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Long-term survival after pancreatic cancer treatment
The American Journal of Surgery 194 (Suppl to October 2007) S127–S130
Long-term survival after pancreatic cancer treatment Emery L. Chen, M.D., Richard A. Prinz, M.D.* Department of General Surgery, Rush University Medical Center, 1653 W Congress Parkway, Suite 785 Jelke-Southcenter, Chicago, IL 60612, USA
Abstract Pancreatic cancer is a nearly lethal disease. Patients have such a poor prognosis because there are no early symptoms. Upon presentation, most patients already have regional and systemic spread of the disease. With cure rates below 3%, long-term survival is difficult to measure. Thus, the assessment of clinical benefit has been based not only on observed 5-year survival but more frequently on actuarial, median, and disease-free survival. Surgery remains the only hope for cure, but median survival remains low despite improvements in peri- and postoperative treatment of complications and sharp decreases in perioperative morbidity and mortality. The addition of adjuvant chemo- and radiotherapy has provided a survival advantage of 6 to 10 months (increasing median survival to 20 months). However, the long-term benefit, if any, is still to be determined. Neoadjuvant therapies are also undergoing evaluation, but their role has not yet been established. True long-term survival may ultimately depend on the development of screening tools that will allow early detection (before regional and systemic spread) of this lethal disease. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Pancreatic cancer; Long-term survival; Early detection
Pancreatic cancer is an almost uniformly fatal disease. According to the American Cancer Society, the estimated new cases and deaths from pancreatic cancer in the United States are nearly identical. Despite advances in molecular biology, biochemistry, and nuclear and radiation medicine, surgical therapy remains the foundation of our efforts to cure patients with this disease. Unfortunately, long-term surgical cure remains elusive and is realized in only a lucky few. In recent years, much effort has gone to identifying adjunctive therapies that might aid in reducing mortality from this disease, but results thus far have been disappointing. However, there is hope on the horizon as our experiences with adjuvant and neoadjuvant therapies improve and new technologies for early detection of this disease emerge. Survival Rates The incidence of pancreatic cancer has increased over the past several decades. Although it is only the 10th most common malignancy in the United States, it is currently the 4th leading cause of cancer deaths (up from 5th 10 years ago) [1]. It is estimated that 33,730 new cases will occur in the United States in 2007 and that 32,300 patients will die of this disease [2]. No other major cancer has such a poor prognosis. According to the National Cancer Database, * Corresponding author. Tel.: ⫹312-942-6379; fax: ⫹312-942-7139. E-mail address: [email protected]
overall 1- and 5-year survival is a dismal 20% and 2%, respectively [3]. Furthermore, our ability to decrease the death rate has not substantially improved over time, in contrast to stomach, prostate, uterine, colon, and rectal cancer. Reasons for its higher mortality are related to the advanced stage of this disease that is typical at presentation. They include the lack of early symptoms, early and frequent vessel wall involvement, and high incidence of liver metastases. These factors make surgical resection for potential cure possible in ⬍20% of patients who present with this disease. In this review, we will define long-term survival as ⱖ5 years. Published 5-year survival figures vary widely and range anywhere between 5% and 40% [4 – 6]. However, true long-term survival is very rarely observed in patients with pancreatic cancer, and it is worth emphasizing that 5-year survival does not equal cure in this disease [5]. In fact, cure is achieved in ⬍3% of patients who have undergone treatment [5,7]. With such a poor prognosis, improvements in therapy are difficult to assess. Beger et al wrote, “assessment of clinical benefit from surgical or medical [pancreatic] cancer treatment should therefore be based on several end points, not only on actuarial survival” [8]. These include median survival (in months), progression/disease-free survival (in months), and actual survival at 1 to 5 years. Surgical Treatment Albert Einstein once defined insanity as “doing the same thing over and over again and expecting to get
