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Keywords:

  • pancreatic cancer;
  • gemcitabine;
  • 5-fluorouracil;
  • radiation;
  • combined modality therapy

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

The purpose of this study was to assess the efficacy and safety of 5-fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer.

METHODS:

Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m2 5 days/week) and weekly gemcitabine (200 mg/m2). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m2 for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity.

RESULTS:

Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events.

CONCLUSIONS:

The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation. Cancer 2011;. © 2010 American Cancer Society.

Pancreatic cancer, the fourth leading cause of cancer death in the United States, 1 remains one of the most treatment-refractory solid malignancies. Approximately 40% of patients with newly diagnosed pancreatic cancer present with locally advanced, nonmetastatic disease.

In 2 randomized trials by the Gastrointestinal Tumor Study Group, the combination of fluorouracil and external beam radiation was shown to be more effective than either modality alone, with a median overall survival of approximately 42 weeks. 2-4 An Eastern Cooperative Oncology Group (ECOG) study, however, failed to demonstrate an advantage of combined modality therapy. 5 The French FFCD-SFRO trial suggested a detriment in survival when combined chemoradiation therapy was compared with gemcitabine alone. 6 However, in this intensive regimen, increased toxicity may have contributed to poor outcome. Despite these conflicting results, efforts over the past 3 decades have attempted to improve the efficacy of chemoradiation, largely by incorporating more active systemic therapy.

Among patients with metastatic or locally advanced pancreatic cancer, gemcitabine therapy has led to a superior clinical benefit when compared with 5-fluorouracil (5FU). 7 Because gemcitabine has been shown to enhance the sensitivity of human pancreatic cancer cells to radiation, 8, 9 several investigators have assessed the impact of gemcitabine when combined with radiation. Most investigators combined lower doses of gemcitabine with conventional radiation. 10-20 An alternative approach has been to combine full-dose gemcitabine with a hypofractionated course of radiation. 21-23 Several groups have combined radiation and gemcitabine with additional agents, including cisplatin, 24-29 oxaliplatin, 30 taxanes, 31, 32 irinotecan, 33 mitomycin, 34 and inhibitors of epidermal growth factor receptor and vascular endothelial growth factor. 35-39

Because 5FU and gemcitabine are both active radiation-sensitizing agents and represent the 2 principal systemic agents for pancreatic cancer, we conducted a phase 1/2 trial combining 5FU, gemcitabine, and radiation in patients with locally advanced disease. The regimen appeared well tolerated, with maximum tolerated doses of 200 mg/m2/day for infusional 5FU and 200 mg/m2/week for gemcitabine with 50.4 Gy of radiation. More recently, Wilkowski et al 40 reported a similar experience in a group of 32 patients, with a median survival of over 13 months. In contrast, a similar phase 1 study of concurrent 5FU, gemcitabine, and radiation led by the ECOG reported unacceptable toxicity. 41 Five of the 7 treated subjects experienced dose-limiting toxicities, 3 of which involved gastrointestinal (GI) bleeding. To clarify the safety and efficacy of this combination, we conducted a multi-institutional phase 2 trial of 5FU, gemcitabine, and external beam radiation therapy in patients with locally advanced pancreatic cancer.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patient Eligibility Criteria

Eligible patients had biopsy-proven, localized, unresectable adenocarcinoma of the pancreas and an ECOG performance score of 0-2. Criteria for unresectability and eligibility included 1 or more of the following: tumor size >5 cm; regional lymph node size >2 cm that could be included within the radiation port; involvement of major vessels, including the superior mesenteric artery, superior mesenteric vein, portal vein, and hepatic artery; and direct extension of tumor to adjacent organs. Staging studies included a chest x-ray and an abdominal/pelvic computed tomography scan; patients underwent a laparotomy or laparoscopy to rule out the presence of occult peritoneal disease. Exclusion criteria included a prior malignancy other than nonmelanoma skin cancer or in situ cervical cancer within the past 5 years, or other major comorbidities such as myocardial infarction within 6 months of study entry. Required laboratory values included a total bilirubin level <2.0 mg/dL, aspartate aminotransferase level ≤3 times the upper limit of normal, creatinine level ≤2.0 mg/dL, white blood cell count ≥3000/mm3, and platelet count ≥100,000/mm3. All patients signed a consent form, and the study was approved by the Human Investigations Committee of each participating Cancer and Leukemia Group B (CALGB) institution.

