The purpose of this study is to retrospectively compare the efficacy and tolerability between three regimens for first-line chemotherapy—gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM)—in patients with advanced pancreatic cancer.
There was a total of 127 patients who underwent chemotherapy for pancreatic cancer between January 2007 and November 2011 at our institution. Patients were treated with either GEM (gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks), GEM-T (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and erlotinib 100 mg daily), or GEM-X (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and capecitabine 850 mg/m2 twice daily for 2 weeks followed by 1 week’s rest) as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were evaluated.
The patient population was divided into groups depending on their first-line treatment: GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved ORR (21.2% vs. 12.7% and 15.9%), PFS (8.9 vs. 5.2 and 3.9 months; p < 0.001), and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. There were higher incidences of some non-hematologic adverse events with GEM-X and GEM-T compared to GEM, but most were grade 1 or 2.
GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in advanced pancreatic cancers. It is worthy to further investigate which agent has a clinical advantage as a combination drug with gemcitabine in pancreatic cancer and to explore the predictive markers leading to personalize anti-cancer treatment.
Pancreatic cancer is one of the most desperate cancers, causing approximately 266,000 deaths worldwide in 2008 [
Fifteen years ago, gemcitabine was used as a first-line chemotherapy to extend the overall survival (OS) to 5.65 months from 4.41 months in advanced pancreas cancer patients who received fluorouracil [
Of the phase III clinical trials, erlotinib (Tarceva; Roche) have presented promising results as a gemcitabine combination partner in pancreatic cancer. Erlotinib combined with gemcitabine demonstrated an improvement in survival compared to gemcitabine monotherapy (GEM; median, 6.24 months vs. 5.91 months; p=0.038) without improving the objective response rate (ORR) [
The issue of which agent may be the best combination with gemcitabine for pancreas cancer has not been studied thus far. The aim of this study is to retrospectively compare the efficacy and toxicity of capecitabine or erlotinib in combination with gemcitabine compared with gemcitabine alone in patients with locally advanced or metastatic pancreatic cancer, and to determine which regimen exhibits a more clinical benefit as a first line chemotherapy in pancreatic cancer.
We collected the data of patients who were diagnosed as inoperable pancreatic adenocarcinoma between January 2007 and November 2011 at the Gangnam Severance Cancer Hospital in South Korea. Patients enrollment eligibility was as follows: histologically or cytologically confirmed ductal adenocarcinoma of the pancreas; unresectable/metastatic disease; treated with one of GEM, gemcitabine plus capecitabine (GEM-X), and GEM-T as first-line treatment; measurable or evaluable lesion; age more than 18 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2; and adequate hematologic (granulocyte count, ≥ 1,500×106/L; platelet count, ≥100×109/L), hepatic (bilirubin < 1.5× upper limit of normal [ULN]), and renal function (serum creatinine < 1.5× ULN) before first-line chemotherapy. Prior radiotherapy for local disease was allowed if the disease progression had been documented and if radiotherapy was completed at least 4 weeks before enrollment. Prior chemotherapy was not permitted, except for postoperative adjuvant treatment or radiosensitizers.
Chemotherapy regimen for each patient was determined by the physician in charge. For the GEM group, gemcitabine (1,000 mg/m2) was given by a 30-minute intravenous infusion on days 1, 8 and 15, every 4 weeks. For GEM-X and GEM-T groups, gemcitabine (1,000 mg/m2) was administered on days 1 and 8, in 3-week cycles. Erlotinib was taken orally at 100 mg daily. Capecitabine was administered orally at 1,700 mg/m2/day (850 mg/m2 twice daily) for 2 weeks, followed by a 1-week rest. All treatments were administered until disease progression or intolerable toxicity. The chemotherapy doses could be reduced or delayed (no more than 1 cycle) to allow recovery from toxicity. Dose reduction in gemcitabine and capecitabine was in accordance to two levels, 850 mg/m2 (level 1) and 700 mg/m2 (level 2) for gemcitabine and 1,500 mg/m2 (level 1) and 1,200 mg/m2 (level 2) for capecitabine. Patients with poorly tolerated diarrhea, skin adverse drug reaction, or any other adverse events related with erlotinib, were managed with drug interruption, followed by a restart of erlotinib. This study was approved by the Institutional Review Board of the Yonsei University.