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different results.” At first glance, there might not seem to be a more fitting statement when applied to our best surgical therapy for pancreatic cancer, the pancreaticoduodenectomy (Kausch-Whipple resection). Since it was developed in the 1930s and 40s and perfected in the 1980s and 90s, this procedure has done little to improve the overall survival rates of patients with pancreatic adenocarcinoma of the head of the gland. Resection cannot have a major impact on the overall cure rate because most patients are unresectable at presentation [1–3,9]. Nevertheless, it is the only chance for cure. The greatest contribution of surgery to the treatment of pancreatic cancer over the last 4 decades is the dramatic drop in perioperative mortality (from 25% to ⬍5%) associated with the Kausch-Whipple procedure [10]. Reasons for improved results include better selection of patients suitable for resection and the reduction of postoperative complications, such as bleeding and pancreatic leaks, to ⬍30%. Yeo and colleagues [6] attribute these improvements to earlier detection and treatment of complications, better critical care, and greater surgical experience. Reasons for treatment failure, however, are many. Most commonly, recurrent disease after resection is found regionally (in the liver and around the peritoneal cavity). The pancreatic bed is the second most common site of failure. These 2 areas comprise ⬎90% of treatment failures, with pulmonary metastases of the site of distant spread in ⬍10% of resected patients [11,12]. These patterns of failure are most likely caused by the difficulty in achieving a true R0 resection. This is because of the fact that lymphatic and perineural spread are common, surgical margins on the vessels (ie, portal vein, superior mesenteric artery and vein) are tight, and lymphatics drain directly into the liver [13]. These are the factors that have led many investigators to examine the role of adjunctive chemoradiotherapy and neoadjuvant therapy and to continue the search for better methods to detect pancreatic cancer before local and regional spread. Adjuvant Radiotherapy and Chemotherapy In the mid and late 1980s, the Gastrointestinal Tumor Study Group (GITSG) published the results of a groundbreaking randomized controlled study on the effects of adjuvant therapy on long-term survival in patients who received surgical treatment for pancreatic cancer [14]. In this 2-armed study, 22 patients were randomly assigned to surgery alone (control group) and 21 patients to surgery followed by weekly 5-fluorouracil (5-FU), 500 mg/m2 by intravenous bolus, combined with two 20-Gy courses of supervoltage radiation (treatment group). They observed a median survival of 11 months in the control group and 20 months in the treatment group. Disease-free survival was 9 months for the control and 11 months for the treatment groups. Actual 5-year survival was at least 5% and 19%, respectively, with a median follow-up time of 66 months. The major flaw of the trial was its low accrual rate. This led to early termination, smaller number of patients, and reduced study power. Although not definitive, the results suggested that the use of adjuvant chemotherapy and radiotherapy might prolong survival after resection for pancreatic
cancer. The survival benefit reported at the time of publication has since continued [13]. The observed 10-year survival was 19% in patients treated with chemoradiotherapy, whereas there were no survivors in the surgery-only group [8,15]. The GITSG was the impetus for several subsequent randomized trials, some that produced contradictory results and others that confirmed benefit. In the largest of these trials, the European Organization for Research and Treatment of Cancer (EORTC) randomly assigned 103 patients to surgery alone (control group) and 104 patients to surgery followed by continuous-infusion 5-FU (25 mg/kg/24 hours, maximum dose 1,500 mg) and 40 Gy external-beam radiation (treatment group) [16]. Median survival for patients was 19 months in the control group and 25 months in the treatment group. Median disease-free survival was 16 months in the control group and 17 months in the treatment group. Actual 5-year survival was calculated to be at least 8% and 11%, respectively. A major weakness of the study was the inclusion of patients with other types of periampullary cancers who generally have a more favorable prognosis. This explains the prolonged median survival of 19 months in the control group. The authors performed subgroup analysis on the 114 patients with pancreatic head cancer (54 in the control group and 60 in the treatment group). The median survival was 13 months for the control and 17 months for the treatment group, more in line with the data seen in the GITSG and European Study Group for Pancreatic Cancer (ESPAC) trials. Disease-free survival data were not reported for this subgroup. The calculated actual 5-year survival rate was at least 2% for the control and 5% for the treatment group. Based on their overall results, the authors concluded that there was insufficient evidence to recommend adjuvant chemoradiotherapy in patients with pancreatic cancer. In 2004, the ESPAC published the results of a large, randomized, multicenter