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Preoperative chemoradiation therapy for adenocarcinoma of the pancreas: The Fox Chase Cancer Center experience, 1986–2003
Surg Oncol Clin N Am 13 (2004) 685–696
Preoperative chemoradiation therapy for adenocarcinoma of the pancreas: The Fox Chase Cancer Center experience, 1986–2003 Ingrid M. Meszoely, MDa, Hao Wang, MSb, John P. Hoffman, MD, FACSa,* a
Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA b Department of Biostatistics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
The delivery of combination chemoradiation therapy in the preoperative setting is a commonly used regimen at the Fox Chase Cancer Center for patients with potentially resectable adenocarcinoma of the pancreas. Chemoradiation therapy followed by surgical resection has been fundamental to the treatment of patients with localized pancreatic cancer at Fox Chase Cancer Center since 1986. This treatment strategy has been favored at this institution for its capacity to provide adjuvant therapy to a greater number of patients and improve patient selection for surgical resection. In addition, local control may improve margin-negative resectability in this patient population and potentially provide a survival benefit. In 1992 the authors published their first series examining the feasibility and effect of chemoradiotherapy delivered in the preoperative setting. This series suggested that this method was safe, with high completion rates, and improved the rates of R0 resections and negative lymph nodes [1]. These findings significantly influenced the institutional approach to the management of localized and potentially resectable pancreatic cancers. Since the authors’ initial experience [1], more effective delivery strategies and new agents have been developed [2–6], and the authors have incorporated these advances into their protocols. Their neoadjuvant experience for localized * Corresponding author. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: [email protected] (J.P. Hoffman). 1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2004.06.013
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pancreatic adenocarcinoma now includes 152 patients treated between September1986 and December 2003. Preoperative therapeutic regimens in this series of patients included 5-fluorouracil (5-FU)–based therapy or gemcitabine, in addition to concomitant delivery of external beam radiation therapy (EBRT). Eighty-one patients underwent potentially curative pancreatic resection following the completion of chemoradiation therapy. In this article the authors review the institutional experience of preoperatively delivered chemoradiation in therapy for localized adenocarcinoma of the pancreas and compare it with their series of patients receiving surgery before adjuvant therapy.
The 5-FU experience Based on the experience of several institutions with the administration of preoperative radiotherapy for localized pancreatic cancer [7–9] and on the evidence suggested by the GITSG phase III trial addressing the radiopotentiating effects of chemotherapy in the adjuvant setting [10], a preoperative chemoradiation therapy pilot study was initiated at Fox Chase Cancer Center in 1986 for patients with potentially resectable stage I to stage III pancreatic cancer [1]. This protocol involved EBRT with a total dose of 5040 cGy in 28 fractions, 180 cGy/fraction, five fractions per week. Initial radiation fields encompassed the gross tumor with a 2- to 3-cm margin to a dose of 3960 cGy, followed by a cone-down field to the gross tumor with a 1- to 2-cm margin for an additional 1080 cGy. On day 2 of radiation, bolus mitomycin C (10 mg/m2) was given followed by a 96-hour continuous infusion of 5-FU (1000 mg/m 2/day). On day 28 an additional 96-day course of 5-FU was initiated. Therapeutic response was assessed by CT scan of the abdomen 4 to 6 weeks after the completion of chemoradiation. Patients without evidence of progression underwent surgical exploration. Following the enrollment of 21 patients, the efficacy and safety of this protocol was evident, and a trial was proposed to and adopted by the Eastern Cooperative Oncology Group (ECOG) in July 1990. Fox Chase Cancer Center enrolled 26 of the 53 patients evaluated in this study. The authors’ initial pilot study using this protocol was published in 1995 [11]. In this study, 34 patients, including those enrolled in the ECOG mycin C. Twenty-five patients (73.5%) were believed to be suitable candidates for resection. Eleven patients (32%) went on to potentially curative resection. Two patients (18.1%) had node-positive disease. One patient (9.1%) had a positive-margin resection. Five patients (45.5%) were diagnosed with tumor recurrence with a median disease-free survival of 27 months. Overall survival was 45 months. These results suggesting better local control with an increased rate of node-negative and negative-margin resections translating into prolonged survival provided significant enthusiasm at the Fox Chase Cancer Center for preoperative treatment of potentially resectable
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pancreatic cancer. Since this publication, patients presenting to Fox Chase Cancer Center with a diagnosis of pancreatic adenocarcinoma with lesions abutting or compressing the superior mesenteric vein or artery have been offered neoadjuvant chemoradiation therapy and post-resectional maintenance chemotherapy. Only patients with 360 involvement of the superior mesenteric artery, occlusion of the superior mesenteric vein down to the level of its first branches, or metastatic disease were excluded. These patients were offered definitive chemoradiation therapy as their sole treatment. Surgical resection followed by adjuvant chemoradiation has been the preferred therapy for patients presenting with imaging studies demonstrating a distinct fat plane between tumor and the mesenteric vessels and without evidence of distant metastases. As of March 1999, 64 patients had been treated on this protocol at the Fox Chase Cancer Center. Twenty-six of these patients were enrolled in the ECOG phase II trial (PD-289). Following restaging with CT scan, 40 patients (62.5%) underwent exploration. Twenty-four of these patients (60%) went onto resection. At the time of initial evaluation, 39 patients (62.5%) were considered to be marginal candidates for resection based on the proximity of the tumor to the superior mesenteric vessels, but 18 of these patients (45%) went on to have a potentially curative resection. Pathologic staging demonstrated that 60% of 5-FU–treated tumors were T1/T2; there were associated regional nodal metastases in only 30%. The rate of marginpositive resection was 29.1%. More than 75% of patients had recurrent disease. Median time to recurrence was 11 months (range, 1–64 months). Only 18% of patients failed locally, with distant failure primarily noted in the liver. Overall survival of this group was 19.5 months (range, 5–89 months). The median overall survival of patients who were not considered to be resectable following the completion of their therapy was 9 months (range, 3–24 months). The prospective multi-institutional ECOG trial (PD-289), using an identical protocol, demonstrated a resection rate of 45% with median survival of only 15.7 months and median disease-free survival of 8.5 months [12]. The low survival rate in this study was thought to reflect the advanced stage of tumors at the time of resection, including regional lymph node involvement and positive- or close-margin resection. Seventy-nine percent of resected patients had tumor recurrence. The majority of these (75%) were distant failure, with 59% occurring in the liver. Although this trial failed to demonstrate improved efficacy, it did confirm safety and tolerability of this type of regimen. In addition, the predominance of distant failure suggested the need to identify more effective systemic agents for this type of protocol. Following the closure of the ECOG trial an additional 26 patients received preoperative 5-FU–based chemoradiation without mitomycin. This additional group of patients brings the authors’ series up to a total of 89 patients treated with 5-FU–based chemoradiation therapy in the preoperative setting. Of all patients receiving preoperative 5-FU–based
