PANCREATIC CANCER: The Bigger Picture

OVERVIEW

In the new millennium, there is hope that a multidisciplinary and integrated approach to pancreatic adenocarcinoma will reveal the mystery of this malignancy, making it amenable to early biochemical or genetic screening and therapy. This article discusses the epidemiology, genetics, malnutritional states, and preoperative evaluation of patients with suspected pancreatic cancer (adenocarcinoma), emphasizing the decision process and the surgical issues that exist in 2001.

The dismal survival

EPIDEMIOLOGY

No clues have been forthcoming from epidemiologic studies to facilitate the early diagnosis of pancreatic cancer. Rare in people less than age 40 years, pancreatic cancer is 50% more common in males, African-Americans, and cigarette smokers, in whom the prevalence is two- to sixfold higher than nonsmokers.6, 30, 36, 66 A direct relationship exists between the number of cigarettes smoked and the development of pancreatic cancer. The mechanism may be N-nitroso compounds in cigarette smoke that

GENETICS

Genetic studies hold promise to understanding of pancreatic cancer. They have revealed a high expression of genetic mutation, particularly with the oncogene K ras, the tumor-suppressor gene p53, and herceptin, expressed in 70% of pancreatic cancers.5, 13, 23, 24, 48, 81, 108, 118 The p53 gene is expressed in as many as 70% of patients with pancreatic cancer.81, 108 K ras mutations occur in 80% to 100% of pancreatic adenocarcinomas. K ras has been found in the stool, pancreatic secretions, and

MALNUTRITION AND CANCER CACHEXIA

Malnutrition is more prevalent than suspected, particularly in hospitalized patients with benign and malignant disease. Several studies have addressed the disappointment, if not futility, of attempting to correct malnutrition preoperatively in cancer patients.10, 19, 22, 102, 107

Explaining and, more importantly, correcting malnutrition and cancer cachexia associated with pancreatic cancer is an unresolved clinical problem. By definition, malnutrition, anorexia, and weight loss associated with

PRESENTATION

Most reports about pancreatic cancer and its evaluation, treatment, and follow-up emanate from centers of special interest in this disease where many patients are referred. Tilleman et al¹⁰³ examined the workup and evaluation of pancreatic cancer in general hospitals and large-volume centers in Holland. Two hundred fifty-three patients were initially analyzed at a general hospital by ultrasonography (97%), CT scanning (56%), endoscopic retrograde cholangiopancreatography (ERCP; 39%), and

IMAGING AND ENDOSCOPY

The advances in radiologic techniques over the past 20 years are described elsewhere in this issue.68, 87The modalities are multiple (Table 1) and have facilitated imaging of the pancreas and improved selection for surgery by identifying patients who have unresectable tumors on the basis of metastasis or invasion of the mesenteric venous system.59, 97 These imaging modalities have had no impact on the natural history or outcome of the disease. Before these modalities, laparotomy was necessary

TUMOR MARKERS

Tumor markers, namely, glycoprotein antigens expressed on the pancreatic cancer cell surface, may help to detect suspected pancreatic cancer.35, 76, 78 The best use of tumor markers is in following up patients with disease. CA 19-9 is used most commonly and is the most sensitive marker for pancreatic cancer; these levels are elevated in 75% or more of patients with pancreatic cancer.35, 78Depending on tumor size and the degree of histologic differentiation, the level of CA 19-9 varies. In

JAUNDICED PATIENTS: TO STENT OR OPERATE?

Individual experience with stents and the jaundiced patient with malignancy far outweigh retrospective and prospective data from studies initiated 15 or more years ago regarding preoperative stenting or direct surgery. The studies evaluated the necessity of preoperative stenting; however, they were flawed. They involved few patients, most of whom did not undergo resection at surgery. Most patients required prolonged, external, in-hospital drainage because percutaneous techniques were used.

