Upper Gastrointestinal Tract Surgery

Patients with a history of surgical procedures for peptic ulcer disease appear to be at an increased risk for pancreatic cancer. The physiologic basis for this apparent risk is unknown, but in an experimental rat system, chronic duodenogastric reflux produced sustained hypergastrinemia and promoted pancreatic carcinogenesis. Other researchers have suggested that the increased risk of pancreatic cancer following peptic ulcer surgery may result from the increased formation of N-nitroso compounds by nitrate-reducing bacteria that proliferate in the relatively achlorhydric stomach.

Cholecystectomy has also been associated with an increased risk of pancreatic cancer. This association is controversial, however, and not all series have supported the claim that cholecystectomy increases risk. The possibility that prior cholecystectomy can influence pancreatic carcinogenesis is supported by observations that CCK, which circulates at higher levels after cholecystectomy, is important in experimental pancreatic carcinogenesis and can stimulate the growth of experimental pancreatic tumors.

Associated medical or surgical factors

Diabetes Mellitus

Diabetes mellitus has been long associated with pancreatic cancer, however, the precise relationship has yet to be defined. Diabetes mellitus has been implicated as both an early manifestation of pancreatic carcinoma and a predisposing factor. It is known that pancreatic cancer can induce peripheral insulin resistance, and the argument that long-standing diabetes mellitus is also a risk factor for pancreatic cancer is supported by a recent cohort study showing that after an initial hospitalization for diabetes, patients had an increased risk of developing pancreatic cancer and that this risk persisted for more than a decade. In addition, a metaanalysis of studies published between 1975 and 1994 showed that pancreatic cancer occurred with increased frequency in patients with long-standing diabetes. The specific type of diabetes mellitus is also a factor; the cohort study described above agreed with other studies that suggested that the increased risk was limited to patients with noninsulin-dependent diabetes or patients whose diabetes was diagnosed before age 40. The mechanisms underlying the association between pancreatic cancer and diabetes are obscure; however, the diabetic state seems to enhance the growth of pancreatic cancer in animal models.

Chronic Pancreatitis

An association between pancreatitis and an increased risk of pancreatic cancer has long been suspected, although the magnitude of the risk remains uncertain. Older clinical studies suggested that chronic forms of pancreatitis, particularly those accompanied by pancreatic calcifications, were most closely associated with the subsequent development of pancreatic cancer. A series of recent reports have validated the epidemiologic association between chronic pancreatitis and pancreatic cancer, but the magnitude of the risk of pancreatic cancer attributable to pancreatitis remains unclear. Calculation of a general estimate of population-attributable risk has suggested that chronic pancreatitis may explain as many as 5% of pancreatic cancer cases.

Recent pathologic and molecular biologic studies have begun to explore the relationship between chronic pancreatitis and pancreatic cancer. Chronic inflammatory processes have long been associated with increased cancer risk. Pathologic examination of lesions along the pancreatic duct has revealed the spectrum of mucous cell hyperplasias (papillary and nonpapillary hyperplastic lesions and atypical hyperplastic lesions) in patients with chronic pancreatitis and patients with pancreatic cancer. The recent report of the identification of mutations in the K- ras oncogene, a mutation found almost universally in established pancreatic cancers, in regions of mucous cell hyperplasia in patients with chronic pancreatitis provides the first molecular link between chronic inflammation and the initiation of multistep pancreatic carcinogenesis. However, additional research is needed because other recent reports failed to identify K- ras mutations in pathologically similar lesions.

Etiologic factors

ETIOLOGIC FACTORS

Recent investigations have identified a number of factors that may contribute to the pathogenesis of pancreatic cancer. These factors can be organized into general areas of risk that include environmental factors, associated medical or surgical factors, heritable genetic factors (familial pancreatic cancer), and occupational exposures.

ENVIRONMENTAL FACTORS

A number of important environmental risk factors have been investigated for their role in the etiology of pancreatic cancer.

Cigarette Smoking.

Cigarette smoking is the most firmly established risk factor associated with pancreatic cancer. Pancreatic malignancies can be induced in animals through long-term administration of tobacco-specific N-nitrosamines or by parenteral administration of other N-nitroso compounds. These carcinogens are metabolized to electrophiles that readily react with DNA, leading to miscoding and activation of specific oncogenes such as K- ras. Induction of pancreatic cancer in these systems can be modulated by additional factors, including changes in bile acid composition, cholecystokinin (CCK) levels, and diet.