The pretreatment baseline evaluation included a complete medical history, a physical examination, vital signs, electrocardiogram, chest radiography, and routine laboratory tests. The serum carbohydrate antigen (CA) 19-9 level was assessed at the baseline. Tumor assessment was performed by a spiral computed tomography scan at the baseline, every 2 cycles. The radiologic tumor response was evaluated in accordance to the Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria ver. 3.0. Clinical and laboratory assessments were conducted throughout the study.
The primary end point was PFS, and the secondary end points were OS and ORR. PFS was calculated from the date of initial drug administration to the date of either disease progression or death, or it was censored at the last follow up. OS was calculated from the date of initial drug administration to the date of death from any cause, or it was censored at the last follow up. Both PFS and OS estimates were calculated using the Kaplan-Meier method, and the survival curves were compared among the treatment arms using the log-rank test. The HR with 95% confidence interval (CI) was used as the primary estimate of the difference between the two arms. The effects of potential prognostic factors were assessed using the Cox’s proportional hazards model. The proportions were compared across the groups using the χ2 test or Fisher’s exact test. Statistical analyses were done with PASW statistics ver. 18.0 (SPSS Inc., Chicago, IL). A p < 0.05 was considered to be statistically significant.
A total of 127 patients were enrolled in this study. Patients received one of the following treatments: GEM (n=47), GEM-T (n=44), or GEM-X (n=36). The median follow-up duration was 27.8 months (range, 1.5 to 71.9 months). Their baseline characteristics are described in
After the protocol-specified treatment, 69 patients received further treatments. A second-line chemotherapy was administered to 31.9%, 52.3%, and 27.7% of patients in the GEM, GEM-T, and GEM-X arms, respectively. The selection of a second-line chemotherapy was up to the individual investigator, and 5-fluorouracil or platinum-based regimens were mostly used.
One hundred twenty-four patients were assessed for response. One patient was lost to follow-up right after the first dose of chemotherapy, and two patients did not undergo the first follow-up tumor assessment due to their refusal.
PFS was significantly prolonged in the GEM-X group compared to the GEM and GEM-T groups (GEM-X vs. GEM; median, 8.9 vs. 5.2 months; HR, 0.46; 95% CI, 0.27 to 0.79; p=0.035, and GEM-X vs. GEM-T; median, 8.9 vs. 3.9 months; HR, 0.36; 95% CI, 0.2 to 0.64; p=0.001). GEM-X significantly reduced the hazard of progression compared with GEM and GEM-T (
In the analysis of GEM-X compared to GEM-T, the results of the subgroup analyses of survival by the baseline characteristic and clinical factor are displayed in
All 127 patients received at least one dose of medication and were available for an assessment of its toxicity. The median number of cycles was 4 (range, 1 to 14), 4 (range, 1 to 21), and 7 (range, 1 to 20) cycles in the GEM, GEM-T, and GEM-X groups, respectively. A total of 239 cycles of GEM, 236 cycles of GEM-T, and 272 cycles of GEM-X were administered. Adverse events are summarized in
We investigated the comparative efficacy of three regimens, GEM, GEM-T, and GEM-X in pancreatic cancer. GEM-X was superior to GEM and GEM-T, and GEM-T presented a similar efficacy to GEM. The OS was improved with GEM-X compared to GEM or to GEM-T. GEM-X also improved the RR and PFS compared to GEM and GEM-T. In all groups, metastatic disease, high CA 19-9, and ECOG 2 were related with poor prognosis.
In a comparative analysis of GEM-X and GEM-T, there was no difference in the extent of disease, age, and ECOG PS of patients. The improvement in PFS with HR of 0.36 supports the beneficial effects of capecitabine over erlotinib. The reduced hazard of progression by capecitabine was consistent across the different subgroups (
The superior efficacy of GEM-X was accompanied by acceptable levels of toxicity. GEM-X was well tolerated and not hard to administer compared to GEM or GEM-T. The relative dose intensity of gemcitabine was not different between the two groups; 98% for GEM-T and 94% for GEM-X, and erlotinib was 96% and of capecitabine was 78%. The dose of capecitabine was reduced for 25% of patients in the GEM-X arm, mostly owing to grade 3 or 4 neutropenia without serious events. There was no other frequent grade 3 or 4 adverse event in the GEM-X arm.