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therapy, only 12 patients (16%) experienced treatment breaks longer than 1 week. Twenty patients (26.3%) experienced grade 3 and 4 toxicity. One death occurred in the second week of treatment following biliary stent– related sepsis resulting in multisystem organ failure. On initial evaluation 64 patients (72%) were considered to be marginal candidates for resection, but a total of 78 patients (87.6%) underwent surgical exploration following the completion of chemoradiation therapy and re-evaluation. Forty patients (44.9%) were found to be resectable at the time of operation. Twenty-seven of these patients (67.5%) had been considered marginal candidates. Pathologic staging of resected tumors demonstrated the majority (60%) to be T1/T2 with node-positive disease in 27.5%. Positive margins were identified in 30%. Thirty-one patients (77.5%) had tumor recurrence with a median time to recurrence of 12 months. Five patients (13%) failed locally. Median overall survival for this group of patients was 20 months. Median overall survival for patients who were not thought to be surgical candidates following the completion of their therapy was 8.5 months. The effect on outcome of mitomycin in the treatment regimen was also evaluated. No statistical difference in disease-free survival or overall survival could be elucidated in the resectable groups treated with 5-FU with or without mitomycin (median disease-free survival, 11 versus 14 months; P = 0.109; median overall survival, 19.5 versus 24.5 months, P = 0.456) or in the unresectable group treated with 5-FU with or without mitomycin (median overall survival, 9 versus 8 months). The number of patients not receiving mitomycin was small, however, and a significant difference may not be apparent in this analysis. Comparison of all patients receiving 5-FU–based chemoradiation followed by surgical resection with patients in the same time period receiving postoperative adjuvant therapy failed to show a survival benefit (median survival, 20 versus 14 months, P = 0.469; median survival for the patients actually receiving postoperative therapy [88% of total number], 10 versus 16 months, P = NS). Median time to recurrence was also not significantly different between the two groups (12 versus 14 months; P = 0.272). Stage, node, and margin status were also similar in both groups and were not influenced by treatment, although patients with margin-negative resections had improved disease-free and overall survival (14 versus 8 months). To determine whether patients with more advanced disease were preferentially treated with preoperative chemoradiation and whether this affected outcome, patients were classified as resectable or as marginally resectable based on the surgeon’s preoperative assessment of the CT scan. Although the majority of patients receiving postoperative adjuvant therapy were considered resectable, this status did not affect outcome. Review of the authors’ entire experience with 5-FU–based therapy in the preoperative period at Fox Chase Cancer Center showed that toxicities were acceptable but no advantage in outcome was evident when compared with patients who received postoperative adjuvant therapy. Although the
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presenting tumor stage varied significantly in this patient population, patients later in the series generally presented with more advanced disease. The preferential selection of this patient population for preoperative therapy will probably obscure the potential benefits that this therapeutic strategy may have when reviewed in a retrospective fashion without strict selection criteria. Preoperative chemoradiation may result in tumor downstaging, consequently improving margin-free resectability rates and therefore overall survival. The gemcitabine experience The use of gemcitabine in a preoperative chemoradiation protocol was based on its efficacy as a radiosensitizer [3] in addition to its superior response and survival rates to 5-FU in patients with stage IV cancer [2]. Since September 1996 the Fox Chase Cancer Center has treated patients with localized and potentially resectable pancreatic cancers with combination gemcitabine-based chemoradiation therapy. The initial 25 patients in this series were treated as a part of a phase I trial [4]. Under this protocol, gemcitabine is given as a 30-minute infusion on a weekly basis for 6 weeks. Gemcitabine doses varied secondary to the inclusion of patients enrolled in the phase 1 trial to establish the maximally tolerated dose (MTD). The starting dose was 300 mg/m2/week with an escalation of 100 mg/m2. A dose of 600 mg/m2/week over 30 minutes was determined to be the MTD. This MTD was in agreement with the phase I trial evaluating the MTD of gemcitabine used to treat unresectable, locally advanced pancreatic cancer [13]. A radiation protocol similar to that used in the 5-FU–based series was employed. EBRT was delivered with a total dose of 5040 cGy in 28 fractions, 180 cGy/fraction, five fractions per week. Initial radiation fields encompassed the gross tumor with a 2- to 3-cm margin to a dose of 3960 cGy, followed by a cone-down field to the gross tumor with a 1- to 2-cm margin for an additional 1080 cGy. Four to 6 weeks following the completion of therapy, patients were evaluated to determine their candidacy for surgical resection. Four to 12 weeks following surgery, gemcitabine was prescribed at 1000 mg/m2 as a 30-minute infusion weekly 3 every 28 days for four cycles. Subsequently, 30 more patients were treated under this protocol. Of the 55 patients enrolled in this protocol, 37 (67.3%) underwent potentially curative resection. Eight patients in this group did not have maintenance therapy following surgical resection because postoperative complications, including one death, prohibited further therapy. Only one patient in this group had refused further therapy. Median overall survival was significantly better for those receiving induction plus maintenance therapy than for those receiving induction therapy only (21 versus 8 months; P = 0.049). This result may reflect the poor postoperative performance status of these patients, which prohibited additional therapy. Median disease-free survival
