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10.1245/ASO.2005.04.503
Annals of Surgical Oncology 12:995-1004 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Docetaxel/Gemcitabine Followed by Gemcitabine and External Beam Radiotherapy in Patients With Pancreatic Adenocarcinoma

J. Marc Pipas, MD, Richard J. Barth, Jr., MD, Bassem Zaki, MD, Michael J. Tsapakos, MD, Arief A. Suriawinata, MD, Michael A. Bettmann, MD, Justin M. Cates, MD, PhD, Gregory H. Ripple, MD, John E. Sutton, MD, Stuart R. Gordon, MD, Carol E. McDonnell, CCRP, Raymond P. Perez, MD, Nancy Redfield, ARNP, Louise P. Meyer, ARNP, John F. Marshall, MD, Bernard F. Cole, PhD and Thomas A. Colacchio, MD

Gastrointestinal Oncology Program, Dartmouth-Hitchcock Medical Center/Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, New Hampshire 03756

Correspondence: Address correspondence and reprint requests to: J. Marc Pipas, MD; E-mail: j.marc.pipas{at}hitchcock.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Pancreatic cancer remains highly lethal. Previous attempts with neoadjuvant therapy in this disease have been inconclusive, but a potential for benefit exists. We conducted a phase II trial of dose-intense docetaxel and gemcitabine followed by twice-weekly gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma.

Methods: Patients with stage I to III disease were eligible. Docetaxel 65 mg/m2 intravenously over 1 hour and gemcitabine 4000 mg/m2 given intravenously over 30 minutes were given on days 1, 15, and 29. On day 43, radiotherapy was begun at 50.4 Gy with gemcitabine 50 mg/m2 intravenously over 30 minutes twice weekly for 12 doses. After treatment, patients were considered for resection.

Results: Twenty-four assessable patients were recruited onto the trial. All but one patient completed a full 12 weeks of therapy. Grade 3 and 4 hematological and nonhematological toxicities were common but manageable, and neutropenic fever did not occur. No patient had local tumor progression. Twelve patients (50%) responded by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria, including one radiographic complete response. Seventeen patients underwent resection after therapy. Margin-negative resections were performed in 13 patients, including 9 patients whose disease was borderline or unresectable before treatment. A treatment effect was seen in all resection specimens. There have been no local recurrences of tumor, and several patients remain alive without evidence of disease.

Conclusions: Docetaxel/gemcitabine followed by gemcitabine/radiotherapy is active in the treatment of pancreatic adenocarcinoma, with manageable toxicity. Tumor downstaging occurs in some patients to allow complete resection. Further investigation of this regimen is warranted.

Key Words: Pancreatic adenocarcinoma • Radiotherapy • Gemcitabine • Docetaxel • Neoadjuvant


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adenocarcinoma of the pancreas is highly lethal, with a 5-year survival of 4%.1 Despite numerous clinical trials, survival has changed little in decades. For patients with limited disease, complete surgical resection offers the only hope for long-term survival. Yet only 30% to 50% of patients taken to surgery with curative intent undergo complete resection; the remainder are found to have locally advanced, unresectable, or metastatic disease.2 No survival benefit is seen for patients with positive surgical margins after resection.3 Long-term survival after complete surgical resection is approximately 20%: patients succumb to both local recurrence and metastatic disease.4 For patients with locally advanced unresectable disease, combined-modality treatment with fluorouracil (5-FU) and radiation has been shown to be tolerable and to confer improved survival when compared with either historically matched controls or radiation alone.5,6

The dismal survival of patients with pancreatic cancer has led to numerous neoadjuvant trials. These attempts have met with only modest success.3 Although neoadjuvant therapy may be more tolerable, survival is not clearly improved over adjuvant treatment for resectable tumors.7 Response rates (RRs) have varied with the regimen, and local control seems improved after resection. However, converting disease from unresectable to resectable remains problematic, and no standard neoadjuvant regimen exists at present. A neoadjuvant approach has several potential advantages, however, including (1) delivery of full-dose treatment unimpeded by potential delays from surgery and its recovery, (2) ability to objectively assess the response of the tumor to newer therapies, and (3) downstaging of the tumor to improve the chance of complete resection.

