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Radiochemoimmunotherapy for pancreatic cancer
The American Journal of Surgery 194 (Suppl to October 2007) S138 –S142
Radiochemoimmunotherapy for pancreatic cancer Angela Märten, Ph.D.*, Markus W. Büchler, M.D., Jan Schmidt, M.D. Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
Abstract After they undergo surgical intervention with curative intention in specialized centers, the 5-year survival rate of patients with carcinoma of the exocrine pancreas is only 15%. The European Study Group For Pancreatic Cancer (ESPAC) –1 trial showed that an increased 5-year survival rate of 21% was achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy, and external-beam radiation. This article discusses the potential role of radiochemoimmunotherapy for adjuvant treatment; describes the ongoing phase III randomized controlled trial, Adjuvant ChemoRadioImmunotherapy of Pancreatic Carcinoma (CapRI); and compares the regimen from the Virginia Mason Clinic with the best arm of ESPAC-1. First data regarding the toxicity are shown. This article illustrates possible modes of action of radiochemoimmunotherapy and shows how translational research might help to shed some light on the underlying mechanisms as well as define predictive markers. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Immunotherapy; Interferon-␣; Multimodality treatment; Pancreatic carcinoma
The 5-year survival rate of patients with resected pancreatic adenocarcinoma is still discouraging, just approximately 10%. There are few randomized data on adjuvant therapy for pancreatic carcinoma. The European Study Group For Pancreatic Cancer (ESPAC) –1 trial assessed the role of adjuvant therapy in a randomized study; 548 patients were enrolled in Europe in this first large randomized trial. There was evidence that adjuvant chemotherapy brought survival benefits. The 5-year survival rate was 21% among patients who received chemotherapy [1]. The data for radiochemotherapy were less promising. However, it must be stated clearly that radiotherapy was not standardized in this trial. The preliminary data from the CONKO 001 trial, which had disease-free survival as the primary objective, confirmed that chemotherapy is superior to best supportive care [2]. The European Organization for Research and Treatment of Cancer (EORTC) trial investigating chemoradiation recently confirmed their conclusion from 1999 that routine use of adjuvant radiochemotherapy is no longer warranted as standard treatment in cancer of the head of the pancreas or the periampullary region; follow-up now has lasted 10 years [3,4]. At present, a clear benefit of chemotherapy, with a 5-year survival rate of approximately 20% in the adjuvant setting, has been proven. The data for radiochemotherapy, confer* Corresponding author. Tel.: ⫹011-49-6221-5639890; fax: ⫹011-496221-568240. E-mail address: [email protected]
ring a survival rate between 10% and 18%, are not convincing. Taking this into account, the overwhelming data for radiochemoimmunotherapy from phase II trials must be verified. The Virginia Mason Experience In 1995, a phase II trial was initiated by the Virginia Mason Clinic, Seattle, WA, combining pancreaticoduodenectomy and adjuvant therapy with 5-fluorouracil (5-FU), cisplatin, interferon-␣, and radiation therapy. Picozzi et al [5] reported treatment and results in a series of 43 patients with high-risk resected pancreatic adenocarcinoma (84% node positive, 19% margin positive). After a median follow-up period of 32 months, the 2-year survival rate was 64% and the 5-year survival rate, 55%. The overall recurrence rate was 12%, of which 80% occurred within 2 years after surgery [6]. However, the investigators reported moderate to severe toxicities during chemoradiation (mainly common toxicity criteria [CTC] grade 3) in 70% of the patients. They were mainly of gastrointestinal origin (anorexia, nausea and vomiting, mucositis, diarrhea, or hypovolemia); therefore, hospitalization was required in 42% of the patients. However, no treatment-related fatalities were reported, and all patients returned to full functional status. In 2005, Picozzi et al presented the American Pancreatic Association (APA) data for now roughly 100 patients and stated a stable 5-year survival rate of 50%.