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of patients who received induction therapy followed by surgery was not significantly different from that of those receiving induction plus maintenance therapy (10 versus 11 months, respectively). Toxicity of this regimen was tolerable, with only 11 patients (24.4%) with documented grade 3 or grade 4 toxicity. Six patients (13.3%) experienced treatment breaks longer than 1 week. Five patients (11.1%) required dose reduction. Following the completion of the authors’ phase I trial, Tempero and colleagues [5,6] demonstrated superior pharmacokinetics of a fixed-dose rate of infusion of gemcitabine with an associated improved survival compared with the 30-minute infusion. The authors subsequently adopted this regimen and altered the gemcitabine infusion to 500 mg/m2/ week over 50 minutes based on a fixed-dose rate of 10 mg/m2/minute (15 patients, 8 resectable, 7 unresectable). Although the total number of patients in this group is small, few toxicities were documented for this group, and grade 3 or grade 4 toxicity was documented in only one patient. Two patients required dose reduction. The same patients also experienced a treatment break of more than 1 week. Median overall survivals for the 30minute and 50-minute infusion regimens were not significantly different (17 versus 20 months; P = 0.464) in the resected group. Median disease-free survival was equivalent in both groups (10 months). The unresected group also had similar median overall survival (8.5 versus 11.5 months; P = 0.178). As of December 2003, 63 patients at the Fox Chase Cancer Center have been treated with preoperative gemcitabine-based chemoradiation therapy. Thirty-one patients underwent preoperative chemoradiation therapy, then surgery, followed by chemotherapy alone. Eight patients underwent preoperative chemoradiation only, followed by surgery. Twenty-two patients (32.7%), despite undergoing chemoradiation therapy, were found not to be surgical candidates either at post-therapy staging or at surgical exploration. Before treatment, 45 patients (71.4%) were thought to be marginal candidates for resection because of the proximity of tumor to the mesenteric vessels. Thirty of these patients (73.2%) went on to potentially curative resection. On pathologic staging, 15 patients (36.6%) were found to have T1/T2 tumors, and 25 (60.1%) had T3 tumors. Eighteen patients (43.9%) had nodal metastases. Twenty-three patients (56.1%) had a positive-margin resection. Of the 41 patients undergoing resection, 29 patients (70.3%) were diagnosed with recurrent disease. Thirty-one patients had been treated with both induction and maintenance therapy, whereas 8 patients had only induction therapy. The median time to recurrence was 10 months. Median overall survival was 20 months. Median survival of patients who did not undergo surgical resection was 9 months (Tables 1 and 2). Comparison of all patients receiving gemcitabine-based chemoradiation followed by surgical resection, patients receiving 5-FU–based therapy, and
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Table 1 Summary of treatment regimens of patients with potentially resectable adenocarcinoma of the pancreas between September 1986 and December 2003 at the Fox Chase Cancer Center Regimen
n
5-FU Resected patients þmitomycin mitomycin Unresected patients þmitomycin mitomycin Gemcitabine Resected patients Induction only Induction þ maintenance 30-minute infusion 50-minute infusion Unresected patients 30-minute infusion 50-minute infusion No preoperative treatment Adjuvant No adjuvant
89 40 24 16 49 20 29 63 41 8 31 29 8 22 15 7 91 81 10
Overall survival (months)
Disease-free survival (months)
20 19.5 24.5 8.5 9 8
12 11 14 NA NA NA
20 8 21 17 20 9 8.5 11.5 14 16 10
10 11 10 10 10 NA NA NA 11 13 6
patients in a similar time period receiving surgery first with intended postoperative adjuvant therapy failed to show a survival difference (median overall survival, 20, 20, and 14 months, respectively; P = 0.469). Median time to recurrence was also not significantly different between the groups (median disease-free survival, 10, 11, and 14 months, respectively; Table 2 Summary of outcomes based on treatment regimens for patients with potentially resectable adenocarcinoma of the pancreas between September 1986 and December 2003 at the Fox Chase Cancer Center Preoperative therapy
5-FU # (%)
Gemcitabine # (%)
None # (%)
Number of patients Marginal candidates Resected Marginal candidates among resected patients T1/T2 T3/T4 Nodeþ Marginþ Recurrence Local Distant Disease-free survival Overall survival
89 78 (87.6) 40 (44.9) 27 (67.5)
63 54 (85.7) 41 (65.1) 30 (73.2)
91 19 (20.9)
24 16 11 12 31 5 26 12 20
15 25 18 23 29 5 24 10 20
40 51 71 55 70 8 62 11 14
(60) (40) (27.5) (30) (77.5) (16) (83.9) months months
(36.6) (60.1) (43.9) (56.1) (70.3) (17.2) (82.8) months months
(43.9) (56.1) (78) (60.4) (76.9) (11.1) (88.5) months months
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P =0.272). Although node-negative and margin-negative resection was more prevalent in the 5-FU–based treatment group, stage, node, and margin status were not influenced by treatment on statistical analysis (P > 0.3). All patients with margin-negative resections had both improved median diseasefree and overall survival as compared with patients with margin-positive resection (14 versus 8 months and 20 versus 13 months, respectively; P \ 0.01). To determine whether patients with more advanced disease were preferentially treated with preoperative gemcitabine-based chemoradiation and, if so, whether this preferential treatment affected outcome, patients were classified as resectable or marginally resectable based on the surgeon’s preoperative assessment of the CT scan. The majority of patients receiving no treatment in the preoperative period were considered resectable, whereas the majority of patients receiving either preoperative gemcitabine-based (73.2%) or 5-FU–based (67.5%) chemoradiation therapy were considered marginally resectable at the time of initial assessment. Median disease-free and overall survivals were similar for those receiving preoperative chemoradiation therapy and those who received chemoradiation therapy only in the postoperative setting. This finding suggests that, despite having more advanced disease, patients receiving preoperative chemoradiation had outcomes similar to those who did not have preoperative chemoradiation therapy. On review of the Fox Chase Cancer Center experience with gemcitabinebased chemoradiation therapy given in the preoperative period, no statistical benefit in disease-free or overall survival could be elucidated with this treatment regimen. Generally, however, patients selected for treatment with preoperative gemcitabine-based chemoradiation therapy presented with more advanced disease than those who received no therapy. Patients receiving preoperative gemcitabine-base therapy may also have more advance disease than the patients receiving 5-FU, because the initial patients in the 5-FU series had clearly resectable disease based on the selection criteria of the phase II protocol. Again this selection bias may obscure the benefits of this therapy. Although these results are disappointing, a positive effect may be obscured by a number of factors. Although a significant number of patients with localized pancreatic adenocarcinoma were treated in the preoperative period with gemcitabine-based chemoradiation therapy, this review is retrospective, nonrandomized, and limited by the lack of strict objective criteria for patient eligibility. In addition, strict objective classification of tumor stage and resectability were not available for all patients at the initial evaluation. Treatment regimens varied for multiple reasons, including graded doses for patients enrolled in the phase I trial [4], lack of maintenance therapy in a small subgroup as the result of postoperative complications, and a change in the infusion protocol of gemcitabine. More definitive information may be obtained from large, prospective, randomized multi-institutionalized protocols.
