What Is the Optimal Treatment of Localized Pancreatic Adenocarcinoma?

October 2, 2008

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.

ABSTRACT: ABSTRACT: The term localized disease as it applies to pancreatic adenocarcinomaencompasses distinct entities associated with varied prognoses andtherapeutic recommendations. These include three disease categories:(1) disease that is localized and resectable, (2) localized disease that isborderline resectable, and (3) unequivocally unresectable pancreaticadenocarcinoma, all representing a continuum. The incorporation ofsystemic chemotherapy into the management of pancreatic adenocarcinomaat all stages has become standard of care, and the basis for this isdiscussed with reference to the major clinical trial landmarks. The roleof radiation therapy (in association with concomitant chemotherapy) inthe management of localized pancreatic adenocarcinoma, however, hasbecome less clear and represents an area of management confusion inthis disease. Going forward, with the expectation of new and improvedsystemic agents, locoregional tumor control and, hence, chemoradiotherapyare 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).

No benefit was seen for patients who underwent chemoradiation, and in fact chemoradiation appeared to be detrimental. The median survival was 15.9 months (95% CI = 13.7–19.9 months) among the 145 patients who were assigned to chemoradiotherapy and 17.9 months (95% CI = 14.8–23.6 months) among the 144 patients who were not assigned to receive chemoradiotherapy (HR for death = 1.28; 95% CI = 0.99–1.66; P = .05). The 2- and 5-year survival estimates were 29% and 10%, respectively, among patients who received chemoradiotherapy, and 41% and 20% among those who did not receive chemoradiotherapy.

A number of criticisms have been leveled at this conclusion, however, based on the complicated trial design and issues with regard to the quality control of the radiation and chemotherapy delivered. It is also important to note that the radiation was given as the initial therapy. It is likely that a proportion of patients will indeed benefit from adjuvant chemoradiation, and the challenge is to better select this subpopulation. For example, patients who undergo an R1 resection or who are node-negative may benefit more from chemoradiation, or conversely, lymph node positivity-being a marker for higher risk of occult metastatic disease-may predict for lack of benefit to chemoradiation.[18,19]

Summary-The role of chemoradiation in the adjuvant treatment of pancreatic adenocarcinoma has diminished both in the context of stronger evidence for systemic therapy alone and also a fuller understanding of the biologic behavior of this disease. That being said, chemoradiation is likely to be an important part of adjuvant treatment for selected patients, and the challenge for the oncologist is to better select these patients. We also anticipate that when systemic therapy improves in this disease, locoregional tumor control will gain in relative importance. In the relative short-term, a planned cooperative/intergroup trial, if it proceeds, will allow the true contribution of chemoradiation to be clarified.

Is there a role for neoadjuvant therapy in resectable disease?

Given the near universal recurrence of pancreatic adenocarcinoma following resection, it becomes imperative to question all components of our current standard approach. This includes the central dogma of upfront, primary surgery. A neoadjuvant approach has a number of theoretical advantages: (1) earlier exposure of micrometastatic disease to systemic therapies, (2) increased compliance to chemotherapy, (3) avoidance of surgery in patients with an early declaration of metastatic disease (it is reasonable to assume that these patients would not have benefited from surgery), (4) may provide an important resource for research in terms of tissue acquistion before and after therapy.

The safety of neoadjuvant therapy has been demonstrated in multiple, mostly single-institution, single-arm phase II studies with particular representation by selected academic centers. Most studies have examined chemoradiation regimens. Very few studies have assessed the role of systemic therapy exclusively.

One such study, by Heinrich et al,[20] involved 28 patients with resectable pancreatic cancer given four preoperative biweekly cycles of gemcitabine at 1,000 mg/m2 and cisplatin at 50 mg/m2. A total of 26 patients (93%) had resectable cancer following restaging posttherapy, and the R0 resection rate was 80%. Histologic tumor response and cytopathic effects were documented in 54% and 83% of patients, respectively. Overall survival was 26.5 months (95% CI = 11.4–41.5 months).