Study Design and Treatment Plan

This was an open-label, nonrandomized phase 2 study. Cycle 1 consisted of radiation at 50.4 Gy in 28 fractions over 5.5 weeks, with 5FU given as a continuous infusion from Monday through Friday at 200 mg/m2/day and gemcitabine given weekly at 200 mg/m2, both given throughout the radiation therapy course. Three weeks after the completion of radiation, patients received gemcitabine at a dose of 1000 mg/m2 over 30 minutes weekly for 3 weeks, followed by a 1-week rest, for 4 4-week cycles.

Radiation was delivered on a linear accelerator with a minimum energy of 6 MV. Patients were simulated on a machine that reproduced the geometry of the treatment machine; multifield techniques were mandatory. Doses were specified to isocenter. Patients were treated to 4500 cGy in 25 fractions to an initial tumor/nodal field, followed by a boost field for an additional 540 cGy in 3 fractions. The gross tumor volume (GTV) included the pancreatic mass and any lymph nodes measuring >1.5 cm as visualized on computed tomography scan. The clinical target volume (CTV) was defined by expanding the GTV for 1-1.5 cm, including the porta hepatic and pancreaticoduodenal nodes for head lesions, and the celiac axis for tumors of both the head and body/tail. The planning target volume (PTV) was based on a 1-cm expansion of the CTV. The boost volume consisted of the GTV with a 1-cm expansion for the boost PTV. Normal tissue constraints included no portion of the spinal cord receiving >4500 cGy, no more than 50% of the combined renal volume receiving >2000 cGy, and no more than 33% of the total liver volume receiving >3000 cGy. All treatment plans were reviewed by the Quality Assurance Review Center (QARC) in Providence, RI, and by the study chair.

Dose Modifications for Adverse Events

Adverse events were scored using version 2.5 of the Common Terminology Criteria for Adverse Events. During cycle 1, a decrease in the platelet count to between 50,000-99,999/mm3 and/or a decrease in the absolute neutrophil count (ANC) to 500-999/mm3 resulted in a 75% dose reduction for gemcitabine and a 50% dose reduction for 5FU. If the ANC decreased below 500/mm3 or the platelet count decreased below 50,000/mm3, chemotherapy and radiation were held until the ANC was ≥1000/mm3 and the platelet count was >100,000/mm3. If treatment was held for more than 3 weeks, the patient was removed from protocol treatment.

For nonhematologic events, both gemcitabine and 5FU were reduced to 75% of the dose for grade 3 toxicity and to 50% of the dose for grade 4 toxicities. Reduced doses of chemotherapy were not re-escalated. Because of concerns about GI bleeding raised by ECOG 2297, 42 stopping rules dictated study termination if more than 10 cases of grade 3 or higher GI bleeding were observed among the first 35 patients. The incidence of bleeding was followed in cohorts of 7 patients, with plans to stop accrual if any of the following proportions of patients had grade 3 or higher GI bleeds: 5 of 7, 6 of 14, 7 of 21, 9 of 28, or 11 of 35.

During cycles 2-5 (gemcitabine alone), the dose of gemcitabine was reduced by 25% for an ANC of 500-999/mm3 and held for an ANC <500/mm3. For grade 3 nonhematologic toxicities, gemcitabine was held and readminstered at a 25% dose reduction when the toxicity had resolved. For grade 4 nonhematologic adverse events, gemcitabine was held and readminstered at a 50% dose reduction when the toxicity had resolved. Dose reductions were continued through all subsequent cycles of gemcitabine.

Patient Monitoring

Patients were assessed weekly via history-taking and physical examination. Laboratory studies—including blood count, blood urea nitrogen, creatinine, bilirubin, aspartate aminotransferase, alkaline phosphatase, and CA19-9—were obtained weekly during combined chemoradiation and before each subsequent cycle of gemcitabine. Blood counts were assessed before each weekly administration of gemcitabine.