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In May 2003, a randomized phase II study sponsored by ECOG (E1200) comparing preoperative gemcitabine and radiotherapy to gemcitabine, 5-FU, and cisplatin followed by radiotherapy and 5-FU for patients with locally advanced, potentially resectable pancreatic cancer was opened and is still accruing appropriate patients. Resectable candidates will proceed to surgical resection followed by adjuvant maintenance therapy with gemcitabine. This combination therapy was based on findings from a phase II study conducted at Emory University. This trial evaluated the response of unresectable pancreatic adenocarcinomas to cisplatin, 5-FU, and gemcitabine followed by 5-FU combined with radiation. (Charles Staley, personal communication). Among 11 patients, there were 4 partial responses and 1 complete response. One patient went on to potentially curative resection with no evidence of tumor in the resected specimen. These findings suggest that patients with locally advanced but potentially resectable pancreatic cancers may benefit from a similar approach using preoperative combination chemotherapy followed by chemoradiotherapy. The primary endpoint of this study is the percentage of margin-free resections achieved in each arm. Secondary endpoints will include efficacy as measured CT scan, percentage of fibrosis in the resected specimens, treatment toxicity, and disease-free and overall survival. The authors are currently actively recruiting patients into this protocol. Conclusions The experience with neoadjuvant therapy for adenocarcinoma of the pancreas at the Fox Chase Cancer Center has been extensive. Treatment with chemoradiation therapy in the preoperative period has been a wellestablished modality at the Fox Chase Cancer Center for the treatment of localized pancreatic cancer since 1986. Since the authors’ initial experience, 81 patients at Fox Chase Cancer Center have undergone potentially curative pancreatic resection following the completion of chemoradiation therapy. During this period, 91 additional patients underwent potentially curative pancreatic resection without preoperative therapy. The majority of this group (89%) received adjuvant postoperative chemoradiation therapy. The overall median survival of all patients undergoing resection was 17 months; the median disease-free survival was 12 months. Patients treated in the preoperative period with chemoradiation therapy had a median overall survival of 20 months and a median disease-free survival of 11 months. Patients presenting with advanced but potentially resectable disease treated with chemoradiation only because of progression of their disease while undergoing treatment had a median survival of 9 months. In this series, a negative prognostic feature for patients undergoing resection for both disease-free and overall survival was a margin-positive resection (14 versus 8 months and 20 versus 13 months, respectively; P\0.05). Whether the surgeon on initial evaluation believed the patient to be a marginal
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candidate for resection approached but did not reach significance (P = 0.08). Pathologic node status and tumor stage did not seem to affect overall or disease-free survival, probably because preoperative therapy converted nodes that were originally positive to negative or undetectable nodes. The authors’ initial effort using chemoradiation in the preoperative setting was a pilot study using 5-FU–based therapy. This study suggested improved local control with improved rates of margin-negative and node-negative resections. This improved local control translated into improved disease-free and overall survival. Secondary to these encouraging results, the 5-FU/ mitomycin–based regimen was adopted as a phase II trial by the ECOG. Disappointingly, this trial did not support the authors’ earlier findings. The majority of patients failed systemically without a survival benefit. This discrepancy was thought to result from the enrollment of patients with locally advanced disease who were otherwise unlikely candidates for potentially curative resection at the time of initial evaluation. These conclusions suggested that better patient selection in addition to more effective systemic therapies are fundamental to the success of preoperative chemoradiation in the treatment of pancreatic cancer. The authors’ current review of all patients at Fox Chase Cancer Center treated with preoperative 5-FU–based therapy also suggests that this regimen does not provide an advantage in overall survival or diseasefree survival as compared with postoperative chemoradiation therapy. The authors, however, did not set up the experience to address this comparison. Sixty-five percent of patients were thought to be marginal candidates for surgical resection at initial evaluation for preoperative therapy, as compared with only 20% of patients receiving postoperative therapy, suggesting more advanced disease in this group of patients. The similar median disease-free and overall survivals in the two groups despite more advanced disease among those receiving preoperative therapy may suggest that preoperative sequencing is the preferred adjuvant treatment method. Only a phase III trial, in which patients are randomly assigned to either treatment sequence after laparoscopic staging, will answer this question. The advent of gemcitabine brought renewed enthusiasm for the optimization of a preoperative regimen in the treatment of localized adenocarcinoma of the pancreas. This agent’s role as a radiosensitizer and the therapeutic effect demonstrated in the adjuvant setting suggested great promise. Although this review of the experience at Fox Chase Cancer Center was not able to demonstrate an advantage of gemcitabine compared with 5-FU–based therapy or postoperative therapy, other institutions have suggested a benefit of this drug when given preoperatively. Again, as with the 5-FU experience, most patients (61%) treated with gemcitabine preoperatively were generally believed to be marginal candidates for surgical resection at initial evaluation. Despite the advanced stage of their disease, they had median disease-free and overall survivals comparable with those of patients receiving postoperative therapy only, again suggesting a potential advantage of chemoradiation therapy in the preoperative period.
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The actual benefit of gemcitabine in the preoperative treatment regimen for localized pancreatic cancer is yet to be elucidated, and the authors’ review has not definitively suggested an advantage over other therapies. The benefit of this drug may be realized only upon completion of randomized, prospective multi-institutional trials currently in progress. Summary Adenocarcinoma of the pancreas continues to have an extremely poor prognosis. At present, surgical resection remains the only instrument for cure. Despite attempts at curative resection, time to recurrence is often brief, with recurrence presenting as both local and distant failure. The addition of postoperative chemoradiation therapy has offered a marginal benefit; therefore other strategies for the treatment of this disease have been aggressively pursued. Initially, the delivery of chemoradiation in the preoperative setting was a strategy theoretically thought to provide an improved resection rate with less toxicity, resulting in superior outcomes including improved recurrence-free and overall survival. After more than a decade of experience, the authors have not substantiated these theoretical advantages. Neither disease-free nor overall survival has been shown to be superior with the delivery of chemoradiation in the preoperative period. Although they had more advanced disease, most patients receiving preoperative therapy and subsequently undergoing potentially curative resection had median disease-free and overall survivals equivalent to those of patients receiving no preoperative therapy. This result suggests a potential superiority of chemoradiation given in the preoperative setting. In addition, a greater number of patients are able to receive a full course of chemoradiation therapy in a more timely fashion, and the effect of this therapy can be more accurately characterized. In addition, it has been shown that patient selection is improved by increasing the latency period before resection for the manifestation of metastatic disease. Improved patient selection minimizes unnecessary surgery. The treatment of pancreatic cancer remains elusive. Current strategies for the treatment of this disease are suboptimal despite persistent efforts to improve outcomes. The benefits of chemoradiation therapy delivered in the preoperative period may potentially provide patients with superior outcomes, although phase III trials have not been performed. The discovery of more effective agents and improved delivery strategies, in addition to a concerted effort by the medical and scientific community to promote multi-institutional controlled, prospective trials, may render this modality superior to the authors’ current treatment regimens. References [1] Hoffman JP, Weese JL, Solin LJ, et al. A single institutional experience with preoperative chemoradiotherapy for stage I–III pancreatic adenocarcinoma. Am Surg 1993;59(8):772–81.
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[2] Burris HA III, Moore MJ, Andersen J, Green MR, Rotherberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as a first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13. [3] Lawrence TS, Eisenbruch A, McGinn CJ, Fields MT, Shewach DS. Radiosensitization by gemcitabine. Oncology 1999;13:55–60. [4] Hoffman JP, McGinn CJ, Szarka C, Morphis J, Cooper HS, Wilkes J, et al. A Phase I study of preoperative gemcitabine with radiation therapy followed by postoperative gemcitabine for patients with localized, resectable pancreatic adenocarcinoma. Proceedings of the American Society of Clinical Oncology 1998;17(1):A1090. [5] Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs 1997;15(4):331–41. [6] Tempero M, Plunkett W, Ruiz van Haperen V, Hainsworth J, Hochster H, Lenzi R, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty minute infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003;21(18):3402–8. [7] Tepper JE, Nardi GL, Suit HD. Carcinoma of the pancreas: review of the MGH experience from 1963–1973. Cancer 1975;37:1519–24. [8] Pilepich MV, Miller HH. Preoperative irradiation in carcinoma of the pancreas. Cancer 1980;46:1945–9. [9] Kopelson G. Curative surgery for adenocarcinoma of the pancreas/ampulla of Vater: the role of adjuvant pre- or postoperative radiation therapy. Int J Rad Oncol Biol Physics 1983;9:911–5. [10] Gastrointestinal Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59: 2006–10. [11] Hoffman JP, Weese JL, Solin LJ, Engstrom P, Agarwal P, Barber LW, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am J Surg 1995;169:71–8. [12] Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson III AB. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group study. J Clin Oncol 1998;16(1):317–23. [13] McGinn CJ, Smith DC, Szarka CE, Pinover WH, Loehrer PJ, Morphis JG, et al. A phase I study of gemcitabine in combination with radiation therapy in patients with localized, unresectable pancreatic cancer. Proceedings of the American Society of Clinical Oncology 1998;17:A1014.