Despite this report, neoadjuvant therapy for resectable pancreatic adenocarcinoma remains an experimental approach, and phase III studies are awaited. At this time, there is no consensus as to the contribution of radiation as a component of neoadjuvant therapy. It is recommended that all neoadjuvant therapy for resectable patients be delievered in the context of a clinical trial.

Localized UnresectablePancreatic Adenocarcinoma

Borderline (Un)resectable

For a pancreatic tumor to be clearly resectable, the following three criteria need to be satisfied[21]: no evidence of distant metastases, a clear fat plane around the celiac and superior mesenteric arteries and patency of the superior mesenteric and portal veins (SMV-PV). Patients with unresectable disease have encasement of the celiac or superior mesenteric artery (defined as involvement of > 180° of the arterial circumference) or occlusion of the SMV-PV confluence.

It is recognized, however, that not all patients who are unresectable are the same, and a continuum exists between patients who are clearly resectable and those who are frankly unresectable. In recent years, a subset of patients have been defined as having disease that is borderline resectable, for whom surgical resection may yet be a possibility in their management. Given that there is little to be gained from attempting surgery when the chances of obtaining negative margins are not high,[22-24] there is a strong rationale for a neoadjuvant approach in this setting.

The definition of borderline-resectable pancreatic cancer changes according to the location of the tumor, as set out by the National Comprehensive Cancer Network (NCCN) guidelines.[21] Authors from the M.D. Anderson Cancer Center group have further refined the definition of this entity to include the following: tumors that exhibit encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis, that is amenable to resection and reconstruction; tumor abutment of the superior mesenteric artery involving < 180° of the circumference of the artery; and short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumor involvement.

This group recently reported their experience of neoadjuvant therapy in 84 patients who were borderline resectable based on their own anatomic criteria (in addition to another 76 patients who were deemed borderline resectable on the basis of performance status and suspicion of metastatic disease).[25] A total of 32 (38%) of the patients who were borderline resectable based on anatomic criteria were able to undergo a (partial) pancreatectomy following neoadjuvant therapy, the vast majority (97%) of whom had clear margins. Similar to other reports relating to this specific entity,[26,27] this was not a prospective study, and in the absence of a control group, it is impossible to know whether these patients did better or worse following the addition of neoadjuvant therapy. In addition, there was a heterogeneity in the neoadjuvant therapy used, although all these patients did receive chemoradiation.

Clearly, prospective randomized studies in this setting would be ideal. However, it is unlikely that the benefit of neoadjuvant therapy could be purely quantified, as there would be ethical concerns about having a “straight-to-surgery” control group in a situation where the chances of obtaining negative margins are not high.

Locally AdvancedPancreatic Cancer

What is the role and timing of radiation therapy?

For disease that is clearly unresectable according to the criteria mentioned above, the role of surgery with curative intent is minimal except for the anecdotal patient.[28] Likewise, the role of radiation therapy has grown increasingly controversial in this setting, as in the adjuvant setting, largely due to a fuller appreciation of the biology of pancreatic cancer and the demonstration of benefit of systemic therapy, albeit in relative terms modest.

These issues diminish the importance of local control measures for this cohort of patients in general, based on the assumption that the majority of them will have subradiologic metastatic disease, which will in time be the main determinant of their prognosis. There is an important exception to this, however-that is, patients who have pain related to the locoregional extent of their disease, for whom a definite palliative benefit exists with the use of chemoradiation.[29] It is also worth emphasizing that the relative utility of chemoradiation in both the locally advanced and adjuvant disease settings will gain increasing importance when systemic therapy improves in this disease.