Gemcitabine (Gemzar; Eli Lilly and Co., Indianapolis, IN) is approved for the treatment of advanced pancreatic cancer. Gemcitabine has been examined in a variety of schedules and exhibits wide schedule-dependent variation in efficacy, toxicity, and maximum-tolerated dose (MTD). A 3-day dosing interval of gemcitabine has been shown to result in more activity than either a weekly or daily dosing schedule when gemcitabine is given intraperitoneally to mice with human tumor xenografts.8 Phase I trials have shown a gemcitabine MTD of 65 mg/m2 given as a twice-weekly infusion over 30 minutes, with thrombocytopenia as dose-limiting toxicity.9

Gemcitabine is a potent radiosensitizer.10 Radio-sensitization correlates with the extent and duration of deoxyadenosine triphosphate depletion and is observed even at noncytotoxic concentrations. Sensitization is optimal when drug incubation precedes irradiation and increases with both gemcitabine concentration and duration of exposure. Evidence suggests that when combined with daily radiotherapy (XRT), gemcitabine has a higher therapeutic index given twice weekly as compared with once weekly.11 On the basis of these data, we and others have completed phase I trials of external beam XRT and twice-weekly gemcitabine for patients with pancreatic adenocarcinoma.12,13 We have established the MTD of twice-weekly gemcitabine at 50 mg/m2 given concurrently with XRT. Dose-limiting toxicity in two patients at 60 mg/m2 consisted of severe upper gastrointestinal (GI) bleeding approximately 1 month after treatment. Six patients had radiographical evidence of a response to treatment, and five underwent complete surgical resection. Three of these had been judged to have unresectable tumor before treatment.

Docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) is approved for advanced breast and lung cancer.14 Several phase II trials have shown docetaxel to have modest single-agent activity in the treatment of advanced pancreatic cancer.15–18 Docetaxel/gemcitabine combinations have been examined in a variety of dosing schedules.19 Rigas et al.,20 at our institution, reported phase I results of an every-2-week regimen. In that trial, 46 patients were treated with a 1-hour docetaxel infusion followed by a 30-minute gemcitabine infusion, without growth factor support. Dose-limiting toxicities (febrile neutropenia and fatigue) were seen at doses of docetaxel 65 mg/m2 and gemcitabine 4000 mg/m2 in previously treated patients. These were recommended doses for chemotherapy-naive patients and allowed for cumulative doses of both drugs that exceeded the dose limits achieved in every-3-week or every-4-week dosing schedules. Combination docetaxel/gemcitabine has previously been shown to be active and tolerable in treatment of advanced pancreatic cancer, with RRs of 7% to 20%.21–24

This study combined short-course, high-dose therapy with docetaxel/gemcitabine followed by combination XRT and twice-weekly gemcitabine in patients with pancreatic adenocarcinoma. The objectives included the evaluation of RR, toxicity, tumor downstaging, resection rate, and recurrence pattern.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility
Eligibility criteria included a signed consent form, biopsy-proven pancreatic adenocarcinoma with measurable stage I to III disease, age >18 years, and a Karnofsky performance status of >70%. Laboratory parameters included creatinine <2.0 mg/dL, white blood cell count ≥3000/µL, hemoglobin ≥10 g/dL, and platelets ≥100,000/µL. Normal bilirubin levels were required, as was an absence of significant hepatic inflammation (AST and/or ALT <5x the upper limit of normal [ULN] if the alkaline phosphatase level was normal, or alkaline phosphatase < 5x the ULN of normal if AST and ALT were less than the ULN). Patients with a history of chemotherapy/XRT or malignancy (except treated basal cell or squamous cell skin cancer or in situ cervical cancer) were excluded. Pretreatment studies included serum CA 19-9, chest radiograph, abdominal computed tomographic (CT) scan, and laparoscopy. Staging was completed within 4 weeks of beginning therapy.

All cases were presented at a multidisciplinary GI oncology tumor board, and determination was made regarding surgical resectability on the basis of CT scan review by the attending radiologist. The tumor was considered unresectable if extrapancreatic disease (including celiac nodes >2 cm in diameter) was present or if the tumor involved more than half of the circumference of the superior mesenteric artery, celiac artery, hepatic artery, portal vein, or superior mesenteric vein or occluded the portal vein or superior mesenteric vein. Tumor was considered borderline resectable if no extrapancreatic disease was present and involvement of the portal vein, superior mesenteric vein, superior mesenteric artery, or celiac or hepatic artery with less than half of the vessel circumference was present. Tumor was considered resectable if it was limited to the pancreas without evidence of major blood vessel involvement. These criteria were based on the findings of two independent groups.25,26 In those studies, only 2 (6%) of 29 cases were resectable if tumor was contiguous to one half or more of the circumference of a major vessel, and 18 (64%) of 28 cases were resectable if tumor was contiguous to less than one half the vessel circumference.