Preoperative chemoradiation therapy for adenocarcinoma of the pancreas: The Fox Chase Cancer Center experience, 1986–2003 Ingrid M. Meszoely, MDa, Hao Wang, MSb, John P. Hoffman, MD, FACSa,* a
Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA b Department of Biostatistics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
The delivery of combination chemoradiation therapy in the preoperative setting is a commonly used regimen at the Fox Chase Cancer Center for patients with potentially resectable adenocarcinoma of the pancreas. Chemoradiation therapy followed by surgical resection has been fundamental to the treatment of patients with localized pancreatic cancer at Fox Chase Cancer Center since 1986. This treatment strategy has been favored at this institution for its capacity to provide adjuvant therapy to a greater number of patients and improve patient selection for surgical resection. In addition, local control may improve margin-negative resectability in this patient population and potentially provide a survival benefit. In 1992 the authors published their first series examining the feasibility and effect of chemoradiotherapy delivered in the preoperative setting. This series suggested that this method was safe, with high completion rates, and improved the rates of R0 resections and negative lymph nodes [1]. These findings significantly influenced the institutional approach to the management of localized and potentially resectable pancreatic cancers. Since the authors’ initial experience [1], more effective delivery strategies and new agents have been developed [2–6], and the authors have incorporated these advances into their protocols. Their neoadjuvant experience for localized * Corresponding author. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: [email protected] (J.P. Hoffman). 1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2004.06.013
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pancreatic adenocarcinoma now includes 152 patients treated between September1986 and December 2003. Preoperative therapeutic regimens in this series of patients included 5-fluorouracil (5-FU)–based therapy or gemcitabine, in addition to concomitant delivery of external beam radiation therapy (EBRT). Eighty-one patients underwent potentially curative pancreatic resection following the completion of chemoradiation therapy. In this article the authors review the institutional experience of preoperatively delivered chemoradiation in therapy for localized adenocarcinoma of the pancreas and compare it with their series of patients receiving surgery before adjuvant therapy.
The 5-FU experience Based on the experience of several institutions with the administration of preoperative radiotherapy for localized pancreatic cancer [7–9] and on the evidence suggested by the GITSG phase III trial addressing the radiopotentiating effects of chemotherapy in the adjuvant setting [10], a preoperative chemoradiation therapy pilot study was initiated at Fox Chase Cancer Center in 1986 for patients with potentially resectable stage I to stage III pancreatic cancer [1]. This protocol involved EBRT with a total dose of 5040 cGy in 28 fractions, 180 cGy/fraction, five fractions per week. Initial radiation fields encompassed the gross tumor with a 2- to 3-cm margin to a dose of 3960 cGy, followed by a cone-down field to the gross tumor with a 1- to 2-cm margin for an additional 1080 cGy. On day 2 of radiation, bolus mitomycin C (10 mg/m2) was given followed by a 96-hour continuous infusion of 5-FU (1000 mg/m 2/day). On day 28 an additional 96-day course of 5-FU was initiated. Therapeutic response was assessed by CT scan of the abdomen 4 to 6 weeks after the completion of chemoradiation. Patients without evidence of progression underwent surgical exploration. Following the enrollment of 21 patients, the efficacy and safety of this protocol was evident, and a trial was proposed to and adopted by the Eastern Cooperative Oncology Group (ECOG) in July 1990. Fox Chase Cancer Center enrolled 26 of the 53 patients evaluated in this study. The authors’ initial pilot study using this protocol was published in 1995 [11]. In this study, 34 patients, including those enrolled in the ECOG mycin C. Twenty-five patients (73.5%) were believed to be suitable candidates for resection. Eleven patients (32%) went on to potentially curative resection. Two patients (18.1%) had node-positive disease. One patient (9.1%) had a positive-margin resection. Five patients (45.5%) were diagnosed with tumor recurrence with a median disease-free survival of 27 months. Overall survival was 45 months. These results suggesting better local control with an increased rate of node-negative and negative-margin resections translating into prolonged survival provided significant enthusiasm at the Fox Chase Cancer Center for preoperative treatment of potentially resectable
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pancreatic cancer. Since this publication, patients presenting to Fox Chase Cancer Center with a diagnosis of pancreatic adenocarcinoma with lesions abutting or compressing the superior mesenteric vein or artery have been offered neoadjuvant chemoradiation therapy and post-resectional maintenance chemotherapy. Only patients with 360 involvement of the superior mesenteric artery, occlusion of the superior mesenteric vein down to the level of its first branches, or metastatic disease were excluded. These patients were offered definitive chemoradiation therapy as their sole treatment. Surgical resection followed by adjuvant chemoradiation has been the preferred therapy for patients presenting with imaging studies demonstrating a distinct fat plane between tumor and the mesenteric vessels and without evidence of distant metastases. As of March 1999, 64 patients had been treated on this protocol at the Fox Chase Cancer Center. Twenty-six of these patients were enrolled in the ECOG phase II trial (PD-289). Following restaging with CT scan, 40 patients (62.5%) underwent exploration. Twenty-four of these patients (60%) went onto resection. At the time of initial evaluation, 39 patients (62.5%) were considered to be marginal candidates for resection based on the proximity of the tumor to the superior mesenteric vessels, but 18 of these patients (45%) went on to have a potentially curative resection. Pathologic staging demonstrated that 60% of 5-FU–treated tumors were T1/T2; there were associated regional nodal metastases in only 30%. The rate of marginpositive resection was 29.1%. More than 75% of patients had recurrent disease. Median time to recurrence was 11 months (range, 1–64 months). Only 18% of patients failed locally, with distant failure primarily noted in the liver. Overall survival of this group was 19.5 months (range, 5–89 months). The median overall survival of patients who were not considered to be resectable following the completion of their therapy was 9 months (range, 3–24 months). The prospective multi-institutional ECOG trial (PD-289), using an identical protocol, demonstrated a resection rate of 45% with median survival of only 15.7 months and median disease-free survival of 8.5 months [12]. The low survival rate in this study was thought to reflect the advanced stage of tumors at the time of resection, including regional lymph node involvement and positive- or close-margin resection. Seventy-nine percent of resected patients had tumor recurrence. The majority of these (75%) were distant failure, with 59% occurring in the liver. Although this trial failed to demonstrate improved efficacy, it did confirm safety and tolerability of this type of regimen. In addition, the predominance of distant failure suggested the need to identify more effective systemic agents for this type of protocol. Following the closure of the ECOG trial an additional 26 patients received preoperative 5-FU–based chemoradiation without mitomycin. This additional group of patients brings the authors’ series up to a total of 89 patients treated with 5-FU–based chemoradiation therapy in the preoperative setting. Of all patients receiving preoperative 5-FU–based
