Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer death and is associated with an extremely poor prognosis: The 5-year survival probability is less than 5% for all stages combined. The only chance for cure or longer survival is surgical resection; however, only approximately 10% to 20% of patients with pancreatic cancer have resectable disease, and even though surgical techniques have improved, most patients who undergo complete resection experience a recurrence. Adjuvant systemic therapy is used to reduce the recurrence rate and improve the outcome of resected pancreatic tumors. There is also a potential role for radiation therapy as part of the treatment for locally advanced disease, although its use in both the adjuvant and neoadjuvant settings remains controversial.
The majority of patients with PC (80%) present with a locally advanced tumor or metastatic disease, and thus palliative systemic therapy, and, in some cases, chemoradiotherapy (CRT) remain the only options for almost all of these patients. Although the use of gemcitabine has been shown to improve survival compared with best supportive care, PC has been relatively resistant to all systemic therapies, including hormonal therapy and cytotoxic chemotherapy. In the last decade, drug development has included a focus on the combination of cytotoxic agents, but this approach has so far not led to a major impact in the clinic. Newer drugs have assessed the efficacy of targeted therapies through the inhibition of important pathways that are involved in the proliferation, invasion, and metastasis of pancreatic tumor cells.
There is growing evidence that the exceptionally poor prognosis in PC is caused by the tumor’s characteristic abundant desmoplastic stroma that plays a critical role in tumor cell growth, invasion, metastasis, and chemoresistance. Carefully designed clinical trials that include translational analysis will provide a better understanding of the tumor biology and its relation to the host stromal cells. Future drug development will involve testing new targeted agents, investigating the efficacy of different combinations strategies, and looking for predictive and prognostic biomarkers.
Treatment of Resectable Disease
Adjuvant Chemoradiation
Surgical resection is the only curative treatment for patients with PC, yet only 10% to 15% of patients have a resectable tumor at the time of diagnosis. Moreover, after surgery, the 5-year survival is less than 20%. In this context, adjuvant chemotherapy, with or without radiotherapy, is the recommended approach after surgery to improve both locoregional control and overall survival (OS).
Several trials have analyzed the efficacy of CRT after pancreaticoduodenectomy ( Table 1 ). The Gastrointestinal Tumor Study Group (GITSG) was the first to document that adjuvant CRT after surgical resection prolonged survival. In this study, radiation was administered in combination with bolus 5-fluorouracil (5-FU) and was followed by maintenance 5-FU. Although the study was terminated prematurely because of a low rate of accrual, a survival advantage was demonstrated for the patients who received the combination treatment in comparison with patients who were treated with surgery alone. A subsequent nonrandomized study by the GITSG confirmed the support for the use of adjuvant CRT, rather than either radiation therapy alone or surgery alone, for patients with resectable disease.
| Study Year | No. of Patients | Protocol Treatments | Median Survival (mos) | P -Value |
|---|---|---|---|---|
| GITSG, 1985 | 49 | CRT (5-FU bolus) Surgery alone | 20 11 | .01 |
| EORTC, 1999 | 218 | CRT (5-FU CI) Surgery alone | 17.1 12.6 | .049 |
| ESPAC1, 2001 | 541 | CT (5-FU bolus) CRT (5-FU bolus) CRT+CT Surgery alone | 19.7 (CT) 14 (non CT) 15.1 (CRT) 16.1 (non CRT) | .005 |
| RTOG 97-04, 2008 | 451 | 5-FU+CRT Gemcitabine+CRT | 16.9 20.5 | .09 |
| CONKO-001, 2007 | 179 175 | Gemcitabine Observation | 22.8 20.2 | .005 |
| ESPAC-3, 2010 | 1088 | 5-FU Gemcitabine | 23 23.6 | .39 |
The European Organization for Research and Treatment of Cancer conducted a trial in which 218 patients with pancreatic and nonpancreatic periampullary adenocarcinoma were randomized to either observation alone or to a combination of radiotherapy and 5-FU (administered as a continuous infusion) after potentially curative resection. No additional postradiation chemotherapy was administered. The preliminary analysis did not find a significant benefit to adjuvant chemoradiation; however, a subsequent statistical reanalysis demonstrated a significant survival improvement with the combination treatment for patients with pancreatic head cancers.
