Efficacy and Factors Affecting Outcome of Gemcitabine Concurrent Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer

Efficacy and Factors Affecting Outcome of Gemcitabine Concurrent Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 1, pp. 159–165, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-...

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Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 1, pp. 159–165, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.04.012

CLINICAL INVESTIGATION

Pancreas

EFFICACY AND FACTORS AFFECTING OUTCOME OF GEMCITABINE CONCURRENT CHEMORADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED PANCREATIC CANCER PIN-I HUANG, M.D.,*y YEE CHAO, M.D., PH.D.,*yz CHUNG-PIN LI, M.D., PH.D.,yx RHEUN-CHUAN LEE, M.D.,y{ KWAN-HWA CHI, M.D.,yk CHENG-YING SHIAU, M.D.,*y LING-WEI WANG, M.D.,*y AND SANG-HUE YEN, M.D.*y * Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan; y National Yang-Ming University School of Medicine, Taipei, Taiwan; z Central Clinic Hospital, Taipei, Taiwan; xDivision of Gastroenterology, Department of Medicine, and { Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; and k Division of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan Purpose: To evaluate the efficacy and prognostic factors of gemcitabine (GEM) concurrent chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer. Methods and Materials: Between January 2002 and December 2005, 55 patients with locally advanced pancreatic cancer treated with GEM (400 mg/m2/wk) concurrently with radiotherapy (median dose, 50.4 Gy; range, 26–61.2) at Taipei Veterans General Hospital were enrolled. GEM (1,000 mg/m2) was continued after CCRT as maintenance therapy once weekly for 3 weeks and repeated every 4 weeks. The response, survival, toxicity, and prognostic factors were evaluated. Results: With a median follow-up of 10.8 months, the 1- and 2-year survival rate was 52% and 19%, respectively. The median overall survival (OS) and median time to progression (TTP) was 12.4 and 5.9 months, respectively. The response rate was 42% (2 complete responses and 21 partial responses). The major Grade 3-4 toxicities were neutropenia (22%) and anorexia (19%). The median OS and TTP was 15.8 and 9.5 months in the GEM CCRT responders compared with 7.5 and 3.5 months in the nonresponders, respectively (both p < 0.001). The responders had a better Karnofsky performance status (KPS) (86 ± 2 vs. 77 ± 2, p = 0.002) and had received a greater GEM dose intensity (347 ± 13 mg/m2/wk vs. 296 ± 15 mg/m2/wk, p = 0.02) than the nonresponders. KPS and serum carbohydrate antigen 19-9 were the most significant prognostic factors of OS and TTP. Conclusion: The results of our study have shown that GEM CCRT is effective and tolerable for patients with locally advanced pancreatic cancer. The KPS and GEM dose correlated with response. Also, the KPS and CA 19-9 level were the most important factors affecting OS and TTP. Ó 2009 Elsevier Inc. Gemcitabine, Chemoradiotherapy, Locally advanced pancreatic cancer, Prognostic factors.

5-FU CCRT is rarely >20% and the effects on disease-related symptoms have not been consistently demonstrated (6, 7). Gemcitabine (GEM, difluorodeoxycytidine) is a nucleoside analog that possesses cytotoxic and potent radiationsensitizing effects. The cytotoxic effect of GEM comes from the incorporation of the triphosphate metabolite into growing DNA, which inhibits DNA synthesis (8). The radiosensitizing effect is thought to be a result of inhibition of ribonucleotide reductase and cell cycle redistribution into the S phase, resulting in a lower threshold for apoptosis (9–11). Preclinical and clinical studies have provided evidence for the effects of GEM against pancreatic cancer