trial to determine the potential benefits of chemoradiotherapy and maintenance chemotherapy in patients with resected pancreatic cancer [17]. Patients were randomly assigned to 1 of 2 arms and analyzed in a 2 ⫻ 2 factorial manner (Fig. 1). There were 69 patients in the observation arm, 73 in the chemoradiotherapy arm (20 Gy external beam radiation ⫹ bolus 500 mg/m2 5-FU), 75 in the chemotherapy-only arm (bolus of 20 mg/m2 leucovorin followed by 425 mg/m2 5-FU), and 72 in the chemoradiotherapy plus chemotherapy arm (combination of the 2 therapies described). The 2 ⫻ 2 design of this trial made it necessary to perform subgroup analysis in place of direct comparison with controls. Therefore, patients who did not receive chemoradiotherapy were evaluated against those who did (144 vs 145, group 1). Similarly, those who did not receive chemotherapy were compared with those who did (142 vs 147, group 2). The investigators reported median survival time in group 1 to be 18 months vs 16 months. In group 2, the median survival was 16 months vs 20 months. Disease-free survival was not reported. Observed 5-year survival (with a median follow-up time of 47 months) was calculated to be at least 9% vs 3% in group 1. In group 2, it was 5% vs 7%. The study showed a significant survival benefit for adjuvant chemotherapy. Conversely, chemoradiotherapy failed to benefit patients and may actually have reduced survival when given before chemotherapy. The
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authors concluded that “standard care for patients with resectable pancreatic cancer should consist of curative surgery followed by adjuvant systemic chemotherapy.” Preliminary data from the Radiation Therapy Oncology Group’s (RTOG) 9704 Study seem to confirm the previously described findings [18]. RTOG 9704 is the largest prospective, randomized trial of its kind to date. Its main objective is to evaluate the impact of the addition of gemcitabine to 5-FU for adjuvant chemotherapy. The study randomized a total of 442 patients into 2 arms. Study patients (221 in each arm) have all undergone curative resection for pancreatic cancer. Patients were then randomized to receive either 5-FU (250 mg/m2/d, continuous infusion [CI] for 3 weeks) or gemcitabine (1,000 mg/m2 weekly ⫻ 3) preand postchemoradiotherapy (50.4 Gy/1.8 Gy/fraction ⫹ 5-FU, 250 mg/m2/d CI ⫻ 5.5 weeks). The study was closed in July 2002 when its accrual goal was reached. The preliminary data show that gemcitabine improved median survival from 17 months to 21 months when compared with 5-FU. The data from the RTOG study confirm the results of the ESPAC and GITSG, which showed a significant benefit of 6 to 10 months of increased median survival time in patients who received adjuvant treatment when compared with those treated with resection alone. Adjuvant immunotherapy is also being explored. In 2003, Picozzi et al [19] reported 43 patients who received a more aggressive protocol of adjuvant chemoradiotherapy. Their protocol applied higher doses of radiotherapy (45–50 Gy, 25 fractions ⫻ 5 weeks) and included 5 weeks of interferon-␣ (3 ⫻ 106 U, days 1 to 35) to a regimen of continuous infusion 5-FU (200 mg/m2/d) and bolus cisplatin (30 mg/m2/d, weekly ⫻ 5). Although associated with higher toxicities, there were no reported deaths from treatment. Results were encouraging, with 29 of 43 patients (67%) still alive after an average follow-up time of 32 months despite a relatively large proportion of stage III disease (84% vs 28% and 48% for the GITSG and EORTC, respectively). Median survival time could not be calculated because over half of the patients were still alive. These remarkable results were based on a small case series and require validation from a large randomized controlled trial. Regional adjuvant chemotherapy is a catheter-directed procedure that allows perfusion of chemoactive drugs to the liver and the pancreatic remnant directly through their feeding vessels. The group at the University of Ulm, Ulm, Germany, noted that median survival times increased and pain decreased in patients with unresectable pancreatic cancer given this treatment through celiac artery infusion (CAI) [20]. In 1999, they published the findings of a series of 26 patients who received CAI (mitoxantrone 10 mg/m2, leucovorin 170 mg/m2, 5-FU 600 mg/m2, and cisplatin 60 mg/m2) after pancreaticoduodenectomy compared with historical controls. The catheters were placed into the celiac artery through the femoral artery and left in place for 5 days of infusion. They found that median survival was 23 months in the treatment group and 10.5 months in the control group. Observed 2- and 3-year survival rates were ⬎50% in the treatment group. In addition, the rate of liver metastasis was reduced to 17%, suggesting that CAI provides hepatic protection. These preliminary data, although promising, require randomized phase III studies to confirm their observations.