At the clinical level, numerous case-control and cohort studies have reported an increased risk of pancreatic cancer for smokers in both the United States and Europe, and current estimates suggest that approximately 30% of pancreatic cancer cases are due to cigarette smoking. Recent studies that have explored the dose-response relationship have shown that the risk of pancreatic cancer increases as the amount and duration of smoking increase and that long-term smoking cessation (more than 10 years) reduces risk by approximately 30% relative to the risk of current smokers. Application of molecular epidemiologic techniques that are being developed for lung cancer may provide greater specificity in linking tobacco exposure with the development of pancreatic cancer and may facilitate the study of chemopreventive strategies.

Dietary Factors

Over the past 10 years, numerous dietary factors have been implicated in pancreatic cancer development. Generally, high intakes of fat or meat increase risk, and diets high in fruits and vegetables reduce risk. When the available studies are analyzed in greater detail, the associations between dietary intake and pancreatic cancer become more complex. For example, high fat intake, usually in the form of high meat intake, increases risk. However, a recent study has suggested that the effect may vary by source of fat and by patient population. Investigators found that large amounts of fat from any source increase the risk of pancreatic cancer in men but that only fat from nonmeat or nondairy sources increases the risk in women. Other studies have reported an increased risk of pancreatic cancer with high total energy intake, high total cholesterol intake, or high ingestion of carbohydrates. These clinical observations are supported by laboratory studies in animal models in which high-fat and high-cholesterol diets have been shown to promote pancreatic carcinogenesis.

Decreased rates for pancreatic cancer have been associated with high consumption of vegetables, citrus fruits, fiber, and vitamin C. The association of diets high in citrus with a reduced risk of pancreatic cancer is particularly interesting given the recent observation that limonene, a natural product found in citrus fruits, is a potent inhibitor of the K- ras oncoprotein.

Data regarding the effect of coffee consumption and excessive alcohol consumption appear conflicting. For each of these factors, a few studies have suggested an increased risk of pancreatic cancer (coffee, alcohol), but most studies conducted over the past 10 years have failed to consistently demonstrate such a risk (coffee, alcohol). In some cases, significant methodologic problems may have confounded interpretation of the data, leading to erroneous conclusions.

New Treatments for Pancreatic Cancer

Pancreatic cancer accounts for approximately 27,000 deaths per year in the United States and 50,000 deaths per year in Europe (excluding the former USSR). Only 1% to 4% of patients with adenocarcinoma of the pancreas will be alive 5 years after diagnosis. Thus, incidence rates are virtually identical to mortality rates. In the United States in 1995, pancreatic cancer was be the fifth leading cause of adult deaths from cancer (after lung, colorectal, breast, and prostate cancers) and was responsible for close to 5% of all cancer-related deaths.

EPIDEMIOLOGY

The incidence of pancreatic cancer declined slightly from 1973 to 1991, with 26,300 new cases (2% of all cancer diagnoses) estimated in 2006. Studies evaluating this trend suggest that the decreased incidence is due to a steady decline in the rate for white men, which peaked during the period 1970 to 1974. By contrast, rates for white women, black men, and black women have not fallen. In Japan, the incidence of cancer of the pancreas has increased sharply from 1.8/100,000 in 1960 to 5.3 in 100,000 in 1985. Overall, incidence in mortality statistics are very similar for the United States and Western Europe. Between 1989 and 1991, mortality rates for pancreatic cancer in the United States were 10 in 100,000 for men, and 7.2 in 100,000 for women. Although overall mortality rates in industrialized societies appear similar, geographically and ethnically dissimilar populations show considerable differences in mortality rates from pancreatic cancer.
The risk of developing pancreatic cancer is low in the first three to four decades of life but increases sharply after age 50, with most patients between ages 65 and 80 at diagnosis. The male to female ratio has ranged from 1.7:1.0 in older series to 1.3:1.0 in a more contemporary series. Historically, the male to female ratio was reported to decrease with age; however, this trend was not observed in a recent series from Memorial Sloan-Kettering Cancer Center. Interestingly, in several animal models of pancreatic cancer, tumors are more reproducibly induced in male animals.
Racial differences in mortality rates for pancreatic cancer have also been observed. Pancreatic cancer mortality rates for American blacks are higher than for any other ethnic group in the United States and are considerably higher than the rates observed for African blacks, suggesting an environmental contribution to this increased risk.