LAPAROSCOPY

In several studies, laparoscopy before laparotomy precluded resection in 30% to 70% of patients with pancreatic cancer.15, 26, 50 The limitations of axial imaging are the inability to detect small liver metastasis and peritoneal or pelvic seeding. Laparoscopy, in combination with the panoply of imaging and endoscopic tests, increases the resectability rate to more than 90%, which is not higher than the author's experience with reconstructed CT scans alone. The author explored 50 consecutive

TUMOR BIOPSY

The need for positive tissue diagnosis before performing a pancreaticoduodenal resection is no longer necessary or an issue (unless there is a bad outcome after resection for what proves to be benign disease, at which time the medicolegal forces may question the applied wisdom). A positive biopsy must be in hand before chemotherapy is initiated. In more than 10% of jaundiced patients, an “obvious” malignant mass in the head of the pancreas proves to be a benign lesion.

PATIENT FACTORS

The ability to tolerate surgical resection is a major part of determining tumor resectability. Patients with pancreatic malignancy tend to be older (80% are > 60 years of age) and more prone to comorbidities, which increase operative risk. Studies have shown that chronological age per se is not a contraindiction to radical pancreatic resection with a risk comparable to younger patients,20, 29 whereas others report a higher mortality rate among resected patients more than 70 years of age.⁹⁴

WHO SHOULD PERFORM PANCREATIC RESECTION?

Several studies have indicated that “practice makes better and safer.”37, 49, 57, 60Mortality and morbidity after pancreatic resection are reduced when 20 or more resections are performed each year per center. Hospital size is not a factor because excellent results have been reported from dedicated centers at community hospitals and university centers.²⁰ There are, however, no legislative guidelines to determine where or who should perform pancreatic resections. Many surgeons quote the best

SURGICAL TECHNIQUES

The theoretic goal of surgery is to cure pancreatic cancer. An illustrated technique and commentary on the pitfalls and perils of pancreaticoduodenal resection (PDR) follow this section. The goal of surgery is to remove all visible tumor safely with low risk for mortality and morbidity and a short hospitalization. Surgery has been a palliative procedure and is seldom curative.16, 17, 109 Surgery ideally includes a “free” margin of tissue and reestablishment of gastrointestinal continuity

REHOSPITALIZATION

The assumption that hospital discharge is the conclusion of the acute care process seems universal because readmission for delayed postoperative complications rarely is discussed. The author's readmission rate is 6%, and readmission is the result of fever, wound complications, patient fears, or anorexia.²⁰ One publication has indicated that 39% of post-PP-PDR patients were readmitted to a hospital.³⁸ Sixty-one percent were rehospitalized because of recurrent tumor complications, but 16% of

CHEMORADIATION THERAPY

The primary limiting factors to successful pancreatic resection for cancer are short-term and long-term survival. This issue outlines the many factors that have decreased the short-term risks and emphasizes that long-term survival remains an unaccomplished goal for most. Many surgeons have been nihilists regarding chemoradiation therapy, believing that quality-of-life issues are significantly worse with chemoradiation and that recovery from pancreatic resection may be lengthy and difficult for

SUMMARY

Despite accurate diagnosis, better radiologic techniques, and safer surgery, long-term survival after surgical therapy for pancreatic cancer is disappointing. Median survival following pancreaticoduodenal resection is 12 to 15 months independent of surgical expertise, hospital size, or technical factors. Subsets of favorable tumors and longer survival times after surgery have been defined and include: small tumor size and low-grade lesions, tumor-free margins, and absence of nodal, venous, or

THE BIGGER PICTURE

Despite 60 years of effort, study and analysis of surgery for pancreatic cancer, tumor biology, and not technique, determines survival. The new millennium can only bring improvement in the treatment of this disease. The current generation of experienced surgeons, oncologists, gastroenterologists, and radiologists can reflect on the technical advances and safety of surgery that are now taken for granted and are part of everyday practice. The younger generation of pancreatologists must first