Treatment
The trial was approved by the Clinical Cancer Review Committee of the Norris Cotton Cancer Center and by the Committee for the Protection of Human Subjects at Dartmouth College. Therapy was initiated with docetaxel/gemcitabine administered intravenously every 2 weeks for three doses (days 1, 15, and 29). Docetaxel 65 mg/m2 was given over 1 hour followed immediately by gemcitabine 4000 mg/m2 over 30 minutes. Body-surface area was calculated according to actual height and weight. Dexamethasone 10 to 20 mg intravenously was given before docetaxel infusion. Additional antiemetics were administered at the physician’s discretion. During combination chemotherapy, patients were monitored with a weekly complete blood count. Before each dose of combination docetaxel/gemcitabine, patients underwent physical examination, and a comprehensive metabolic profile was obtained. Dose adjustments for day 15 and 29 chemotherapy were based on clinical assessment and laboratory evaluation. Chemotherapy was held for an absolute neutrophil count <1500/µL or platelets <100,000/µL. If treatment was held, the patient was reassessed in 1 week and treated at full dose if counts had recovered. If treatment was delayed an additional week or if the nadir was accompanied by platelets <25,000/µL or absolute neutrophil count <500/µL, then doses of both drugs were decreased by 25%. Dose re-escalation or use of growth factors was not permitted. Chemotherapy was held for any nonhematological toxicity judged grade ≥2 and resumed when toxicity resolved to grade ≤1. For any resolved grade 3 or 4 nonhematological toxicity, doses of both drugs were reduced by 25% on the subsequent cycle. If grade 3 or 4 toxicity recurred after dose reduction, then doses were reduced an additional 25%. After three doses of induction chemotherapy, patients underwent a repeat abdominal CT scan.

On day 43, patients began treatment with twice-weekly gemcitabine and XRT. Gemcitabine 50 mg/m2 was administered as a 30-minute infusion twice weekly (Monday/Thursday or Tuesday/Friday) with XRT for 12 doses. Infusion was completed one half to 2 hours before XRT and was given only on days when radiation was delivered. GI prophylaxis with a proton pump inhibitor was administered during chemotherapy/XRT and was continued for an additional month after treatment. During combination therapy, patients were evaluated weekly in the clinic, and laboratory tests were obtained before each dose of gemcitabine. Scheduled treatment was held for neutrophil counts of <1000/µL, platelet counts of <50,000/µL, or grade 3 or 4 nonhematological toxicity.

XRT was delivered by using CT-based three-dimensional conformal planning. Gross tumor volume (GTV) was defined as all known disease, including proven nodal disease as determined by planning CT or other modalities. The primary planning target volume included the GTV with 2–3-cm margins in all directions, and the potential nodal involvement of the porta hepatis and the peripancreatic, superior mesenteric, and celiac axis. For patients with pancreatic tail lesions, the porta hepatis nodes were generally not included in the treatment area. The primary planning target volume was treated to a total dose of 45 Gy in 25 fractions of 1.8 Gy on a once-daily 5 days per week schedule. The secondary planning target volume included the GTV with a 1- to 1.5-cm margin on all sides, including proven nodal involvement. The secondary planning target volume received an additional boost of 5.4 Gy to a total dose of 50.4 Gy in 28 fractions. The maximum dose to the spinal cord was limited to 45 Gy. No more than one half of the volume of the liver received more than 35 Gy. The equivalent of one kidney received less than 17 Gy.

Four weeks after completion of treatment, patients underwent restaging. Response was based on a comparison with the pretreatment CT scan according to Therasse et al.27 CT examinations were performed on a General Electric (Milwaukee, WI) Lightspeed 16-slice scanner by using a pancreatic imaging protocol, which consisted of 3- to 5-mm slice thickness and intravenous contrast. All patients were scanned during the portal-venous phase of intravenous contrast with oral contrast. Some of the patients were also scanned during the arterial phase. The addition of the arterial phase did not affect the measurement data. All CT scans were reviewed with an attending radiologist (M.J.T. or M.A.B.), and the definitions of response were based on these images. Pretreatment and posttreatment lesion size and the extent of peri-vascular invasion were recorded. Complete response was defined as the disappearance of tumor on CT scan; partial response, as a ≥30% decrease in the lesion size on CT scan without the appearance of new lesions; and progressive disease, as a ≥20% increase in the size of the lesion on CT scan or the development of new lesions. Ascites alone did not signify progression unless it was cytologically positive. Stable disease was defined as neither sufficient shrinkage to qualify for partial response nor a sufficient increase to qualify for progressive disease. Patients whose tumors were judged resectable or borderline resectable by CT scan criteria after treatment were offered laparotomy.