Statistical Analysis

The primary endpoint was the proportion of patients surviving nine months. Secondary endpoints included: overall survival (OS), measured from study entry to death from any cause; time-to-tumor progression (TTP), measured from study entry to documented progression of disease or death from any cause; CA19-9 response, defined as ≥75% decrease from the baseline maintained for 2 consecutive measurements at least 4 weeks apart among patients with an elevated baseline CA19-9; and toxicity. The prior protocol for patients with locally advanced pancreatic cancer, CALGB 89805, studied concurrent gemcitabine (40 mg/m2 twice weekly) and radiation therapy in a similar patient population. Based on the median survival of 8 months in that study, 17 it was determined that a median survival of ≤9 months in the current protocol would be considered unworthy of further investigation. An accrual goal of 78 evaluable patients to be followed for a minimum of 9 months was targeted, resulting in 80% power to distinguish between median survival rates of 9 and 13 months. If the 90% lower confidence bound estimate for the proportion of patients surviving 9 months were to exceed 0.5, the regimen would be considered for further investigation.

Patient registration and data collection were managed by the CALGB Statistical Center. Data quality was ensured via careful review of data by CALGB Statistical Center staff and by the study chairperson. All analyses were based on the study database frozen on March 3, 2009, and were performed by CALGB statisticians using SAS version 9.1 (SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patient Characteristics

Eighty-one patients from 15 institutions in the United States were accrued between November 2001 and October 2004, 78 of whom were eligible for analysis. Three patients who canceled their registration before starting any protocol treatment were excluded from the analysis. Pretreatment characteristics of the eligible patients are shown in Table 1. Thirty-six percent of patients underwent palliative bypass surgery before starting treatment, and 47% underwent the placement of a biliary stent. The majority of patients had stage T4 tumors with vascular involvement.

Table 1. Patient Characteristics
CharacteristicsNo. (%)
  1. All values are No. (%) unless indicated otherwise.

Sex
 Men39 (50)
 Women39 (50)
Race
 White70 (90)
 Hispanic American1 (1)
 African American or black6 (7)
 Asian1 (1)
Age
 Mean (SD)62.3 (9.8)
Performance status
 027 (34)
 14 (58)
 26 (8)
Size, cm
 Mean (SD)3.7 (1.7)
 Median (range)3.8 (0-8.8)
Grade
 Well-differentiated8 (10)
 Moderately differentiated19 (24)
 Poorly differentiated17 (22)
 Undifferentiated2 (3)
 Unknown32 (41)
Tumor stage
 213 (17)
 314 (18)
 451 (65)
Nodal stage
 050 (64)
 121 (27)
 X7 (9)
Location
 Head67 (87)
 Body16 (21)
 Tail5 (7)
Vessel involvement69 (89)
Baseline CA19-9
 Mean (SD)1288 (2130)
 Median (range)402 (3-10,854)

Efficacy

The median survival of the 78 eligible patients was 12.2 months (Figure 1, Table 2) with four patients reported alive at 39, 52, 58, and 60 months of follow-up. The estimated 1-year survival was 51% (95% confidence interval [CI], 0.4-0.62). The 90% lower confidence bound for the proportion of patients surviving 9 months was 0.64. The Kaplan-Meier survival estimate at 9 months was 73% (95% CI, 0.62-0.82). The probability of being progression-free (Figure 2, Table 2) was 0.54 (95% CI, 0.42-0.64) at 9 months and 0.40 (95% CI, 0.29-0.50) at 1 year. The median TTP was 10 months (95% CI, 6.4-12.0).

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Figure 1. Overall survival for all patients is shown.

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Figure 2. Time to progression for all patients is shown.

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Table 2. Survival and Time to Progression
Proportion of patients surviving 9 mo0.731
90% lower confidence bound0.64
Median follow-up time, mo
 No. of patients alive4
 Median (range)55.2 (38-60)
Overall survival
 No. of patients censored (%)4 (5.1)
 Kaplan-Meier estimate, 9-month  survival (95% CI)0.73 (0.62-0.82)
 Kaplan-Meier estimate, 12-month  survival (95% CI)0.51 (0.40-0.62)
Time to progression
 No. of patients censored (%)3 (3.8)
 3-month survival estimate (95% CI)0.90 (0.81-0.95)
 Kaplan-Meier estimate, 9-month  survival (95% CI)0.54 (0.42-0.64)
 Kaplan-Meier estimate, 12-month  survival (95% CI)0.40 (0.29-0.50)