INTRODUCTION Pancreatic cancer is one of the leading causes of cancer death in worldwide, with >80% of these patients having advanced disease at diagnosis. About 40–45% of these patients present with metastatic disease and 20–40% with locally advanced disease. The median survival time for patients with metastatic disease and locally advanced disease is 3–6 and 9-13 months, respectively (1–4). Concurrent chemoradiotherapy with 5fluorouracil as a radiosensitizer (5-FU CCRT) is considered the standard treatment. It provides a modest prolongation in survival (median, 10 months as reported by the Gastrointestinal Tumor Study Group [5]). The response rate of patients to Reprint requests to: Sang-Hue Yen, M.D., Cancer Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 112, Taiwan. Tel: (+886) 2-2875-7015; Fax: (+886) 2-2874-9425; E-mail: [email protected]

P.-I. Huang, M.D., Y. Chao, M.D., Ph.D., and C.-P. Li, M.D., Ph.D., contributed equally to this manuscript. Conflict of interest: none. Received March 3, 2008, and in revised form March 31, 2008. Accepted for publication April 7, 2008. 159

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(12–15), leading to the use of GEM in combination with RT. GEM-based CCRT has been widely investigated using various dosing schedules, but the optimal combination of GEM and radiotherapy (RT) remains to be established. Gastrointestinal and hematologic toxicities are the main dose-limiting factors to GEM-based chemoradiotherapy. We have previously reported on the efficacy and toxicity of CCRT using GEM (600 mg/m2) and 5-FU (500 mg/m2) for patients with locally advanced pancreatic cancer (LAPC) (16). The median overall survival (OS) time and median time to progression (TTP) was 14.5 and 7.1 months for the GEM CCRT group and 6.7 and 2.7 months for the 5-FU CCRT group (p = 0.027 and p = 0.019), respectively. The response rate was 50% for the GEM CCRT group and 13% for the 5-FU CCRT group. In the GEM CCRT group, 78% were able to complete the full dose of RT; moreover, 56% were able to receive >75% of the GEM dose intensity during CCRT. With the intent of lowering the toxicity of GEM CCRT and improving compliance, we modified this protocol by (1) reducing the GEM dose to 400 mg/m2/wk when combined with RT and (2) limiting the irradiated volume to gross tumor only (primary tumor and radiologically evident lymph nodes), with a safe margin to overcome internal organ motion and daily setup error. The purpose of this study was to evaluate the efficacy and toxicity of GEM CCRT using this regimen in patients with LAPC. In addition, factors affecting the response to GEM CCRT (400 mg/m2) were investigated. METHODS AND MATERIALS Patients and evaluations Between January 2002 and December 2005, the data from all patients with histologically or cytologically confirmed LAPC treated at our institute were reviewed. Patients treated with GEM combined with other chemotherapeutic agents (5-FU, cisplatin, or oxaliplatin) during CCRT were excluded. A total of 55 patients were identified and included in this study. The institutional review board at Taipei Veterans General Hospital approved this study. All patients provided written informed consent. The pretreatment evaluation included a complete history and physical examination, complete blood counts, liver function tests, blood tumor markers, chest X-rays, and contrast-enhanced computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the abdomen. The disease was staged according to the 2002 American Joint Committee on Cancer classification (17). LAPC was defined as tumors involving the celiac axis or superior mesenteric artery (Stage III) as determined by CT/MRI imaging or exploratory surgery findings.

Radiotherapy All patients received external beam RT. Three-dimensional conformal RT was delivered through high-energy linear accelerators (Clinac 2100C, 2100CD, Varian, Palo Alto, CA). All target volumes were contoured slice by slice on the treatment planning CT images. The thickness of the CT slice for treatment planning was 5 mm. The gross tumor volume was defined as the gross tumor mass on the CT images, including the primary tumor and adjacent visible lymph nodes. The clinical target volume was defined as the gross tumor volume plus 0.5 cm. The planning target volume was defined as the clinical target

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volume plus 1-cm margins to overcome respiratory movement, intestinal motility, and positioning variability. Radiation (range, 26–61.2 Gy; median, 50.4) was delivered using 1.8–2-Gy daily fractions. Initially, all patients were scheduled to receive $45 Gy through coplanar or non-coplanar three- or four-field technique. An additional 5.4–16.2 Gy was delivered to the gross tumor volume with a 1-cm margin, in accordance with each patient’s general performance.