Pathologic Evaluation
Surgical specimens were evaluated according to a standardized College of American Pathologists pancreas (exocrine) protocol to provide the information necessary for pathologic staging. This protocol is based on the American Joint Committee on Cancer/International Union Against Cancer tumor-node-metastasis classification, 6th edition. The bile duct, pancreatic neck, posterior pancreatic, and uncinate margins were evaluated grossly and microscopically. The posterior pancreatic and uncinate margins were inked as part of the gross evaluation of the specimen. The specimen was then cut perpendicular to the inked margin for microscopic analysis. Representative sections of gastric and duodenal margins were also submitted. The residual tumor was serially cut and submitted in its entirety for microscopic analysis. In addition to standard pathologic staging, specimens were also graded for the percentage tumor kill in response to therapy according to Evans et al.28

This was a phase II study conducted in two stages, with a target RR of 20%. Thirteen assessable patients were accrued in the first stage. Accrual was suspended if the RR was <20%, excluding an RR of >20% with P = .05. Otherwise, accrual was expanded to 24 patients, yielding a 95% confidence interval for the RR with half-width no greater than ±20% and with the actual half-width depending on the observed RR. Exact methods based on binomial distribution were used to compute 95% confidence intervals for RRs. Toxicity was scored by using the National Cancer Institute Common Toxicity Criteria and the Radiation Therapy Oncology Group Radiation Morbidity Scoring Schema.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between January 2002 and February 2004, twenty-five patients were enrolled onto the study. One patient had a metastatic tumor in retrospect before beginning therapy; this patient was considered non-assessable and was replaced. All others were assessable for both toxicity and response. The mean patient age was 65 years (range, 43–83 years). Thirteen patients (54%) presented with unresectable disease, seven (29%) presented with borderline resectable disease, and four (17%) presented with radiographically resectable tumors.

Response
Treatment response is outlined in Table 1Go. A partial response to induction docetaxel/gemcitabine occurred in three patients. After completion of therapy, 12 patients (50%) met criteria for response by CT as outlined in the Methods section, including 11 partial responses and 1 complete response. The patient whose disease manifested a complete response had been judged unresectable before therapy because of 270° involvement of both the superior mesenteric artery and the celiac artery. Representative pretreatment and posttreatment scans of two responding patients are shown in Figure 1Go. Of the three patients who had progressive disease after therapy, two had met criteria for a partial response locally but were found to have small-volume liver metastases at operation. The third patient had obvious liver metastases but a stable primary tumor on posttreatment scan. All three of these patients had been judged surgically unresectable before therapy. No tumor exhibited local progression through treatment, and no patient whose disease seemed resectable before treatment had unresectable disease after therapy.


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  		TABLE 1. Response to therapy
 

Figure 1
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  		FIG. 1. Representative pretreatment and posttreatment computed tomographic scans in responding patients. The pancreatic body mass before (A) and after (B) treatment shows tumor response (arrows). The pancreatic head mass before (C) and after (D) treatment shows tumor response (arrows).

 
Toxicity and Dosing
During induction docetaxel/gemcitabine, all patients received three doses of treatment. Sixteen patients received full-dose treatment. Eight patients required dose reduction in doses 2 and 3 because of toxicity resulting from neutropenia (five patients) and from transaminitis, nausea/vomiting, or diarrhea (one patient each). Two patients were hospitalized during induction chemotherapy: one for biliary stent occlusion and one for nausea/vomiting and urinary tract infection. There were no episodes of neutropenic fever at any time during treatment.

During combined gemcitabine/radiation treatment, patients received a median of 9 doses of sensitizing gemcitabine out of 12 planned (range, 7–12). Three patients received all 12 doses. A variety of toxicities contributed to holding one or more doses of gemcitabine, most commonly dehydration, fatigue, and/or nausea. One patient was removed from treatment after 41.4 Gy of XRT because of general decline. All others received full-dose XRT to 50.4 Gy as planned. Full listings of all grade ≥3 toxicities are shown in Table 2Go.


