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10.1245/s10434-007-9384-x
Annals of Surgical Oncology 14:2088-2096 (2007)
© 2007 Society of Surgical Oncology
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Original Article

A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin

Daniel H. Palmer, MRCP, PhD1, Deborah D. Stocken, PhD1, Helen Hewitt, RGN1, Catherine E. Markham, RGN2, A. Bassim Hassan, PhD1, Philip J. Johnson, FRCP, MD1, John A. C. Buckels, FRCS, MD2 and Simon R. Bramhall, FRCS, MD2

1 Cancer Research UK Institute for Cancer Studies and Clinical Trials Unit, University of Birmingham, Vincent Drive, Birmingham, B15 2TT, United Kingdom
2 The Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, United Kingdom

Correspondence: Address correspondence and reprint requests to: Daniel H. Palmer, MRCP, PhD; E-mail: Daniel.Palmer{at}uhb.nhs.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Survival after surgery for pancreas cancer remains low. This improves with adjuvant chemotherapy, but up to 30% patients do not receive the prescribed treatment. Neoadjuvant therapy may increase the proportion of patients who receive all treatment components, may downstage disease before surgery, and may provide early treatment of micrometastases. This randomized phase 2 study compares gemcitabine-based chemotherapy regimens to identify the most promising regimen for future study.

Methods: Fifty patients with potentially resectable pancreas lesions were enrolled onto the study. Twenty-four patients were randomized to gemcitabine (1000 mg/m2) every 7 days for 43 days; 26 patients were randomized to gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2), 7 to the original schedule (omitting day 22) and 19 to a revised schedule due to neutropenia (omitting days 15 and 36). The primary outcome measure was resection rate.

Results: Patients who were allocated to gemcitabine received a median of 85% of the planned dose. Patients who were allocated to combination treatment received a median of 88% and 92% of the planned gemcitabine and cisplatin doses, respectively. There were 10 episodes of grade III/IV hematological toxicity in each group. Twenty-seven patients (54%) underwent pancreatic resection, 9 (38%) in the gemcitabine arm and 18 (70%) in the combination arm, with no increase in surgical complications. To date, 34 patients (68%) have died. Twelvemonth survival for the gemcitabine and combination groups was 42% and 62%.

Conclusions: Chemotherapy can be safely administered before pancreatic surgery. Combination therapy with gemcitabine and cisplatin is associated with a high resection rate and an encouraging survival rate, suggesting that further study is warranted.

Key Words: Neoadjuvant chemotherapy • Pancreatic cancer • Randomized phase 2 trial • Gemcitabine • Cisplatin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pancreatic cancer is the fifth most common cause of cancer death in the West, with an annual incidence of 28,000 in the United States and overall 5-year survival of <1%.1,2 For patients with localized disease, radical surgery may afford long-term benefit. However, epidemiological studies indicate that the overall resection rate may be <3%,3 and even in specialist institutions, it is reported to be only 15% to 20%.4–9 Even in patients who undergo resection, 5-year survival remains only 7% to 24%, and median survival is only approximately 1 year in most series, indicating that surgery alone is usually inadequate.10 These disappointing results are likely attributable to early vascular dissemination such that subclinical metastases are present at the time of diagnosis in most patients.11 This hypothesis underpins the investigation of adjuvant chemotherapy and/or radiotherapy after surgery. The Gastrointestinal Tumor Study Group study indicated a marked improvement in median survival in patients who received adjuvant chemoradiotherapy compared with those treated by surgery alone (20 vs. 11 months, respectively).12 However, this study was small, with only 43 patients, and larger studies have failed to corroborate its findings. For example, a European Organization for the Research and Treatment of Cancer study that randomized 218 patients to adjuvant chemoradiotherapy or to no further treatment demonstrated no significant difference in overall survival or local recurrence. Notably, 20% of patients did not receive the assigned adjuvant therapy as a result of postoperative complications or patient refusal.13

