Pancreatic cancer. Management

M. Hidalgo Pascual, E. Ferrero Herrero, P. Peláez Torres¹, M. J. Castillo Fé¹, O. Bonachia Naranjo¹,
M. Labalde Martínez¹ and F. Botella Ballesteros¹

Universidad Complutense. ¹Service of General Surgery and Digestive B. Hospital Universitario 12 de Octubre.
Madrid, Spain

 

ABSTRACT

Pancreatic cancer still represents a serious medical concern for which no adequate solution has thus far been found. Surgery is the only appropriate therapy, but has a survival rate of around 30-35% at three years, with an operative mortality below 3% and an operative morbidity approaching 10% of radically resected patients, all of which applies to surgery performed by expert teams in highly experienced sites.

Key words: Pancreatic cancer. Management.

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Hidalgo Pascual M, Ferrero Herrero E, Peláez Torres P, Castillo Fé MJ, Bonachia Naranjo O, Labalde Martínez M, Botella Ballesteros F. Pancratic cancer. Management. Rev Esp Enferm Dig 2004; 96: 784-795.

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Recibido: 24-06-04.
Aceptado: 30-06-04.

Correspondencia: Manuel Hidalgo Pascual. Servicio de Cirugía General y Digestivo B (5ª planta). Hospital Universitario 12 de Octubre. Ctra. de Andalucía km. 5,400. 28041 Madrid. Tel.: 913 908 240. Fax: 913 908 062. e-mail: mhidalgo.hdoc@salud.madrid.org

 

INTRODUCTION

Potential measures against pancreatic cancer are theoretically many; however, these are matter-of-factly restricted to surgery solely, since other therapeutic procedures do not represent currently valid alternatives. Medical treatment offers no potential for improvement whatsoever except in the management of pain, which may also be said of neoadjuvancy (radiotherapy and/or chemotherapy).

From diagnostic confirmation on, actions are clearly laid out in figure 1. Patients must be categorized within stages I to IV according to grade of involvement, and only stages I and II (local tumors extending into neighboring tissues) are eligible for radical surgery, provided an intraoperative staging of node chains and adjacent suspect lesions is performed. Stage III tumors (metastases to regional lymph nodes) are eligible for resection extending to involved territories, or for palliative bypass surgery. Patients with stage IV disease should only be treated using any of the various bypass surgery procedures and pain management techniques.

SURGICAL TREATMENT

Therapy is complex and only occasionally is seen to heal. Surgical treatment is the only valid option with proven effectiveness. However, long-term survival rates are small (1,2), even though actuarial survival has increased during the past three decades in patients with pancreatic cancer undergoing cephalic duodeno-pancreatectomy (3-7). According to data from Johns Hopkins Hospital (3), 3-year survival was 14% during the 1970s, and then increased to 21% during the 1980s and to 36% during the 1990s. These significant results have also been acknowledged by the Universitauml;tsklinikum Mannheim, in Germany (4), and the Memorial Sloan-Kettering Cancer Center, New York (5). Similarly, other reports support these data (3-7). Operative mortality for cephalic duodeno-pancreatectomy in expert centers is below 3% (8,9).

According to a paper by D'Amico (10), who reviewed 50 studies reported between 1980 and 1986 including 16,923 patients with pancreatic cancer, operability was 80%, resectability was 11%, and overall 5-year survival was 4% for resected patients, which clearly illustrates the magnitude of the problem. Other therapeutic options on which we shall comment later (radiotherapy, chemotherapy) have shown discouraging results.

SURGICAL OPTIONS

Preoperative biliary decompression

Bile drainage has been performed for many years prior to surgery. The experience by Dr. Alan O. Whipple on duodeno-pancreatectomy was preceded by obstruction decompression using a bypass. Retrospective studies suggested that previous decompression using cholecystostomy resulted in a reduction of operative mortality from 50 to 8% (11,12). Similarly, transhepatic percutaneous biliary drainage resulted in operative mortality going down to 8.2% (13).

Our current option is endoscopic or percutaneous biliary drainage using interventionist radiography, which has the theoretical appeal of providing a similar drainage with a lower risk of complications. In an extensive series of 595 cases reported in six European and Japanese sites success rate was 97.5% (14). Complication rates were small (4%). A major complication is cholangitis. Mortality is below 2%. A number of studies recommend this therapy (13,14).

Resection surgery

Surgical resection continues to be the only current option to potentially heal pancreatic cancer. Candidates to resection must be carefully selected through preoperative screening.