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Neoadjuvant Chemoradiotherapy The recent experience with adjuvant chemoradiotherapy revealed many of its limitations. For example, treatment with postoperative chemoradiotherapy is often delayed because of the morbidity and prolonged recovery associated with the Kausch-Whipple procedure. Up to 30% of patients do not receive therapy as planned. The studies are prone to selection bias, with the patients who recover quickest and have better performance status eligible to participate in these trials. Up to 33% to 40% of patients in the EORTC and ESPAC trials did not even receive the planned amount of radiation or chemotherapy studied in the trial. For these reasons, the MD Anderson Group reported a study of preoperative chemoradiotherapy in 2001 [21]. This was one in a series of studies evaluating neoadjuvant therapy from this group dating back to 1988. Patients deemed surgical candidates by radiographic criteria received preoperative chemoradiotherapy (standard fraction of 50.4 Gy over 5.5 weeks in the first 28 patients and then rapid fraction of 30 Gy over 2 weeks in subsequent patients ⫹ CI 5-FU, 300 mg/m2/d) followed by surgical resection of the tumor (4 to 5 weeks after the end of chemoradiotherapy) with and without intraoperative radiation therapy (IORT) (74 with and 58 without). Analysis was performed in a series of 132 patients. Median survival was 21 months from the time of tissue diagnosis, comparable to the treatment arms of the GITSG and ESPAC trials. Disease-free survival was not reported. Actual 5-year survival was not reported and could not be calculated. Flaws of the study included selection bias, failure to use the principle of intent to treat, and delay of treatment from time of diagnosis to surgical resection (7 to 9 weeks based on the described protocol). Because of this, up to 40% of patients deemed resectable at the start of the treatment plan had disease progress to stage III or IV by the end of preoperative treatment and were excluded from the trial. A more recent trial from the same group evaluated the efficacy of gemcitabine in place of 5-FU– based chemoradiotherapy [22]. The results showed that despite a longer time from enrollment to surgery (11 to 12 weeks vs 7 to 9 weeks), the number of patients deemed unresectable after preoperative therapy was reduced to 25% (compared with 40% with 5-FU– based chemoradiotherapy). In addition, there were 2 pathologic complete responses, a finding not observed with 5-FU– based therapy. With a follow-up time of at least 2 years, the median survival of the patients who underwent resection was 36 months. Earlier Diagnosis It is well known that treatment failure is determined by the extent of lymph node involvement, local invasion of blood vessel walls, perineural infiltration, and amount of microscopic disease left behind [11,12]. It stands to reason that earlier detection of pancreatic cancer would lead to a substantial reduction in treatment failures and improved survival after therapy. With the advent of DNA microarrays (“gene chips”), a paradigm shift was achieved. Before this, gene expression was examined one at a time. Now, tens of thousands of genes can be examined on a single array. With this technology, many investigators are pursuing the socalled “molecular fingerprints” of various malignancies, in-
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cluding pancreatic cancer. For example, of 45,000 genes expressed in pancreatic cancer cells, only 183 were overexpressed when compared with normal pancreatic cells [23]. These investigators then focused on the secreted protein in serum of 1 of the overexpressed genes, TIMP-1. They found that when combined with the standard serum markers for pancreatic cancer, CEA and CA 19-9, they were able to detect 60% of patients with pancreatic cancer while maintaining a specificity of 100%. Other researchers have applied 2-dimensional gel electrophoresis and mass spectrometry to identify protein expression profiles that may eventually serve as diagnostic markers or therapeutic targets [24]. Furthermore, efforts at screening high-risk patients with serial imaging studies (ultrasound and endoscopic retrograde cholangiopancreatography) with and without pancreatic juice cytology have yielded positive early results [25,26]. These findings suggest that new and better tumor markers and screening techniques are being found to help improve early diagnosis and may eventually lead to better long-term survival in pancreatic cancer. In summary, cure rates for pancreatic cancer in the head of the gland remain low. However, long-term survival, based not only on actuarial survival but also on observed 5-year, median, and disease-free survival data, has improved substantially over the past 20 years. There has been nearly a doubling in median survival times (eg, from 11 to 20 months in the GITSG trial). This is likely multifactorial and because of advances in operative and perioperative treatments (in particular, adjuvant chemoradiotherapy) used against pancreatic cancer. There are also promising, novel treatments that still require validation in large randomized controlled trials. Ultimately, the best hope for dramatic improvements in long-term survival appears to depend on the early detection of this disease. References [1] Howe HL, Wu X, Ries L, et al. Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/ Latino populations. Cancer 2006;107:1711– 42. [2] Common cancer types. National Cancer Institute website. Available at: http://www.cancer.gov/concertopics/commoncancers. Accessed October 7, 2006. [3] Cancer statistics 2006. American Cancer Society. Available at: http:// www.cancer.org. Accessed October 7, 2006. [4] Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;221:59 – 66. [5] Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg 1996;223:273–9. [6] Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997;226:248 –57.
