Inoperable Pancreatic Cancer: Standard of Care

Inoperable pancreatic adenocarcinoma is a dilemma that oncologists frequently encounter. Only 15% to 20% of patients are diagnosed when cancer of the pancreas is still surgically resectable. However, pancreaticoduodenectomy is the only curative option for this disease and should be offered to all patients who meet resection criteria and do not have significant comorbidities. For inoperable pancreatic cancer, the goals of treatment are to palliate symptoms and prolong life. Improved survival in locally advanced disease has been demonstrated with chemoradiation plus fluorouracil or with gemcitabine (Gemzar) alone. In metastatic disease, single-agent gemcitabine has been associated with improvement in symptoms and survival. Trials combining various chemotherapeutic agents with gemcitabine have not had a significant impact on overall survival, although meta-analyses suggest a small benefit. The targeted agent erlotinib (Tarceva) has shown a modest improvement in overall survival in combination with gemcitabine. This combination is another option for first-line therapy in patients with locally advanced or metastatic disease. Despite these recent advances, survival for patients with inoperable pancreatic cancer continues to be poor. Future investigations need to focus on understanding the molecular nature of this malignancy, with the goal of developing interventions based on this knowledge.

TABLE 1

Inoperable Pancreatic Cancer Definitions

Cancer of the pancreas is the fourth leading cause of cancer death in the United States.[1] It is one of the most challenging malignancies, since the majority of patients will have advanced disease on presentation.[2] Only 15% to 20% of all patients with newly diagnosed pancreatic cancer will meet the criteria for resection.[2,3] Unless a reliable screening test is found, these statistics are unlikely to improve. Currently, the overall 1-year survival rate for all stages is 20%, with a 5-year survival of < 5%.[2] The median survival times for patients with locally advanced and metastatic disease are 9 to 12 months and 3 to 6 months, respectively (Table 1).[1,2,4,5] Despite extensive investigations aimed at improving surgery, radiation, and systemic therapy for this disease, little progress has been made to improve overall mortality in recent years. This article discusses the current standards of care for treatment of inoperable pancreatic cancer.

Epidemiology

The American Cancer Society estimates that more than 37,000 people will be diagnosed with pancreatic cancer in the United States in 2007. Reflecting the high mortality, it is predicted that over 33,000 people will die from the disease in the same year. Males and females are equally at risk. The peak incidence is in the 7th decade, with only 10% of pancreatic cancer cases occurring before age 50.[1]

Risk factors for pancreatic cancer include advanced age (> 60) and cigarette smoking. In addition, diabetes mellitus and chronic pancreatitis have been associated with this disease.[6] It is estimated that 5% to 10% of pancreatic cancers result from an inherited genetic factor. BRCA2 is the most common gene linked to pancreatic adenocarcinoma. Other hereditary syndromes such as hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, Peutz-Jeghers syndrome and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have also been associated with cancer of the pancreas.[6]

Signs and Symptoms

Since the majority (> 70%) of pancreatic cancers occur in the head of the pancreas, symptoms are generally caused by compression of surrounding structures. Painless jaundice, caused by impingement of the bile duct, is the classic sign of pancreatic cancer. However, most patients describe an antecedent period of abdominal or back pain, followed by darkening of the urine and jaundice.[7] Weight loss and depression are also common symptoms.[8] On physical examination, the classic Courvoisier's sign of a palpable gallbladder is present in < 50% of patients.[7] Lesions in the pancreatic tail are more likely to present with pain in the abdomen or signs of metastatic disease.

Diagnosis

Contrast-enhanced computerized tomography (CT) is the preferred imaging modality for evaluation of the biliary tree and pancreas. Magnetic resonance imaging (MRI) is an alternative for patients who cannot undergo contrast-enhanced CT.[9] In patients presenting with an inoperable pancreatic head mass causing biliary obstruction, endoscopic retrograde cholangiopancreatography (ERCP) with stent placement should be performed to relieve the obstruction.

