Original Article

Neoadjuvant Gemcitabine, Docetaxel, and Capecitabine Followed by Gemcitabine and Capecitabine/Radiation Therapy and Surgery in Locally Advanced, Unresectable Pancreatic Adenocarcinoma William H. Sherman, MD1; Kyung Chu, NP2; John Chabot, MD1,4; John Allendorf, MD1,6; Beth Ann Schrope, MD1,4; Elizabeth Hecht, MD1,7; Brian Jin, MD1,7; David Leung, MD, PhD1,7; Helen Remotti, MD1,5; Gisella Addeo, MD1,8; Inna Postolov, MD; Wei Tsai, PhD1,9; and Robert L. Fine, MD1,3

BACKGROUND: This prospective study was undertaken to assess toxicity, resectability, and survival in pancreatic adenocarcinoma patients presenting with locally advanced, unresectable disease treated with neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) and gemcitabine and capecitabine (GX)/radiation therapy (RT). METHODS: All patients presenting to the Pancreas Center were evaluated for eligibility. Forty-five patients (mean age, 64 years; range, 44-83 years)—34 patients deemed unresectable because of arterial involvement and 11 patients deemed unresectable because of extensive venous involvement—were treated with 6 cycles of GTX. Those with arterial involvement were treated with GX/RT after chemotherapy. RESULTS: The GTX and GX/RT treatments were tolerated with the expected drug-related toxicities. There were no bowel perforations, cases of pancreatitis, or delayed strictures. Among those with arterial involvement, 29 underwent subsequent resection, with 20 (69%) achieving R0 resections. All 11 patients with venous-only involvement underwent resection, with 8 achieving R0 resections and 3 achieving complete pathologic responses. For the arterial arm, the 1-year survival rate was 71% (24 of 34 patients), and the median survival was 29 months (95% confidence interval, 21-38 months). Thirteen patients (38%) have not relapsed (range, 5-491 months). For the venous arm, the median survival has not been reached at more than 42 months. Six patients (55%) in the venous arm did not experience recurrence (range, 6.2-421 months). CONCLUSIONS: GTX plus GX/RT is an effective neoadjuvant regimen that can be safely administered to patients up to at least the age of 83 years. It is associated with a high response rate, a high rate of R0 resections, and prolonged overall survival. CanC 2014 American Cancer Society. cer 2015;121:673-80. V KEYWORDS: capecitabine, docetaxel, gemcitabine, pancreatic cancer, radiation therapy.

INTRODUCTION More than 45,000 new cases of adenocarcinoma of the pancreas are diagnosed in the United States each year. Fewer than 6% of these patients are expected to survive 5 years. Less than 15% of these patients are considered classically resectable. Even with resection, the 5-year survival rate is less than 25%.1 Approximately 30% of these patients present with involvement of local blood vessels. Those presenting with tumors involving the portal vein, superior mesenteric vein, or short segment hepatic artery are borderline-resectable. Because of the high surgical mortality rate associated with arterial reconstruction, those with celiac artery involvement, superior mesenteric artery involvement, or significant hepatic artery involvement are not considered surgically resectable. Extensive venous involvement also precludes surgery. When borderline-resectable patients undergo resection, their 3-year survival rate has been 23%2 to 34%,3 and this is similar to results observed with resectable pancreatic cancers. The goal of surgery is R0 resection: complete resection with negative tumor margins. When chemotherapy/radiotherapy regimens are used without resection, the median survival is approximately 12 months.2,3,6-22 R0 resection means negative microscopic margins, but a negative surgical margin is a qualitative observation. Chang et al4 noted that those

Corresponding author: William H. Sherman, MD, Department of Medicine, Columbia University, 88 Central Park West, New York, NY 10023; [email protected] 1 Pancreas Center, Columbia University, New York, New York; 2Department of Medicine, New York University, New York, New York; 3Department of Medicine, Columbia University, New York, New York; 4Department of Surgery, Columbia University, New York, New York; 5Department of Pathology, Columbia University, New York, New York; 6Department of Surgery, Winthrop University Hospital, Mineola, New York; 7Department of Radiology, Columbia University, New York, New York; 8 Department of Radiation Oncology, Columbia University, New York, New York; 9Department of Biostatistics, Columbia University, New York, New York.