Of the 56 patients with an elevated serum CA19-9 level at study baseline, 29 (52%) experienced a sustained CA19-9 response, defined as a >75% decrease lasting for at least 2 measurements more than 4 weeks apart. When compared with patients who did not experience a sustained CA19-9 response, patients with a sustained response exhibited a trend toward improved OS (median, 13 vs 9 months; P = 0.11) and a statistically significant improvement in TTP (median, 12.3 vs 5.7 months; P = 0.007) (Figures 3 and 4). Based on Response Evaluation Criteria in Solid Tumors, 19 (24%) patients experienced an objective response, of whom 5 (6%) had a complete response and 14 (18%) had a partial response. The median response duration was 5.5 months, with minimum and maximum durations of 1 and 52.2 months, respectively (including 12 patients with progressive disease and 4 patients who died without documented progression). In addition, 41 (53%) patients had stable disease as their best response, 14 (18%) patients had progressive disease, and 4 (5%) patients were unevaluable. The median time to objective response was 3.6 months (range, 1.7-9.0 months).

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Figure 3. Overall survival analyzed according to CA19-9 response is shown.

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Figure 4. Time to progression analyzed according to CA19-9 response is shown.

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Patterns of Failure

Twenty-eight (36%) of the patients had local progression in the pancreas as the first site of failure. The next most common site of disease progression was in the liver, which occurred in 23 (30%) patients, followed by the lung (8 patients [10%]) and peritoneum (7 patients [9%]).

Treatment Modifications

Twenty-seven patients (35%) completed all protocol therapy. The most common reason for discontinuing treatment was progressive disease, which occurred in 21 (27%) patients. Nine (12%) patients discontinued treatment because of adverse events. Other common reasons for discontinuing protocol treatment included being switched to nonprotocol therapy (9%) and patient refusal (9%).

A total of 64 patients (82%) had at least 1 treatment modification during the course of therapy at a mean of 22 days after beginning protocol treatment. Twenty-two patients had a single dose modification. The maximum number of dose adjustments was 5 (in 2 patients).

Radiotherapy Quality Assurance

All of the radiation therapy treatment plans were reviewed by QARC in Providence, RI, and by the study chair. Major deviations were defined as field borders that transected the gross tumor (GTV) or potential tumor-bearing areas (CTV). In addition, a dose discrepancy of more than 10% above or below the recommended dose at the prescription point, or exceeding the recommended dose to adjacent critical organs was considered a major deviation. Of the 78 patients who started radiation therapy, 65 were scored as appropriate, 3 had major deviations, and 7 had minor deviations. The remaining 3 patients were unevaluable due to insufficient data. Sixty-eight (87%) patients completed the planned 28 fractions to a total dose of 5040 cGy. Ten patients discontinued radiation, 1 each after 3, 4, 13, 21, 22, and 24 fractions, and 2 each after 25 and 26 fractions.

Adverse Events

Among the 78 patients, 55 (71%) experienced grade 3 or higher nonhematological adverse events possibly attributed to treatment and 50 (64%) patients experienced grade 3 or higher related hematological adverse events (Table 3). The most common nonhematological events were GI-related in 32 (41%) patients and constitutional and metabolic/laboratory-related in 19 (24%) patients each.

Table 3. Commonly Observed Treatment-Related Adverse Events, Grade 3 and Higher
CategoryGrade 3Grade 4Grade 5
  1. All data are presented as No. (%).

Blood/bone marrow40 (51)10 (13)0
 Hemoglobin6 (8)1 (1)0
 Total white blood cells30 (38)6 (8)0
 Lymphopenia20 (26)00
 Neutropenia16 (21)7 (9)0
 Thrombocytopenia11 (14)1 (1)0
 Transfusion: platelets1 (1)00
 Transfusion: packed red blood cells4 (5)00
Nonhematological47 (60)21 (27)2 (3)
 Cardiovascular (general)3 (4)1 (1)0
 Constitutional symptoms17 (22)2 (3)0
 Gastrointestinal29 (37)3 (4)0
 Hemorrhage2 (3)2 (3)1 (1)
 Hepatic7 (9)00
 Infection/febrile neutropenia8 (10)01 (1)
 Metabolic/laboratory17 (22)2 (3)0
 Neurology5 (6)00
 Pain8 (10)1 (1)0

Without regard to attribution, 11 patients (14%) had at least 1 episode of GI bleeding during the study or follow-up period, 5 of which were considered grade 3 or higher and possibly related to treatment. Neither a palliative surgical bypass nor placement of a stent correlated with an increased risk of GI bleeding. Five of these 11 gastrointestinal hemorrhages were localized within the radiation field.