The foothold of chemoradiation for locally advanced pancreatic cancer was established on the basis of a number of small clinical trials stretching back to the 1960s. Two of these studies demonstrated a survival benefit for (5-FU–based) chemoradiation compared to radiotherapy alone.[30,31] Two other studies from the same era compared chemotherapy alone to chemoradiation. In a trial by the GITSG, a benefit was demonstrated for chemoradiation plus chemotherapy compared to chemotherapy alone.[32] The chemotherapy consisted of streptozocin (Zanosar), mitomycin, and 5-FU, and the 1-year survival benefit was 41% compared to 19%. The other trial, conducted by the Eastern Cooperative Oncology Group (ECOG), compared 5-FU/chemoradiation with chemotherapy alone, but failed to demonstrate a survival benefit.[28,32,33]

FFCD-SFRO Study-The value of chemoradiation in locally advanced pancreatic cancer has not been quantified in the modern clinical trial era. In an attempt to address this question in the era of gemcitabine, a phase III study was performed by the Fdration Francophone de Cancrologie Digestive–Socit Franaise de Radiothrapie Oncologique (FFCD-SFRO) in France.[34,35] In this study-the first for nearly 20 years to address this question-119 patients (of a planned 176) were randomized to undergo induction chemoradiation (with 5-FU at 300 mg/m2/24 h as a continuous infusion, days 1–5 every week, and cisplatin at 20 mg/m2/d, days 1–5 during weeks 1 and 5) followed by gemcitabine, or go straight to chemotherapy with gemcitabine.

The study was stopped prior to its planned enrollment due to an inferior survival in the chemoradiation group (median survival = 8.6 vs 13 months; P = .014). Although this study is not a definitive answer to the question of chemoradiation, it does add to the growing body of opinion that the benefit of chemoradiation in locally advanced pancreatic cancer is most likely confined to a carefully selected subgroup.

Recently, a similar study design of initial systemic therapy compared to chemoradiation was reported, comparing gemcitabine alone (1,000 mg/m2 weekly × 3 every 4 weeks for seven cycles) to chemoradiation (50.4 Gy in 28 fractions plus gemcitabine at 600 mg/m2 weekly × 6) followed by five cycles of gemcitabine alone (1,000 mg/m2 weekly × 3 every 4 weeks).[36] The trial was stopped early due to slow accrual (N = 74, out of a planned 316). The median survival times were 9.2 months (95% CI = 7.8–11.4) and 11.0 months (95% CI = 8.4–15.5) for the two arms, respectively (P = .044).

GERCOR Studies-In an interesting attempt to tease out the benefit of chemoradiation, investigators from the Groupe Cooprateur Multidisciplinaire en Oncologie (GERCOR) performed a retrospective analysis of 181 patients with locally advanced pancreatic adenocarcinoma who had been entered on prior prospective GERCOR studies and who had been offered chemoradiation (at the discretion of the investigator), but only if they had remained metastasis-free after 3 months.[37] For patients who were metastasis-free after initial chemotherapy, a survival advantage was seen if they proceeded to chemoradiation, compared to those who continued with chemotherapy alone (median overall survival = 15.0 and 11.7 months, respectively; P = .0009).

These data suggest that radiotherapy may offer a survival benefit in selected patients with disease that is proven to be localized after a test of time. This is an attractive concept as it allows patients to be selected for chemoradiation while receiving systemic therapy for their disease and also gives time for the logistics of the chemoradiation to be organized. The underlying principle is that patients who progress systemically prior to chemoradiation in all likelihood would not have derived a survival benefit from chemoradiation anyway, and is analogous to the concept that patients who develop disease progression during neoadjuvant therapy for resectable disease presumably would not have benefitted from surgery had it gone ahead.

The same investigators have performed a prospective phase II study based on a similar model, ie, induction chemotherapy (with gemcitabine and oxaliplatin [Eloxatin]) for a 2-month period, followed by chemoradiation if the patient has remained metastasis-free.[38] In this study, 15% of patients did not go on to receive chemoradiation, which is lower than the 29% rate described in the earlier report. The authors speculate that this may have been due to the shorter period of induction (2 vs 3 months) and the lower amount of chemotherapy administered. The median overall survival achieved in this study was 12.2 months, which is in the upper level of the survival rate range reported for patients with locally advanced pancreatic cancer. This attractive concept needs to be assessed definitively, and a phase III randomized study is currently being performed by the same group in Europe.