In contrast, the controversial results of the European Study Group for Pancreatic Cancer (ESPAC-1) suggested a detrimental effect on survival with adjuvant CRT compared with adjuvant chemotherapy or surgery alone. In this 4-arm trial, 541 patients were randomized, based on a 2 × 2 factorial design, to one of the following arms: (1) Observation, (2) concomitant CRT alone with 500 mg/m 2 of 5-FU IV bolus during the first 3 days of radiation therapy and repeated after a planned 2-week break, (3) chemotherapy alone with leucovorin, 20 mg/m 2 bolus plus 5-FU, 425 mg/m 2 administered for 5 consecutive days and repeated every 28 days for 6 cycles, or (4) CRT followed by chemotherapy. No difference was found in survival between patients assigned to CRT (median survival, 15.5 months) versus observation (median survival, 16.1 months; P = .24). A trend to a survival advantage for those patients treated with chemotherapy alone (median survival, 17.4 months) versus observation alone (15.9 months; P = .19) was described. Despite criticisms of the study design, including criticism of the enrollment criteria and radiation therapy techniques, the authors concluded that adjuvant CRT did not offer any OS advantage, whereas a potential benefit existed for adjuvant chemotherapy alone after surgical resection.
To determine if the addition of gemcitabine to adjuvant 5-FU chemoradiation improved survival for patients with resected PC, 451 patients were randomized to either 5-FU (250 mg/m 2 per day) or gemcitabine (1000 mg/m 2 weekly) for 3 weeks before CRT and for 12 weeks after CRT therapy (Intergroup/RTOG 97-04 phase III trial). Chemoradiation with a continuous infusion of 250 mg/m 2 per day 5-FU during radiation therapy was the same for all patients. In this phase III trial, patients with pancreatic head tumors had a median survival of 20.5 months in the gemcitabine groups versus a 16.9 months in the 5-FU group ( P = .09). Grade 4 hematologic toxicity was reported in 1% of the fluorouracil group and 14% of the gemcitabine group ( P <.001) without a difference in febrile neutropenia or infection. Although the survival improvement was not significant, the authors concluded that the addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected PC. A long-term follow-up of this trial was recently published. The 5-year results of this study demonstrate that the previously observed improvement in 3-year OS with the addition of gemcitabine to adjuvant fluorouracil-based CRT for patients with pancreatic head tumors was not seen at 5 years: OS was 22% with gemcitabine versus 18% with 5-FU. A trend toward significance in improvement of OS in the gemcitabine arm was seen on a multivariate analysis ( P = .08).
Several institutions have prospectively or retrospectively demonstrated the utility of adjuvant CRT compared with surgery alone. The Johns Hopkins Hospital–Mayo Clinic Collaborative Study recently reported a large collaborative analysis of 1092 patients who underwent resection with curative intent. Compared with the OS for those undergoing surgery alone, the OS was longer for recipients of CRT (median OS 21.1 vs 15.5 months; P >.001). In the multivariate analysis, after adjusting for different variables, OS remained superior for patients treated with adjuvant CRT compared with those who received surgery alone.
The European Organization for Research and Treatment of Cancer’s phase II trial assessed the toxicity of gemcitabine followed by gemcitabine concurrent with radiation. The results showed that adjuvant gemcitabine followed by the combination of gemcitabine and radiation (50.4 Gy) was feasible and only slightly more toxic than gemcitabine alone, pointing to a further evaluation of this multimodal approach in a phase III trial.
Adjuvant Chemotherapy
To test the hypothesis that gemcitabine after resection improves disease-free survival, the CONKO-001 study randomized 368 (354 were elegible for intent-to-treat-analysis) patients with completely resected PC to 6 cycles of gemcitabine or surgery alone. The study demonstrated a significant improvement in its primary endpoint of disease-free survival for patients receiving postoperative gemcitabine (13.4 vs 6.9 months; P <.001) but without an improvement in OS (22.1 vs 20.2 months; P = .06). However, the recently reported 5-year results demonstrated a significant improvement in OS with a median and 5-year survival rate of 22.8 months and 21% in the gemcitabine arm and 20.2 months and 9% in the surgery alone arm ( P = .005).