Similarly, the European Study Group for Pancreatic Cancer (ESPAC-1) study, which used a 2 x 2 randomization between no adjuvant therapy and chemotherapy and/or radiotherapy, showed that adjuvant radiotherapy did not improve survival (radiotherapy vs. no radiotherapy: 175 vs. 178 patients; 5-year survival, 10% vs. 20%, P = .05; median survival, 15.5 vs. 16.1 months). Conversely, adjuvant chemotherapy produced a statistically significant improvement in overall survival (chemotherapy vs. no chemotherapy: 238 vs. 235 patients; 5-year survival, 21% vs. 8%, P = .009; median survival, 19.7 vs. 14 months, P < .0005). These data indicate that external-beam radiotherapy may not be a key component of adjuvant treatment, but that chemotherapy is an essential component.14 Because three-quarters of first relapses occur as distant metastases (predominantly hepatic), this suggests that the emphasis for adjuvant therapy should be on improving systemic treatment of micrometastases.

A major drawback of adjuvant therapy for pancreas cancer is the marked and consistent failure of 20% to 30% of patients to receive the designated therapy as a result of post-operative complications, delayed surgical recovery, patient refusal, comorbidity, or early disease recurrence.13,15,16 This may be overcome by the use of neoadjuvant therapy so that more patients may receive potentially beneficial adjuvant treatment. Other theoretical advantages of this approach include the following: early treatment of micrometastases; conversion of nonresectable to resectable disease; delaying surgery, thus sparing those who already have occult metastases the morbidity and mortality of major surgery if disseminated disease becomes apparent at the time of reassessment; reduced risk of tumor seeding at the time of surgery; treatment better tolerated than postoperative therapy; and reduction in overall treatment time.

Potential disadvantages of neoadjuvant therapy include the following: requirement for biliary decompression before chemotherapy and potential for complications associated with biliary stents; delayed surgery, allowing progression to a nonresectable stage in patients whose disease did not respond to therapy; lack of preoperative tissue diagnosis (risk of seeding if a preoperative biopsy is performed); and potential for increase in postoperative complications. Several small phase 1 and 2 studies, particularly those investigating the role of neoadjuvant chemoradiotherapy, have reported the ability to downstage locally advanced disease from a nonresectable to resectable stage.17–19 A limitation of such studies is that the definition of resectability is subjective: a "nonresectable" tumor may be resectable in a specialist institution. In general, neoadjuvant studies of chemoradiotherapy have demonstrated good local disease control but with high rates of subsequent distant metastases, again emphasizing that efforts may be better concentrated on the intensification of systemic therapy.20,21

Gemcitabine (difluorodeoxycytidine) is a deoxycytidine analogue that competes for incorporation into DNA inhibiting its synthesis. Two phase 2 studies treating a total of 78 patients with advanced pancreas cancer demonstrated modest activity, with a partial response rate of approximately 10% and a further 30% achieving stable disease.22,23 Gemcitabine is currently the standard treatment for advanced pancreas cancer on the basis of a randomized study comparing gemcitabine with 5-fluorouracil in 126 patients in which a small but clinically important survival advantage and higher clinical benefit response (based on improvements in pain control, weight, and Karnofsky Performance Status) favoring gemcitabine were observed.24

The rationale for the combination of gemcitabine with cisplatin is based on the differing mechanisms of action of the two drugs such that no cross-resistance and nonoverlapping, dose-limiting toxicities are observed. Experimental data suggest that a combination of the two drugs provided on an appropriate schedule (either simultaneously or one right after the other) can act synergistically. Synergy may be mediated by inhibition of ribonucleotide reductase by gemcitabine, depleting the deoxynucleotide pool required for DNA replication and thereby inhibiting excision repair of cisplatin-induced DNA crosslinks, or by gemcitabine incorporation into DNA, facilitating cisplatin crosslink formation.25,26

Clinical studies of this combination that have used several dosing schedules have confirmed high activity in a range of human malignancies.27,28 Notably, fractionation of the total cisplatin dose reduces toxicity, allows outpatient treatment, and may optimize its synergistic interaction with gemcitabine.29