Resecting therapy, a radical approach, includes the following three options: cephalic duodeno-pancreatectomy; total pancreatectomy or total duodeno-pancreatectomy; corporocaudal pancreatectomy, and regional pancreatectomy (15-17). The most common approach is bilateral subcostal laparotomy, which provides full access into the upper abdomen. A star-shaped (Mercedes-Benz-like) incision is rarely used.

Primary contraindications of resection include liver metastases and extrahepatic serosal implants. Evidence of positive lymphadenopathies in the portal area precludes resection. Rarely, when the histologic diagnosis of carcinoma is unclear, a decision for or against pancreatic resection must be made. If the tumor extends into or adheres to the celiac trunk or the origin of the common hepatic artery, resection is contraindicated and should be rejected. When hepatic vessels are tumor-free, the suprapancreatic portal vein and hepatic artery are dissected. The common bile duct and hepatic artery are easily identified, and the absence of local tumor invasion is established. The surgeon must assess whether the upper mesenteric artery is involved. The origin of the upper mesenteric artery is only rarely involved in the absence of a virtually total infiltration of the portal vein.

Cephalic duodeno-pancreatectomy (Whipple's procedure)

This is the procedure of choice for most pancreatic head and body cancers, as it complies with oncologic surgery criteria, and the latest technical modifications usually find a better physiology at the biliary and gastrojejunal segments. The order of dissection is dependent upon personal preference. Occasionaly, a mobilization of the third and fourth duodenal portions, Treitzrsquo; ligament, and first jejunal loop should be attempted early during the surgical procedure, prior to gastric dissection. Dividing the stomach first may be easier to ensure a subsequent access to the pancreas. Pylorus preservation is the technique with more adepts nowadays (18). It was first introduced by Traverso and Longmire (1978) in an attempt to preserve the pylorus, which entails fewer gastrointestinal disturbances (19-22).

Most recent reports provide encouraging results regarding longer survival with scarce operative morbidity, provided the technique is performed by expert teams. Laparoscopic duodenopancreatectomy and distal resections offer no additional benefits when compared to traditional approaches (23).

Corporocaudal pancreatectomy (distal pancreatectomy)

This procedure, which includes splenectomy, is to be indicated for localized tumors arising in the tail of the gland. However, various circumstances contribute to this technique being only rarely performed, including that tumors located in the tail of the pancreas are uncommon, that they are widely spread at the time of diagnosis, and radicality is controversial. A laparoscopic distal pancreatectomy technique has been described recently (23).

Total duodeno-pancreatectomy

During the 1960s, the overall lack of satisfaction with survival following cephalic pancreatectomy greatly influenced the consideration of total pancreatectomy as the procedure of choice for pancreatic cancer regardless of its site. Complete glandular excission further allows a full histologic study, which led to a frequent finding of multifocal tumors. Alternatively, this procedure allows a more complete dissection of lymph nodes, and also eliminates the source of many complications following Whipple's procedure: pancreatojejunal anastomosis fistula.

A number of technical variations are intended to improve quality of life by diminishing gastrointestinal disturbances such as the dumping syndrome. Pylorus preservation (a technique first described by Longmire-Transverso) (15), is a good attempt at keeping the gastric reservoir, but improves neither postoperative outcome nor gastroparesis and benefits are thus limited (24). Results regarding survival and complications are very similar to those obtained with cephalic duodeno-pancreatectomy.

Extended resection

It has been suggested that pancreatic resection should include the resection of the portal vein, upper mesenteric artery and celiac trunk, as well as an extended lymphadenectomy (16,25). This "regional pancreatectomy", as described by Fortner in 1973, has experienced further developments and been severely criticized, as it entails a high operative morbidity and mortality while survival has remained very much as it was (26,27).

Bypass procedures

Between 1970 and 1979, 34% of the 46,888 patients surgically operated upon in England and Wales had pancreatic cancer; of these, 95% had a biliary-digestive bypass performed for jaundice relief. In only 5% was resection feasible. Pancreatic bypass-related in-hospital mortality was 20 versus 14% in relation to pancreatic resection. Since 80% of patients with pancreatic carcinoma present with obstructive jaundice, and resection is only possible for 25% of these, bile drainage is of paramount importance regarding palliation (28-30). In a series including more than 8,000 patients with non-resectable pancreatic carcinoma, Sarr and Cameron demonstrated that patients receiving a biliary bypass had a lower operative mortality rate (19%) as compared to patients undergoing diagnostic laparotomy (26%) (31). Biliary bypass may be of several types: cholecystojejunostomy, choledocoduodenostomy, or choledocojejunostomy (31). A review of 1,114 patients showed that all these modalities led to survival rates in the range of 4.8 to 7.8 months (31). Surgical bypasses have been replaced of late by endoprostheses, which are introduced and placed using endoscopic retrograde cholangio-pancreatography (ERCP) or transparietohepatic puncture (TPHP) (32,33).