0002-9610/00/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.05.012
A. Märten et al. / The American Journal of Surgery 194 (Suppl to October 2007) S138 –S142
The CapRI Experience Because the Virginia Mason group reported such encouraging results in improving survival rates, there has been considerable interest in gaining increased experience with this therapy combination in an effort to confirm the results, evaluate the toxicity profile, and gain new insights into the mechanism of success underlying this regimen. Therefore, in August 2004, a phase III trial to compare the Virginia Mason scheme with the best arm of the ESPAC-1 trial was started. The Adjuvant ChemoRadioImmunotherapy of Pancreatic Carcinoma (CapRI) study is an open, controlled, prospective, randomized multicenter trial to evaluate the postoperative overall survival of patients with pancreatic adenocarcinoma receiving radiochemotherapy, including interferon-␣ 2b administration, compared with adjuvant chemotherapy alone. The treatment is offered to a heterogeneous group of people— of both sexes, with a wide age range, and who have heterogeneous characteristics and comorbidities— under clinical conditions. Four centers in Germany and 1 center in Italy are participating in CapRI. The study was designed and conducted by the Department of Surgery at the University of Heidelberg, Germany [7]. CapRI focuses on patients ⬎18 years old treated with pancreatic head resection for pancreatic adenocarcinoma starting in August 2004. A total of 110 patients must be enrolled in the study to achieve a difference in hazard on level ␣ ⫽ .05 and with a power of 80%. Men and women ⬎18 years old with biopsy-proven and completely resected (R0 or R1) pancreatic adenocarcinoma are considered for participation in the study. The primary objective is to compare the overall survival rate at 2 years after surgery between 2 different methods of adjuvant treatment: (1) therapy with 5-FU, cisplatin, and interferon-␣ 2b combined with radiation and (2) standard treatment from the ESPAC-1 trial with 5-FU plus folinic acid. Secondary objectives are to determine the role and the mechanism of interferon-␣ 2b in patients’ chemoradiation regimen, toxicity of the regimen, disease-free interval, and quality of life. Different factors are tested in terms of their potential role as predictive markers. Treatment schemes are nearly identical to those described in the ESPAC-1 trial or in the Virginia Mason scheme. For practical reasons, the dosage of interferon-␣ was modified from every other day to 3 times per week (Fig. 1). As of October 2006, 86 patients have been enrolled in the study. The observed toxicity profile has been quite different from the published data from the Virginia Mason experience. Patients enrolled in arm A of the CapRI trial have CTC grade 3 to 4 toxicities (85% were grade 3), primarily leukopenia (50%), followed by electrolyte disturbance (14%), stomatitis, and vomiting (10%); 5% of patients had diarrhea, fatigue, and hypovolemia. Electrolyte disturbance (hypocalcemia) was easily prevented by oral supplementation. In arm B (the Mayo scheme), side effects have been less pronounced: 16% of patients had diarrhea, 8% had leukopenia, and 8% had hypovolemia CTC grade 3 to 4 (60% had CTC grade 3 hypovolemia). Mechanism of Radiochemoimmunotherapy Radiosensitizing properties of 5-FU and cisplatin are well known. Because ESPAC-1 and the EORTC trial were
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not able to show any superiority of radiochemotherapy compared with chemotherapy [8], it was hypothesized that the addition of interferon-␣ was the crucial step in the multimodality therapy. The incorporation of interferon-␣ 2b into a combined modality treatment program seems to offer a number of theoretical advantages. These include (1) the radiosensitization effects of interferon-␣ 2b and 5-FU, perhaps synergistically [9]; (2) enhanced 5-FU– based bioavailability; (3) a synergistic inhibition of pyrimidine metabolism with 5-FU; and (4) an independent immunomodulatory effect of interferon-␣ 2b [10]. Interferon-␣ 2b and 5-FU have been used advantageously together in several cancer settings but not as part of a combined modality program [11]. Cisplatin also has a radiosensitizing effect and shares similar properties of cytotoxic synergy with interferon-␣ 2b