Tissue for pathologic evaluation should be obtained from the pancreatic lesion under CT or endoscopic ultrasound (EUS) guidance. EUS is preferred, since it is another modality for visualization of the mass and the surrounding vascular structures.[10,11] If a patient presents with metastatic lesions in addition to a pancreatic mass, biopsy of a metastatic lesion is usually preferred to obtain the diagnosis.

Staging

Adequate imaging with dynamic-phase spiral CT of the pancreas is critical to evaluate the relationship of the tumor to the important structures surrounding the pancreas.[9] EUS is also helpful in this assessment.[10] In addition, imaging of the remaining abdomen and the lungs should be performed to evaluate for metastatic disease. Per the National Comprehensive Cancer Network (NCCN) guidelines,[12] head of the pancreas tumors are classified into three categories:

• Resectable tumors have no evidence of metastatic disease and the primary tumor is associated with patent superior mesenteric (SMV) and portal veins as well as a clear fat plane around the superior mesenteric artery (SMA) and celiac axis.

• Unresectable tumors encase the SMA or celiac axis, invade or encase the aorta or inferior vena cava (IVC), have metastatic lesions including para-aortic or celiac lymph nodes, are associated with SMV or portal vein occlusion, or invade the SMV below the transverse mesocolon.

• Borderline resectable tumors have severe unilateral SMV/portal vein impingement, gastroduodenal artery encasement up to the origin at the hepatic artery, or tumor abutment on SMA, or are tumors with limited involvement of the IVC, partial SMV occlusion, or invasion into the colon or mesocolon.

Management of borderline resectable cancer of the pancreas remains under debate, as these patients are at high risk for having margin-positive surgery.[13] The remainder of this article focuses on the management of inoperable pancreas cancer.

Treatment

Supportive Care

The primary goals of therapy for inoperable pancreatic cancer are to palliate symptoms and prolong survival. However, treatment of metastatic cancer of the pancreas is challenging since patients are often symptomatic from their disease. Symptom control should always be a priority and may be the primary focus in patients with a poor performance status. Pain is a frequent complaint in pancreatic cancer and can be alleviated with a celiac plexus block or narcotic analgesics.[14] Palliative radiotherapy may also be considered to improve pain control. Duodenal obstruction is a less common problem, which can be alleviated with stenting.[15]

Fluorouracil-Based Chemoradiation

For locally advanced pancreatic cancer, combination therapy with chemotherapy and radiation is often a mainstay of treatment in the United States. Fluorouracil (5-FU) is the classic chemotherapeutic agent that has been combined with radiation therapy (RT). A randomized trial by the Mayo Clinic in the 1960s showed improved outcomes with the combination of 5-FU and RT vs RT alone in patients with locally advanced pancreatic cancer.[16]

The Gastrointestinal Tumor Study Group (GITSG) then completed a three-arm, randomized trial of 106 patients, comparing 60 Gy of split-course RT alone vs 5-FU with 40 Gy of split-course RT or 5-FU with 60 Gy of split-course RT.[4] In the two arms receiving concurrent chemoradiation, maintenance 5-FU was given following completion of radiotherapy. Median survival was improved from 22.9 weeks in the arm receiving RT alone to 44.2 weeks in the two arms receiving concurrent chemoradiation. Since the publication of these trials, concurrent 5-FU and RT has been considered a standard of care for locally advanced pancreatic cancer.

Given the beneficial effects seen with mitomycin in other gastrointestinal diseases,[17,18] the Eastern Cooperative Oncology Group (ECOG) tested mitomycin at 10 mg/m² with 1,000 mg/m²/d of continuous-infusion 5-FU concurrently with RT (59.4 Gy) compared to RT alone (59.4 Gy). Mitomycin with 5-FU during radiation did not improve overall survival compared to those who received RT alone (8.4 vs 7.1 months; P = .16). However, it has been suggested that the trial may have been underpowered.[19] Also, in contrast to the GITSG trial, chemotherapy was not given after RT, and laparotomy was required prior to study entry to exclude metastatic disease.