[7] Gudjonsson B. Cancer of the pancreas. 50 years of surgery. Cancer 1987;60:2284–303. [8] Beger H, Rau B, Gansauge F, et al. Treatment of pancreatic cancer: challenge of the facts. World J Surg 2003;27:1075– 84. [9] Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13. [10] Birkmeyer JD, Finlayson SRG, Tosteson ANA, et al. Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 1999;125:250 – 6. [11] Sperti C, Pasquali C, Piccoli A, Pedrazzolli S. Recurrence after resection for adenocarcinoma of the pancreas. World J Surg 1997; 21:195–200. [12] Griffin JF, Smalley SR, Jewell W, et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer 1990;66:56 – 61. [13] Beger HG, Gansauge F, Birk D. Lymph node dissection. In: Cameron JL, ed. Pancreatic Cancer. Hamilton, London, Ontario: BC Decker, 2001:123–32. [14] Kalser MH, Ellenber SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899 –903. [15] Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006 –10. [16] Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region. Phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999;230:776 – 84. [17] Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200 –10. [18] Saif MW. Pancreatic cancer: highlights from the 42nd annual meeting of the American Society of Clinical Oncology, 2006. J Pancreas 2006;7:337– 48. [19] Picozzi VJ, Kozarek RA, Traverso LW. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2004;185:476 – 80. [20] Beger HG, Gansauge F, Buchler MW, Link KH. Intraarterial adjuvant chemotherapy after pancreaticoduodenectomy for pancreatic cancer: significant reduction in occurrence of liver metastasis. World J Surg 1999;23:946 –9. [21] Breslin TM, Hess KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123–32. [22] Wolff RA, Evans DB, Crane CH, et al. Initial results of a preoperative gemcitabine (GEM)-based chemoradiation for respectable pancreatic adenocarcinoma. Proc Am Soc Clin Oncol 2002;21:130a (abstr 516). [23] Zhou W, Sokoll LJ, Bruzek DJ, et al. Identifying markers for pancreatic cancer by gene expression analysis. Cancer Epidemiol Biomarkers Prev 1998;7:109 –12. [24] Shen J, Person MD, Zhu J, et al. Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res 2004;64:9018 –26. [25] Tanaka S, Nakaizumi A, Ioka T, et al. Periodic ultrasonography checkup for the early detection of pancreatic cancer: preliminary report. Pancreas 2004;28:268 –72. [26] Canto MI, Goggins M, Hruban RH, et al. Screening for early pancreatic neoplasia in high risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 2006;4:766 – 81.
Long-term survival after pancreatic cancer treatment Emery L. Chen, M.D., Richard A. Prinz, M.D.* Department of General Surgery, Rush University Medical Center, 1653 W Congress Parkway, Suite 785 Jelke-Southcenter, Chicago, IL 60612, USA
Abstract Pancreatic cancer is a nearly lethal disease. Patients have such a poor prognosis because there are no early symptoms. Upon presentation, most patients already have regional and systemic spread of the disease. With cure rates below 3%, long-term survival is difficult to measure. Thus, the assessment of clinical benefit has been based not only on observed 5-year survival but more frequently on actuarial, median, and disease-free survival. Surgery remains the only hope for cure, but median survival remains low despite improvements in peri- and postoperative treatment of complications and sharp decreases in perioperative morbidity and mortality. The addition of adjuvant chemo- and radiotherapy has provided a survival advantage of 6 to 10 months (increasing median survival to 20 months). However, the long-term benefit, if any, is still to be determined. Neoadjuvant therapies are also undergoing evaluation, but their role has not yet been established. True long-term survival may ultimately depend on the development of screening tools that will allow early detection (before regional and systemic spread) of this lethal disease. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Pancreatic cancer; Long-term survival; Early detection
Pancreatic cancer is an almost uniformly fatal disease. According to the American Cancer Society, the estimated new cases and deaths from pancreatic cancer in the United States are nearly identical. Despite advances in molecular biology, biochemistry, and nuclear and radiation medicine, surgical therapy remains the foundation of our efforts to cure patients with this disease. Unfortunately, long-term surgical cure remains elusive and is realized in only a lucky few. In recent years, much effort has gone to identifying adjunctive therapies that might aid in reducing mortality from this disease, but results thus far have been disappointing. However, there is hope on the horizon as our experiences with adjuvant and neoadjuvant therapies improve and new technologies for early detection of this disease emerge. Survival Rates The incidence of pancreatic cancer has increased over the past several decades. Although it is only the 10th most common malignancy in the United States, it is currently the 4th leading cause of cancer deaths (up from 5th 10 years ago) [1]. It is estimated that 33,730 new cases will occur in the United States in 2007 and that 32,300 patients will die of this disease [2]. No other major cancer has such a poor prognosis. According to the National Cancer Database, * Corresponding author. Tel.: ⫹312-942-6379; fax: ⫹312-942-7139. E-mail address: [email protected]