GEM administration All patients were scheduled to receive GEM (Gemzar, Eli Lily, Indianapolis, IN) 400 mg/m2 infused for 30 min on the Monday of each week for 6 weeks during the radiation course. GEM was given each week, and the infusion started approximately 60 min before RT. The dose adjustment was evaluated each week by medical oncologists. A full weekly dose of 400 mg/m2 GEM was given if the absolute granulocyte count was $1,500/mm3, and the platelet count was $75,000/mm3 on the scheduled day of chemotherapy. The dose of GEM was reduced by 25% if the absolute granulocyte count was <1,500/mm3 and $1,000/mm3 or the platelet count was <75,000/ mm3 and $50,000/mm3. GEM was withheld for an absolute granulocyte count of <1,000/mm3, a platelet count of <50,000/mm3, or Grade 2 nonhematologic toxicity. Dose re-escalation was not allowed after dose reduction. After CCRT completion, a re-escalated full dose of GEM at 1,000 mg/m2 was given once weekly for 3 weeks and repeated every 4 weeks as maintenance therapy until intolerance or disease progression.

Evaluation and follow-up All patients were evaluated once weekly during the whole course of CCRT. Performance status, weight, complete blood count, and serum biochemistry findings were collected at every clinic visit. After CCRT completion, the patients were evaluated every 2–3 months with chest radiography, CT, or MRI in the first year and every 4–6 months thereafter. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, version 2 (18). The disease response was evaluated according to the World Health Organization response criteria (19).

Statistical analysis Descriptive statistics (mean, median, and proportions) were calculated to characterize the patients, treatment features, and toxicities after treatment. The TTP was measured from the first day of RT to the date of any evidence of an increase in primary tumor size or the appearance of distant metastasis on serial axial CT scans. OS was calculated from the first day of RT to the date of death. An unpaired Student t test was used to compare the continuous variables between groups. The chi-square test or Fisher’s exact test was used to compare the categorical variables. Cutoff values were determined for each factor according to the best discrimination between patients with or without a tumor response. This was done using optimal values for sensitivity and specificity from a receiver operating characteristics curve analysis. The TTP and OS were estimated using the Kaplan-Meier method and compared using the log–rank test. Variables affecting OS and TTP were analyzed using Cox’s proportional hazard model. Univariate and stepwise multivariate logistic regression analyses were performed to explore variables influencing the treatment response.

RESULTS Patient characteristics The patient characteristics are summarized in Table 1. The study included 33 men and 22 women, with a median age of

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Table 1. Patient characteristics Characteristic

Value

Patients (n) Gender (n) Male Female Age (y) Median Range KPS #80 >80 Presenting symptoms Jaundice Abdominal pain Anorexia Nausea/vomiting Body weight loss CEA (ng/mL) Median Range CA 19-9 (U/mL) Median Range Lymph node stage N0 N1 Tumor histologic type Adenocarcinoma Mucinous adenocarcinoma Tumor location Head Head/body Body Body/tail Maximal axial tumor area (cm2) Median Range Mean GEM dose (mg/m2/wk) Mean radiation dose (Gy)

55 33 (60) 22 (40) 64 39–88 32 (58) 23 (42) 17 (31) 37 (67) 22 (40) 9 (16) 23 (22) 5.7 1.1–187 789 3–12,132 24 (44) 31 (56) 52 (95) 3 (5) 32 (58) 2 (4) 18 (33) 3 (5) 20 4–88 317  11 50.6  1.1

Abbreviations: KPS = Karnofsky performance status; CA 19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; GEM = gemcitabine. Data in parentheses are percentages.