These broad epidemiologic categories do little to identify persons at high risk for pancreatic cancer. To define high-risk groups, we must consider the contribution of specific etiologic factors.

Adjuvant Chemotherapy

Early studies showed a lower risk of relapse when fewer than six nodes were involved and no node was 2 cm; and higher when 6 nodes or more were involved, any node was larger than 2 cm, or extranodal extension was present.
Surveillance is a treatment choice for compliant patients with fewer than six involved nodes and none larger than 2 cm. Surveillance requires close monitoring, and chemotherapy is reserved for patients who relapse. Patient compliance, psychologic factors, age, or other issues may make adjuvant chemotherapy the preferred choice in rare patients. Three or four cycles of cisplatin-based therapy will be required at relapse according to disease status at that time.

Adjuvant chemotherapy remains a strong consideration in patients when six nodes or more are involved, any node is larger than 2 cm, or there is extranodal extension. In the late 1970s, treatment programs based on cisplatin, vinblastine, and bleomycin were given as adjuvant therapy following RPLND, and nearly 100% of patients survived relapse free. Considerable treatment-related morbidity was associated with these regimens, prompting efforts to reduce toxicity. Two cycles of cisplatin-based chemotherapy are nearly always effective in preventing relapse. A randomized trial showed that observation with standard treatment at relapse and two cycles of adjuvant chemotherapy had equivalent survival. Etoposide has replaced vinblastine in adjuvant regimens. A recent study suggests that etoposide plus cisplatin alone is adequate, and that bleomycin is unnecessary as part of adjuvant therapy.

Disorders information

MANAGEMENT OF CLINICAL STAGE II (LOW TUMOR BURDEN)

SEMINOMA

Low tumor burden stage II seminoma includes all patients with retroperitoneal metastases measuring 5 cm or smaller in maximum transverse diameter. This encompasses both clinical stages IIA and IIB. Radiation therapy is the treatment of choice for most patients with these stages of disease. The radiation portal is fundamentally the same as that of patients with clinical stage I disease. Fractionation is the same except that a boost of approximately 500 to 750 rad is administered to involved lymph nodes. Relapses occur in from 5% to 15%, and death from seminoma is rare. Prophylactic mediastinal radiation therapy is not indicated, because relapses solely in the anterior or posterior mediastinum are infrequent. The combination of supradiaphragmatic and infradiaphragmatic radiation therapy results in chemotherapy intolerance, a high rate of treatment-related mortality due to chemotherapy, and a greater than expected death rate from disease due to the inability to administer adequate doses of chemotherapy.
There are exceptions to the need for radiation therapy for clinical stage I and nonbulky clinical stage II seminoma:
A horseshoe kidney is a contraindication to retroperitoneal radiation therapy due to the high likelihood of radiation-induced renal failure. Observation is preferred in clinical stage I, and primary chemotherapy is the treatment of choice for clinical stage II.
Patients who develop a second metachronous testicular germ cell tumor and who have undergone a prior RPLND or received radiation therapy should be observed frequently if clinical stage I disease is present, and undergo primary chemotherapy in the unlikely event that the disease is confined to residual retroperitoneal lymph nodes.
Inflammatory bowel disease may also be a contraindication to radiation therapy. Discussions with an experienced radiation oncologist would be indicated under such circumstances. If the decision is not to administer radiation therapy, then the management policies noted earlier for patients with a horseshoe kidney should be followed.

NONSEMINOMATOUS GERM CELL TUMORS

Low tumor burden clinical stage II nonseminomatous GCT encompasses disease ipsilateral to the primary tumor, at or below the renal hilum, not associated with tumor-related back pain, and limited to the primary landing zone. The presence of suprahilar or retrocrural lymphadenopathy, bilateral retroperitoneal nodal metastases, back pain, or contralateral lymph nodes (even if the ipsilateral lymph nodes do not appear to be involved) generally implies unresectable disease (e.g., tumor-associated back pain) or a higher likelihood of metastatic disease (suprahilar and retrocrural adenopathy), and initial chemotherapy is preferred. Ipsilateral solitary lymph nodes smaller than 3 cm are best handled by RPLND. Lymph nodes between 3 and 5 cm, even if solitary, may be associated with more extensive disease than can be detected on abdominal CT scan.