and 5-FU in both experimental and clinical cancer settings (Fig. 2) [12]. Furthermore, there is growing evidence that the combination of chemotherapy with immunotherapy acts synergistically and not antagonistically. Chemotherapy delivers by tumor destruction a broad range of tumor antigens to the immune system [13–15]; the immunosuppressive features of tumors are decreased because of tumor debulking; and lymphopenia abolishes regulatory T-cells and clears the space for tumor-reactive cells [16,17]. Immunotherapy could boost spontaneous responses to endogenous antigens cross-presented from tumor cells destroyed by chemotherapy without need of specific peptides, vaccinations, or other laborious strategies. The timing seems to be crucial; chemotherapy in parallel to immunotherapy or closely followed by immunotherapy seems to be most effective [18]. In a previous study, it was demonstrated in vitro that interferon-␣ has direct inhibitory properties and that it decreases the enhanced proliferation rate and vascular endothelial growth factor secretion that results even after a single treatment with cisplatin [19]. Studies focusing on the immunomodulatory effect of interferon-␣ showed an activation of natural killer (NK) cells and their ability to lyse tumor cells as well by Fas-induced apoptosis as by perforin release. Pretreatment of tumor cells with 5-FU in combination with other drugs showed a significant increase in the susceptibility of tumor cells against NK cells; therefore, the importance of synergistic effects between all single agents in multimodality treatment was again proven. Interestingly, treatment of tumor cells with interferon-␣ induced a switch to the immunoproteasome and for this reason enhanced their vulnerability to T-cells [20]. Orthotopic animal studies have clearly shown that addition of interferon-␣ to chemotherapy or radiotherapy significantly improves patient outcome. Patients undergoing treatment schemes, including interferon-␣, showed an average of 70% fewer metastases than those receiving monochemotherapy or radiotherapy. The tumors of animals treated with chemotherapy and radiotherapy plus interferon-␣ were infiltrated with immune cells. It is known from human analysis that lymphocyte infiltration results in a better prognosis [21,22]. Interestingly, it could be shown that these cells were tumor specific and that the antitumor response could be transferred into untreated animals by injection of tumor-infiltrating lymphocytes from a treated donor mouse. In elegant intravital microscopy experiments, it was shown that the vessel density in tumors decreases in chemoimmunotreated
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Fig. 1. Treatment scheme of the CapRI trial. Study arm A: (1) external beam radiation at 50.4 Gy in 28 fractions on days 1 to 38; (2) administration of 5-FU, 200 mg/m2/d, by continuous intravenous (IV) infusion on days 1 to 38; IV administration of cisplatin, 30 mg/m2, for 60 minutes on days 1, 8, 15, 22, 29, and 36 (6 doses); (4) subcutaneous administration of interferon-␣ 2b, 3,000,000 U 3 times/wk, on days 1 to 38 (17 total doses); (5) continuous administration of 5-FU, 200/mg/m2/d, on days 64 to 101 and days 120 to 161. Study arm B: Folinic acid (D-L form), 20 mg/m2 IV bolus injection, followed by 5-FU IV bolus injection, 425 mg/m2/d, given on 5 consecutive days every 28 days for 6 cycles, ie, for 24 weeks.
Fig. 2. Mechanism of interferon-␣ alone and in combination with chemotherapy and radiotherapy. 5-FU, cisplatin, and interferon-␣ are radiosensitizers [1]. Interferon-␣ is also a chemosensitizer [1]. Interferon-␣ enhances NK cell–mediated cytotoxicity and, to a lesser extent, CD8 cell proliferation. Interferon-␣ acts antiangiogenically and enhances leukocyte– endothelium interactions [3]. Treatment with interferon-␣ induces the switch to the immunoproteasome, resulting in increased immunogenicity. Cisplatin induces rapid cell regrowth, and this could be prevented by interferon-␣ [5]. Chemotherapy as well as radiotherapy induces NF-B, known to promote growth of pancreatic carcinoma. Interferon-␣ inhibits NF-B upregulation or even downregulates NF-B [6]. 5-FU makes pancreatic tumor cells more susceptible to interferon-␣–triggered NK cell attacks [7]. Interferon-␣ induces upregulation of Fas, thus resulting in increased NK cell cytotoxicity [8].