The ESPAC-3 phase III randomized trial was designed to determine whether fluorouracil or gemcitabine is superior in terms of OS as adjuvant treatment after resection of PC. A total of 1088 patients were randomized to receive either gemcitabine or 5-FU plus folinic acid. In contrast with the findings for nonresected advanced PC, there was no significant difference in OS between patients treated with postoperative adjuvant 5-FU plus folinic acid and patients who were treated with gemcitabine. However, gemcitabine showed a superior toxicity profile with fewer treatment-related serious adverse events (7.5%) compared with 14% of patients receiving 5-FU plus folinic acid ( P <.001). The lower toxicity and the ease of administration of gemcitabine in a weekly treatment schedule led to consideration of this treatment as the standard of care for most patients (see Table 1 ).
Although a growing body of literature indicates a benefit of adjuvant treatment in localized PC after a potentially curative resection, the vast majority of tumors recur and the patients succumb to their disease a short time after diagnosis.
To summarize, strong evidence from randomized trials suggest that adjuvant chemotherapy (gemcitabine or 5-FU) is the standard treatment option. However, there remains controversy regarding the role of adjuvant CRT. Future clinical trials exploring different adjuvant chemotherapy or chemoradiation schedules, as well as the integration of novel cytotoxic and targeted agents, could elucidate which is the best option to improve the outcome for patients with resected PC. The ESPAC-4 trial is evaluating the addition of the oral fluropyrimidine, capecitabine, to gemcitabine after resection of localized PC. The RTOG0848 trial will analyze whether both erlotinib and fluoropyrimidine-based chemoradiation improves the survival of patients treated with gemcitabine as adjuvant treatment for patients with resected head of PC.
Preoperative Chemoradiation
Neoadjuvant, or preoperative, therapy has been used to improve survival in resectable PC. There are several reasons to consider a neoadjuvant approach, such as:
- 1
Early treatment of micrometastasis disease;
- 2
Extension of potentially curative treatment to patients with borderline disease;
- 3
Increasing the rates of negative margin resections and decrease local failure rates; and
- 4
Improving the selection of patients for whom resection will not offer a survival benefit.
A rigorous meta-analysis of 56 phase I and II trials studying the effect of neoadjuvant therapy was completed. Interestingly, for patients with resectable tumors who received neoadjuvant therapy, resection frequencies and survival after neoadjuvant therapy were similar to those patients with primarily resected tumors treated with adjuvant therapy, showing no advantage of neoadjuvant therapy for patients with resectable tumors. However, among patients with initially staged unresectable tumors, one third were resected after neoadjuvant therapy, with survival comparable with those patients with initially resectable tumors.
Recently, a large pancreatic series from the California Cancer Surveillance Program for Los Angeles County retrospectively identified 458 patients with nonmetastatic PC who underwent definitive pancreatic resection and received systemic chemotherapy. In contrast with the conclusions of the meta-analysis, patients who received neoadjuvant therapy presented a lower rate of lymph node positivity (45%) and improved OS (34 months) compared with the adjuvant group of patients (65% [ P = .11] and 19 months [ P = .003], respectively). In the multivariate analysis, neoadjuvant therapy remained an independent predictor of improved survival ( P = .013). The authors suggested that this strategy should be considered an acceptable alternative to the initial surgery treatment in operable PC.
To summarize, although neoadjuvant CRT can be administered safely, the recommended practice for resectable disease outside the clinical trial setting should be surgery followed by adjuvant chemotherapy with or without radiation.
Treatment of Locally Advanced Disease
Thirty percent of patients with PC present with a locally advanced unresectable primary tumor. Locally advanced PC is most commonly described by T4 lesions, in which the primary tumor involves branches of the celiac axis or the superior mesenteric artery. The standard treatment for locally advanced PC can involve CRT, which has been highly debated over the last 30 years, or chemotherapy alone.
Several prospective, randomized trials have shown a benefit with chemoradiation compared with best supportive care, radiation, or chemotherapy alone in the management of locally advanced disease ( Table 2 ).