Gemcitabine-Based Chemoradiation

In vitro, gemcitabine has exhibited significant radiosensitizing properties, even at non-cytotoxic doses.[20] This prompted several clinical studies of concurrent gemcitabine and radiation, which was found to be unexpectedly toxic.[21,22] The ECOG sought to determine the maximum tolerated dose of gemcitabine administered with a protracted venous infusion of 5-FU (200 mg/m²/d) and 59.4 Gy of RT. Dose-limiting toxicity was seen in two of three patients at the 100-mg/m²/wk dose level and three of four patients at the 50-mg/m²/wk dose level.[23] In a Cancer and Leukemia Group B (CALGB) trial, twice-weekly gemcitabine (40 mg/m²) with concurrent RT to 50.4 Gy resulted in 60% grade 3/4 hematologic toxicity and 42% grade 3/4 gastrointestinal toxicity.[21]

Given the unacceptable toxicity rates seen in these trials and the hypothesis that a more effective regimen for pancreatic cancer would be one that addresses both the local and distant sites of failure, attempts were made to give standard-dose gemcitabine with modified RT fields. A phase I trial from the University of Michigan delivered gemcitabine at 1,000 mg/m² while testing the dose of RT to the gross tumor without elective nodal treatment. The dose level of 36 Gy in 2.4-Gy fractions was selected for further testing.[24]

The subsequent multi-institutional phase II trial of full-dose gemcitabine with small-field RT (gross tumor volume plus a 1-cm margin to 36 Gy in 2.4-Gy fractions) was completed in patients with nonmetastatic cancer of the pancreas. Of the 20 patients thought to have resectable disease before treatment, 85% underwent pancreatic resection and 94% had negative margins. Of the patients who had surgery, 41% were alive with no recurrence at a median follow-up of 18 months.[25,26] A follow-up phase II trial of the same gemcitabine/RT regimen with the addition of bevacizumab (Avastin) is near completion.[27]

Another phase II study tested induction gemcitabine at 1,000 mg/m² for 7 weeks followed by gemcitabine at 400 mg/m² weekly for 3 of 4 weeks in two cycles given concurrently with 50.4 Gy of RT in 28 fractions. After combined chemoradiation, gemcitabine maintenance therapy was given. Although this was a small study of 20 patients, the regimen was well-tolerated and disease stabilization was noted.[28]

Paclitaxel-Based Chemoradiation

The radiosensitizing properties of paclitaxel may stem from its ability to force cells to arrest at the G2/M checkpoint, a radiosensitive phase of the cell cycle, although other hypotheses have been proposed.[29,30] The Radiation Therapy Oncology Group (RTOG) performed a phase II trial of large-field RT (50.4 Gy) with concurrent weekly paclitaxel (50 mg/ m²).[31] At a median follow-up of 20.6 months, the investigators found a median survival of 11.2 months, with 39% of patients experiencing grade 3 toxicity and 5% experiencing grade 4 toxicity (primarily hypersensitivity reactions). In addition, there was one treatment-related death from infection. The RTOG has recently completed a phase II trial of weekly gemcitabine, paclitaxel, and RT followed by the farnesyl-transferase inhibitor tipifarnib (115777, Zarnestra).

Single-Agent Gemcitabine

Prior to the development of gemcitabine, 5-FU was the standard of care for advanced pancreatic cancer. In 1997, Burris et al published a randomized study comparing gemcitabine to 5-FU. A total of 126 patients with symptomatic locally advanced or metastatic disease were randomized to either gemcitabine at 1,000 mg/m² weekly for 7 weeks, then 1 week off, followed by gemcitabine at 1,000 mg/ m² weekly for 3 of every 4 weeks, or 5-FU dosed at a 600-mg/m² bolus once weekly. The study was designed with a primary outcome evaluating for a clinical benefit response, a composite endpoint incorporating pain, performance status, and weight gain. A clinical benefit was shown in 23.8% of the gemcitabine group vs 4.8% of the 5-FU group. In addition, the secondary outcome of median overall survival was significantly different at 5.65 months in the gemcitabine arm and 4.41 months in the 5-FU arm. The 1-year survival was 18% vs 2%, favoring gemcitabine. Based on these data, gemcitabine became the standard of care for inoperable pancreatic cancer.[32]