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  		TABLE 2. Grade 3 and 4 toxicities
 
Thirteen patients were hospitalized during treatment for various reasons. Three were hospitalized with signs or symptoms of blocked biliary stents, and eight were admitted with GI complaints (nausea/vomiting, constipation, or dehydration/weight loss). One patient developed acute respiratory distress syndrome secondary to gemcitabine, and another developed pneumocystis pneumonia from chronic, inappropriate corticosteroid use. Both of these patients recovered fully. There were no deaths on the protocol.

Surgical Resection
Nineteen patients underwent laparotomy, and 17 of these underwent surgical resection of disease: 14 patients underwent pancreaticoduodenectomy, and 3 had distal pancreatectomy. As stated, two patients were found to have small-volume liver metastases not seen on CT scan. Resection attempts on these two patients were aborted. Thirteen patients who underwent resection of tumor also received intraoperative XRT. Pathology results of tumor resections are listed in Table 3Go. Of the 17 patients who underwent resection, 13 (76%) had negative surgical margins. This included four of seven previously unresectable and five of six previously borderline resectable patients. All four patients whose disease had been judged radiographically resectable before therapy also underwent margin-negative resection. All patients but one had a negative pancreatic parenchymal margin. That patient also had direct tumor involvement of the left adrenal gland. Three other patients had microscopic tumor involvement of the uncinate margin. All tumor specimens showed evidence of a grade ≥IIa treatment effect. There were no pathologic complete responses, although six specimens showed ≥80% tumor kill.


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  		TABLE 3. Pathologic results in patients undergoing resection
 
Two patients died in the postoperative period: one from aspiration pneumonia that occurred on the planned day of discharge and the other from small-bowel ischemia induced by jejunal tube feedings. Both deaths occurred more than 30 days after completion of the protocol. Although these deaths were unfortunate, after careful review neither was judged to be directly related to neoadjuvant therapy.

Recurrence Pattern and Survival
After completion of therapy, all patients were followed up with quarterly history and physical examinations and routine laboratory evaluation. In addition, twice-yearly chest radiographs and abdominal CT scans were performed to monitor for recurrence.

At a median follow-up of 22 months, 10 patients were alive, and 5 remained disease free. All five of these patients underwent margin-negative resection. Cause of death in the 14 other patients included progressive disease (n = 9), postoperative complications (n = 2), stroke (n = 1), chronic obstructive pulmonary disease (n = 1), and unknown (n = 1). In the nine patients who died as a result of progressive tumor, seven died with liver metastases, one from peritoneal metastases, and one from lung metastases. None of the 17 patients who underwent resection developed local recurrence. Furthermore, none of the patients whose disease was unresectable exhibited local progression. The Kaplan-Meier survival curve produced by using the product-limit method is shown in Figure 2Go. The median survival for all patients on the trial was 14 months from enrollment.


Figure 2
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  		FIG. 2. Kaplan-Meier survival curve.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Pancreatic cancer remains a devastating disease. In 2003, an estimated 30,700 cases were diagnosed, resulting in approximately 30,000 deaths.29 Despite multiple clinical trials, there has been little improvement in survival for patients with metastatic disease. Although newer agents are being investigated in the setting of advanced disease, the greatest effect of therapy on survival will likely occur in patients who present with more localized tumors.

In the United States, adjuvant 5-FU/XRT is an accepted treatment in patients who have undergone complete resection, provided that they have recovered sufficiently from surgery. Attempts to improve adjuvant therapy continue, and the Radiation Therapy Oncology Group has completed a randomized trial comparing gemcitabine with 5-FU given before and after 5-FU/XRT following margin-negative tumor resection.30 Results of that study are pending, but even if they are positive, there will be no effect on the large number of patients who present with locally advanced, unresectable tumor. For these patients, no standard of care exists. As a result, most patients who present with even organ-confined disease will die. Single-modality XRT long ago was shown to palliate pain caused by locally advanced tumors, but it had no clear effect on disease progression or survival.31 Single-agent gemcitabine has been considered an acceptable palliative measure, but it is also unlikely to result in major objective responses or to change the resectability status of the tumor.

