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What Is the Optimal Treatment of Localized Pancreatic Adenocarcinoma?

What Is the Optimal Treatment of Localized Pancreatic Adenocarcinoma?

ABSTRACT: ABSTRACT: The term localized disease as it applies to pancreatic adenocarcinoma encompasses distinct entities associated with varied prognoses and therapeutic recommendations. These include three disease categories: (1) disease that is localized and resectable, (2) localized disease that is borderline resectable, and (3) unequivocally unresectable pancreatic adenocarcinoma, all representing a continuum. The incorporation of systemic chemotherapy into the management of pancreatic adenocarcinoma at all stages has become standard of care, and the basis for this is discussed with reference to the major clinical trial landmarks. The role of radiation therapy (in association with concomitant chemotherapy) in the management of localized pancreatic adenocarcinoma, however, has become less clear and represents an area of management confusion in this disease. Going forward, with the expectation of new and improved systemic agents, locoregional tumor control and, hence, chemoradiotherapy are anticipated to have a greater role and impact.

The challenge presented by adenocarcinoma of the pancreas is reflected by the fact that the incidence of this disease—almost 38,000 cases predicted in the United States for 2008[1]—approximates its mortality rate. Surgical removal of locally confined disease is the only realistic curative option. Even in that circumstance, however, the relapse rate is high, such that surgical resection (with adjuvant chemotherapy) is viewed by many as delaying rather than eliminating disease recurrence. Similarly, for patients with localized disease that is unresectable and unequivocally staged as T4, treatment is essentially palliative in intent.

In discussing the management of localized pancreatic cancer—with regard to both standard therapies and areas of controversy—it is important to delineate various categories that are distinct both with regard to prognosis and therapeutic approach. The most important distinction to be made is between resectable and unresectable localized disease. For localized disease that is resectable, we intend to focus on three major questions: (1) What is the benefit of adjuvant chemotherapy? (2) What is the role of (chemo)radiation therapy in this context? and (3) Is there a role for neoadjuvant chemotherapy?

For localized disease that is unresectable, a distinction needs to be made between borderline-unresectable disease and disease that is unequivocally inoperable. For discussion of these categories, we will focus on two questions: (1) What is the role of (chemo)radiation therapy? (2) What is the optimal systemic therapy or combination of systemic drugs? The latter question has applicability to the metastatic setting, which is not otherwise under discussion in this review.

Localized Resectable Pancreatic Adenocarcinoma

What is the benefit of adjuvant chemotherapy?

The rationale for adjuvant chemotherapy in pancreatic adenocarcinoma is the same as that applied to other solid tumor types: the presumptive eradication of micrometastases after surgical removal of all gross disease. This rationale has demonstrated proof of principle in the form of a documented survival benefit in prospective randomized studies in colorectal, gastric, lung, and breast cancer.[2-5]

In pancreatic adenocarcinoma, the case for adjuvant chemotherapy has been established relatively recently, although the historical precedent for adjvuant chemoradiotherapy and chemotherapy dates back to the Gastrointestinal Tumor Study Group (GITSG) trial.[6,7] Older small randomized studies of adjuvant systemic therapy (without chemoradiation) using a variety of fluorouracil (5-FU)–based regimens did not show a significant survival benefit compared to observation.[8-10]

ESPAC-1—In 2004, Neoptolemos et al published an updated report of the European Study Group for Pancreatic Cancer (ESPAC-1) trial in the New England Journal of Medicine, evaluating the role of adjuvant therapy in pancreatic adenocarcinoma (Table 1).[11] This trial had an unusual design comprising four groups of approximately 70 patients each: (1) surgery alone; (2) chemotherapy alone; (3) chemoradiation alone; and (4) chemoradiation followed by chemotherapy. This design allowed the investigators to isolate and compare the relative benefits of chemotherapy and chemoradiation. The chemotherapy consisted of 5-FU/leucovorin (at doses of 425 mg/m2 and 20 mg/m2, respectively) given daily for 5 days every 4 weeks, for six cycles of treatment.

With regard to the chemotherapy question, the median survival was 20.1 months (95% confidence interval [CI] = 16.5–22.7 months) for those who received chemotherapy and 15.5 months (95% CI = 13.0–17.7 months) for those who did not receive chemotherapy (hazard ratio [HR] for death = 0.71).[11] The 2- and 5-year survival estimates were 40% and 21%, respectively, among patients who received chemotherapy, compared to 30% and 8%, respectively, among patients who received no chemotherapy. The investigators concluded that 5-FU–based chemotherapy offered a survival advantage whereas chemoradiation offered no such benefit and may in fact be detrimental to outcome (see below).