overall 1- and 5-year survival is a dismal 20% and 2%, respectively [3]. Furthermore, our ability to decrease the death rate has not substantially improved over time, in contrast to stomach, prostate, uterine, colon, and rectal cancer. Reasons for its higher mortality are related to the advanced stage of this disease that is typical at presentation. They include the lack of early symptoms, early and frequent vessel wall involvement, and high incidence of liver metastases. These factors make surgical resection for potential cure possible in ⬍20% of patients who present with this disease. In this review, we will define long-term survival as ⱖ5 years. Published 5-year survival figures vary widely and range anywhere between 5% and 40% [4 – 6]. However, true long-term survival is very rarely observed in patients with pancreatic cancer, and it is worth emphasizing that 5-year survival does not equal cure in this disease [5]. In fact, cure is achieved in ⬍3% of patients who have undergone treatment [5,7]. With such a poor prognosis, improvements in therapy are difficult to assess. Beger et al wrote, “assessment of clinical benefit from surgical or medical [pancreatic] cancer treatment should therefore be based on several end points, not only on actuarial survival” [8]. These include median survival (in months), progression/disease-free survival (in months), and actual survival at 1 to 5 years. Surgical Treatment Albert Einstein once defined insanity as “doing the same thing over and over again and expecting to get
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different results.” At first glance, there might not seem to be a more fitting statement when applied to our best surgical therapy for pancreatic cancer, the pancreaticoduodenectomy (Kausch-Whipple resection). Since it was developed in the 1930s and 40s and perfected in the 1980s and 90s, this procedure has done little to improve the overall survival rates of patients with pancreatic adenocarcinoma of the head of the gland. Resection cannot have a major impact on the overall cure rate because most patients are unresectable at presentation [1–3,9]. Nevertheless, it is the only chance for cure. The greatest contribution of surgery to the treatment of pancreatic cancer over the last 4 decades is the dramatic drop in perioperative mortality (from 25% to ⬍5%) associated with the Kausch-Whipple procedure [10]. Reasons for improved results include better selection of patients suitable for resection and the reduction of postoperative complications, such as bleeding and pancreatic leaks, to ⬍30%. Yeo and colleagues [6] attribute these improvements to earlier detection and treatment of complications, better critical care, and greater surgical experience. Reasons for treatment failure, however, are many. Most commonly, recurrent disease after resection is found regionally (in the liver and around the peritoneal cavity). The pancreatic bed is the second most common site of failure. These 2 areas comprise ⬎90% of treatment failures, with pulmonary metastases of the site of distant spread in ⬍10% of resected patients [11,12]. These patterns of failure are most likely caused by the difficulty in achieving a true R0 resection. This is because of the fact that lymphatic and perineural spread are common, surgical margins on the vessels (ie, portal vein, superior mesenteric artery and vein) are tight, and lymphatics drain directly into the liver [13]. These are the factors that have led many investigators to examine the role of adjunctive chemoradiotherapy and neoadjuvant therapy and to continue the search for better methods to detect pancreatic cancer before local and regional spread. Adjuvant Radiotherapy and Chemotherapy In the mid and late 1980s, the Gastrointestinal Tumor Study Group (GITSG) published the results of a groundbreaking randomized controlled study on the effects of adjuvant therapy on long-term survival in patients who received surgical treatment for pancreatic cancer [14]. In this 2-armed study, 22 patients were randomly assigned to surgery alone (control group) and 21 patients to surgery followed by weekly 5-fluorouracil (5-FU), 500 mg/m2 by intravenous bolus, combined with two 20-Gy courses of supervoltage radiation (treatment group). They observed a median survival of 11 months in the control group and 20 months in the treatment group. Disease-free survival was 9 months for the control and 11 months for the treatment groups. Actual 5-year survival was at least 5% and 19%, respectively, with a median follow-up time of 66 months. The major flaw of the trial was its low accrual rate. This led to early termination, smaller number of patients, and reduced study power. Although not definitive, the results suggested that the use of adjuvant chemotherapy and radiotherapy might prolong survival after resection for pancreatic
cancer. The survival benefit reported at the time of publication has since continued [13]. The observed 10-year survival was 19% in patients treated with chemoradiotherapy, whereas there were no survivors in the surgery-only group [8,15]. The GITSG was the impetus for several subsequent randomized trials, some that produced contradictory results and others that confirmed benefit. In the largest of these trials, the European Organization for Research and Treatment of Cancer (EORTC) randomly assigned 103 patients to surgery alone (control group) and 104 patients to surgery followed by continuous-infusion 5-FU (25 mg/kg/24 hours, maximum dose 1,500 mg) and 40 Gy external-beam radiation (treatment group) [16]. Median survival for patients was 19 months in the control group and 25 months in the treatment group. Median disease-free survival was 16 months in the control group and 17 months in the treatment group. Actual 5-year survival was calculated to be at least 8% and 11%, respectively. A major weakness of the study was the inclusion of patients with other types of periampullary cancers who generally have a more favorable prognosis. This explains the prolonged median survival