The clinical trial number for this study is NCT01065870. DOI: 10.1002/cncr.29112, Received: July 8, 2014; Revised: September 7, 2014; Accepted: September 8, 2014, Published online December 9, 2014 in Wiley Online Library (wileyonlinelibrary.com)

Cancer

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Original Article

patients with surgical margins less than 2 mm have a median survival less than 14 months, with only 16% alive at 3 years and 4% alive at 5 years. If the margin is less than 1 mm, survival is worse, and this results in a high incidence of local failure and a median disease-free survival of only 5.5 months.4,5 Therefore, the definition of R0 resection should require a minimum 2-mm margin of normal tissue, which is an unlikely event for those with arterial involvement without neoadjuvant therapy or arterial reconstruction. Various schedules of radiation therapy (RT) with sensitizing chemotherapy have been used to treat patients with locally advanced disease.2,3,6-22 Neoadjuvant studies designed to increase resectability have often excluded patients with arterial involvement. Treatment options include RT in a standard fashion (up to 50.4 Gy) combined with 5-fluorouracil, capecitabine, and gemcitabine (with or without other agents) or stereotactic RT.2,3,6-22 To date, no regimen appears to be clearly superior despite differences in patient selection. The median survivals range from 11.5 to 13.4 months. For any neoadjuvant regimen to be effective, it must induce a high rate of tumor regression. The gemcitabine, docetaxel, and capecitabine (GTX) regimen demonstrated a tumor response rate close to 50% according to the Response Evaluation Criteria in Solid Tumors (RECIST).23 5-Fluorouracil and gemcitabine are both radiosensitizing agents. They are the 2 most active agents against pancreatic cancer. Therefore, our protocol was designed for GTX to shrink the tumor and eliminate micrometastatic disease. Gemcitabine and capecitabine (GX) with RT were then given to those presenting with arterial involvement to eradicate any tumor on the arterial margins. MATERIALS AND METHODS This prospective study was approved by the institutional review board of Columbia University. All patients who presented to the Pancreas Center of New York–Presbyterian Hospital between February 2010 and December 2013 were evaluated at the weekly pancreas conference. Those who were thought to have locally advanced disease on the basis of original diagnostic studies—computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, endoscopic ultrasound, or aborted surgical resection—and for whom surgery would be possible if the tumor regressed were considered eligible for this study. The ineligible group comprised patients deemed never to be resectable even with tumor regression: patients with cavernous transformation of the portal vein or tumor 674

involving branch points of major vessels and patients with other malignancies or other underlying medical conditions that would make them ineligible for surgery, RT, or chemotherapy. After informed consent was obtained, patients underwent laparoscopy and additional imaging to exclude metastatic disease. The time between the initial presentation to the Pancreas Center and the completion of the baseline studies did not exceed 10 days. Patients were stratified into those with arterial involvement and those with extensive venous-only involvement. Any arterial involvement placed a patient in the arterial arm. Because of the low rate of accrual in the venous-only arm, the study was closed to accrual after the last patient in the arterial arm completed treatment. The primary aim of the study was to achieve resection in at least 50% of the patients in the arterial arm. Patients were also followed for survival and sites of relapse. Statistical Analysis

The data analysis included descriptive statistics for all variables. Frequency tables were used to evaluate the distributions of categorical and discrete variables. Statistical analyses were performed with the SPSS statistical program to plot Kaplan-Meier survival and progression-free survival. Pretreatment Studies

All patients had baseline MRI and/or CT scans with contrast. When possible, baseline positron emission tomography (PET)/CT was also performed. All radiological images were reviewed by at least 2 radiologists to confirm the degree of vascular involvement. If the bilirubin level was elevated and the bile duct needed stenting, treatment was delayed until the bilirubin level fell to less than 3.0 mg/dL. Chemotherapy Treatment Schedule

GTX was administered on a 3-week cycle for 6 cycles to both the arterial patients and the venous-only patients. Doses and dose adjustments for toxicities are outlined in Table 1. Imaging was obtained after every 3 cycles of chemotherapy and 3 weeks after RT. RT With Chemotherapy Schedule

All patients in the arterial arm before surgery and only those patients in the venous arm after R1 resection received GX/RT. Standard-dose RT was delivered by intensity-modulated radiation therapy or conformal fields to 5040 cGy along with capecitabine at 1000 mg twice a Cancer

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Unresectable Locally Advanced Pancreatic Cancer/Sherman et al

TABLE 1. GTX Schedule and Adjustments for Toxicity

Day 11 CBC or Other Toxicity WBC < 2.0 or APC < 1000 Agent

Platelets < 75,000

Hand/Foot, Grade 3/4

Mucositis/Diarrhea, Grade 3/4

Hypotension, Grade 3/4

Hold Treatment and Modify Dose for Future Treatment as Follows:

Capecitabine (1500 mg/m2, days 1-14)a Gemcitabine (750 mg/m2, days 4 and 11) Docetaxel (30 mg/m2, days 4 and 11)

0% 10% 10%

0% 10% 10%

Decrease 25% 0% 0%

Decrease 25% 0% 0%

0% 0% 100%

Abbreviations: APC, absolute phagocyte count; CBC, complete blood count; GTX, gemcitabine, docetaxel, and capecitabine; GX, gemcitabine and capecitabine; RT, radiation therapy; WBC, white blood count. a The capecitabine dose was decreased to 600 mg/M2 for 12 days for women more than 70 years old and men more than 75 years old. b Repeat the treatment cycle every 21 days.