| Study Year | No. of Patients | Protocol Treatments | Median Survival (mos) | P -Value |
|---|---|---|---|---|
| CRT vs best supportive care | ||||
| Shinchi, 2002 | 31 | CRT (50.8 Gy + 5-FU) Best supportive care | 13 6.4 | <.01 |
| CRT vs RT | ||||
| Moertel, 1981 | 194 | RT (60 Gy) CRT (40 Gy + 5-FU) CRT (60 Gy + 5-FU) | 5.3 9.7 9.3 | <.01 |
| Cohen, 2005 | 108 | RT(59.4 Gy) CRT (50.4 Gy + 5-FU + MMC) | 7.1 8.4 | .16 |
| CRT vs CT | ||||
| GITSG, 1988 | 43 | CT (5-FU + streptomycin + MMC) CRT (54 Gy + 5-FU) | 7.4 9.7 | NA |
| Hazel, 1981 | 30 | CT (5-FU + lomustine) CRT (46 Gy + 5-FU) | 7.8 7.3 | NA |
| Klaasen, 1985 | 91 | CT (5-FU) CRT (40 Gy + 5-FU) | 8.2 8.3 | NA |
| Chauffert, 2007 | 119 | CT (gemcitabine) CRT (60 Gy + 5-FU + cisplatin) | 13 8.6 | .03 |
| Loherer, 2008 | 74 | CT (gemcitabine) CRT (50.4 Gy + gemcitabine) | 9.2 11 | .044 |
Only 1 randomized trial, including 31 patients, compared CRT (continuous infusion of 5-FU at 200 mg/m 2 per day concomitantly with a planned total dose of 50.4 Gy) with best supportive care. The study results demonstrated a significant benefit of CRT for OS ( P <.001) and quality of life ( P <.001).
The earliest trial, published in 1969 by the GITSG, included patients randomized to receive either 35 to 40 Gy radiation plus 5-FU or the same radiation therapy plus a placebo. Although this study included patients with different types of GI cancers, the median survival in the combined modality arm was significantly higher than in the radiation therapy only arm (10.4 vs 6.3 months). In 1981, Moertel and colleages published a study in which 194 patients with locally advanced PC were randomized to receive a split-course radiation schedule, either alone (60 Gy) or combined with 5-FU (500 mg/m 2 on the first 3 days of each 20 Gy radiation). The combined modality arms (60Gy plus 5-FU or 40Gy plus 5-FU) showed an improved median time-to-tumor progression, as well as improved OS (9.7 and 9.3 vs 5.3 months in the radiotherapy arm; P <.01). A study comparing standard radiotherapy (59.4 Gy) with CRT using mitomycin and 5-FU showed no difference between the 2 arms (8.4 months for CRT vs 7.1 months for radiotherapy; P <.16). In both trials, higher hematologic and digestive toxicities were presented in the CRT arms.
Several randomized trials compared CRT to chemotherapy alone. In the first 3 trials, published before 1990, CRT (doses ranging from 40 to 54 Gy) was compared with different chemotherapy regimens, including 5-FU; lomustine and 5-FU; and streptomycin, mitomycin and 5-FU. Only the GITSG study, using mitomycin and 5-FU, showed a significant improvement in median survival (9.7 vs 7.4 months) for the chemoradiation arm, with a higher 1-year survival rate (41% vs 19% in the chemotherapy group; P <.02). Therefore, the use of different chemotherapy agents with radiation therapy failed to demonstrate a survival advantage compared with 5-FU, which tends to have less toxicity.
The clinical benefits of gemcitabine in the metastatic setting and its radiosensitizing properties have merited the exploration of this agent’s use in locally advanced PC. In the recent French FFCD-SFRO study, CRT was delivered to a total dose of 60 Gy concurrently with cisplatin (20 mg/m 2 during weeks 1 and 5 of radiotherapy) and 5-FU (continuous infusion at 300 mg/m 2 per day). The patients in the chemotherapy arm were treated with gemcitabine (1000 mg/m 2 per week). In contrast with the initial hypothesis of the trial, OS was shorter in the CRT arm. Higher grade 3 to 4 toxicity rates were observed in the CRT arm compared with the chemotherapy arm (66% vs 40%, respectively).
The ECOG phase III trial (E4201), comparing gemcitabine (600 mg/m 2 weekly) plus radiotherapy (50.4 Gy) followed by weekly gemcitabine (1000 mg/m 2 weekly, 3 of 4 weeks) with gemcitabine alone, was prematurely closed owing to low recruitment. With 74 patients included, a higher median OS was observed in the CRT arm (11 vs 9.2 months; P <.044).
Two meta-analyses that included most of the studies previously mentioned compared CRT with exclusive radiotherapy and CRT with chemotherapy alone in patients with locally advanced PC. Although, there is a significant variability between the different studies analyzed, the main conclusions of the meta-analyses were that:
- 1
CRT increase OS compared with radiotherapy alone; and
- 2
OS was not significantly different between CRT and chemotherapy alone.