Along the same lines, the significance of surgical staging with laparoscopy for patients with locally advanced disease is also reflected by the fact that up to 37% of patients have subclinical peritoneal or surface liver metastases and would not benefit from localized therapies.[39] This has important implications for clinical trial design when chemoradiation strategies are included, as failure to surgically stage patients with locally advanced pancreatic cancer may result in a dilution of the radiotherapy effect due the presence of patients with unappreciated metastatic disease. However, the counterbalance to this argument is that if chemoradiation is not going to be administered as the initial treatment strategy (emerging consensus), the need to surgically stage upfront is a less compelling argument as time on systemic therapy prior to the administration of chemoradiation can establish the biology of the cancer course.

Summary-The role of chemoradiation in the management of locally advanced, clearly unresectable pancreatic adenocarcinoma, has changed in recent times, with a trend toward induction systemic therapy. This seems to be the most pragmatic approach for selecting patients who will genuinely benefit from local therapy and avoiding intensive chemoradiation in patients who in all likelihood will not benefit from it.

What are the effective chemoradiation regimens?

Numerous phase II studies have demonstrated the efficacy and feasibility of particular chemoradiation regimens.[40-44] As stated above, however, the exact contribution made by the chemoradiation component has not been isolated. The situation is further complicated by the prevailing tendency in the design of phase III studies to group locally advanced pancreatic cancer with metastatic disease in comparing one chemotherapy regimen to another.

The role of 5-FU as a radiation sensitizer was proposed by Heidelberger in 1958.[45] In the early studies in the field referred to above, the chemotherapy component consisted of 5-FU given as a bolus. This has largely been replaced by the use of continuous-infusion 5-FU on the basis of phase I and II studies demonstrating efficacy and safety, and follows the trend in other gastrointestinal malignancies.[46-48] Capecitabine (Xeloda), an oral fluoropyrimidine, has been shown to be safe and effective at 1,600 mg/m2 (in two divided doses).[49-51] Randomized trials are lacking, however. Gemcitabine as a radiosensitizer has been explored in phase I and II studies, but the optimal dose and schedule remains uncertain. Several groups have reported on the safety and efficacy of twice-weekly gemcitabine at 40 mg/m2 with radiation.[52-54] The use of higher doses of gemcitabine have also been reported but with varying outcomes in terms of tolerability.[55-58]

Hong et al evaluated the efficacy and toxicity of full-systemic-dose gemcitabine and a single dose of cisplatin with concurrent radiotherapy in 41 patients with locally advanced pancreatic cancer.[59] Patients received weekly gemcitabine (1,000 mg/m2) and cisplatin (70 mg/m2 on days 1 and 29) with concurrent radiotherapy (45 Gy in 25 fractions). Treatment was completed in 38 of 41 patients (92.7%). The overall response rate was 24.4%, and six patients (14.6%) underwent pancreatic resection. The median survival time of 16.7 months was at the higher end of the spectrum. The treatment appeared to be well tolerated.

What is the most effective systemic regimen?

Leaving aside the chemoradiation question, what is the best systemic therapy for locally advanced pancreatic cancer? Gemcitabine became established as a cornerstone drug in pancreatic adenocarcinoma in 1997, following a phase III study that demonstrated an improvement in clinical benefit and survival (a secondary endpoint in the study) compared to 5-FU.[12] Progress since then has been modest and mixed. Phase III cooperative group studies exploring the addition of the biologic agents bevacizumab (Avastin)[60] and cetuximab (Erbitux)[61] to gemcitabine in advanced pancreatic adenocarcinoma have been negative, a particularly disappointing outcome given their demonstrated efficacy in other gastrointestinal cancers and the preclinical rationale for their use in pancreatic adenocarcinoma.