64 years (range, 39–88 years). The median follow-up time was 10.8 months (range, 1.9–39.8 months). The initial presenting symptoms were abdominal/back pain in 34 patients (62%), anorexia in 24 (44%), body weight loss >5% in 29 (53%), nausea/vomiting in 21 (38%), and jaundice in 19 (35%). Response to treatment Of the 55 patients, 52 were assessable for a treatment response by CT or MRI. Three patients without image studies were considered to have progressive disease because they had died during or within 2 weeks after CCRT. The median interval from the date of CCRT completion to the date of the response assessment was 2.1 months (range, 0.9–3.2 months). After CCRT, of the 55 patients, 2 (4%) achieved a complete response and 21 (38%) achieved a partial response. The objective response rate (complete response plus partial response) was 42%. Of the remaining 32 patients,

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15 had stable disease and 17 had progressive disease. None of the patients with a partial response underwent surgical resection because of persistent tumor infiltration of the adjacent vessels. Of the 2 patients with a complete response, 1 developed local recurrence 6 months after CCRT and 1 developed local recurrence and peritoneal metastases at 8 and 33 months, respectively, after CCRT. For the 21 patients with an initial partial response, 15 had disease progression during the subsequent follow-up period, with local progression in 2 patients, distant metastases in 4, and both local and distant failure in 9. OS and TTP The median OS was 12.4 months (95% confidence interval, 10–15.6), with a 1-year and 2-year survival rate of 52% and 19%, respectively (Fig. 1). The cause of death was cancer related in 43 patients, pneumonia in 2 patients (not related to cancer or treatment), and unknown in 2 patients. The median TTP was 5.9 months (95% confidence interval, 4.2–7.2; Fig. 1). Locoregional progression developed in 10 patients (23%), distant metastasis in 15 patients (35%), and both locoregional and distant failure in 18 patients (42%). In those with distant metastasis, the liver was the most frequent site, observed in 17 patients (40%), followed by peritoneal metastases in 8 (19%), lung metastases in 6 (14%), bony metastases in 5 (12%), and other sites (kidney and pleura) in 2 (2%). Responder vs. nonresponder The patient characteristics were compared between the GEM CCRT responders (complete response and partial response) and nonresponders (stable disease and progressive disease; Table 2). The median OS and TTP in the responders was 15.8 and 9.5 months, respectively. Nonresponders had a median OS and TTP of 7.5 months and 3.5 months, respectively (both p < 0.001). No significant differences were found between responders and nonresponders in age, gender, tumor location, tumor size, clinical N stage, radiation dose delivered, pretreatment carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA 19-9), or Grade 3-4 toxicities. However, the Karnofsky performance status (KPS, p = 0.005) and the GEM dose intensity delivered (p = 0.02)

Fig. 1. Kaplan-Meier survival curves of overall survival (OS) and time to progression (TTP).

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Table 2. Gemcitabine concurrent chemoradiotherapy: responders vs. nonresponders

Table 3. Toxicity Grade (n)

Variable Gender Male Female Age (y) Median Range KPS #80 >80 Mean KPS N stage N0 N1 Primary tumor location Head Head/body Body Body/tail Mean CEA (ng/mL) Mean CA 19-9 (U/mL) Tumor histologic type Adenocarcinoma Mucinous adenocarcinoma Mean tumor size (cm2) Mean radiation dose (Gy) Gemcitabine dose (mg/m2/wk) Grade 3-4 toxicity Neutropenia Anemia Nausea Vomiting Anorexia TTP (mo) Median 95% CI OS (mo) Median 95% CI

Responders (n = 23)

Nonresponders (n = 32)

12 (52.2) 11 (47.8)

21 (65.6) 11 (34.4)

62 39–88

64 41–83

p

Toxicity

0.41

Hematologic Neutropenia Anemia Thrombocytopenia Gastrointestinal Nausea Vomiting Anorexia Diarrhea Bleeding Obstruction

0.59 0.005 8 (34.8) 15 (65.2) 86  2

24 (75.0) 8 (25.0) 77  2

11 (48) 12 (52)