Similarly, digestive bypassing should be assessed. A retrospective study established that 50% of patients who did not have a gastric bypass performed and survived for 6 or more months most probably developed duodenal obstruction and hence required surgery. Other studies suggested a mortality rate of 10 to 20% (34,35).

RESULTS

Surgery is the only curative procedure, and results regarding long-term survival following surgical resection are unsatisfactory (4), albeit survival rates have considerably increased during the past few years in hospitals where excision is carried out by expert surgical teams (2,30,36). Parallel therapies have only minimally improved mean survival, and palliative procedures only provide limited benefits (37,38).

Age was never a hindrance for resection. Patients older than 70 years have no higher perioperative mortality, and their survival is similar to that of younger patients (30,39). Most recent reports provide experience with patient populations older than 80 years, with similar results when compared to those obtained in younger subjects (40). The morbidity and mortality for this surgery have both tapered down over time. However, long-term survival is small. Multiple reports each year clearly show that the number of patients who are free from disease in the long run remains stable (28-31,39).

Treatment of compliations

Many physicians have had claims against the resection of pancreatic adenocarcinoma in the light of its high operative morbidity (20 to 30%). In current series operative mortality is around 5%. It is commonly associated with pancretojejunal anastomotic dehiscence. The high rate of leaks after pancreatojejunostomy has been an argument in favor of total pancreatectomy. In fact, these complications are negligible and absolutely uncommon, and should not be included in a rationale against resection in view of the scarce operative mortality, which stands below 5% (2,38). Furthermore, octeotride use may favor fistular control and closure (41).

Metabolic complications include diabetes mellitus and exocrine pancreatic failure. The development of insuline-dependent diabetes mellitus depends upon the size of the pancreatic remnant, and, therefore, a number of pancreatic functional reserve studies are under investigation (42).

In the presence of acute diarrhea or fat malabsorption, the ingestion of supplemental pancreatic enzymes in each meal is extremely beneficial. Generally, the recurrence of pain, obstructive jaundice, or intrahepatic metastasis, as well as the development of ascites, are omens of relatively impending death, and only require symptomatic or palliative management.

Neoadjuvancy

Radiotherapy for resectable disease

For resectable disease radiation therapy has been used in an attempt to improve the control of the local disease and survival (43,44). The issue of persistent locoregional disease as a continuation of surgical resection in stage I disease was recently emphasized in a Japanese series of necropsy studies. Of eight patients with T1 and T2 tumors, six had microscopic metastatic disease in lymph nodes at the pancreatic bed, and four had microscopically compromised para-aortic regional nodes. This showed the possibility that local recurrence in early pancreatic cancer may be corrected using parallel radiotherapy (44). Preoperative radiotherapy has been used in two small series (45,46) with discouraging, uncertain results. Of late, two groups (47) performed prospective, randomized studies of introperative and postoperative radiatherapy in patients with resected pancreatic cancer. Local control of disease was clearly improved in the IORT group. Thus, intraoperative radiotherapy may seemingly improve local control of disease with acceptable morbidity.

Radiotherapy for non-resectable carcinomas

Healing surgery is not possible for most patients with locoregional disease, and radiotherapy may under certain circumstances relieve both signs and symptoms from local disease, and likely prolong survival; how-ever, its use should be decided upon on an individual basis, given that survival is prolonged within narrow limits (48). Recent studies support this position with 10-month mean survivals, similar to a number of surgical series with resectable pancreatic carcinoma (49).

Specialized radiotherapy modalities

Since local control is achieved in less than 50% of patients with non-resectable pancreatic carcinoma, experimental radiation methods have been used, often in association with external therapy, to deliver more effective dosages. Intraluminal brachytherapy in the duct of Wirsung has been used in patients with non-resectable carcinoma (50). Interstitial radiation involves the placement of radioactive sources within the pancreas parenchyma. Iodine 125 is the most commonly used nuclide in pancreatic implants (I¹²⁵). Memorial Hospital has the most extensive experience in using I¹²⁵ implants for non-resectable pancreatic carcinoma (51). Further studies are required to more specifically assess this new therapy.