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therapy, only 12 patients (16%) experienced treatment breaks longer than 1 week. Twenty patients (26.3%) experienced grade 3 and 4 toxicity. One death occurred in the second week of treatment following biliary stent– related sepsis resulting in multisystem organ failure. On initial evaluation 64 patients (72%) were considered to be marginal candidates for resection, but a total of 78 patients (87.6%) underwent surgical exploration following the completion of chemoradiation therapy and re-evaluation. Forty patients (44.9%) were found to be resectable at the time of operation. Twenty-seven of these patients (67.5%) had been considered marginal candidates. Pathologic staging of resected tumors demonstrated the majority (60%) to be T1/T2 with node-positive disease in 27.5%. Positive margins were identified in 30%. Thirty-one patients (77.5%) had tumor recurrence with a median time to recurrence of 12 months. Five patients (13%) failed locally. Median overall survival for this group of patients was 20 months. Median overall survival for patients who were not thought to be surgical candidates following the completion of their therapy was 8.5 months. The effect on outcome of mitomycin in the treatment regimen was also evaluated. No statistical difference in disease-free survival or overall survival could be elucidated in the resectable groups treated with 5-FU with or without mitomycin (median disease-free survival, 11 versus 14 months; P = 0.109; median overall survival, 19.5 versus 24.5 months, P = 0.456) or in the unresectable group treated with 5-FU with or without mitomycin (median overall survival, 9 versus 8 months). The number of patients not receiving mitomycin was small, however, and a significant difference may not be apparent in this analysis. Comparison of all patients receiving 5-FU–based chemoradiation followed by surgical resection with patients in the same time period receiving postoperative adjuvant therapy failed to show a survival benefit (median survival, 20 versus 14 months, P = 0.469; median survival for the patients actually receiving postoperative therapy [88% of total number], 10 versus 16 months, P = NS). Median time to recurrence was also not significantly different between the two groups (12 versus 14 months; P = 0.272). Stage, node, and margin status were also similar in both groups and were not influenced by treatment, although patients with margin-negative resections had improved disease-free and overall survival (14 versus 8 months). To determine whether patients with more advanced disease were preferentially treated with preoperative chemoradiation and whether this affected outcome, patients were classified as resectable or as marginally resectable based on the surgeon’s preoperative assessment of the CT scan. Although the majority of patients receiving postoperative adjuvant therapy were considered resectable, this status did not affect outcome. Review of the authors’ entire experience with 5-FU–based therapy in the preoperative period at Fox Chase Cancer Center showed that toxicities were acceptable but no advantage in outcome was evident when compared with patients who received postoperative adjuvant therapy. Although the
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presenting tumor stage varied significantly in this patient population, patients later in the series generally presented with more advanced disease. The preferential selection of this patient population for preoperative therapy will probably obscure the potential benefits that this therapeutic strategy may have when reviewed in a retrospective fashion without strict selection criteria. Preoperative chemoradiation may result in tumor downstaging, consequently improving margin-free resectability rates and therefore overall survival. The gemcitabine experience The use of gemcitabine in a preoperative chemoradiation protocol was based on its efficacy as a radiosensitizer [3] in addition to its superior response and survival rates to 5-FU in patients with stage IV cancer [2]. Since September 1996 the Fox Chase Cancer Center has treated patients with localized and potentially resectable pancreatic cancers with combination gemcitabine-based chemoradiation therapy. The initial 25 patients in this series were treated as a part of a phase I trial [4]. Under this protocol, gemcitabine is given as a 30-minute infusion on a weekly basis for 6 weeks. Gemcitabine doses varied secondary to the inclusion of patients enrolled in the phase 1 trial to establish the maximally tolerated dose (MTD). The starting dose was 300 mg/m2/week with an escalation of 100 mg/m2. A dose of 600 mg/m2/week over 30 minutes was determined to be the MTD. This MTD was in agreement with the phase I trial evaluating the MTD of gemcitabine used to treat unresectable, locally advanced pancreatic cancer [13]. A radiation protocol similar to that used in the 5-FU–based series was employed. EBRT was delivered with a total dose of 5040 cGy in 28 fractions, 180 cGy/fraction, five fractions per week. Initial radiation fields encompassed the gross tumor with a 2- to 3-cm margin to a dose of 3960 cGy, followed by a cone-down field to the gross tumor with a 1- to 2-cm margin for an additional 1080 cGy. Four to 6 weeks following the completion of therapy, patients were evaluated to determine their candidacy for surgical resection. Four to 12 weeks following surgery, gemcitabine was prescribed at 1000 mg/m2 as a 30-minute infusion weekly 3 every 28 days for four cycles. Subsequently, 30 more patients were treated under this protocol. Of the 55 patients enrolled in this protocol, 37 (67.3%) underwent potentially curative resection. Eight patients in this group did not have maintenance therapy following surgical resection because postoperative complications, including one death, prohibited further therapy. Only one patient in this group had refused further therapy. Median overall survival was significantly better for those receiving induction plus maintenance therapy than for those receiving induction therapy only (21 versus 8 months; P = 0.049). This result may reflect the poor postoperative performance status of these patients, which prohibited additional therapy. Median disease-free survival