animals. Furthermore, more leukocytes roll and stick to the endothelium, which is the first step before infiltration into the tumor. Chemotherapy alone decreased the numbers of attaching leukocytes [23]. This is in accordance with the observations made in parallel to the CapRI study. One day after interferon-␣ injection, patients in the multimodality treatment arm showed a significant increase in spontaneous NK cell– mediated cytotoxicity; however, this effect faded after repeated injections. Five days after the first interferon-␣ injection, interleukin-12 and tumor-necrosis factor (TNF)–␣ serum levels peaked. A significant increase of monocytes, peripheral dendritic cells, CD40⫹ cells, central and effector memory T-cells, and CD8 cells was observed; however, CD4 cells decreased during therapy. Furthermore, immune cells releasing Granzyme B after stimulation with the tumor
antigens CA 19.9 and MUC-1 protein increased during therapy. All of these effects were observed only after radiochemoimmunotherapy, and none of them were noted after chemotherapy alone [20]. Discussion Adjuvant therapy in potentially curatively resected adenocarcinoma of the pancreas has become standard treatment in recent years. As the first, large multicenter randomized controlled trial (RCT), the ESPAC-1 trial clearly favored adjuvant chemotherapy over best supportive care [1]. Preliminary data from the CONKO 001 trial confirmed this observation [2]. Furthermore, ESPAC-1 showed that adjuvant chemotherapy is superior to postoperative chemoradiation [1]. However, the quality of the radiochemotherapeutic
A. Märten et al. / The American Journal of Surgery 194 (Suppl to October 2007) S138 –S142
regimen in the ESPAC-1 trial has been disputed. The EORTC trial, comparing chemoradiation with best supportive care, recently confirmed with a follow-up of 10 years the conclusion that routine use of adjuvant radiochemotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region [3,4]. Because the data from phase III RCTs regarding radiochemotherapy are not encouraging, the confirmed data for radiochemoimmunotherapy are urgently needed. The Virginia Mason study group in Seattle, WA, published promising data in a phase II study involving immunotherapy and chemoradiation in the adjuvant setting [5]. The reliability of the data has been intensively discussed, and source data verification has been performed by the National Cancer Institute). In the current setting with a reference adjuvant treatment from an RCT and promising data from a phase II trial, there is the ideal basis for a controlled trial comparing the 2 most current and successful regimens. Jaffee et al [24] investigated a different approach for radiochemoimmunotherapy. They treated patients with a gene-modified granulocyte/macrophage/colony–stimulating factor—secreting allogeneic pancreatic cancer cell vaccine in combination with radiochemotherapy. This approach showed safety in a phase I trial with 14 patients which indicated also a clinical benefit, especially in patients showing an immune response [24]. They focused in the immunomonitoring on the pancreatic tumor antigen mesothelin. Mesothelin is a transmembrane glycoprotein and derives from a larger protein, called mesothelin/megakaryocyte potentiating factor, overexpressed by most pancreatic tumors [25–27]. In 2005 a phase II trial with 60 patients completed enrollment; first reported data with a 2-year survival of 70% appears very encouraging [28]. In the accompanying immunomonitoring of this study, again mesothelin-specific lymphocytes were identified in subjects who demonstrated evidence of immune and clinical responses. It is clearly too early to draw any final conclusion from 2 phase II trials dealing with radiochemoimmunotherapy, but these data cannot be ignored. The only possible way to deal with them is to test them in a phase III RCT, such as the CapRI trial. In addition to the primary objective of determining overall survival, CapRI has a broad accompanying scientific component. So far, only trials including immunotherapy have attempted to shed light on the underlying mechanisms as well as define predictive markers far behind the classical ones as age, resection margins, and others. Translational research might help to answer the question why radiochemoimmunotherapy might be so effective when radiochemotherapy is, at best, as good as chemotherapy. The data from the Jaffee group, the in vitro and in vivo data investigating interferon-␣, and the observations made in the CapRI patients might help to answer this question. At present, in our opinion everything points toward a major impact of the immunotherapeutic aspect in this multimodality treatment. However, it must be emphasized that immunotherapy should be combined with chemotherapy or radiochemotherapy because a complex interacting network is needed to control pancreatic carcinoma. The results of the CapRI trial will definitely advance clinical and scientific knowledge on the adjuvant treatment of pancreatic carcinoma because it may confirm
