas Society, 1996). Western patients are staged according to the rules of the UICC. Both systems have their weaknesses and their strengths. The Japanese system is very precise in defining the local tumor growth, and the involvement of various structures adjacent to the pancreas. Applying JPS staging in pancreatic cancer patients demand a very intricate pathological work-up of the resected specimen. Therefore, the Japanese system is probably more accurate, but is also more complicated to use.

Apart from tumor size and location several other factors are recorded.

For serosal, retroperitoneal, nerve-plexus, duodenal, venous and arterial involvement separate classifications are provided. Also seventeen different lymph node stations are defined with several undergroups adding up to 34 individual lymph nodes sites.

All of these characteristics are documented individually.

Due to this reason, it has probably not been applied in Western countries.

Much in contrast, the system proposed by UICC (International Union Against Cancer, 1997) is quite simple to apply but is less precise in describing the characteristics of the local tumor growth than the Japanese system. The UICC system considers lymphnode metastases as the most important factor, next to the tumor size.

The extent of lymphatic involvement is basically classified either as node positive (N1) or node negative (N0) with the minor discrimination between N1a and N1b signifying one, or more than one, involved lymph node

Indication for surgery and technical approach

Surgical removal of the pancreatic neoplasm offers the only chance for cure in this patient group. Contraindications against resection of a ductal adenocarcinoma of the pancreas are distant metastases and gross tumor invasion into the mesenteric root demanding extensive arterial and venous vessel resection. Despite the commonly accepted contraindications, the majority of patients with cancer of the head of the pancreas are managed operatively. Biliary or duodenal obstruction in the present of distant metastases demand a gastric or biliary bypass. These bypass procedures carry an acceptable operative mortality of less than 5% and, therefore, should be favored in patients with a life expectancy of less than 6 months.

The presence of regional lymph node metastasis is not considered as a contradiction against resection.

The standard resectional therapy for cancer of the pancreatic head is the partial pancreaticoduodenectomy, first performed by Kausch in 1912 and Whipple in 1934. Over the last half century, Whipple's operation has been modified although few of the changes can be considered. His original operation spared the pylorus and included occlusion of the pancreatic duct. Subsequently, the operation was further modified by adding a pancreato-jejunostomy.

Cancer of the body or the tail of the pancreas is treated by subtotal pancreatic left resection, the resection line is defined by the exact tumor location. A safety margin of 2 cm is considered to be sufficient.

Extended resection in pancreatic cancer

Lymph node and perivascular dissection

From a theoretical point of view, more extended surgery in cases of pancreatic cancer might improve long-term survival rates in cases where no tumor is left behind. Beginning from the first reports from Japan at the end of the Eighties, concerning the comparison of so called radical vs. standard or traditional lymphnode dissection, the value of the systematic lymphnode dissection in the radical surgical treatment of ductal tumors is a much debated issue. The supporters of an extended approach can do no more than base the rationale on the therapeutic efficacy of lymphadenectomy. This includes the removal of potential malignant tissue and the interruption of lymphatic tumor spread.

Apart from the necessity to perform a radical lymphnode dissection, other Japanese surgeons have stressed the fact that, in order to offer the individual patient the maximum chance of survival, a radical procedure should not be confined to lymphadenectomy but should also include the removal of retroperitoneal connective tissue including the celiac nerve plexus.

Following this rationale, several Japanese groups have reported favorable results. In summary, the numerous studies from Japan show an impressively high 5 year survival rate in pancreatic cancer patients. As expected, the best results were achieved for patients suffering from small tumors without lymphnode metastases. Nevertheless, even for patients in advanced stages undergoing extended resections, had improved survival compared to standard resection. It has to be noted, however, that none of these studies can be rated above an evidence level of III.

In Western countries, similar studies were conducted, however, with different results. None of the involved groups could demonstrate an significant survival benefit in patients undergoing radical resection.

Presently only one prospective randomized multicenter study dealing with this issue is available. Involving 5 Italian and one American institution, a total number of 81 patients with ductal adenocarcinoma of the pancreatic head entered this prospective clinical study (Pedrazzoli et al., 1998).