13 (40) 19 (60)

0.002 0.78

1

2

3

4

5 (9) 10 (18) 0 (0)

10 (18) 12 (22) 1 (2)

10 (18) 6 (11) 0 (0)

2 (4) 2 (4) 0 (0)

13 (24) 14 (25) 12 (22) 6 (11) 0 (0) 0 (0)

7 (13) 4 (7) 14 (25) 0 (0) 0 (0) 0 (0)

8 (15) 5 (9) 8 (15) 1 (2) 1 (2) 1 (2)

1 (2) 1 (2) 2 (4) 0 (0) 0 (0) 0 (0)

Data in parentheses are percentages. 0.99

13 (57) 1 (4) 8 (35) 1 (4) 10.7  2.6 688  257 21 (91) 2 (9)

19 (60) 1 (3) 10 (31) 2 (6) 16.8  7.2 1,384  393

0.49 0.18 0.57

31 (97) 1 (3)

22.2  4.3

23.4  2.5

0.81

52.9  1.4

49.2  1.6

0.12

347  13

296  15

0.02

4 (17) 3 (13) 3 (13) 2 (9) 3 (13)

8 (25) 5 (16) 6 (19) 4 (13) 7 (22)

0.50 0.79 0.57 0.66 0.40 <0.001

9.5 5.9–13.1

3.5 2.3–5.4 <0.001

15.8 12.4–26.2

7.5 6.1–10.9

Abbreviations: TTP = time to progression; OS = overall survival; CI = confidence interval; other abbreviations as in Table 1. Data in parentheses are percentages.

were significantly different between these two groups. Although not statistically significant, nonresponding patients had a greater percentage of Grade 3-4 toxicity and pretreatment CEA/CA 19-9 levels compared with responding patients. A trend was noted toward a negative correlation of GEM dose intensity and Grade 3-4 toxicities (p = 0.07). Additional analysis using a logistic regression model showed that a KPS >80 was the only significant factor predicting the treatment response (odds ratio, 5.4, p = 0.03). Toxicity/tolerability All 55 patients were evaluable for toxicity (Table 3). Of the 55 patients, 19 (35%) had severe Grade 3-4 toxicities during

CCRT, including 14 (26%) with gastrointestinal toxicity and 17 (31%) with hematologic toxicity. Gastrointestinal bleeding occurred in 1 patient 3 weeks after the start of CCRT, and RT was discontinued at a dose of 26 Gy. One patient had intestinal obstruction and required surgical intervention at the fourth week of treatment. He stopped RT at a dose of 30.6 Gy. Of the 55 patients, 49 (89%) completed the scheduled radiation dose of $45 Gy. Fourteen patients had at least one interruption (rest >3 days) in the RT course. Of these 14 patients, 8 went on to complete the scheduled regimen of RT, and 6 discontinued treatment. The reasons for early RT discontinuation included intestinal obstruction in 1 patient, gastrointestinal bleeding in 1, refusal to undergo additional treatment because of severe nausea/vomiting in 3, and a switch to herbal treatment in 1. The GEM dose intensity was 317  11 mg/m2/wk (80%). Neutropenia was the most common reason for a GEM dose reduction (63%). Prognostic factors On the univariate analysis of survival, a KPS >80 (p = 0.001) and CA 19-9 level #1,000 U/mL (p = 0.009) were prognostic indicators for better survival (Table 4). For the TTP, the significant prognostic factors were a KPS >80 (p = 0.002) and CA 19-9 level #1,000 U/mL (p = 0.01). Multivariate analysis using a Cox proportional hazards model showed that KPS and serum CA 19-9 were the most independent predictive factors of OS and TTP (Table 4). KPS and serum CA 19-9 correlated strongly with OS and TTP for patients with LAPC treated with GEM CCRT (Figs. 2 and 3). DISCUSSION For years, the standard treatment of LAPC has been 5-FU CCRT. Despite treatment, however, most patients die of local recurrence and metastasis after treatment, and the prognosis remains poor. In 2003, we first demonstrated that GEM CCRT improves OS, TTP, response rates, and quality of survival for LAPC patients compared with 5-FU CCRT.