Intraoperative radiotherapy

IORT has been used for patients with non-resectable pancreatic carcinoma, and also following radical surgery in selected cases (52,53). In a pilot study at Howard University (54) the mean survival rate was only 6 months in patients with non-resectable pancreatic carcinoma who were treated with IORT. Kyoto University, Japan, has the most extensive experience, with 108 patients. This study demosntrated positive results regarding pain relief. Mean survival was 6 months. A number of these series indicate decreased local relapse, but the development of metastatic disease is still a major concern (47,55), as are operative complications secondary to radiotherapy. Other recent reports (52,55) include similar results, with mean survivals exceeding 2 years on occasion.

Radiation using charged particles

Helium ions as well as pi mesons have been used in patients with non-resectable pancreatic cancer. Results have been encouraging at both Los Alamos Laboratory and Berkeley University, but further studies and a greater number of patients are needed (56,57).

Chemotherapy

Most patients with pancreatic adenocarcinoma have non-resectable, non-curable disease, and their survival is therefore predictably short, only 14 weeks on average, with less than 10% being still alive at 1 year following diagnosis. Furthermore, in a considerable number of patients, symptoms will require palliation. Patients typically complain of malaise, malabsorption, weight loss, abdominal pain, intestinal motor disorders, impaired liver function, obstructive jaundice, and effusion. As a result of this constellation of symptoms most patients simply cannot tolerate intensive chemotherapy. For more than three decades, great efforts have been made in order to identify systematically effective agents (58-60), but no such satisfacory agent for patients with pancreatic adenocarcinoma has been identified yet (60,61).

Drugs that are most commonly used include 5-flou-rouracil (5-FU), mitomycin C, streptozotocin, doxorubicin, and methyl-CCNU. Of these agents only 5-FU has been quoted as having a response rate higher than 20%, with no significant evidence of superior effectiveness for bolus administration versus weekly therapy. Nitrousureas have been researched and used (62-64). Other drugs including BCNU, CCNU, methyl-CCNU, and chlorozotocin have been assessed, but their benefits proved discouraging.

Similarly, anthracyclines have also been investigated. Doxorubicin was assessed in a small group of patients as single therapy (65), as were melphalan and phosphamide (66,67). Gemcytabine (68) is the most recently researched drug for this purpose.

Polychemotherapy

The poor results of single-drug chemotherapies for pancreatic adenocarcinoma have led investigators to search for suitable combination approaches. Response rates from studies including BCNU, streptozotocin, methyl-CCNU, and mitomycin C range from 5 to 33%. Mean survival time for the whole of the treated population oscillates between 9 and 26 weeks. No single two-drug combination was satisfactorily palliative or increased survival (66,67). In 1980, Smith et al. (69) described their results with the FAM program: 5-FU, adriamycin, and mitomycin C every 8 weeks. The objective response rate in 27 patients was 37% (70). In 1986 Oster et al. reported on 184 patients receiving both FAM (5-fluorouracil, adriamycin, mitomycin) and SMF (streptozotocin, mitomycin, 5-fluorouracil). These authors also found no treatment was really satisfactory (71). Other treatments yielded similar results (72).

Based on available data, no single combination program can be recommended for patients out of clinical treatment possibilities. Studies are currently ongoing with other drugs, either alone or in combination with 5-FU (cyclophosphamide, methotrexate, vincristine, mitomycin, cisplatin, etc.) (73-76), but definite results are still pending. Similarly, other phase III studies used cisplatin combined with ARA-C and caffeine (77), gemcytabine either alone or in combination with capacitabine (68), 5-FU (78), or cisplatin alone (79).

Novel therapies

Novel therapies are being investigated for the management of pancreatic cancer. Biological response modifiers are being experimentally assessed. Studies using interferon and gamma-interferon combined with other drugs seemingly open up new expectations (80-82) that must however be carefully assessed. Similarly, interleukins and lymphocyte activators may play a major role in these patients (83,84).

Alternatively, accurate studies on monoclonal antibodies are currently ongoing. There have been a number of reports on the 17-1A antibody, a monoclonal antibody derived from an IgG2a protein that is useful for colorectal carcinoma. Preliminary results in humans showed (85,86) that 17-1A is well tolerated, but circulating specific antibodies were seen in treated patients. Phase III studies are currently assessing 17-1A antibodies in patients with pancreatic cancer, but no definite results are available as yet (86,87).

Combined chemotherapy and radiotherapy treatments are being investigated for locally advanced carcinoma: gemcytabine (300 mg/m²) is specifically used, with an objective response rate of 29.2% (1 full and 6 partial remissions) (88) but severe toxicity too. Adjuvant radiotherapy and 5-FU have been combined in a phase III study following pancreatic cancer curative resection with good tolerability but scarce benefits; hence this should not be used as standard therapy (89); similar results were obtained for locally advanced cancer (90).

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