Phase 2 studies in patients with advanced pancreas cancer have reported objective response rates of 11% to 31%, with overall median survival of 7 to 10 months.30–32 This compares favorably to reported response rates of 6% to 11% and median survival of 4 to 6 months with gemcitabine alone.22–24

Phase 3 studies have demonstrated greatly improved responses rates (26.4% vs. 9.2%; P = .02) and progression-free survival (20 weeks vs. 8 weeks; P = .048) with gemcitabine plus cisplatin compared with gemcitabine alone and with modest toxicity, in particular with no marked increase in hematological toxicity.33,34

These data provide a sound basis for investigating these active chemotherapy regimens in the neoadjuvant setting. The rationale underlying the current study is that preoperative chemotherapy will provide early treatment of micrometastatic disease and increase operability to improve survival. The aim of the study was to assess the role of neoadjuvant chemotherapy for patients with potentially resectable pancreatic cancer by using gemcitabine alone or in combination with cisplatin. Because both regimens were considered experimental in this setting, a randomized phase 2 trial design was used with a "pick the winner" strategy in the event of both regimens demonstrating clinical activity.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Patients with clinical and radiological evidence of cancer of the head of pancreas that was considered to be resectable on contrast-enhanced computed tomographic (CT) scan and suitable for surgical exploration were eligible for this study. Patients with tumor surrounding >180° of the circumference of the portal or superior mesenteric vein, or direct tumor extension to either the superior mesenteric artery or the coeliac axis, or with evidence of extrapancreatic disease were considered nonresectable. Patients who had received previous treatment for pancreatic cancer, or patients whose malignant pancreatic disease was clinically or radiologically in doubt were ineligible for the study. Other criteria for patient entry were the following: Karnofsky Performance Status score of >60%; adequate hematological function; adequate renal function (glomerular filtration rate >60 mL/min calculated by the Cockcroft formula35); and adequate liver function with bilirubin <50 µm/L (after biliary stenting if necessary).

All patients received a trial information sheet and provided written informed consent before study entry.

Trial Design and Statistics
Patients were randomized to preoperative chemotherapy with either gemcitabine or gemcitabine plus cisplatin. Randomization was stratified by surgeon. The trial was originally designed with a third arm containing gemcitabine followed by external-beam radiotherapy. This arm was discontinued after recruitment of seven patients because of radiotherapy quality-control issues and emergence of data from the ESPAC-1 study indicating that radiotherapy may not play an important role as an adjuvant to surgery in this setting. Target recruitment was based on phase 2 sample size methodology:36 35 patients per arm would allow 90% probability of selecting the best treatment to take forward to the phase 3 setting if it was superior by an absolute difference of 20%.

The primary outcome measure was resection rate. Secondary measures were radiological response (according to International Union Against Cancer criteria), toxicity, survival, and proportion of negative resection margins. Pancreatic transection margin, bile duct, and retroperitoneal margins were evaluated.

CT scanning was performed before commencement and at completion of chemotherapy. Exit CT scans were assessed by the radiologist and the surgeon for resectability. Bidimensional measurements of the primary pancreatic mass were taken from the entry and exit CT scans by the same radiologist. Surgical exploration was undertaken unless there was evidence of metastatic disease not evident on the entry scan.

Survival was calculated from date of randomization to death from any cause, or censor date. Survival estimates were calculated by the Kaplan-Meier method. Analyses were carried out on an intent-to-treat basis. Adverse events were graded according to National Cancer Institute common toxicity criteria.

This was single-center study and was approved by the local research ethics committee and monitored by an independent data monitoring committee. Study conduct conformed to the Declaration of Helsinki clinical trial practice guidelines.

Treatment
Gemcitabine Alone
Gemcitabine was administered at a dose of 1000 mg/m2 in 500 mL .9% saline by intravenous infusion over 30 minutes, every 7 days for 43 days. Antiemetic therapy comprised intravenous dexamethasone (4 mg) and granisetron (3 mg).