In attempts to optimize response to gemcitabine, ECOG designed the phase III E6201 study. Two arms of this study compared fixed-dose-rate gemcitabine at 1,500 mg/m² over 150 minutes weekly every 3 of 4 weeks vs gemcitabine at 1,000 mg/m² over 30 minutes on the same schedule used in the Burris study. Median overall survival was not significantly different between the two groups at 4.9 months using the standard 30-minute dosing of gemcitabine vs 6.0 months in the fixed-dose-rate group.[33]

Fluoropyrimidine/Gemcitabine Combination Chemotherapy

TABLE 2

Phase III Trial of Gemcitabine/Fluorouracil Combinations in Pancreatic Cancer

Further efforts to improve outcomes in pancreatic cancer have centered on the combination of other chemotherapeutic agents with gemcitabine (Table 2). Several randomized, controlled studies have compared single-agent gemcitibine to the combination of gemcitabine with either 5-FU or capecitabine (Xeloda).

The ECOG E2297 study randomized 322 patients with advanced pancreatic cancer to either gemcitabine at 1,000 mg/m² weekly for 3 of 4 weeks or gemcitabine at 1,000 mg/m² followed by 5-FU at 600 mg/m² on the same schedule. Median overall survival was not statistically different at 6.7 months in the combination arm compared to 5.4 months in the single-agent arm.[34]

In 2005, the phase III CONKO-002 study combining infusion 5-FU, leucovorin, and gemcitabine was reported. In this study, 473 subjects with locally advanced or metastatic pancreatic cancer were treated with either gemcitabine at 1,000 mg/m² weekly for 7 of 8 weeks for 1 cycle, then every 3 of 4 weeks or 5-FU at 750 mg/m² as a continuous 24-hour infusion, modulated by leucovorin at 200 mg/m² with gemcitabine at 1,000 mg/m² given on days 1, 8, 15, and 22 every 6 weeks. The primary outcome-median overall survival-was equivalent, at 6.2 months in the gemcitabine arm and 5.85 months in combination arm.[35]

Two phase III studies have used capecitabine, an oral fluoropyrimidine, instead of intravenous 5-FU. The study by Cunningham et al randomized 533 patients with either locally advanced or metastatic disease to gemcitabine at 1,000 mg/m² on the schedule used in the Burris study with or without capecitabine at 1,660 mg/m² daily on days 1 to 21 of a 28-day schedule. A statistically significant improvement in median overall survival of 7.4 months, compared to 6.0 in the gemcitabine-alone arm, was noted with the combination therapy.[36]

However, another phase III study of this combination did not show any benefit. This study by Herrmann et al randomized patients to either gemcitabine at 1,000 mg/m² every week for 7 of 8 weeks for 1 cycle, then every 3 of 4 weeks, or capecitabine at 650 mg/m² bid on days 1 to 14 and gemcitabine at 1,000 mg/m² on days 1 and 8 of each 3-week cycle. The median overall survival did not reach statistical significance at 8.4 months in the combination group and 7.2 months in the treatment group.[37] Recently, Fine et al reported phase II data on 23 patients with metastatic pancreas cancer treated with 3-week cycles of capecitabine at 750 mg/m² twice daily for 14 days with gemcitabine at 750 mg/m² over 75 minutes and docetaxel (Taxotere) at 30 mg/m² on days 4 and 11 (GTX). Promising response rates (> 30%) and median progression-free survival were seen. However, these results need to be confirmed in phase III trials.[38]

Platinum/Gemcitabine Combination Chemotherapy

TABLE 3

Phase III Trial of Gemcitabine/Platinum Combinations in Pancreatic Cancer

Several investigations combining platinum compounds with gemcitabine have also been reported for advanced pancreatic cancer (Table 3). In 2003, Heinemann et al reported a randomized, phase III study in 195 patients comparing 28-day cycles of either gemcitibine at 1,000 mg/m² with cisplatin at 50 mg/m² on days 1 and 15 or gemcitabine at 1,000 mg/m² on days 1, 8, and 15. Median overall survival was 7.5 months in the combination arm vs 6.0 months in the single-agent gemcitabine arm. This was not a statistically significant difference.[39]