All patients received a “traditional” partial pancreatoduodenoectomy. After intraoperative randomization a supplementary extensive radical removal of lymphatic and connective tissue adjacent to the primary operative specimen followed. This included the lymph node stations in the hepatic hilum, along the aorta, laterally to both renal hila and the circumferential clearance of the celiac trunc and the superior mesenteric artery. The results of this study showed that there was no significant difference in overall actuarial survival between the two groups. Subgroup analysis which was done “a posteriori” revealed a significant longer survival in lymph node positive patients who received a radical procedure (p < 0.05).

The lymphnode status of patients plays a cardinal role in determining the prognosis.

Unfortunately, preoperative staging is very unreliable regarding the presence and extent of lymphnode involvement. The lymphnode or N factor can only be clarified after surgical resection and the reliability of lymphnode negativity is directly related to the size of the specimen sent to the pathologist and thus, the extent of the lymphadenectomy performed. Patients undergoing a standard resection without clearance of the more distal lymphnode stations carry the risk of being staged false negative for lymphnode metastases. In addition, there is frequently a lack of any correlation between tumor diameter and lymphnode positivity which in some cases may be present as in many of 50% of small tumors less than 2 cm (Hermanek, 1991). There is only very few data existing, establishing the topographical. distribution of lymphnode areas effected by the spread of pancreatic tumors (Cubilla et al., 1978; Kawarada et al., 1994; Ishikawa et al., 1997). All studies confirm that the lymphnode areas (JPS) No. 13 (posterior to the head of the pancreas), 17 (anterior to the head of the pancreas) and 14 (around the superior mesenteric artery) are the most frequently involved areas in cases of pancreatic head cancer.

Our own results of the lymphnode involvement in 102 consecutive Ro resections in UICC III patients support these findings. Interestingly lymph node area No. 16 (inter-aorto-caval region) was affected in 30% of patients with head cancer. Tumors located in the uncinate process showed, when being resectable at all, a high frequency (65%) of involved lymph nodes around the superior mesenteric artery (area No. 14, table II).

Table II. Distribution of involved lymph nodes in ductal cancer of the pancreas (UICC III).

Table II

Distribution of involved lymph nodes in ductal cancer of the pancreas (UICC III).

The extent of lymphatic metastases tend to increase with the tumor diameter, although studies investigating small pancreatic cancers did reveal lymphnode metastases also to area 14 and 16, thus, indicating a poor correlation of the N factor as compared to the N factor (Kayahara et al., 1996).

Furthermore recent studies identified distant tumor cell manifestations even in cases where the patient was considered to have received a curative resection.

These “micrometastasis” were found in the peritoneal cavity, the bone marrow, the liver and in lymph nodes which were classified as tumor free (Hosch et al., 1997; Thorban et al., 1996; Inoue et al., 1995; Gerhard et al., 1994). There is, however, uncertainty about the clinical impact of these disseminated tumor cells. Further studies will have to prove if these are epiphenomena or contribute to the prognosis of the patient (Heeckt et al., 1992; Warshaw, 1991).

Preservation of the pylorus

After various historical reports on pylorus preservation in resections for pancreatic cancer, Longmire and Traverso revived the idea of reducing the resection during the partial duodenopancreatectomy with preservation of the pylorus and a small part of the post-pyloric duodenum. This concept has been advocated in the mean time by several groups. The initial concern that this procedure is not oncologically sound is not supported by the majority of the published clinical trials (evidence level III). Excepted from pylorus preservation should be pancreatic tumors in close vicinity of this area and tumors with lymph node metastasis to the pyloric region (JPS 6, 4a).

Most of these studies, however could demonstrate a better nutritional recovery for patients with preservation of the pylorus (evidence level III).

A recommendation to preserve the pylorus can be given but so far only on the basis of non randomized trials.