Retroperitoneal Lymph Node Dissection

The standard approach to patients with clinical stage IIA and some IIB tumors has been RPLND. The priority is to perform a definitive therapeutic operation, following which there is a minimum likelihood of infield recurrence. Margins of resection should not be compromised in an attempt to maintain ejaculatory function. Nerve-sparing dissection may be possible, depending on the location of disease.

Observation. Chemotherapy

Observation

The driving forces for early observation studies in clinical stage I patients were the infertility resulting from RPLND (due to retrograde ejaculation) and the apparent absence of therapeutic benefit (i.e., orchiectomy was a curative procedure or systemic disease occurred in the absence of retroperitoneal disease). The ability of cisplatin-based chemotherapy to cure systemic disease directly permitted observation studies, because cure of low-burden disease was more than 95% and treatment of relapse would not compromise survival. Relapse occurs in 25% to 30% of patients who are observed. A higher likelihood of retroperitoneal or systemic relapse was associated with T2-4 tumors and lymphatic or vascular invasion in T1 tumors. Some studies suggested that a high percentage of embryonal carcinoma and other histologic features also predicted a higher likelihood of relapse. However, the correlation between lymphatic-vascular invasion and the presence of embryonal carcinoma is high, and general agreement on histologic criteria for relapse independent of vascular or lymphatic invasion does not exist. Therefore, vascular-lymphatic invasion is the critical pathologic predictor for relapse in tumors confined to the testis. The retroperitoneum is the site of relapse in approximately two thirds of patients; the lungs or markers alone, in approximately one third; and other visceral sites, much less frequently. There is a slightly higher likelihood that both chemotherapy and modified bilateral RPLND ( not nerve sparing) are needed in order to achieve the same cure rate.

Patients with clinical stage I nonseminomatous GCT with a T1 tumor without vascular-lymphatic invasion and serum tumor markers that are normal or declining at half-life should be offered both surgical and observation options. If RPLND is chosen, it should be of the nerve-sparing type, thereby preserving ejaculatory capacity in the majority of patients. Frequent CT scans of the abdomen are unnecessary once an RPLND has been performed. If surveillance is chosen, then a possibly unnecessary RPLND is avoided, limiting therapy to orchiectomy alone in at least 70% of the patients (i.e., those who never relapse). Patient compliance cannot be overemphasized. A physical examination, chest x-ray, and determinations of AFP and hCG levels are required at monthly intervals in the first year, every other month in the second year, quarterly in the third year, and less frequently thereafter. An abdominal CT scan is required quarterly in the first year, every 4 months in the second year, and every 6 months beginning in the third year. Visits and evaluations should be annual in the fifth year and beyond. In both situations, relapses are extremely uncommon after 2 years and have only very rarely been observed after 5 years, in contrast to seminoma.

Chemotherapy

There are few data regarding chemotherapy as initial treatment of clinical stage I disease when the risk of retroperitoneal disease is high. In three reports of patients receiving two cycles of cisplatin-based chemotherapy, fewer than 5% relapsed and about 1% died of GCT. Although this approach avoids RPLND and the duration of therapy is brief, a majority of these patients would be exposed to the transient (e.g., myelosuppression), permanent (e.g., neuropathy), and delayed (e.g., Raynaud’s phenomenon, acute leukemia) toxicities of chemotherapy. The data are not yet mature and follow-up is short; this approach should be considered investigational.

Rarely, patients with clinical stage I disease are found to have persistently elevated serum concentrations of AFP or hCG after orchiectomy. If these markers increase or plateau at an elevated level after a period of observation (4 weeks or less), metastatic disease is present. This group of patients should receive initial systemic chemotherapy, because the disease is often not limited to the retroperitoneum. An RPLND should be done only if clinical studies at the conclusion of therapy demonstrate new disease.

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