of 19 months in the control group. The authors performed subgroup analysis on the 114 patients with pancreatic head cancer (54 in the control group and 60 in the treatment group). The median survival was 13 months for the control and 17 months for the treatment group, more in line with the data seen in the GITSG and European Study Group for Pancreatic Cancer (ESPAC) trials. Disease-free survival data were not reported for this subgroup. The calculated actual 5-year survival rate was at least 2% for the control and 5% for the treatment group. Based on their overall results, the authors concluded that there was insufficient evidence to recommend adjuvant chemoradiotherapy in patients with pancreatic cancer. In 2004, the ESPAC published the results of a large, randomized, multicenter trial to determine the potential benefits of chemoradiotherapy and maintenance chemotherapy in patients with resected pancreatic cancer [17]. Patients were randomly assigned to 1 of 2 arms and analyzed in a 2 ⫻ 2 factorial manner (Fig. 1). There were 69 patients in the observation arm, 73 in the chemoradiotherapy arm (20 Gy external beam radiation ⫹ bolus 500 mg/m2 5-FU), 75 in the chemotherapy-only arm (bolus of 20 mg/m2 leucovorin followed by 425 mg/m2 5-FU), and 72 in the chemoradiotherapy plus chemotherapy arm (combination of the 2 therapies described). The 2 ⫻ 2 design of this trial made it necessary to perform subgroup analysis in place of direct comparison with controls. Therefore, patients who did not receive chemoradiotherapy were evaluated against those who did (144 vs 145, group 1). Similarly, those who did not receive chemotherapy were compared with those who did (142 vs 147, group 2). The investigators reported median survival time in group 1 to be 18 months vs 16 months. In group 2, the median survival was 16 months vs 20 months. Disease-free survival was not reported. Observed 5-year survival (with a median follow-up time of 47 months) was calculated to be at least 9% vs 3% in group 1. In group 2, it was 5% vs 7%. The study showed a significant survival benefit for adjuvant chemotherapy. Conversely, chemoradiotherapy failed to benefit patients and may actually have reduced survival when given before chemotherapy. The
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authors concluded that “standard care for patients with resectable pancreatic cancer should consist of curative surgery followed by adjuvant systemic chemotherapy.” Preliminary data from the Radiation Therapy Oncology Group’s (RTOG) 9704 Study seem to confirm the previously described findings [18]. RTOG 9704 is the largest prospective, randomized trial of its kind to date. Its main objective is to evaluate the impact of the addition of gemcitabine to 5-FU for adjuvant chemotherapy. The study randomized a total of 442 patients into 2 arms. Study patients (221 in each arm) have all undergone curative resection for pancreatic cancer. Patients were then randomized to receive either 5-FU (250 mg/m2/d, continuous infusion [CI] for 3 weeks) or gemcitabine (1,000 mg/m2 weekly ⫻ 3) preand postchemoradiotherapy (50.4 Gy/1.8 Gy/fraction ⫹ 5-FU, 250 mg/m2/d CI ⫻ 5.5 weeks). The study was closed in July 2002 when its accrual goal was reached. The preliminary data show that gemcitabine improved median survival from 17 months to 21 months when compared with 5-FU. The data from the RTOG study confirm the results of the ESPAC and GITSG, which showed a significant benefit of 6 to 10 months of increased median survival time in patients who received adjuvant treatment when compared with those treated with resection alone. Adjuvant immunotherapy is also being explored. In 2003, Picozzi et al [19] reported 43 patients who received a more aggressive protocol of adjuvant chemoradiotherapy. Their protocol applied higher doses of radiotherapy (45–50 Gy, 25 fractions ⫻ 5 weeks) and included 5 weeks of interferon-␣ (3 ⫻ 106 U, days 1 to 35) to a regimen of continuous infusion 5-FU (200 mg/m2/d) and bolus cisplatin (30 mg/m2/d, weekly ⫻ 5). Although associated with higher toxicities, there were no reported deaths from treatment. Results were encouraging, with 29 of 43 patients (67%) still alive after an average follow-up time of 32 months despite a relatively large proportion of stage III disease (84% vs 28% and 48% for the GITSG and EORTC, respectively). Median survival time could not be calculated because over half of the patients were still alive. These remarkable results were based on a small case series and require validation from a large randomized controlled trial. Regional adjuvant chemotherapy is a catheter-directed procedure that allows perfusion of chemoactive drugs to the liver and the pancreatic remnant directly through their feeding vessels. The group at the University of Ulm, Ulm, Germany, noted that median survival times increased and pain decreased in patients with unresectable pancreatic cancer given this treatment through celiac artery infusion (CAI) [20]. In 1999, they published the findings of a series of 26 patients who received CAI (mitoxantrone 10 mg/m2, leucovorin 170 mg/m2, 5-FU 600 mg/m2, and cisplatin 60 mg/m2) after pancreaticoduodenectomy compared with historical controls. The catheters were placed into the celiac artery through the femoral artery and left in place for 5 days of infusion. They found that median survival was 23 months in the treatment group and 10.5 months in the control group. Observed 2- and 3-year survival rates were ⬎50% in the treatment group. In addition, the rate of liver metastasis was reduced to 17%, suggesting that CAI provides hepatic protection. These preliminary data, although promising, require randomized phase III studies to confirm their observations.