Although erlotinib plus gemcitabine has presented superior survival over gemcitabine alone in a phase III trial, the median survival gain was only 0.33 months [
Though FOLFIRINOX consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin was considered as one of the first-line regimens for pancreatic cancer [
This study was performed to evaluate the efficacy of capecitabine in combination with gemcitabine compared with gemcitabine with or without erlotinib in patients with locally advanced or metastatic pancreatic cancer. The addition of capecitabine to gemcitabine presented promising outcomes over GEM-T in pancreatic cancer. It is worthy to further investigate which agent has the clinical advantage as a combination drug with gemcitabine for pancreatic cancer and to explore predictive markers for each regimen leading to personalized anti-cancer treatment.
Conflict of interest relevant to this article was not reported.
This study was supported by faculty research grant from Yonsei University College of Medicine for 2011 (6-2011-0113, 6-2011-0146).
Kaplan-Meier curves for PFS (A) and OS (B) of the GEM (red line), GEM-T (green line), and GEM-X arms (blue line). PFS, progression-free survival; OS, overall survival; GEM, gemcitabine; GEM-T, gemcitabine plus erlotinib; GEM-X, gemcitabine plus capecitabine; HR, hazard ratio; CI, confidence interval.
Patient characteristics
Characteristic | Total (n=127) | GEM (n=47) | GEM-T (n=44) | GEM-X (n=36) |
---|---|---|---|---|
Age (yr) | ||||
Median (range) | 65 (32-84) | 68 (41-84) | 63 (32-78) | 63 (38-77) |
Gender | ||||
Male | 72 (56.7) | 25 (53.2) | 25 (56.8) | 22 (61.1) |
ECOG performance status | ||||
0 or 1 | 116 (91.3) | 41 (87.2) | 41 (93.2) | 34 (94.5) |
2 | 11 (8.7) | 6 (12.8) | 3 (6.8) | 2 (5.5) |
Extent of disease | ||||
Locally advanced | 46 (36.2) | 21 (44.7) | 11 (25) | 14 (38.9) |
Distant metastatic | 68 (53.5) | 25 (53.2) | 26 (59.1) | 17 (47.2) |
Recurred | 13 (10.3) | 1 (2.1) | 7 (15.9) | 5 (13.9) |
CA 19-9 >500 U/mL | 64 (51.2) | 25 (54.3) | 23 (53.5) | 16 (44.4) |
Primary site | ||||
Head | 73 (57.5) | 30 (63.8) | 22 (50) | 21 (58.3) |
Body | 36 (28.3) | 12 (25.5) | 14 (31.8) | 10 (27.8) |
Tail | 14 (11) | 4 (8.5) | 6 (13.6) | 4 (11) |
Total | 2 (1.5) | 1 (2.1) | 0 | 1 (2.8) |
Metastatic site | ||||
Liver | 49 (38.6) | 13 (27.7) | 21 (47.7) | 15 (41.7) |
Peritoneum | 22 (17.3) | 9 (19.1) | 7 (15.9) | 6 (16.7) |
Lung | 16 (12.6) | 11 (23.4) | 4 (9) | 1 (2.8) |
Distant lymph node | 8 (6.3) | 3 (6.4) | 2 (4.5) | 3 (8.3) |
Other | 7 (5.5) | 2 (4.2) | 4 (9) | 1 (2.8) |
Prior therapy | ||||
Chemotherapy |
11 (8.7) | 0 (0) | 6 (13.6) | 5 (13.9) |
Radiotherapy | 7 (5.5) | 1 (2.1) | 4 (9) | 2 (5.5) |
Values are presented as number (%). GEM, gemcitabine; GEM-T, gemcitabine plus erlotinib; GEM-X, gemcitabine plus capecitabine; ECOG, Eastern Cooperative Oncology Group; CA 19-9, carbohydrate antigen 19-9 (normal range, 0.8 to 24.0).
Used as a radiosensitizer or adjuvant treatment.
Tumor response
Variable | GEM (n=47) | GEM-T (n=44) | GEM-X (n=33) |
---|---|---|---|
Objective response rate | |||
Partial response | 6 (12.7) | 7 (15.9) | 7(21.2) |
Stable disease | 24 (51) | 19 (43.1) | 17 (47.2) |
Progressive disease | 17 (36.1) | 18 (40.1) | 9 (27.3) |
Disease control rate | 30 (63.8) | 26 (59.1) | 24 (72.7) |
Treatment duration (wk) | 17 | 10.4 | 22.8 |
95% CI | 10.6-23.3 | 7.7-13.0 | 12.7-32.9 |
Values are presented as number (%). GEM, gemcitabine; GEM-T, gemcitabine plus erlotinib; GEM-X, gemcitabine plus capecitabine; CI, confidence interval.