Gemcitabine Plus Cisplatin
Gemcitabine (1000 mg/m2) was administered as above, followed immediately by cisplatin at a dose of 25 mg/m2 over 1 hour in 500 mL .9% saline. Before cisplatin administration, patients were hydrated with 500 mL .9% saline plus 20 mmol potassium chloride intravenously over 1 hour, followed by 100 mL 10% mannitol over 15 minutes. In the original protocol, this regimen was administered every 7 days for 43 days, with the omission of treatment on day 22 (3 weeks of treatment followed by a rest week). Planned analysis of the toxicity data for the first 15 patients demonstrated high grade III/IV hematological toxicity with this regimen, leading to a modified schedule that omitted treatment on days 15 and 36 (2 weeks of treatment followed by a rest week).29

All patients received ciprofloxacin (250 mg orally twice a day) during treatment with chemotherapy to reduce the risk of infection, particularly infection due to biliary stents. Patients were monitored weekly (clinical assessment, blood count, and biochemical profile) before receiving treatment.

Patients did not receive additional adjuvant chemotherapy or radiotherapy after successful surgical resection.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Fifty patients were enrolled onto the study between November 1999 and May 2003; 24 patients were randomized to gemcitabine and 26 patients to gemcitabine plus cisplatin (7 to the original schedule and 19 to the revised schedule). After a second planned review of the data by the independent data monitoring committee, recruitment was closed.

Demographics were well balanced between the two groups (Table 1Go). Median age was 66 years, with 26 male and 24 female subjects and 10 current smokers (20%). Thirty-eight patients (76%) had a Karnofsky Performance Status score of 90% or 100% at study entry. The median (interquartile range) time from diagnosis (within 10 days of referral to specialist unit) to randomization was 14 (range, 7–35) days. Most patients underwent endoscopic biliary stenting before study entry. Two patients had delayed entry of 63 and 71 days as a result of slow resolution of hyperbilirubinemia after stenting.


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  		TABLE 1. Patient characteristics
 
Treatment
Twenty-two of 24 patients randomized to gemcitabine received treatment with a total of 137 cycles of chemotherapy (Table 2Go). Two patients did not start treatment (one due to unresolved jaundice, and one due to pretreatment death 4 days after randomization). Patients received a median of 86% (range, 71%–100%) of the planned gemcitabine dose.


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  		TABLE 2. Treatment received
 
Twenty-four of 26 patients randomized to gemcitabine plus cisplatin received treatment with a total of 114 cycles (Table 2Go). Two patients did not start treatment (one due to poor Karnofsky Performance Status score, and one due to low creatinine clearance). Patients received a median of 88% (range, 40%–100%) planned gemcitabine dose: 85% (range, 71%–100%) in 6 patients and 88% (range, 40%–100%) in 18 patients receiving drugs according to the original and revised schedules, respectively. Patients also received a median of 92% (range, 40%–100%) planned cisplatin dose: 83% (range, 67%–100%) in 6 patients and 100% (range, 40%–100%) in 18 patients receiving the original and revised schedules, respectively.

Toxicity
Treatment with gemcitabine alone was well tolerated, with no grade III/IV nonhematological toxicity. Grade III/IV hematological toxicity (mostly neutropenia) was experienced by nine patients (12 episodes in a total of 137 cycles of treatment).

Treatment with gemcitabine plus cisplatin was also generally well tolerated. Grade III/IV hematological toxicity was experienced by 10 patients (10 episodes in a total of 114 cycles of treatment). Planned analysis after 15 patients had been randomized between the two chemotherapy regimens confirmed a higher proportion of patients experiencing hematological toxicity in the combination arm, with 6 patients needing hospitalization for grade 3 or higher toxicity, each necessitating a treatment delay and prompting the adoption of the revised schedule as detailed above, which resulted in fewer delays or omissions in treatment. Grade III/IV nonhematological toxicity was uncommon, with one episode of nausea, two episodes of fatigue, and one episode of constipation reported.