Oxaliplatin (Eloxatin) has also been investigated with gemcitabine in unresectable pancreas cancer. A study by Louvet et al randomized 313 patients to either gemcitabine at 1,000 mg/m² over 100 minutes on day 1 and oxaliplatin at 100 mg/m² on day 2 every 2 weeks or gemcitabine at 1,000 mg/m² over 30 minutes weekly. Median overall survival was not found to be significantly different at 9.0 months in the combination arm and 7.1 months in the gemcitabine arm.[40] Furthermore, the ECOG 6201 trial previously discussed also investigated this combination with a third arm consisting of gemcitabine at 1,000 mg/m² given on day 1 and oxaliplatin at 100 mg/m² on day 2 of each 14-day cycle. Again, median overall survival was not statistically different-5.9 months for the combination arm vs 4.9 months in the gemcitabine arm.[33]

Gemcitabine Combination Chemotherapies Summary

Based on these studies, it does not appear that gemcitabine combination therapy with 5-FU or platinum agents is beneficial in advanced pancreatic cancer. Additional studies combining gemcitabine with pemetrexed (Alimta), irinotecan (Camptosar), and other agents also have not shown a statistically significant overall survival benefit.[41,42]

However, meta-analyses have found some benefit to combination therapy. The largest meta-analysis evaluated 113 randomized controlled trials. A total of 51 trials involving 9,970 patients met the inclusion criteria and were incorporated in the analysis. Survival was improved with gemcitabine combination chemotherapy when compared to gemcitabine alone (hazard ratio [HR] = 0.91; 95% confidence interval [CI] = 0.85–0.97), with subset analysis showing the benefit only with platinum or capecitabine combinations.[43] Several other smaller meta-analyses also support this finding.[44,45] This suggests that there is an incremental benefit to gemcitabine combinations. Therefore, in patients with good performance status, combination chemotherapy may be a reasonable treatment approach.

Non–Gemcitabine-Containing Chemotherapy Regimens

A recent phase II study compared FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin), a non–gemcitabine-containing regimen, to standard-dose gemcitabine. This study showed a response rate in the FOLFIRINOX arm of 31.8%, which was significantly superior to gemcitabine alone.[46] The survival data have not yet been reported for this study.

Targeted Therapies

TABLE 4

Phase III Trial of Gemcitabine/Targeted Agent Combinations in Pancreatic Cancer

The poor outcome of inoperable pancreatic carcinoma with current treatment modalities has led to investigations with new molecularly targeted agents (Table 4). Erlotinib (Tarceva), a small-molecule tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), was the first targeted agent to demonstrate an improved outcome in pancreatic cancer patients. The addition of erlotinib at 100 to 150 mg daily to gemcitabine at 1,000 mg/m² weekly given per the schedule used in the original Burris trial improved overall survival (HR = 0.82, 95% CI = 0.69–0.99) and progression-free survival (HR = 0.79, 95% CI = 0.64–0.92) in a randomized trial of 569 patients with locally advanced or metastatic pancreatic cancer.[47] Although this study showed a statistically significant improvement in overall survival, it translated into only a 2-week difference between the two groups.

In contrast, the Southwest Oncology Group (SWOG) recently reported negative results with cetuximab (Erbitux), a monoclonal antibody to EGFR. In the S0205 study, subjects with locally advanced or metastatic pancreatic cancer were randomized to gemcitabine at 1,000 mg/m² weekly per the schedule used in the Burris trial, with or without cetuximab at 250 mg/m² weekly after a one-time loading dose of 400 mg/m². Median overall survival was 6.4 months in the combination arm vs 5.9 months in the gemcitabine arm.[48]

In addition, Burtness et al conducted a randomized phase II trial of irinotecan and docetaxel with or without cetuximab in patients with good performance status and no prior chemotherapy for metastatic disease (ECOG 8200).[49] No difference in overall survival or progression-free survival was noted. Regardless of the addition of cetuximab, the toxicity of irinotecan and docetaxel was high, with 33% to 40% of patients having grade 3/4 diarrhea.