Sixty-five (88%) of the deaths in the study population were secondary to disease progression. Two deaths (2%) were considered treatment-related, 1 resulting from GI bleeding and 1 resulting from sepsis without neutropenia. Three deaths resulted from causes other than treatment or disease.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

The benefit for treating locally advanced, nonmetastatic pancreatic cancer remains limited, with median survival ranging from 8 to 10 months.43 In the current study of 78 patients, a combination of gemcitabine and 5FU with radiation therapy conferred a median OS of 12.2 months and a median TTP of 10 months. In a previous phase 1/2 trial of gemcitabine, 5FU and concurrent radiation therapy, we similarly observed a median survival of 12 months in patients with locally advanced disease. These results compare favorably with previous studies of 5FU with radiation that have reported a median OS of 9 months and a median TTP of ≤8 months.

Subsequent studies have also yielded median survivals well above the historical level of 9 months. This gradual improvement in outcome over the past several years is apparent for studies of both radiation with gemcitabine10, 11, 14, 15, 17-23, 44 and other chemoradiation combinations.3, 27, 39, 40, 45-50 The reasons for this improvement are speculative, but they may include slightly improved treatment regimens, improved staging that excludes patients without easily apparent metastatic disease, improved supportive care, and improved salvage chemotherapy.

The current trial found the combination of 5FU and gemcitabine with concurrent radiation to be tolerable, though toxicity was moderate. Twelve percent of patients discontinued protocol therapy due to adverse events, and 82% had at least one treatment modification. Our incidence of adverse events was comparable with that of other recent cooperative group trials in this patient population, including a study of radiation with concurrent capecitabine and bevacizumab39 and a trial of radiation with concurrent gemcitabine and cisplatin.29 In contrast to a prior ECOG trial,51 the incidence and severity of GI bleeding was manageable.

Our trial met its target of 50% of patients surviving for at least 9 months; 9-month survival was 73% and median overall survival was 12.2 months. A similarly designed trial of 32 patients combining higher doses of weekly gemcitabine and infusional 5FU with radiation, followed by gemcitabine and cisplatin, observed a median OS of 13.6 months, although toxicity in that trial was considerable.40

The merits of combined chemoradiation as initial treatment for locally advanced pancreatic cancer have been questioned by the results of a recent randomized trial that demonstrated a superior outcome for patients receiving gemcitabine alone compared with chemoradiation followed by gemcitabine.6 An alternative approach has been examined in which patients receive initial chemotherapy, with chemoradiation offered only to those patients without disease progression. In a retrospective study of 188 patients who had received 3 months of initial chemotherapy, 128 patients who did not demonstrate progressive disease received either further chemotherapy or combined chemoradiation. Although such nonrandomized data must be interpreted with caution, the median progression-free survival and OS for the patients receiving chemoradiation were 10.8 and 15 months, respectively, compared with 7.4 and 11 months for those treated with chemotherapy alone.52 Other investigations have similarly suggested a benefit to selecting patients for combined chemoradiation after induction chemotherapy.53-55 Such an approach potentially avoids radiation in patients who are destined to manifest metastatic disease, limiting local therapy to those who are most likely to derive a benefit. One promising strategy for future studies may be to build on this schedule of induction chemotherapy followed by chemoradiation with the addition of targeted agents emerging from an improved understanding of pancreatic cancer biology.56-59

We have demonstrated the feasibility of combining both 5FU and gemcitabine with radiation, with several long-term survivors and a superior OS compared with historical levels of 8-10 months. Although this regimen has achieved the predefined goals of improving median survival beyond 9 months with acceptable morbidity, the observed median survival of 12 months is similar to the results of other recent phase 2 trials in patients with locally advanced pancreatic cancer. Given the many other treatment regimens that similarly appear to confer a 12-month median survival, we do not recommend further study of this treatment combination in future trials.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

The research for CALGB 80003 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman) and to the CALGB Statistical Center (Stephen George, PhD, CA33601). (See list of participating instutions for further CALGB grant information.) The research was also supported, in part, by a grant from Eli Lilly and Company. Richard Goldberg has financial interests in Sanofi Aventis, Amgen, and Astra Zeneca. William Blackstock has financial interests in Sanofi Aventis, Eli Lilly Oncology, and Sicel Technologies. Charles Fuchs has financial interests in Astra-Zeneca, Imclone, Amgen, Pozen, Genentech, Roche, Genomic Health, Alnylam, and Merck.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
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