Hazard ratio of survival by pretreatment characteristics (GEM-X arm vs. GEM-T arm)
Factor | No. | PFS |
OS |
||||
---|---|---|---|---|---|---|---|
HR | 95% CI | p-value | HR | 95% CI | p-value | ||
GEM-X:GEM-T | 80 | 0.36 | 0.20-0.64 | 0.001 |
0.52 | 0.28-0.96 | 0.037 |
Age (yr) | |||||||
≤65 | 46 | 0.36 | 0.16-0.81 | 0.013 |
0.33 | 0.14-0.76 | 0.01 |
>65 | 34 | 0.24 | 0.08-0.68 | 0.007 |
0.94 | 0.35-2.48 | 0.903 |
ECOG performance status | |||||||
0 or 1 | 75 | 0.38 | 0.21-0.70 | 0.002 |
0.57 | 0.30-1.10 | 0.095 |
2 | 5 | 0.01 | 0.00-153.5 | 0.36 | 0.01 | 0.00-153.5 | 0.36 |
Disease status | |||||||
Locally advanced | 25 | 0.25 | 0.07-0.85 | 0.027 |
0.43 | 0.13-1.46 | 0.179 |
Distant metastatic | 43 | 0.36 | 0.16-0.77 | 0.009 |
0.45 | 0.19-1.07 | 0.074 |
CA 19-9 (U/mL) | |||||||
≤500 | 40 | 0.27 | 0.11-0.62 | 0.002 |
0.6 | 0.24-1.52 | 0.285 |
>500 | 39 | 0.58 | 0.26-1.28 | 0.182 | 0.45 | 0.19-1.05 | 0.067 |
GEM-X, gemcitabine plus capecitabine; GEM-T, gemcitabine plus erlotinib; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; ECOG, Eastern Cooperative Oncology Group; CA 19-9, carbohydrate antigen 19-9.
p<0.05.
Toxicity and dosage modifications
Variable | GEM (n=47) |
GEM-T (n=44) |
GEM-X (n=36) |
|||
---|---|---|---|---|---|---|
Total | G3/4 | Total | G3/4 | Total | G3/4 | |
Hematologic toxicity | ||||||
Anemia | 47 (100) | 9 (19.1) | 44 (100) | 7 (15.9) | 34 (94.4) | 3 (8.3) |
Neutropenia | 33 (70.2) | 15 (31.9) | 30 (68.2) | 15 (34.1) | 30 (83.3) | 16 (44.4) |
Thrombocytopenia | 41 (87.2) | 5 (10.6) | 28 (63.6) | 1 (2.3) | 23 (63.8) | 2 (5.6) |
Non-hematologic toxicity | ||||||
Diarrhea | 9 (19.1) | 0 | 16 (36.4) | 0 | 5 (13.9) | 0 |
Hand-foot syndrome | 0 | 0 | 0 | 0 | 3 (8.3) | 0 |
Skin rash | 1 (2.1) | 0 | 11 (25) | 0 | 2 (5.6) | 0 |
Anorexia/nausea | 33 (70.2) | 0 | 30 (68.2) | 0 | 27 (75) | 0 |
Vomiting | 6 (12.7) | 0 | 6 (13.6) | 0 | 4 (11.2) | 0 |
Infection | 16 (34) | 11 (23.4) | 5 (11.4) | 4 (9.1) | 5 (13.9) | 5 (13.9) |
Dose reduction | ||||||
Gemcitabine | 13 (27.6) | 12 (27.2) | 12 (33.3) | |||
Erlotinib or capecitabine | - | 0 | 9 (25) | |||
Treatment discontinuation | ||||||
Progressive disease | 43 (91.5) | 38 (86.4) | 32 (88.9) | |||
Toxicity | 1 (2.1) | 1 (2.3) | 1 (2.8) | |||
Refuse | 3 (6.4) | 5 (11.4) | 3 (8.3) |
Values are presented as number (%). GEM, gemcitabine; GEM-T, gemcitabine plus erlotinib; GEM-X, gemcitabine plus capecitabine.