No chemotherapy-related biliary stent complications were observed with either chemotherapy regimen. No differences in the frequency of postoperative complications were observed between the two arms, and in particular, no surgical complications related to myelosuppression were seen. Pancreatic leak rates were approximately 10% in both arms (gemcitabine alone, 1 of 9; gemcitabine plus cisplatin, 2 of 18), and all were successfully managed conservatively. No enteric leaks occurred in either group. Median length of hospital stay for patients undergoing successful resection was 10 days in the gemcitabine group (range, 7–31 days) and 9 days in the combination group (range, 8–29 days).

Outcome
Outcome data for the 50 patients are summarized in Tables 3Go and 4Go. In total, 27 patients (54%) underwent pancreatic resection, 9 (38%) randomized to gemcitabine alone and 18 (70%) to combination treatment. Eighteen patients (36%) underwent biliary bypass. Five patients (10%) did not undergo surgery (one gemcitabine alone and four combination treatment) because of progressive disease (liver metastases in two patients, liver and pulmonary metastases in one patient, superior mesenteric vein encasement in one patient, and one pretreatment death).


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  		TABLE 3. Patient outcome data
 

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  		TABLE 4. Patient survival
 
Seven of the nine resections in the gemcitabine group were for ductal adenocarcinoma of the head of pancreas, one other cancer (adenocarcinoma of the intrapancreatic bile duct), and one nonmalignant disease (chronic pancreatitis). Fourteen of the 18 resections in the combination group were for ductal adenocarcinoma with two other cancers (malignant neuroendocrine tumor of ampulla, neuroendocrine carcinoma of the head of pancreas) and two non-malignant lesions (focal pancreatitis and chronic pancreatitis). In retrospect, in the two cases of neuroendocrine tumor, there were no features, such as vascular enhancement, to suggest this diagnosis pre-operatively. Similarly, the three cases of chronic pancreatitis had apparent mass lesions in the head of the pancreas associated with dilatation of common bile duct and pancreatic duct consistent with a radiological diagnosis of pancreas cancer.

Of the 24 resections for malignant disease, 6 patients (25%) had positive posterior resection margins (2 [25%] gemcitabine and 4 [25%] combination), and 15 (63%) had positive lymph nodes (6 [75%] gemcitabine and 9 [56%] combination).Overall, one partial response was seen. This patient received gemcitabine plus cisplatin and then underwent resection for ductal adenocarcinoma. Thirty-two patients had stable disease (16 in each treatment group), 21 of whom underwent resection. Ten patients had progressive disease (five in each treatment group), one of whom underwent resection.

To date, 34 patients (68%) have died (Table 4Go). Median follow-up of the 16 patients still alive was 28 months (interquartile range, 22–38; range, 15–58). Twelve-month survival from randomization for the gemcitabine and combination groups was 42% and 62%, respectively. Twelve-month survival from randomization was 78% and 22% for the pancreatic resection and biliary bypass groups, respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Curative surgery for pancreas cancer is limited by the high frequency of relapse, usually with distant metastases, presumably as a result of early dissemination of micrometastases. This provides a rational basis for adjuvant therapy, and indeed, post-operative chemotherapy has been shown to greatly improve overall survival.14,37 However, adjuvant treatment is limited by a consistent and high number of patients who do not receive the prescribed therapy. This problem may be circumvented by the use of neoadjuvant therapy that allows a greater proportion of patients to receive chemotherapy and earlier treatment of micrometastases. Because relapse is predominantly at distant sites, intensification of systemic therapy may further improve cure rates, and this may be optimized in the preoperative setting, where chemotherapy is better tolerated than postoperatively.15

The current study investigated two chemotherapy regimens, and our findings provide insight into several questions pertaining to neoadjuvant therapy for pancreas cancer. We have demonstrated that neoadjuvant chemotherapy was safe and well tolerated, allowing the delivery of most of the planned chemotherapy. In particular, there were no chemotherapy-related biliary stent complications. This is in contrast to the stent problems reported in studies of preoperative chemoradiotherapy.38 Further, no increase in postoperative complications was observed.