Cytotoxic combinations of gemcitabine with capecitabine and platinum agents do appear to offer a small incremental benefit, particularly in patients with good performance status. Heinemann et al performed a randomized study of gemcitabine in combination with cisplatin vs gemcitabine alone.[62] This study showed an overall survival benefit that was not statistically significant (7.5 vs 6.0 months; HR = 0.80; P = .15). This was similar in magnitude to two other studies of platinum combinations in advanced pancreatic cancer.[63,64] A meta-analysis of randomized trials indicated a significant survival benefit for combination regimens when gemcitabine was combined with either platinum analogs (HR = 0.85; 95% CI = 0.76–0.96, P = .010) or fluoropyrimidines (HR = 0.90; 95% CI = 0.81–0.99, P = .030).[65] In a subgroup analysis, patients with a good performance status appeared to benefit from cytotoxic combinations (HR = 0.76; 95% CI = 0.67–0.87; P < .0001), whereas patients with a poor performance status seemed to have no survival benefit from combination chemotherapy.

Gemcitabine/Erlotinib Combination-The first trial to show a survival benefit for any combination therapy in pancreatic cancer-which led to US Food and Drug Administration approval of this combination for front-line treatment in 2005-was a study by Moore et al, in which 569 patients with untreated locally advanced or metastatic pancreatic cancer were randomized to receive gemcitabine with either erlotinib or placebo. The investigators found a very modest but statistically significant improvement in progression-free survival (HR = 0.77; 95% CI = 0.64–0.92; P = .004), 1-year survival (23% vs 17%; P = .023), and median overall survival (6.24 vs 5.91 months, HR = 0.82; 95% CI = 0.69–0.99; P = .038) favoring the erlotinib arm.[66]

As has been the experience with epidermal growth factor receptor (EGFR) inhibitors in colorectal cancer and lung cancer, the occurrence of a rash was associated with an improved survival. The median survival rates for patients with grade 0, 1, and 2+ rash were 5.3, 5.8, and 10.5 months, respectively; and the 1-year survival rates were 16%, 9%, and 43% (P < .001). These data suggest that although the benefit for the entire cohort is small, a specific subpopulation of patients do benefit significantly from the addition of erlotinib.

The molecular basis of sensitivity/resistance to erlotinib in pancreatic cancer is unclear. Unlike the case in non–small-cell lung cancer, predictive EGFR mutations are distinctly uncommon.[67] Likewise, the relationship between K-ras mutations and response to tyrosine kinase inhibition (a well established inverse relationship in lung and colon cancer) has not been elucidated for pancreatic cancer.[68,69]

We performed a phase I study of gemcitabine-based chemoradiotherapy in the locally advanced setting in association with erlotinib, which demonstrated the feasibility of this combination.[70] While recognizing the limitations of survival endpoints in phase I studies, the impressive survival of 18.4 months is reflective of both the potential efficacy of this therapy in the first-line setting and the fact that all the patients in this study were surgically staged.


The term localized disease as it applies to pancreatic adenocarcinoma encompasses distinct entities with varied prognoses and therapeutic recommendations. These include three categories: disease that is localized and resectable; disease that is borderline (un)resectable, and unequivocally unresectable pancreatic cancer. The incorporation of systemic therapy into the management of all stages of pancreatic adenocarcinoma has become standard of care, except for the preoperative resectable setting, where this is an attractive but experimental approach.

Questions remain about how adjuvant therapy can be further optimized, but there can be no doubt that gemcitabine has become a treatment backbone based on the CONKO-001 study and, to a lesser extent, the RTOG studies. The role of radiation therapy (in association with concomitant chemotherapy) in the management of localized pancreatic adenocarcinoma remains an area of confusion when disease is either locally resectable or unresectable. The current trend toward using the biology of the disease (as it becomes evident over a period of chemotherapy) to better select patients who will benefit from chemoradiation seems to be the most pragmatic way to proceed, until we have a better means of predicting tumor behavior and more active systemic agents.



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