RTOG 9704—Given that gemcitabine (Gemzar) has modestly more efficacy in metastatic disease than 5-FU,[12] the rationale was strong to consider its use in the adjuvant setting. The Radiation Therapy Oncology Group (RTOG) 9704 trial compared gemcitabine and 5-FU in a 451-patient study.[13] All patients received adjuvant 5-FU–based chemoradiation followed by 4 months of chemotherapy—either 5-FU by continuous infusion at 250 mg/m2 or weekly doses of gemcitabine at 1,000 mg/m2. The chemotherapy was given for 1 month prior to, and 3 months following chemoradiation.

The investigators observed a benefit from gemcitabine but only for patients with tumors in the head of the pancreas. These patients had a median survival of 20.5 months and a 3-year survival rate of 31% in the gemcitabine group vs 16.9 months and 22% in the 5-FU group (HR = 0.82; 95% CI = 0.65–1.03; P = .09). This difference reached statistical significance when a multivariate analysis was performed evaluating preplanned stratified variables. These included nodal status, which was found to strongly affect survival (P = .001), and gemcitabine therapy, which yielded a hazard ratio of 0.80 (95% CI = 0.63–1.00; P = .05) toward improved survival.

CONKO-001—Perhaps the best data with regard to adjuvant gemcitabine are derived from the Charit Onkologie (CONKO)-001 study, published in 2007 and recently updated.[14,15] The design of the CONKO-001 trial was somewhat more pure than the RTOG study, as none of the patients received chemoradiation. It was a straightforward comparison of chemotherapy vs observation following resection.

The trial met its primary endpoint, with disease-free survival being 13.4 months in the gemcitabine arm and 6.9 months in the observation arm (P < .001). Estimated disease-free survival rates at 3 and 5 years were 23.5% and 16.0% in the gemcitabine group vs 8.5% and 6.5% in the observation group, respectively. Gemcitabine significantly improved median overall survival (22.8 vs 20.2 months, P = .005). Estimated survival rates at 3 and 5 years were 36.5% and 21.0% for the gemcitabine-treated group, compared to 19.5% and 9% for the observation group.

Summary—We now have level 1 evidence supporting gemcitabine’s use in the adjuvant setting for resected pancreatic adenocarcinoma. Ongoing and planned phase III adjvuant studies in Europe will address the benefit of the addition of erlotinib (Tarceva) to gemcitabine (CONKO-005) and capecitabine (Xeloda) to gemcitabine (ESPAC-4).

What is the role of chemoradiation in the adjuvant treatment of pancreatic adenocarcinoma?

The majority of patients who experience a recurrence following resection of pancreatic adenocarcinoma develop metastatic disease, often with a component of locoregional recurrence. In addition, approximately 10% to 15% of patients with ostensibly operable disease will have subradiologic extrapancreatic disease discovered at exploration.[16] An increasing awareness of these factors along with the validation of systemic therapy’s role in the adjuvant setting has led to a diminution of the role of radiotherapy in the adjuvant management of pancreatic adenocarcinoma in recent years. Nevertheless, local recurrence is common and an important cause of morbidity, and arguably, chemoradiation has a favorable impact on local control and potentially overall survival, although the latter has been difficult to demonstrate.

GITSG Trial—As was the case in the locally advanced setting (discussed below), the historical precedent for chemoradiation was set by the GITSG, which randomly assigned 43 patients who had undergone a curative resection to receive surgery alone or chemoradiotherapy followed by maintenance 5-FU chemotherapy (Table 2).[6] The median survival was significantly longer in the adjuvant-treatment group than in the surgery-alone group (20 vs 11 months), with 5-year survival estimates of 18% and 8%, respectively.

EORTC Trial—In an attempt to replicate these results, the European Organisation for Research and Treatment of Cancer (EORTC) randomly assigned 218 patients with pancreatic or ampullary tumors to adjuvant chemoradiotherapy (but no maintenance chemotherapy) or surgery alone.[17] Although there was a trend toward a survival benefit for the treatment arm, with median survivals of 17 and 13 months in the treatment and observation groups, respectively, and 5-year survival estimates of 23% and 10%, these differences were not statistically significant. For many, the results of this study allowed the interpretation that the GITSG trial had indeed been vindicated, but that the study was simply underpowered.

ESPAC-1—The design of the ESPAC-1 study allowed for a comparison of patients who received adjuvant chemoradiation and those who did not.[11] Chemoradiotherapy consisted of a 20-Gy dose to the tumor given in 10 daily fractions over a 2-week period plus an intravenous bolus of 5-FU (500 mg/m2 on each of the first 3 days of radiotherapy and again after a planned break of 2 weeks).

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