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or demystify the remarkable results from the Virginia Mason study group. References [1] Neoptolemos J, Stocken D, Friess H, et al. The final results of the European Study Group for Pancreatic Cancer randomized controlled trial of adjuvant chemoradiotherapy and chemotherapy in patients with resectable pancreatic cancer. N Eng J Med 2004;350:1200 – 1210. [2] Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267–277. [3] 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 –774. [4] Smeenk H, van Eijck C, Tran K, et al. In IHPBA, Edinburgh, UK. [5] Picozzi VJ, Kozarek RA, Traverso LW. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2003;185:476 – 480. [6] Picozzi VJ, Traverso LW. The Virginia Mason approach to localized pancreatic cancer. Surg Oncol Clin North Am 2004;13:663– 674, ix. [7] Knaebel H, Märten A, Schmidt J, et al. Phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma—CapRI [ISRCTN62866759]. BMC Cancer 2005;5:. [8] Stocken DD, Buchler MW, Dervenis C, et al. Meta-analysis of randomized adjuvant therapy trials for pancreatic cancer. Br J Cancer 2005;92:1372–1381. [9] Holsti LR, Mattson K, Niiranen A, et al. Enhancement of radiation effects by alpha interferon in the treatment of small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1987;13:1161–1166. [10] Pazdur R. Fluorouracil and recombinant interferon alfa-2a in advanced gastrointestinal neoplasms. Br J Haematol 1991;79:56 –59. [11] Pazdur R, Ajani JA, Patt YZ, et al. Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol 1990;8:2027–2031. [12] Etienne MC, Bernard S, Fischel JL, et al. Dose reduction without loss of efficacy for 5-fluorouracil and cisplatin combined with folinic acid. In vitro study on human head and neck carcinoma cell lines. Br J Cancer 1991;63:372–377. [13] Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature 2000;407:784 –788. [14] Rovere P, Sabbadini MG, Vallinoto C, et al. Delayed clearance of apoptotic lymphoma cells allows cross-presentation of intracellular antigens by mature dendritic cells. J Leukoc Biol 1999;66:345–349. [15] Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, crosspriming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 2003;170:4905– 4913. [16] Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 2002;62:2353–2358. [17] Polak L, Turk JL. Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature 1974;249: 654 – 656. [18] Lake R, Robinson B. Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer 2005;5:397– 405. [19] Ma J, Patrut E, Schmidt J, et al. Synergistic effects of interferon-alpha in combination with chemoradiation on human pancreatic adenocarcinoma. World J Gastroenterol 2005;11:1521–1528. [20] Schmidt J, Patrut E, Ma J, et al. Immunomodulatory impact of interferon-alpha in combination with chemotherapy of pancreatic adenocarcinoma (CapRI). Cancer Immunol Immunother 2006;55: 1396 – 405. [21] Yoshida N, Abe H, Ohkuri T, et al. Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small
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cell lung carcinoma and their prognostic significance. Int J Oncol 2006;28:1089 –1098. [22] Romano F, Cesana G, Caprotti R, et al. Preoperative IL-2 immunotherapy enhances tumor infiltrating lymphocytes (TILs) in gastric cancer patients. Hepatogastroenterology 2006;53:634 – 638. [23] Zhu Y, Tibensky I, Krempien R, et al. Interferon alpha enhances anti-tumor effect of chemoradiotherapy in an orthotopic mouse model for pancreatic carcinoma. Gastroenterology; submitted. [24] Jaffee EM, Hruban RH, Biedrzycki B, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001;19:145–156.
[25] Hassan R, Bera T, Pastan I. Mesothelin: a new target for immunotherapy. Clin Cancer Res 2004;10:3937–3942. [26] Swierczynski SL, Maitra A, Abraham SC, et al. Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays. Hum Pathol 2004;35:357–366. [27] Argani P, Iacobuzio-Donahue C, Ryu B, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res 2001;7:3862– 3868. [28] Laheru D, Biedrzycki B, Abrams R, et al. (2005) in Pancreas Club, Chicago, IL.
Radiochemoimmunotherapy for pancreatic cancer Angela Märten, Ph.D.*, Markus W. Büchler, M.D., Jan Schmidt, M.D. Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
Abstract After they undergo surgical intervention with curative intention in specialized centers, the 5-year survival rate of patients with carcinoma of the exocrine pancreas is only 15%. The European Study Group For Pancreatic Cancer (ESPAC) –1 trial showed that an increased 5-year survival rate of 21% was achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy, and external-beam radiation. This article discusses the potential role of radiochemoimmunotherapy for adjuvant treatment; describes the ongoing phase III randomized controlled trial, Adjuvant ChemoRadioImmunotherapy of Pancreatic Carcinoma (CapRI); and compares the regimen from the Virginia Mason Clinic with the best arm of ESPAC-1. First data regarding the toxicity are shown. This article illustrates possible modes of action of radiochemoimmunotherapy and shows how translational research might help to shed some light on the underlying mechanisms as well as define predictive markers. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Immunotherapy; Interferon-␣; Multimodality treatment; Pancreatic carcinoma