Two retrospective studies have shown a potential survival improvement of induction chemotherapy before CRT. This strategy may improve selection of those patients who benefit from CRT after a short course of chemotherapy. The phase III trial LAP07 being conducted by the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) may help to clarify the role of induction chemotherapy. In this ongoing study, patients with a controlled tumor after the first 4 months of induction chemotherapy are randomly assigned between CRT and 2 additional cycles of chemotherapy.
In conclusion, the optimal treatment for locally advanced PC remains controversial. CRT increases OS when compared with exclusive radiotherapy or best supportive care, but survival does not change for patients treated with CRT when compared with patients treated with chemotherapy with gemcitabine. The addition of CRT after 3 to 4 months of induction chemotherapy is a promising approach that has to be validated in prospective trials.
Treatment of Locally Advanced Disease
Thirty percent of patients with PC present with a locally advanced unresectable primary tumor. Locally advanced PC is most commonly described by T4 lesions, in which the primary tumor involves branches of the celiac axis or the superior mesenteric artery. The standard treatment for locally advanced PC can involve CRT, which has been highly debated over the last 30 years, or chemotherapy alone.
Several prospective, randomized trials have shown a benefit with chemoradiation compared with best supportive care, radiation, or chemotherapy alone in the management of locally advanced disease ( Table 2 ).
| Study Year | No. of Patients | Protocol Treatments | Median Survival (mos) | P -Value |
|---|---|---|---|---|
| CRT vs best supportive care | ||||
| Shinchi, 2002 | 31 | CRT (50.8 Gy + 5-FU) Best supportive care | 13 6.4 | <.01 |
| CRT vs RT | ||||
| Moertel, 1981 | 194 | RT (60 Gy) CRT (40 Gy + 5-FU) CRT (60 Gy + 5-FU) | 5.3 9.7 9.3 | <.01 |
| Cohen, 2005 | 108 | RT(59.4 Gy) CRT (50.4 Gy + 5-FU + MMC) | 7.1 8.4 | .16 |
| CRT vs CT | ||||
| GITSG, 1988 | 43 | CT (5-FU + streptomycin + MMC) CRT (54 Gy + 5-FU) | 7.4 9.7 | NA |
| Hazel, 1981 | 30 | CT (5-FU + lomustine) CRT (46 Gy + 5-FU) | 7.8 7.3 | NA |
| Klaasen, 1985 | 91 | CT (5-FU) CRT (40 Gy + 5-FU) | 8.2 8.3 | NA |
| Chauffert, 2007 | 119 | CT (gemcitabine) CRT (60 Gy + 5-FU + cisplatin) | 13 8.6 | .03 |
| Loherer, 2008 | 74 | CT (gemcitabine) CRT (50.4 Gy + gemcitabine) | 9.2 11 | .044 |
Only 1 randomized trial, including 31 patients, compared CRT (continuous infusion of 5-FU at 200 mg/m 2 per day concomitantly with a planned total dose of 50.4 Gy) with best supportive care. The study results demonstrated a significant benefit of CRT for OS ( P <.001) and quality of life ( P <.001).
The earliest trial, published in 1969 by the GITSG, included patients randomized to receive either 35 to 40 Gy radiation plus 5-FU or the same radiation therapy plus a placebo. Although this study included patients with different types of GI cancers, the median survival in the combined modality arm was significantly higher than in the radiation therapy only arm (10.4 vs 6.3 months). In 1981, Moertel and colleages published a study in which 194 patients with locally advanced PC were randomized to receive a split-course radiation schedule, either alone (60 Gy) or combined with 5-FU (500 mg/m 2 on the first 3 days of each 20 Gy radiation). The combined modality arms (60Gy plus 5-FU or 40Gy plus 5-FU) showed an improved median time-to-tumor progression, as well as improved OS (9.7 and 9.3 vs 5.3 months in the radiotherapy arm; P <.01). A study comparing standard radiotherapy (59.4 Gy) with CRT using mitomycin and 5-FU showed no difference between the 2 arms (8.4 months for CRT vs 7.1 months for radiotherapy; P <.16). In both trials, higher hematologic and digestive toxicities were presented in the CRT arms.
Several randomized trials compared CRT to chemotherapy alone. In the first 3 trials, published before 1990, CRT (doses ranging from 40 to 54 Gy) was compared with different chemotherapy regimens, including 5-FU; lomustine and 5-FU; and streptomycin, mitomycin and 5-FU. Only the GITSG study, using mitomycin and 5-FU, showed a significant improvement in median survival (9.7 vs 7.4 months) for the chemoradiation arm, with a higher 1-year survival rate (41% vs 19% in the chemotherapy group; P <.02). Therefore, the use of different chemotherapy agents with radiation therapy failed to demonstrate a survival advantage compared with 5-FU, which tends to have less toxicity.