day for 5 days and gemcitabine at 750 mg/m2 over the course of 90 minutes on day 5 of weeks 1, 2, 4, and 5 of RT (starting with the first full week of RT). The radiation field covered the tumor with a 2-cm margin. Patients received darbepoetin if the hemoglobin level was less than 10.5 g/dL during RT. Patients and Methods

Fifty-nine patients with unresectable, locally advanced pancreatic cancer (American Joint Committee on Cancer stage III) were evaluated for this trial. Fourteen patients were ineligible: 5 with liver metastasis by laparoscopy, 2 with peritoneal metastasis by laparoscopy, 3 with positive PET scans, 2 with liver metastasis on MRI review, 1 with direct extension into the liver on MRI review, and 1 with a primary renal cancer. With respect to the PET/CT findings, 2 patients had extensive liver metastases that were evident on the noncontrast CT portion of the PET/CT scan. These metastases appeared between the time of the original scan and the PET/CT scan. The average age was 64 years (standard deviation, 10.2 years; range, 44-83 years; Table 2). Thirty-four patients had arterial involvement. Only 1 of the 10 patients with the involvement of a single artery did not have venous involvement. Forty-three of the remaining 45 patients completed 6 cycles of GTX: 32 in the arterial arm and 11 in the venous-only arm. Two of the arterial patients did not complete 6 cycles of GTX: one with a biliary stent died after an episode of sepsis 3 days after chemotherapy, and the Cancer

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second changed treatment after the development of a new liver lesion that, in retrospect, was probably a small abscess. Surgical resection of the residual tumor was attempted 3 weeks after the completion of chemotherapy for the venous arm and 4 to 5 weeks after the completion of RT for the arterial arm. The degree of vascular involvement at presentation is shown in Table 2. Twenty-four patients had more than 1 artery involved: the celiac artery and either the hepatic artery or superior mesenteric artery. Another 5 patients had more than 180-degree encasement of a single artery. Five venous-only patients had more than 1 vein involved. The other 4 had encasement of the vein for more than 3 cm.

RESULTS Chemotherapy

The carbohydrate antigen 19-9 level was elevated in 33 patients (median, 501; range, 48-6363 U/ml.). With chemotherapy, 27 of these patients had a >85% decrease in or normalization of carbohydrate antigen 19-9. On the first scan after cycle 3, 12 patients had a 30% or greater decrease in the tumor. On the second scan after cycle 6, before either RT or surgery, 20 patients (44%) had a decrease in the greatest measurement of the pancreatic mass of more than 30%. One patient (2.2%) progressed during the 18 weeks of GTX therapy. Only 1 patient progressed during RT 675

Original Article TABLE 2. Patient Characteristics Characteristics

Arterial Arm

Venous Arm

34 44-83 15/19

11 44-77 4/7

26 4 3 1 336 (48-6363) 8.3 (2.4-29.6)

9 1 1 0 267 (95-1561) 6.1 (3.5-14.4)

0 0 8 0 2 24

2 4 0 0 0 5

Chemotherapy results, n (%) or n/N (%) Response by RECIST Partial response by cycle 6 Complete response Stable disease Progression Early death Ca 19-9 decrease > 85% or to normal

10 (29) 17 (50) 3 (9) 12 (35) 1 (3) 1 (3) 19/25 (76)

2 (18) 3 (27) 0 8 (73) 0 0 8/8 (100)

Surgical results, n Resected (R0/R1) Postoperative deaths

29 (20/9) 4

11 (8/3) 0

Presenting characteristics Patients, n Age, range, y Sex: male/female, n Race, n White Black Hispanic Asian Ca 19-9 U/ml (when elevated), median (range) Tumor area cm2, median (range) Vascular involvement, n Portal vein only SMV only SMA only Celiac artery only Hepatic artery only Multiple arteries/veins

Comment

MR, CT, EUS 1 with EUS only 3 with >180-degree encasement 2 with >180-degree encasement Portal vein and SMV (venous arm) Celiac artery 1 another (arterial arm)

Sepsis

Abbreviations: Ca 19-9, carbohydrate antigen 19-9; CT, computed tomography; EUS, endoscopic ultrasound; MR, magnetic resonance; RECIST, Response Evaluation Criteria in Solid Tumors; SMA, superior mesenteric artery; SMV, superior mesenteric vein.

and the intervening 3 to 5 weeks. One patient, as noted earlier, died after sepsis while on chemotherapy. Surgical Results