Multiple neoadjuvant chemoradiotherapy protocols have been evaluated for both resectable and locally advanced disease. Single-agent and combination regimens using 5-FU, cisplatin, and paclitaxel have yielded evidence of radiographical and pathologic responses.28,32,33 Gemcitabine in low doses can be safely combined with XRT with modest efficacy, as we and others have shown. Various dosing perturbations of gemcitabine/XRT have been explored. These have included once-weekly gemcitabine infusion with full-dose radiation and full-dose gemcitabine with dose-escalating XRT.34,35 A trial combining weekly gemcitabine, infusional 5-FU, and XRT resulted in unacceptable toxicity, including severe GI bleeding, thrombocytopenia, and Stevens-Johnson syndrome.36 A phase I trial of twice-weekly gemcitabine, cisplatin, and XRT, however, revealed an acceptable toxicity profile and has led to a follow-up phase II trial.37

Our study combined a chemotherapeutic regimen (docetaxel/gemcitabine) with known activity against pancreatic cancer sequentially with gemcitabine/XRT to maximize the therapy against local tumors. Our intent was to induce an objective tumor response to allow for margin-negative resection, decreased local relapse rates, and decreased rates of metastasis. Doses of docetaxel and gemcitabine in our regimen were higher than any previously attempted in this disease but were well tolerated even without growth factor support. All patients were able to receive three doses as planned, although several had dose reductions in doses 2 and 3 secondary to low or prolonged blood count nadirs. The RR of 13% to initial chemotherapy is similar to what others have reported with these drugs. We did, however, see several patients whose disease exhibited a minor response to induction chemotherapy, and it may be that increasing the number of doses would have increased the response. Other investigators have shown neoadjuvant activity for this combination and have reported evidence of high surgical resectability rates after treatment.38 In designing the trial, effort was made to maximize therapy while not overextending the duration of neoadjuvant therapy. Our decision to use three doses of docetaxel/gemcitabine was arbitrary but allowed for the entire duration of treatment to be 3 months.

We followed induction chemotherapy with full-dose XRT and twice-weekly sensitizing gemcitabine. This portion of treatment resulted in more toxicity, and GI side effects were common but manageable. Hospital admissions related to treatment were common. However, all patients except one completed all 6 weeks of XRT and were able to tolerate a median of 75% of the planned gemcitabine doses. This included an 83-year-old woman who subsequently underwent successful margin-negative resection. Our decision to add GI prophylaxis during XRT was based on our experience with treatment-induced GI bleeding, as well as an episode of bleeding in the first study patient, who did not receive prophylaxis. After this, GI bleeding was not a major problem.

The overall RR of 50% is remarkable for this disease and is especially encouraging when combined with the high rate of margin-negative pathologic results (76%) in the 17 patients who underwent resection. Most encouraging are the four patients who presented with unresectable disease and whose response to therapy allowed for margin-negative resection of tumor. Pathologic responses in resected specimens reflected the clinical efficacy seen, with a grade ≥IIa response in all specimens. It is important to note that no patient had local growth of disease during therapy. This is critical to the success of any neoadjuvant treatment, especially for patients with resectable disease.

Our study suffers the same limitations as many others in the treatment of pancreatic cancer: specifically, it was a single-institutional trial with a small number of patients. Additionally, it could be argued that the very high doses of gemcitabine used in our trial added little to efficacy because maximum intracellular {alpha}',{alpha}'-difluorodeoxycytidine 5'-triphosphate concentrations may be achieved at lower doses.39 Despite the activity of our regimen, no pathologic complete response was seen, and three surgical specimens had a positive uncinate margin. Nevertheless, given the high RR and complete resection rate and the excellent local disease control, we believe that it is reasonable to consider this regimen for patients with nonmetastatic pancreatic cancer, especially those with borderline or unresectable tumor. Increased responses to treatment, reliable downstaging of tumors, and high margin-negative resection rates will be necessary if significant improvements in long-term outcome are to be achieved in pancreatic cancer. We believe that, given the results shown here, our regimen should be the foundation of a larger confirmatory trial that would identify any advantage in survival.


   ACKNOWLEDGMENTS
 
Supported by a grant from Aventis Pharmaceuticals, Bridgewater, NJ.


   FOOTNOTES
 
M.A.B. is now at Wake-Forest University Baptist Medical Center, Winston-Salem, North Carolina; J.M.C. is now at Van-derbilt University, Nashville, Tennessee.

Received for publication April 6, 2005. Accepted for publication July 27, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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