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Neoadjuvant Chemoradiotherapy The recent experience with adjuvant chemoradiotherapy revealed many of its limitations. For example, treatment with postoperative chemoradiotherapy is often delayed because of the morbidity and prolonged recovery associated with the Kausch-Whipple procedure. Up to 30% of patients do not receive therapy as planned. The studies are prone to selection bias, with the patients who recover quickest and have better performance status eligible to participate in these trials. Up to 33% to 40% of patients in the EORTC and ESPAC trials did not even receive the planned amount of radiation or chemotherapy studied in the trial. For these reasons, the MD Anderson Group reported a study of preoperative chemoradiotherapy in 2001 [21]. This was one in a series of studies evaluating neoadjuvant therapy from this group dating back to 1988. Patients deemed surgical candidates by radiographic criteria received preoperative chemoradiotherapy (standard fraction of 50.4 Gy over 5.5 weeks in the first 28 patients and then rapid fraction of 30 Gy over 2 weeks in subsequent patients ⫹ CI 5-FU, 300 mg/m2/d) followed by surgical resection of the tumor (4 to 5 weeks after the end of chemoradiotherapy) with and without intraoperative radiation therapy (IORT) (74 with and 58 without). Analysis was performed in a series of 132 patients. Median survival was 21 months from the time of tissue diagnosis, comparable to the treatment arms of the GITSG and ESPAC trials. Disease-free survival was not reported. Actual 5-year survival was not reported and could not be calculated. Flaws of the study included selection bias, failure to use the principle of intent to treat, and delay of treatment from time of diagnosis to surgical resection (7 to 9 weeks based on the described protocol). Because of this, up to 40% of patients deemed resectable at the start of the treatment plan had disease progress to stage III or IV by the end of preoperative treatment and were excluded from the trial. A more recent trial from the same group evaluated the efficacy of gemcitabine in place of 5-FU– based chemoradiotherapy [22]. The results showed that despite a longer time from enrollment to surgery (11 to 12 weeks vs 7 to 9 weeks), the number of patients deemed unresectable after preoperative therapy was reduced to 25% (compared with 40% with 5-FU– based chemoradiotherapy). In addition, there were 2 pathologic complete responses, a finding not observed with 5-FU– based therapy. With a follow-up time of at least 2 years, the median survival of the patients who underwent resection was 36 months. Earlier Diagnosis It is well known that treatment failure is determined by the extent of lymph node involvement, local invasion of blood vessel walls, perineural infiltration, and amount of microscopic disease left behind [11,12]. It stands to reason that earlier detection of pancreatic cancer would lead to a substantial reduction in treatment failures and improved survival after therapy. With the advent of DNA microarrays (“gene chips”), a paradigm shift was achieved. Before this, gene expression was examined one at a time. Now, tens of thousands of genes can be examined on a single array. With this technology, many investigators are pursuing the socalled “molecular fingerprints” of various malignancies, in-
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cluding pancreatic cancer. For example, of 45,000 genes expressed in pancreatic cancer cells, only 183 were overexpressed when compared with normal pancreatic cells [23]. These investigators then focused on the secreted protein in serum of 1 of the overexpressed genes, TIMP-1. They found that when combined with the standard serum markers for pancreatic cancer, CEA and CA 19-9, they were able to detect 60% of patients with pancreatic cancer while maintaining a specificity of 100%. Other researchers have applied 2-dimensional gel electrophoresis and mass spectrometry to identify protein expression profiles that may eventually serve as diagnostic markers or therapeutic targets [24]. Furthermore, efforts at screening high-risk patients with serial imaging studies (ultrasound and endoscopic retrograde cholangiopancreatography) with and without pancreatic juice cytology have yielded positive early results [25,26]. These findings suggest that new and better tumor markers and screening techniques are being found to help improve early diagnosis and may eventually lead to better long-term survival in pancreatic cancer. In summary, cure rates for pancreatic cancer in the head of the gland remain low. However, long-term survival, based not only on actuarial survival but also on observed 5-year, median, and disease-free survival data, has improved substantially over the past 20 years. There has been nearly a doubling in median survival times (eg, from 11 to 20 months in the GITSG trial). This is likely multifactorial and because of advances in operative and perioperative treatments (in particular, adjuvant chemoradiotherapy) used against pancreatic cancer. There are also promising, novel treatments that still require validation in large randomized controlled trials. Ultimately, the best hope for dramatic improvements in long-term survival appears to depend on the early detection of this disease. References [1] Howe HL, Wu X, Ries L, et al. Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/ Latino populations. Cancer 2006;107:1711– 42. [2] Common cancer types. National Cancer Institute website. Available at: http://www.cancer.gov/concertopics/commoncancers. Accessed October 7, 2006. [3] Cancer statistics 2006. American Cancer Society. Available at: http:// www.cancer.org. Accessed October 7, 2006. [4] Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;221:59 – 66. [5] Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg 1996;223:273–9. [6] Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997;226:248 –57.
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