The remaining 30 arterial patients underwent surgery. Twenty-five had Whipple operations, 2 underwent distal pancreatectomy, and 2 underwent Appleby procedures (the resection included the celiac axis and the common hepatic artery.) Three patients also received electroporation of any possible residual tumor on the celiac artery; they included 1 patient who underwent only electroporation without resection of the residual mass. All 11 venous-only patients had Whipple operations. There were 4 postoperative deaths: pulmonary embolus (n 5 1), hepatic infection and septic shock (n 5 1), extensive clotting (n 5 1), and progressive hepatic failure from hepatic steatosis (n 5 1). There were 4 postoperative infections, 1 pancreatic fistula, 1 bile duct leak, and 1 peripancreatic fluid collection. The average duration of hospitalization for those undergoing a Whipple operation was 7 days. 676

Pathology Findings

Twenty-nine patients with arterial involvement (85%) underwent resection: 20 (69%) underwent R0 resection, and 9 (31%) underwent R1 resection. There was 1 complete response. Surgical margins were negative in 25, but the scattered residual tumor cells were within 2 mm of the posterior surgical margin in 5 patients, so they were considered R1 resections as defined in this study. The tumor specimens contained dense fibrous tissue. All but the patient with a complete response had scattered foci of microscopic tumor cells scattered within the dense fibrous tissue, and this made it difficult to accurately assess the extent of residual disease. The size of the residual tumor, including the area of scattered microscopic tumor foci, ranged from 0.12 to 2.8 cm2. Twenty-one patients had negative lymph nodes, whereas 8 patients had 1 to 5 positive lymph nodes. In the 11 patients with venous-only involvement, there were 8 R0 resections and 3 R1 resections. There were 3 complete responses. Two of the 3 patients with R1 resections received GX/RT after their recovery from Cancer

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TABLE 3. Grade 3/4 Toxicity During Chemotherapy

Toxicity

Grade

Events, n

Patients Experiencing This Toxicity, n

3/4 3/4 3/4 3 3 3 3 4 3 3 3/4 3 3 3

19/0 5/2 5/2 1 4 3 4 1 1 1 2/1 1 1 3

19/0 5/2 5/2 1 4 3 4 1 1 1 2/1 1 1 3

TABLE 4. Sites of Recurrence and Time to Recurrence Arterial Arm Site

Leukopenia Anemia Thrombocytopenia Mucositis Hand and foot syndrome Hypotension Asthenia Dyspnea Nausea Diarrhea Biliary infection/abscess Peripheral arterial ischemiaa Retinal vein occlusion Venous thrombosis

n

PFS, mo

Venous Arm n

Local 2 6.6, 23.6 1 2 Liver 6 3.6-15.1 (9.7)a Lung 0 0 0 Peritoneum 3 4.8-27.4 (12.3)a Abdominal wall 1 3 0 Multiple 1 (liver/local) 4 1 (local/liver) 1 5.6 0 Clinicalb Total 13 4

PFS, mo 26.1 3.8, 10.4

11.9

Abbreviation: PFS, progression-free survival from diagnosis. a The data are presented as ranges (with medians in parentheses). b Rising carbohydrate antigen 19-9 levels, increasing pain, and inability to eat (site undocumented).

There were stent infections (grade 2) in 7 patients. Preexisting peripheral vascular disease.

surgery. Seven specimens had no positive lymph nodes, whereas the remaining 4 had 1 to 5 involved nodes. Toxicity GTX chemotherapy

The incidence of grade 3 and 4 toxicities is listed in Table 3. Aside from the expected myelosuppression, hand-foot syndrome occurred in 4 (9%), mucositis occurred in 1, and hypotension occurred in 3. Three patients with biliary stents developed fevers, which were presumed to be related to cholangitis. Another 3 patients with biliary stents developed liver abscesses. Seven (16%) had the GT doses decreased by 10%, and 4 (9%) had capecitabine decreased by 25%. GX/RT

The most common side effect was nausea. Two patients needed hospitalization for dehydration. There were no infections or bowel perforations. RT did not need to be withheld for low blood counts or a failure to maintain adequate food and fluid intake. Because of low blood counts during week 5 of RT, gemcitabine was not given to 8 patients. The gastrointestinal side effects markedly improved within 3 weeks of the completion of RT. Thirteen patients (29%) went to the emergency room during treatment. Three visits were probably related to their chemotherapy treatment, and 2 were probably related to their RT treatment: weakness and hypotension from dehydration. The remaining 8 visits were due to vascular thrombosis, which is common in pancreatic cancer, or fevers in patients with biliary stents. Cancer

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Figure 1. Overall survival for the arterial and venous arms. The median overall survival was 32.5 months (95% CI, 2836.9 months). The median survival for the arterial arm was 29 months (95% CI, 17.9-40 months). The median survival for the venous arm had not been reached at 44 months. Survival was significantly different for the arterial and venous arms (P

radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma.

This prospective study was undertaken to assess toxicity, resectability, and survival in pancreatic adenocarcinoma patients presenting with locally ad...
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