The 5-year survival rate of patients with resected pancreatic adenocarcinoma is still discouraging, just approximately 10%. There are few randomized data on adjuvant therapy for pancreatic carcinoma. The European Study Group For Pancreatic Cancer (ESPAC) –1 trial assessed the role of adjuvant therapy in a randomized study; 548 patients were enrolled in Europe in this first large randomized trial. There was evidence that adjuvant chemotherapy brought survival benefits. The 5-year survival rate was 21% among patients who received chemotherapy [1]. The data for radiochemotherapy were less promising. However, it must be stated clearly that radiotherapy was not standardized in this trial. The preliminary data from the CONKO 001 trial, which had disease-free survival as the primary objective, confirmed that chemotherapy is superior to best supportive care [2]. The European Organization for Research and Treatment of Cancer (EORTC) trial investigating chemoradiation recently confirmed their conclusion from 1999 that routine use of adjuvant radiochemotherapy is no longer warranted as standard treatment in cancer of the head of the pancreas or the periampullary region; follow-up now has lasted 10 years [3,4]. At present, a clear benefit of chemotherapy, with a 5-year survival rate of approximately 20% in the adjuvant setting, has been proven. The data for radiochemotherapy, confer* Corresponding author. Tel.: ⫹011-49-6221-5639890; fax: ⫹011-496221-568240. E-mail address: [email protected]
ring a survival rate between 10% and 18%, are not convincing. Taking this into account, the overwhelming data for radiochemoimmunotherapy from phase II trials must be verified. The Virginia Mason Experience In 1995, a phase II trial was initiated by the Virginia Mason Clinic, Seattle, WA, combining pancreaticoduodenectomy and adjuvant therapy with 5-fluorouracil (5-FU), cisplatin, interferon-␣, and radiation therapy. Picozzi et al [5] reported treatment and results in a series of 43 patients with high-risk resected pancreatic adenocarcinoma (84% node positive, 19% margin positive). After a median follow-up period of 32 months, the 2-year survival rate was 64% and the 5-year survival rate, 55%. The overall recurrence rate was 12%, of which 80% occurred within 2 years after surgery [6]. However, the investigators reported moderate to severe toxicities during chemoradiation (mainly common toxicity criteria [CTC] grade 3) in 70% of the patients. They were mainly of gastrointestinal origin (anorexia, nausea and vomiting, mucositis, diarrhea, or hypovolemia); therefore, hospitalization was required in 42% of the patients. However, no treatment-related fatalities were reported, and all patients returned to full functional status. In 2005, Picozzi et al presented the American Pancreatic Association (APA) data for now roughly 100 patients and stated a stable 5-year survival rate of 50%.
0002-9610/00/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.05.012
A. Märten et al. / The American Journal of Surgery 194 (Suppl to October 2007) S138 –S142
The CapRI Experience Because the Virginia Mason group reported such encouraging results in improving survival rates, there has been considerable interest in gaining increased experience with this therapy combination in an effort to confirm the results, evaluate the toxicity profile, and gain new insights into the mechanism of success underlying this regimen. Therefore, in August 2004, a phase III trial to compare the Virginia Mason scheme with the best arm of the ESPAC-1 trial was started. The Adjuvant ChemoRadioImmunotherapy of Pancreatic Carcinoma (CapRI) study is an open, controlled, prospective, randomized multicenter trial to evaluate the postoperative overall survival of patients with pancreatic adenocarcinoma receiving radiochemotherapy, including interferon-␣ 2b administration, compared with adjuvant chemotherapy alone. The treatment is offered to a heterogeneous group of people— of both sexes, with a wide age range, and who have heterogeneous characteristics and comorbidities— under clinical conditions. Four centers in Germany and 1 center in Italy are participating in CapRI. The study was designed and conducted by the Department of Surgery at the University of Heidelberg, Germany [7]. CapRI focuses on patients ⬎18 years old treated with pancreatic head resection for pancreatic adenocarcinoma starting in August 2004. A total of 110 patients must be enrolled in the study to achieve a difference in hazard on level ␣ ⫽ .05 and with a power of 80%. Men and women ⬎18 years old with biopsy-proven and completely resected (R0 or R1) pancreatic adenocarcinoma are considered for participation in the study. The primary objective is to compare the overall survival rate at 2 years after surgery between 2 different methods of adjuvant treatment: (1) therapy with 5-FU, cisplatin, and interferon-␣ 2b combined with radiation and (2) standard treatment from the ESPAC-1 trial with 5-FU plus folinic