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Second-Line Therapy for Gemcitabine-Refractory Pancreatic Cancer: Is There a Standard?

Second-Line Therapy for Gemcitabine-Refractory Pancreatic Cancer: Is There a Standard?

ABSTRACT: Gemcitabine (Gemzar) has been the standard treatment for metastatic pancreatic cancer based primarily on clinical benefits. To date, no standard guideline for second-line treatment of pancreatic cancer has been established. Data supporting the use of second-line therapy compared to best supportive care is lacking. We reviewed the published literature on second-line chemotherapy for pancreatic cancer. Most studies were published in abstract form with small numbers of patients. No single drug has been studied extensively in this setting. Benefits of second-line therapy seem to be modest, at the cost of drug toxicity, and randomized phase III trials are still needed. Future studies in the second-line setting should not only use response or overall survival as an outcome measure but should consider using clinical benefit as treatment endpoints. The incorporation of costs, cost-effectiveness analysis, and cost-benefit analysis into these studies should be considered as well.

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. According the American Cancer Society, about 37,680 new cases are anticipated in the year 2008, and 34,290 patients will die from the disease.[1] This malignancy is a very aggressive tumor, and patients often present with advanced-stage disease. Surgical resection, when possible, provides the only opportunity for cure. Even with R0 resection, pancreatic cancer still carries an overall dismal prognosis, and therefore adjuvant treatment is offered.

Treatment with the pyrimidine antagonist gemcitabine (Gemzar) has been the standard of care for metastatic pancreatic cancer for more than a decade, based on a phase III randomized trial in which 126 patients with advanced symptomatic pancreatic cancer were randomized to gemcitabine vs fluorouracil (5-FU). The primary endpoint of this study was clinical benefit, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. The investigators found a clinical benefit in 23.8% of gemcitabine-treated patients compared to 4.8% of 5-FU–treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU–treated patients, respectively (P = .0025).[2]

Since then, multiple agents have been tested in combination with gemcitabine in order to Table 1improve overall outcome in patients with metastatic pancreatic cancer, with limited success. In a randomized phase III trial, the combination of gemcitabine and erlotinib (Tarceva) led to a median survival of 6.24 months compared to 5.91 months in the gemcitabine-only arm, which was statistically significant.[3] That said, the meaning of a 2-week survival difference at the expense of increased toxicity and cost might not be significant.

Capecitabine (Xeloda), a prodrug of 5-FU, has also been combined with gemcitabine in phase III trials in patients with metastatic pancreatic cancer. Preliminary results of one such study were presented at the 13th annual European Cancer Conference (ECCO) in 2005 and reportedly demonstrated a survival benefit for combined therapy over gemcitabine alone.[4] However, the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group did a similar study with the same combination and failed to show any survival benefits; median overall survival was 8.4 months in the combination arm vs 7.2 months in the single-agent arm. (P = .234).[5] Other gemcitabine combinations failed to show any benefits compared to gemcitabine alone.

Gemcitabine is also widely used in the adjuvant setting, based on data from the Charit Onkologie (CONKO) study. In this open, multicenter, randomized controlled phase III trial, patients who received gemcitabine after resection had a significantly longer median disease-free survival and a trend toward improved overall survival compared to observation.[6]

To date, the role of second-line treatment after gemcitabine failure is unclear, and no standard treatment approach has been defined. In this review, we summarize the published results of second-line treatment in patients with pancreatic cancer, and discuss future strategies. We identified 9 single-agent studies (5 in abstract form only) and 24 multidrug studies (13 in abstract form only). The regimens used, response rates, and progression-free and overall survival data are summarized in Tables 1, 2, and 3.

Second-Line Therapy for Metastatic Pancreatic Cancer

Progression-free survival is generally short in pancreatic cancer. A large percentage of patients with metastatic and resected pancreatic cancer who were treated with gemcitabine will be in relatively good clinical condition when their disease relapses, and they will require second- and even third-line therapy.

Benefit from second-line treatment vs best supportive care alone was suggested in a preliminary report of a randomized phase II trial in which 46 (out of a planned 165) patients with gemcitabine-refractory pancreatic cancer were randomized to best supportive care with or without chemotherapy (5-FU, leucovorin, and oxaliplatin [Eloxatin] combination).[7] The chemotherapy group had a significantly longer median overall survival (40 vs 34 weeks, P = .0312).

Although many regimens have shown modest activity in the second-line treatment of pancreatic cancer, it is not clear whether that modest response translates into survival or clinical benefit.

Cytotoxic Agents

Platinum Drugs

Platinum compounds have been used in the first-line treatment of pancreatic cancer with modest activity, which has encouraged their use in the salvage setting. As presented at the 2007 American Society of Clinical Oncology (ASCO) annual meeting, pooled data and meta-analysis showed an overall survival benefit of a platinum-based regimen in the first-line treatment of metastatic pancreatic cancer.[8]

Oxaliplatin, because of its better toxicity profile, was used in combination with thymidylate synthetase inhibitors such as 5-FU or capecitabine in gemcitabine-refractory pancreatic cancer. Doses of oxaliplatin ranged from 85 to 130 mg/m2. Response rates ranged from 3% to 23%,[7,9-11] with median overall survival ranging from 20 to more than 48 weeks. These combinations produced grade 3/4 gastrointestinal (GI) toxicities, neutropenic fever, and neuropathy.

Oxaliplatin has also been used in combination with raltitrexed (Tomudex)[12] and gemcitabine.[13] Response rates were modest (24% at best), with a median survival of approximately 20 weeks. This combination produced significant GI and hematologic toxicities.

Gemcitabine was used with platinum compounds as a salvage regimen in gemcitabine-pretreated patients. Combining gemcitabine and cisplatin with regional hyperthermia in 12 patients showed an encouraging time to disease progression and median 1-year event-free survival.[14,15] Gemcitabine was also used in combination with oxaliplatin in a phase II trial of 33 patients.[13] The response rate was 23%, and overall survival was approximately 26 weeks. Toxicities included neuropathy as well as GI and hematologic effects.

Riess et al[16] reported promising results at the annual ASCO meeting in 2007. Patients were randomized to 5-FU at 2 g/m2 and leucovorin at 200 mg/m2 on days 1, 8, 15, and 22 (FF regimen) vs FF plus oxaliplatin, 85 mg/m2, on days 8 and 22. The preliminary overall survival result favored the oxaliplatin arm.

In trials using platinum compounds, many did not report any data about quality-of-life measures during and after treatment. In the study by Reni et al,[12] 71% of patients completed a quality-of-life questionnaire and more than a 40% improvement was observed in health-care satisfaction, body image, fear for future health, and pain. These measures, however, were not specifically validated to reflect quality of life in this population. In another study combining liposomal cisplatin with gemcitabine in previously treated patients with pancreatic cancer,[15] authors reported clinical benefits in 33% of patients for a median of 3 months.

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