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Table 4. Univariate and multivariate analysis results of prognostic factors Variable Univariate analysis OS KPS #80 CA 19-9 >1,000 U/mL TTP KPS #80 CA 19-9 >1,000 U/mL Multivariate analysis OS KPS #80 CA 19-9 >1,000 U/mL TTP KPS #80 CA 19-9 >1,000 U/mL

HR (95% CI)

p

3.47 (1.72–6.97) 2.59 (1.27–5.30)

0.001 0.009

3.07 (1.50–6.25) 2.50 (1.24–5.02)

0.002 0.010

2.71 (1.30–5.64) 2.36 (1.14–4.90)

0.008 0.021

2.82 (1.34–5.93) 2.62 (1.26–5.46)

0.006 0.010

Abbreviations: HR = hazard ratio; other abbreviations as in Tables 1 and 2.

Furthermore, GEM CCRT was shown to have a similar tolerability. In that study, the case number was small, with only 18 patients enrolled. In the present study, we have further validated the role of GEM CCRT in patients with LAPC. The 42% response rate, median OS of 12.4 months, and incidence of Grade 3-4 toxicities of 35% were comparable to those achieved in other GEM CCRT studies (13, 16, 20–24). Various prognostic factors have been reported for LAPC. In our analysis, KPS and CA 19-9 were the most independent

Fig. 3. (a) Overall survival and (b) time to progression as influenced by carbohydrate antigen 19-9 (CA 19-9) level.

Fig. 2. (a) Overall survival and (b) time to progression as influenced by Karnofsky performance status (KPS).

predictive factors for OS and TTP. The importance of performance status as a predictor for survival has been reported in other series (25–28). A possible explanation is that patients with poor performance status have more aggressive disease, a greater tumor burden, and less tolerance for, or an unwillingness to receive, treatment. Similarly, CA 19-9 is a useful tumor marker for pancreatic cancer to represent the tumor burden or disease aggressiveness. We did not find statistical significance for other prognostic factors that were reported in other series such as CEA, body weight loss, jaundice, and hemoglobin. Recently, Krishnan et al. (29) analyzed 247 LAPC patients treated with CCRT. They reported that KPS was the only independent prognostic factor for disease-free survival, and both hemoglobin and KPS were important prognostic factors for OS (29). All in all, performance status has been the most important prognostic factor for LAPC. Tumor response is a valuable predictor for better outcome in the treatment of LAPC. Our results showed that both OS and TTP were longer in the responding group (15.8 and 9.5 months, respectively) compared with the nonresponding group (7.5 and 3.5 months, respectively). It is important to select patients with LAPC who can benefit from GEM CCRT. We tried to identify the factors affecting the response to GEM CCRT. The pretreatment CA 19-9 level, a prognostic factor for OS and TTP, was greater in the nonresponder population but was not significantly different between these two groups (p = 0.18), which might have been because of the relatively

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Table 5. Comparison of tumor response and toxicity Variable Response Complete Partial Stable disease Progressive disease Grade 3-4 toxicity Neutropenia Anemia Thrombocytopenia Nausea Vomiting

GEM-400 CCRT (n = 55)

GEM-600 CCRT (n = 18) (16)

2 (4) 21 (38) 15 (27) 17 (31)

4 (22) 5 (28) 4 (22) 5 (28)

12 (22) 8 (15) 0 (0) 9 (16) 6 (11)

6 (33) 4 (22) 0 (0) 6 (33) 3 (17)

Abbreviations: GEM = gemcitabine; 400, 600 = 400, 600 mg/m2/ wk, respectively; CCRT = concurrent chemoradiotherapy. Data in parentheses are percentages.