A potential drawback of neoadjuvant chemotherapy is that delaying surgery may allow disease in some patients to progress to a nonresectable stage, although conversely, patients with subclinical metastases at diagnosis may be spared major surgery if these become apparent at the time of restaging. In the current study, radiological disease progression was seen in 10 patients. Three of these developed distant metastases likely to have been present at presentation and thus were spared futile surgery. Six patients had disease that remained potentially resectable at restaging despite disease progression, and proceeded to undergo surgery. Thus, only one patient had local disease progression that precluded surgical exploration.

Because preoperative percutaneous biopsy of pancreatic masses is relatively contraindicated because of the risk of peritoneal seeding that would compromise curative surgery, the resulting absence of a histological diagnosis risks the exposure of patients who do not have cancer to unnecessary chemotherapy in the neoadjuvant context.39 In the current study, only three patients (6%) did not have cancer. This is in line with accepted clinical and radiological diagnostics expected of an experienced multidisciplinary team, whose error rate should be <10%.40 In a further three cases, the diagnosis was not ductal adenocarcinoma of the head of pancreas; instead, they were ampullary neuroendocrine tumor, adenocarcinoma of intrapancreatic bile duct, and neuroendocrine tumor of head of pancreas. At the time of recruitment to this study, endoscopic ultrasound and fine-needle aspiration were not routinely available. With the advent of these techniques and their safe use for performing preoperative pancreatic biopsy, future studies of neoadjuvant therapy in this setting would be enhanced by pretreatment confirmation of adenocarcinoma of the pancreas by endoscopic ultrasound.

Importantly, chemotherapy in this study was well tolerated with no treatment-related deaths.

A comparison of resection and survival data for the current study with that of a historical series of patients referred to our institution between 1997 and 1999 is summarized in Table 5Go.41 In this period, 251 patients with a variety of diagnoses were referred for consideration of pancreatic surgery. Data for 133 patients who underwent exploratory laparotomy for suspected pancreatic tumor—and thus comparable to the trial population—were available. Outcomes for patients in the trial compare favorably with this historical series, many of whom received adjuvant chemotherapy and/or radiotherapy as part of the ESPAC-1 study. Thirty-eight percent of patients receiving neoadjuvant gemcitabine underwent resection. This is comparable to the resection rate of 42% in our own series.4–10,42–47 However, the resection rate of 70% in the combination chemotherapy arm was far greater.


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  		TABLE 5. Comparison of resection rate and survival between study patients and historical series from our institution
 
The most important determinants of overall survival in pancreas cancer are disease stage and the ability to achieve complete tumor clearance. R0 and node-negative resections are associated with long-term survival, but there is little impact on survival after R1 resection.4–10,42–47 Most surgical series report an R1 resection rate of 30% to 40%. Thus, the 75% R0 and 44% node-negative resection rates observed in this study in patients receiving gemcitabine plus cisplatin suggest downstaging by neoadjuvant chemotherapy and may contribute to much improved overall survival.

In conclusion, improved outcome for patients with pancreas cancer will result from increasing the resection rate and from more effective systemic therapy to eradicate occult metastases. Both of these goals may be achieved by neoadjuvant chemotherapy with gemcitabine in combination with cisplatin, as evidenced by a high resection rate (70%), with a substantial proportion of R0 and node-negative resections. We have shown that neoadjuvant chemotherapy can be safely administered before pancreatic surgery and that combination therapy with gemcitabine and cisplatin seems more efficacious than gemcitabine alone. These data indicate that randomized phase 3 trials of neoadjuvant chemotherapy that use this combination are warranted.


   ACKNOWLEDGMENTS
 
Supported by Eveson Charitable Trust (Registered Charity 1032204) and from an educational grant from Eli Lilly. We thank V. Archer, P. Mulholland, D. Mirza, D. Mayer, D. Candinas, J. Oliff, and S. Hussain for their support for the study and their help preparing the manuscript.

Received for publication October 10, 2006. Accepted for publication January 17, 2007.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
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