Vessel Involvement

Invasion of the portal venous system is a frequent finding during resection of pancreatic head tumors. In some series it is described in as many as 60% of all cases. The resection and reconstruction is advisable if a complete tumor removal (Ro resection) can be achieved and if sufficient experience with this technically demanding procedure is present. Only limited experience with the resection and reconstruction of the involved superior mesenteric artery is reflected in the literature. It seems that this addition to the resection has no influence on survival in these advanced cases, but carries the risk of increased morbidity and mortality associated with the procedure.

Prognostic factors (table I)

Accepted prognostic factors are tumor size, the presence of lymphnode metastases, blood vessel invasion and the number of units of blood transfused during, or in the direct postoperative course. Furthermore, differences in tumor biology have also be found to be prognostic influence, such as DNA ploidy status, tumor grading, the presence of Kiras or P-53 mutations (Cameron et al., 1991; Allison et al., 1991).

The primary prognosticator influencing survival in patients with pancreatic cancer is resectability. This has been shown in various large series which do, however not reach evidence levels below III due to their retrospective and mostly single institution design. Despite the fact that resectability is not a clearly defined term this finding holds true not only in Western countries but also in Japan where traditionally a more aggressive approach with higher resectability rates is found.

Among patients who received a tumor resection complete tumor removal proved to be of the highest prognostic influence. The absence of residual tumor (i.e. Ro-resection) was accompanied in most series with a five year survival rate of more than 30%. In comparison the same institutions comparable patient populations with residual tumor (R1 or R2) did not have any five year survivors (Cameron et al., 1991; Imaizumi, 1996; Trede et al., 1990).

The role of surgery in the palliation of pancreatic cancer

The vast majority of patients with pancreatic cancer are presenting for palliation rather than cure as a result of metastatic disease and local irresectability. Thus determining the optimal palliative strategy serves the largest patient group suffering from this disease. Optimum palliation should achieve relief of symptoms without risk of further compromising quality of life or the survival of the affected patient.

Biliary obstruction leading to jaundice, pruritus and nausea as well as duodenal obstruction with the inability of oral feeding has to be resolved and control of pain achieved.

In patients with an estimated life expectancy of less than 6 month interventional techniques should be favored: Endoscopic stent placement for the relief of jaundice and percutaneous alcohol injection of the celiac ganglion for pain control is advisable. Percutaneous transhepatic decompression is associated with higher morbidity and should be reserved for those patients were endoscopic stent placement is not possible.

Jaundiced patients who undergo surgical staging and are found to be irresectable should be treated by Y-en Roux hepatico-jejunostomy.

Gastro-enterostomy even in the absence of severe duodenal obstruction should be performed to avoid reoperation due to later complete obstruction. If technically feasible these palliative procedures can be performed laparoscopically.

Surgical palliation of jaundice by cholecysto-jejunostomy or choledocho-duodenstomy are found to be inferior concerning long term relief.

Palliative resection

By definition a large percentage of pancreatic resection are palliative since no complete tumor removal could be accomplished. These resections, however, are mostly carried out with the intention to cure. Due to positive resection margins or residual tumor in the vicinity of the mesenteric root this goal may not be achieved. A resection of a pancreatic head tumor despite present distant metastasis or gross vascular involvement have no positive impact on survival nor life quality as compared to bypass procedures. Therefore palliative resection in the light of histologically proven distant metastasis and/or gross vascular/retroperitoneal involvement can not be advised.

Summary

The primary goal of surgical therapy of pancreatic cancer is complete tumor removal (Ro). Palliative resection to reduce the tumor burden is not advisable.

Preoperative diagnostics should consist of conventional ultrasound and a high resolution CT or MRI. Endoscopic ultrasound may be helpful for local staging of the disease. Laparoscopy offers an exact staging and the possibility for palliation in patients with metastatic disease.

Contraindication for resection are distant metastasis, gross retroperitoneal tumor invasion and severe invasion of the mesenteric root.

Palliation in the jaundiced patient is accomplished either by endoscopic stent placement or a bypass procedure (Y-en Roux hepatico-jejunostomy). A gastroenterostomy should be performed even if minor duodenal obstruction is present to avoid reoperations.

Figure 1. Diagnostic algorithm in pancreatic cancer.

Figure 1

Diagnostic algorithm in pancreatic cancer.

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