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of patients who received induction therapy followed by surgery was not significantly different from that of those receiving induction plus maintenance therapy (10 versus 11 months, respectively). Toxicity of this regimen was tolerable, with only 11 patients (24.4%) with documented grade 3 or grade 4 toxicity. Six patients (13.3%) experienced treatment breaks longer than 1 week. Five patients (11.1%) required dose reduction. Following the completion of the authors’ phase I trial, Tempero and colleagues [5,6] demonstrated superior pharmacokinetics of a fixed-dose rate of infusion of gemcitabine with an associated improved survival compared with the 30-minute infusion. The authors subsequently adopted this regimen and altered the gemcitabine infusion to 500 mg/m2/ week over 50 minutes based on a fixed-dose rate of 10 mg/m2/minute (15 patients, 8 resectable, 7 unresectable). Although the total number of patients in this group is small, few toxicities were documented for this group, and grade 3 or grade 4 toxicity was documented in only one patient. Two patients required dose reduction. The same patients also experienced a treatment break of more than 1 week. Median overall survivals for the 30minute and 50-minute infusion regimens were not significantly different (17 versus 20 months; P = 0.464) in the resected group. Median disease-free survival was equivalent in both groups (10 months). The unresected group also had similar median overall survival (8.5 versus 11.5 months; P = 0.178). As of December 2003, 63 patients at the Fox Chase Cancer Center have been treated with preoperative gemcitabine-based chemoradiation therapy. Thirty-one patients underwent preoperative chemoradiation therapy, then surgery, followed by chemotherapy alone. Eight patients underwent preoperative chemoradiation only, followed by surgery. Twenty-two patients (32.7%), despite undergoing chemoradiation therapy, were found not to be surgical candidates either at post-therapy staging or at surgical exploration. Before treatment, 45 patients (71.4%) were thought to be marginal candidates for resection because of the proximity of tumor to the mesenteric vessels. Thirty of these patients (73.2%) went on to potentially curative resection. On pathologic staging, 15 patients (36.6%) were found to have T1/T2 tumors, and 25 (60.1%) had T3 tumors. Eighteen patients (43.9%) had nodal metastases. Twenty-three patients (56.1%) had a positive-margin resection. Of the 41 patients undergoing resection, 29 patients (70.3%) were diagnosed with recurrent disease. Thirty-one patients had been treated with both induction and maintenance therapy, whereas 8 patients had only induction therapy. The median time to recurrence was 10 months. Median overall survival was 20 months. Median survival of patients who did not undergo surgical resection was 9 months (Tables 1 and 2). Comparison of all patients receiving gemcitabine-based chemoradiation followed by surgical resection, patients receiving 5-FU–based therapy, and
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Table 1 Summary of treatment regimens of patients with potentially resectable adenocarcinoma of the pancreas between September 1986 and December 2003 at the Fox Chase Cancer Center Regimen
n
5-FU Resected patients þmitomycin mitomycin Unresected patients þmitomycin mitomycin Gemcitabine Resected patients Induction only Induction þ maintenance 30-minute infusion 50-minute infusion Unresected patients 30-minute infusion 50-minute infusion No preoperative treatment Adjuvant No adjuvant
89 40 24 16 49 20 29 63 41 8 31 29 8 22 15 7 91 81 10
Overall survival (months)
Disease-free survival (months)
20 19.5 24.5 8.5 9 8
12 11 14 NA NA NA
20 8 21 17 20 9 8.5 11.5 14 16 10
10 11 10 10 10 NA NA NA 11 13 6
patients in a similar time period receiving surgery first with intended postoperative adjuvant therapy failed to show a survival difference (median overall survival, 20, 20, and 14 months, respectively; P = 0.469). Median time to recurrence was also not significantly different between the groups (median disease-free survival, 10, 11, and 14 months, respectively; Table 2 Summary of outcomes based on treatment regimens for patients with potentially resectable adenocarcinoma of the pancreas between September 1986 and December 2003 at the Fox Chase Cancer Center Preoperative therapy
5-FU # (%)
Gemcitabine # (%)
None # (%)
Number of patients Marginal candidates Resected Marginal candidates among resected patients T1/T2 T3/T4 Nodeþ Marginþ Recurrence Local Distant Disease-free survival Overall survival
89 78 (87.6) 40 (44.9) 27 (67.5)
63 54 (85.7) 41 (65.1) 30 (73.2)
91 19 (20.9)
24 16 11 12 31 5 26 12 20
15 25 18 23 29 5 24 10 20
40 51 71 55 70 8 62 11 14
(60) (40) (27.5) (30) (77.5) (16) (83.9) months months
(36.6) (60.1) (43.9) (56.1) (70.3) (17.2) (82.8) months months
(43.9) (56.1) (78) (60.4) (76.9) (11.1) (88.5) months months
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P =0.272). Although node-negative and margin-negative resection was more prevalent in the 5-FU–based treatment group, stage, node, and margin status were not influenced by treatment on statistical analysis (P > 0.3). All patients with margin-negative resections had both improved median diseasefree and overall survival as compared with patients with margin-positive resection (14 versus 8 months and 20 versus 13 months, respectively; P \ 0.01). To determine whether patients with more advanced disease were preferentially treated with preoperative gemcitabine-based chemoradiation and, if so, whether this preferential treatment affected outcome, patients were classified as resectable or marginally resectable based on the surgeon’s preoperative assessment of the CT scan. The majority of patients receiving no treatment in the preoperative period were considered resectable, whereas the majority of patients receiving either preoperative gemcitabine-based (73.2%) or 5-FU–based (67.5%) chemoradiation therapy were considered marginally resectable at the time of initial assessment. Median disease-free and overall survivals were similar for those receiving preoperative chemoradiation therapy and those who received chemoradiation therapy only in the postoperative setting. This finding suggests that, despite having more advanced disease, patients receiving preoperative chemoradiation had outcomes similar to those who did not have preoperative chemoradiation therapy. On review of the Fox Chase Cancer Center experience with gemcitabinebased chemoradiation therapy given in the preoperative period, no statistical benefit in disease-free or overall survival could be elucidated with this treatment regimen. Generally, however, patients selected for treatment with preoperative gemcitabine-based chemoradiation therapy presented with more advanced disease than those who received no therapy. Patients receiving preoperative gemcitabine-base therapy may also have more advance disease than the patients receiving 5-FU, because the initial patients in the 5-FU series had clearly resectable disease based on the selection criteria of the phase II protocol. Again this selection bias may obscure the benefits of this therapy. Although these results are disappointing, a positive effect may be obscured by a number of factors. Although a significant number of patients with localized pancreatic adenocarcinoma were treated in the preoperative period with gemcitabine-based chemoradiation therapy, this review is retrospective, nonrandomized, and limited by the lack of strict objective criteria for patient eligibility. In addition, strict objective classification of tumor stage and resectability were not available for all patients at the initial evaluation. Treatment regimens varied for multiple reasons, including graded doses for patients enrolled in the phase I trial [4], lack of maintenance therapy in a small subgroup as the result of postoperative complications, and a change in the infusion protocol of gemcitabine. More definitive information may be obtained from large, prospective, randomized multi-institutionalized protocols.