small case number in this study. The responding patients had a better KPS (mean, 86 vs. 77, p = 0.002) and had received a greater GEM dose intensity (mean, 347 vs. 296 mg/m2/ wk, p = 0.02) than did the nonresponding patients. We found a trend for Grade 3-4 toxicities to correlate with a lower GEM dose intensity (p = 0.07). The lower GEM dose intensity delivered in the nonresponding group might have been because of treatment toxicities and/or disease symptoms causing interruption or treatment incompleteness. Patients with a good performance status seemed to be more tolerant of this combination treatment and were able to receive a greater GEM dose, thus providing a better treatment response. The treatment efficacy and toxicity in the present study using a GEM dose of 400 mg/m2/wk (GEM-400) were compared with those of our previous clinical trial using a GEM dose of 600 mg/m2/wk (GEM-600). A comparison of treatment responses and toxicities is listed in Table 5. GEM400 CCRT produced a median survival of 12.4 months, inferior to the 14.5 months for the GEM-600 CCRT group. The median TTP for the GEM-400 and GEM-600 groups was 5.9 and 7.1 months, respectively. The objective response rate in the GEM-400 group was also inferior to that of the GEM-600 group (42% vs. 50%). When combined with RT, the efficacy using GEM-400 was poorer than that for GEM-600. This might have been caused by a smaller radiosensitizing effect when the dose of GEM was reduced from 600 to 400. Another possibility is the patient selection in the previous clinical trial. However, the patients in the GEM-400 and GEM-600 studies had no significant differences in age, gender, tumor size, lymph node stage, CA 19-9 level, CEA level, or radiation dose; the only differences

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were in the performance status and GEM dose intensity. Patients in the GEM-600 CCRT group had a better KPS (89  2) than the patients in the GEM-400 CCRT group (81  1.4; p = 0.003). The GEM dose intensity delivered in the GEM-600 CCRT was also greater than that in the GEM-400 group (457  31 vs. 317  11 mg/m2/wk; p < 0.001). The inferior outcome in the present GEM-400 CCRT group might have been related to the worse KPS and lower GEM dose intensity received. Despite this, the median survival of 12.4 months in after GEM-400 CCRT was still comparable to that of other series using similar regimens. However, the GEM-400 regimen has the advantage of fewer adverse effects compared with the GEM-600 regimen. The data comparison was done using a small number of patients and no statistically significant comparison was possible. In the GEM-400 CCRT group, we found that of the patients with a KPS >80, 74% completed >75% of the intended GEM dose and 48% completed the full GEM dose during CCRT. In contrast, only 44% and 25% of patients with a KPS of #80 were able to complete >75% and 100%, respectively, of the intended GEM dose during CCRT. In the previous GEM-600 CCRT study, for patients with a KPS >80, 63% and 31% were able to receive >75% and the full intended GEM dose, respectively, during CCRT. With a lower GEM dose in CCRT, patients had better compliance but a smaller survival benefit. In a Phase II clinical trial, Okusaka et al. (22) reported that 90% of the patients completed the scheduled GEM dose of 250 mg/m2/wk combined with a radiation dose of 50.4 Gy. The median progressionfree and survival time was 4.4 and 9.5 months, respectively. On the basis of these findings, patients with a good performance status (KPS >80) should receive a greater GEM dose (400–600 mg/m2) combined with conventional RT to maximize treatment efficacy. However, patients with a poor performance (KPS #80) should receive a lower GEM dose (<400 mg/m2), depending on tolerance. CONCLUSION A GEM dose of 400 mg/m2/wk combined with conventional radiation doses is tolerable and shows promising efficacy against LAPC. The KPS and CA 19-9 are the most important prognostic factors predicting for OS and TTP. A better treatment response is associated with better performance status and a greater GEM dose delivered. A better understanding of the factors affecting the outcome could contribute to the selection of patients in this heterogeneous population who could benefit from the combined treatment modality.

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