In the CALGB 80303 trial, bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), was tested. This phase III study randomized 590 patients with locally advanced or metastatic pancreatic cancer to gemcitabine at 1,000 mg/m² on days 1, 8, and 15 every 28 days, with or without bevacizumab at 10 mg/kg every 2 weeks. Median overall survival was equivalent, at 5.8 and 6.1 months in the combination and single-agent arms, respectively.[5]

Although these results were discouraging, inhibition of angiogenesis may still play a role in advanced pancreatic cancer. A phase II study by Tempero et al combined fixed-dose-rate gemcitabine at 1,000 mg/m² with cisplatin at 20 mg/m² and bevacizumab at 10 mg/kg on days 1 and 15 of 28-day cycles. In 53 patients, this regimen resulted in a median overall survival of 8.0 months and estimated 1-year survival of 40%.[50]

Discussion

For many decades the medical community has been striving to improve outcomes for patients afflicted with pancreatic cancer. This has been challenging, given the location of this tumor near vital vascular structures, the biologically aggressive nature of these cancers with early metastasis, and their resistance to traditional chemotherapy and radiation. Over the years, progress has been made in diagnostic imaging, endoscopic techniques, surgical interventions, and the delivery of radiation therapy and chemotherapy. In addition, beyond traditional chemotherapy, we are now seeing preliminary signs that targeted therapies may be useful in this disorder.

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Bevacizumab (Avastin)
Capecitabine (Xeloda)
Cetuximab (Erbitux)
Docetaxel (Taxotere)
Erlotinib (Tarceva)
Fluorouracil (5-FU)
Gemcitabine (Gemzar)
Irinotecan (Camptosar)
Leucovorin
Mitomycin
Oxaliplatin (Eloxatin)
Paclitaxel
Pemetrexed (Alimta)
Sorafenib (Nexavar)
Tipifarnib (115777, Zarnestra)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Despite this progress, adenocarcinoma of the pancreas remains one of the most lethal malignancies. It is important that physicians continue to focus on improving care for these patients. Although 15% to 20% of these cancers are potentially resectable at diagnosis, only about half of these patients actually undergo a successful resection.[3] Pancreaticoduodenectomy has an acceptably low morbidity and mortality when performed at high-volume centers and should be offered to more patients with early-stage disease.[51] In addition, further investigations into the risk factors and genetic determinants for this malignancy need to be performed in order to define populations in whom screening tests may be appropriate.

Future Investigations

It is also time to change the design of clinical trials for inoperable pancreas cancer. Although many phase II studies with combinations of various chemotherapeutic and targeted agents with gemcitabine have shown promise, only the preliminary analysis for one phase III trial with capecitabine and the phase III study with erlotinib have been positive.[36,47] This discrepancy is in part due to phase II studies including a greater proportion of patients with locally advanced disease and good performance status, both of which are associated with longer survival.

Studies investigating new therapeutic agents or combinations need to be designed separately for patients with good performance status and locally advanced disease. This has been a successful paradigm in other malignancies. In advanced hepatocellular carcinoma, a recent study showed improved overall survival with sorafenib (Nexavar). However, enrollment in this study was limited to patients with good performance status and Child-Pugh status.[52] Furthermore, since gemcitabine combinations have not yielded significant improvements in pancreatic cancer, it is time to move beyond the randomized study comparing gemcitabine with or without another study drug as the basis for study design.

Future trials need to incorporate our ever-increasing understanding about the molecular characteristics of this cancer, both to develop new targeted agents and to identify biomarkers to predict treatment effect. These changes in our research endeavors and new paradigms for trial design offer the best hope to reduce the high mortality related to this disease.

Financial Disclosure:Dr. Benson has received research support and is a consultant for Eli Lilly, Genentech, Roche, Sanofi-Aventis, Pfizer, ImClone, Bristol-Myers Squibb, and Amgen.

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