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In May 2003, a randomized phase II study sponsored by ECOG (E1200) comparing preoperative gemcitabine and radiotherapy to gemcitabine, 5-FU, and cisplatin followed by radiotherapy and 5-FU for patients with locally advanced, potentially resectable pancreatic cancer was opened and is still accruing appropriate patients. Resectable candidates will proceed to surgical resection followed by adjuvant maintenance therapy with gemcitabine. This combination therapy was based on findings from a phase II study conducted at Emory University. This trial evaluated the response of unresectable pancreatic adenocarcinomas to cisplatin, 5-FU, and gemcitabine followed by 5-FU combined with radiation. (Charles Staley, personal communication). Among 11 patients, there were 4 partial responses and 1 complete response. One patient went on to potentially curative resection with no evidence of tumor in the resected specimen. These findings suggest that patients with locally advanced but potentially resectable pancreatic cancers may benefit from a similar approach using preoperative combination chemotherapy followed by chemoradiotherapy. The primary endpoint of this study is the percentage of margin-free resections achieved in each arm. Secondary endpoints will include efficacy as measured CT scan, percentage of fibrosis in the resected specimens, treatment toxicity, and disease-free and overall survival. The authors are currently actively recruiting patients into this protocol. Conclusions The experience with neoadjuvant therapy for adenocarcinoma of the pancreas at the Fox Chase Cancer Center has been extensive. Treatment with chemoradiation therapy in the preoperative period has been a wellestablished modality at the Fox Chase Cancer Center for the treatment of localized pancreatic cancer since 1986. Since the authors’ initial experience, 81 patients at Fox Chase Cancer Center have undergone potentially curative pancreatic resection following the completion of chemoradiation therapy. During this period, 91 additional patients underwent potentially curative pancreatic resection without preoperative therapy. The majority of this group (89%) received adjuvant postoperative chemoradiation therapy. The overall median survival of all patients undergoing resection was 17 months; the median disease-free survival was 12 months. Patients treated in the preoperative period with chemoradiation therapy had a median overall survival of 20 months and a median disease-free survival of 11 months. Patients presenting with advanced but potentially resectable disease treated with chemoradiation only because of progression of their disease while undergoing treatment had a median survival of 9 months. In this series, a negative prognostic feature for patients undergoing resection for both disease-free and overall survival was a margin-positive resection (14 versus 8 months and 20 versus 13 months, respectively; P\0.05). Whether the surgeon on initial evaluation believed the patient to be a marginal
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candidate for resection approached but did not reach significance (P = 0.08). Pathologic node status and tumor stage did not seem to affect overall or disease-free survival, probably because preoperative therapy converted nodes that were originally positive to negative or undetectable nodes. The authors’ initial effort using chemoradiation in the preoperative setting was a pilot study using 5-FU–based therapy. This study suggested improved local control with improved rates of margin-negative and node-negative resections. This improved local control translated into improved disease-free and overall survival. Secondary to these encouraging results, the 5-FU/ mitomycin–based regimen was adopted as a phase II trial by the ECOG. Disappointingly, this trial did not support the authors’ earlier findings. The majority of patients failed systemically without a survival benefit. This discrepancy was thought to result from the enrollment of patients with locally advanced disease who were otherwise unlikely candidates for potentially curative resection at the time of initial evaluation. These conclusions suggested that better patient selection in addition to more effective systemic therapies are fundamental to the success of preoperative chemoradiation in the treatment of pancreatic cancer. The authors’ current review of all patients at Fox Chase Cancer Center treated with preoperative 5-FU–based therapy also suggests that this regimen does not provide an advantage in overall survival or diseasefree survival as compared with postoperative chemoradiation therapy. The authors, however, did not set up the experience to address this comparison. Sixty-five percent of patients were thought to be marginal candidates for surgical resection at initial evaluation for preoperative therapy, as compared with only 20% of patients receiving postoperative therapy, suggesting more advanced disease in this group of patients. The similar median disease-free and overall survivals in the two groups despite more advanced disease among those receiving preoperative therapy may suggest that preoperative sequencing is the preferred adjuvant treatment method. Only a phase III trial, in which patients are randomly assigned to either treatment sequence after laparoscopic staging, will answer this question. The advent of gemcitabine brought renewed enthusiasm for the optimization of a preoperative regimen in the treatment of localized adenocarcinoma of the pancreas. This agent’s role as a radiosensitizer and the therapeutic effect demonstrated in the adjuvant setting suggested great promise. Although this review of the experience at Fox Chase Cancer Center was not able to demonstrate an advantage of gemcitabine compared with 5-FU–based therapy or postoperative therapy, other institutions have suggested a benefit of this drug when given preoperatively. Again, as with the 5-FU experience, most patients (61%) treated with gemcitabine preoperatively were generally believed to be marginal candidates for surgical resection at initial evaluation. Despite the advanced stage of their disease, they had median disease-free and overall survivals comparable with those of patients receiving postoperative therapy only, again suggesting a potential advantage of chemoradiation therapy in the preoperative period.
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The actual benefit of gemcitabine in the preoperative treatment regimen for localized pancreatic cancer is yet to be elucidated, and the authors’ review has not definitively suggested an advantage over other therapies. The benefit of this drug may be realized only upon completion of randomized, prospective multi-institutional trials currently in progress. Summary Adenocarcinoma of the pancreas continues to have an extremely poor prognosis. At present, surgical resection remains the only instrument for cure. Despite attempts at curative resection, time to recurrence is often brief, with recurrence presenting as both local and distant failure. The addition of postoperative chemoradiation therapy has offered a marginal benefit; therefore other strategies for the treatment of this disease have been aggressively pursued. Initially, the delivery of chemoradiation in the preoperative setting was a strategy theoretically thought to provide an improved resection rate with less toxicity, resulting in superior outcomes including improved recurrence-free and overall survival. After more than a decade of experience, the authors have not substantiated these theoretical advantages. Neither disease-free nor overall survival has been shown to be superior with the delivery of chemoradiation in the preoperative period. Although they had more advanced disease, most patients receiving preoperative therapy and subsequently undergoing potentially curative resection had median disease-free and overall survivals equivalent to those of patients receiving no preoperative therapy. This result suggests a potential superiority of chemoradiation given in the preoperative setting. In addition, a greater number of patients are able to receive a full course of chemoradiation therapy in a more timely fashion, and the effect of this therapy can be more accurately characterized. In addition, it has been shown that patient selection is improved by increasing the latency period before resection for the manifestation of metastatic disease. Improved patient selection minimizes unnecessary surgery. The treatment of pancreatic cancer remains elusive. Current strategies for the treatment of this disease are suboptimal despite persistent efforts to improve outcomes. The benefits of chemoradiation therapy delivered in the preoperative period may potentially provide patients with superior outcomes, although phase III trials have not been performed. The discovery of more effective agents and improved delivery strategies, in addition to a concerted effort by the medical and scientific community to promote multi-institutional controlled, prospective trials, may render this modality superior to the authors’ current treatment regimens. References [1] Hoffman JP, Weese JL, Solin LJ, et al. A single institutional experience with preoperative chemoradiotherapy for stage I–III pancreatic adenocarcinoma. Am Surg 1993;59(8):772–81.
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[2] Burris HA III, Moore MJ, Andersen J, Green MR, Rotherberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as a first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13. [3] Lawrence TS, Eisenbruch A, McGinn CJ, Fields MT, Shewach DS. Radiosensitization by gemcitabine. Oncology 1999;13:55–60. [4] Hoffman JP, McGinn CJ, Szarka C, Morphis J, Cooper HS, Wilkes J, et al. A Phase I study of preoperative gemcitabine with radiation therapy followed by postoperative gemcitabine for patients with localized, resectable pancreatic adenocarcinoma. Proceedings of the American Society of Clinical Oncology 1998;17(1):A1090. [5] Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs 1997;15(4):331–41. [6] Tempero M, Plunkett W, Ruiz van Haperen V, Hainsworth J, Hochster H, Lenzi R, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty minute infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003;21(18):3402–8. [7] Tepper JE, Nardi GL, Suit HD. Carcinoma of the pancreas: review of the MGH experience from 1963–1973. Cancer 1975;37:1519–24. [8] Pilepich MV, Miller HH. Preoperative irradiation in carcinoma of the pancreas. Cancer 1980;46:1945–9. [9] Kopelson G. Curative surgery for adenocarcinoma of the pancreas/ampulla of Vater: the role of adjuvant pre- or postoperative radiation therapy. Int J Rad Oncol Biol Physics 1983;9:911–5. [10] Gastrointestinal Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59: 2006–10. [11] Hoffman JP, Weese JL, Solin LJ, Engstrom P, Agarwal P, Barber LW, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am J Surg 1995;169:71–8. [12] Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson III AB. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group study. J Clin Oncol 1998;16(1):317–23. [13] McGinn CJ, Smith DC, Szarka CE, Pinover WH, Loehrer PJ, Morphis JG, et al. A phase I study of gemcitabine in combination with radiation therapy in patients with localized, unresectable pancreatic cancer. Proceedings of the American Society of Clinical Oncology 1998;17:A1014.