The clinical benefits of gemcitabine in the metastatic setting and its radiosensitizing properties have merited the exploration of this agent’s use in locally advanced PC. In the recent French FFCD-SFRO study, CRT was delivered to a total dose of 60 Gy concurrently with cisplatin (20 mg/m 2 during weeks 1 and 5 of radiotherapy) and 5-FU (continuous infusion at 300 mg/m 2 per day). The patients in the chemotherapy arm were treated with gemcitabine (1000 mg/m 2 per week). In contrast with the initial hypothesis of the trial, OS was shorter in the CRT arm. Higher grade 3 to 4 toxicity rates were observed in the CRT arm compared with the chemotherapy arm (66% vs 40%, respectively).
The ECOG phase III trial (E4201), comparing gemcitabine (600 mg/m 2 weekly) plus radiotherapy (50.4 Gy) followed by weekly gemcitabine (1000 mg/m 2 weekly, 3 of 4 weeks) with gemcitabine alone, was prematurely closed owing to low recruitment. With 74 patients included, a higher median OS was observed in the CRT arm (11 vs 9.2 months; P <.044).
Two meta-analyses that included most of the studies previously mentioned compared CRT with exclusive radiotherapy and CRT with chemotherapy alone in patients with locally advanced PC. Although, there is a significant variability between the different studies analyzed, the main conclusions of the meta-analyses were that:
- 1
CRT increase OS compared with radiotherapy alone; and
- 2
OS was not significantly different between CRT and chemotherapy alone.
Two retrospective studies have shown a potential survival improvement of induction chemotherapy before CRT. This strategy may improve selection of those patients who benefit from CRT after a short course of chemotherapy. The phase III trial LAP07 being conducted by the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) may help to clarify the role of induction chemotherapy. In this ongoing study, patients with a controlled tumor after the first 4 months of induction chemotherapy are randomly assigned between CRT and 2 additional cycles of chemotherapy.
In conclusion, the optimal treatment for locally advanced PC remains controversial. CRT increases OS when compared with exclusive radiotherapy or best supportive care, but survival does not change for patients treated with CRT when compared with patients treated with chemotherapy with gemcitabine. The addition of CRT after 3 to 4 months of induction chemotherapy is a promising approach that has to be validated in prospective trials.
Treatment of Metastatic and Recurrent Disease
Single Agent
The standard treatment for patients with advanced metastatic or recurrent PC is systemic chemotherapy. However, responses rates (RR) to the current available drugs are low and treatment should be considered palliative. For many years, the most active chemotherapeutic agent used in the treatment for patients with advanced PC has been 5-FU. In different phase II studies, patients treated with 5-FU achieved a RR from 0% to 20% with a median survival of 4 to 5 months. The modulation of 5-FU with other agents, such as leucovorin, did not show clear evidence of increased RR in phase II studies. Many subsequent studies were developed to evaluate different 5-FU combinations; however, in randomized phase III studies, the survival of patients treated with 5-FU alone was not different from that of patients treated with more aggressive and more toxic chemotherapeutic regimens.
In 1997, a randomized phase III clinical trial compared gemcitabine with 5-FU in 126 patients with advanced metastatic PC who had not received prior systemic therapy ( Table 3 ). Patients were randomized to receive gemcitabine (800 mg/m 2 as a 30-minute intravenous injection weekly for 3 consecutive weeks followed by 1 week of rest) or 5-FU (600 mg/m 2 once a week). Although the RR was 5.4% for gemcitabine and 0% for 5-FU, a positive clinical benefit response (a combination of performance status, analgesic usage, and measurements of pain) was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU–treated patients ( P = .002). There was an overall disease control rate (partial response plus stable disease) of 45% with gemcitabine versus 19% with 5-FU. The median times-to-tumor progression were 3.8 and 1.9 months and the median survival durations were 5.7 and 4.4 months for gemcitabine and 5-FU–treated patients, respectively ( P = .002). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Because of these results, gemcitabine was approved as first-line treatment of metastatic PC in the United States and many other countries and currently is considered the standard agent for the treatment of this disease.
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