acid. Secondary objectives are to determine the role and the mechanism of interferon-␣ 2b in patients’ chemoradiation regimen, toxicity of the regimen, disease-free interval, and quality of life. Different factors are tested in terms of their potential role as predictive markers. Treatment schemes are nearly identical to those described in the ESPAC-1 trial or in the Virginia Mason scheme. For practical reasons, the dosage of interferon-␣ was modified from every other day to 3 times per week (Fig. 1). As of October 2006, 86 patients have been enrolled in the study. The observed toxicity profile has been quite different from the published data from the Virginia Mason experience. Patients enrolled in arm A of the CapRI trial have CTC grade 3 to 4 toxicities (85% were grade 3), primarily leukopenia (50%), followed by electrolyte disturbance (14%), stomatitis, and vomiting (10%); 5% of patients had diarrhea, fatigue, and hypovolemia. Electrolyte disturbance (hypocalcemia) was easily prevented by oral supplementation. In arm B (the Mayo scheme), side effects have been less pronounced: 16% of patients had diarrhea, 8% had leukopenia, and 8% had hypovolemia CTC grade 3 to 4 (60% had CTC grade 3 hypovolemia). Mechanism of Radiochemoimmunotherapy Radiosensitizing properties of 5-FU and cisplatin are well known. Because ESPAC-1 and the EORTC trial were
S139
not able to show any superiority of radiochemotherapy compared with chemotherapy [8], it was hypothesized that the addition of interferon-␣ was the crucial step in the multimodality therapy. The incorporation of interferon-␣ 2b into a combined modality treatment program seems to offer a number of theoretical advantages. These include (1) the radiosensitization effects of interferon-␣ 2b and 5-FU, perhaps synergistically [9]; (2) enhanced 5-FU– based bioavailability; (3) a synergistic inhibition of pyrimidine metabolism with 5-FU; and (4) an independent immunomodulatory effect of interferon-␣ 2b [10]. Interferon-␣ 2b and 5-FU have been used advantageously together in several cancer settings but not as part of a combined modality program [11]. Cisplatin also has a radiosensitizing effect and shares similar properties of cytotoxic synergy with interferon-␣ 2b and 5-FU in both experimental and clinical cancer settings (Fig. 2) [12]. Furthermore, there is growing evidence that the combination of chemotherapy with immunotherapy acts synergistically and not antagonistically. Chemotherapy delivers by tumor destruction a broad range of tumor antigens to the immune system [13–15]; the immunosuppressive features of tumors are decreased because of tumor debulking; and lymphopenia abolishes regulatory T-cells and clears the space for tumor-reactive cells [16,17]. Immunotherapy could boost spontaneous responses to endogenous antigens cross-presented from tumor cells destroyed by chemotherapy without need of specific peptides, vaccinations, or other laborious strategies. The timing seems to be crucial; chemotherapy in parallel to immunotherapy or closely followed by immunotherapy seems to be most effective [18]. In a previous study, it was demonstrated in vitro that interferon-␣ has direct inhibitory properties and that it decreases the enhanced proliferation rate and vascular endothelial growth factor secretion that results even after a single treatment with cisplatin [19]. Studies focusing on the immunomodulatory effect of interferon-␣ showed an activation of natural killer (NK) cells and their ability to lyse tumor cells as well by Fas-induced apoptosis as by perforin release. Pretreatment of tumor cells with 5-FU in combination with other drugs showed a significant increase in the susceptibility of tumor cells against NK cells; therefore, the importance of synergistic effects between all single agents in multimodality treatment was again proven. Interestingly, treatment of tumor cells with interferon-␣ induced a switch to the immunoproteasome and for this reason enhanced their vulnerability to T-cells [20]. Orthotopic animal studies have clearly shown that addition of interferon-␣ to chemotherapy or radiotherapy significantly improves patient outcome. Patients undergoing treatment schemes, including interferon-␣, showed an average of 70% fewer metastases than those receiving monochemotherapy or radiotherapy. The tumors of animals treated with chemotherapy and radiotherapy plus interferon-␣ were infiltrated with immune cells. It is known from human analysis that lymphocyte infiltration results in a better prognosis [21,22]. Interestingly, it could be shown that these cells were tumor specific and that the antitumor response could be transferred into untreated animals by injection of tumor-infiltrating lymphocytes from a treated donor mouse. In elegant intravital microscopy experiments, it was shown that the vessel density in tumors decreases in chemoimmunotreated
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Fig. 1. Treatment scheme of the CapRI trial. Study arm A: (1) external beam radiation at 50.4 Gy in 28 fractions on days 1 to 38; (2) administration of 5-FU, 200 mg/m2/d, by continuous intravenous (IV) infusion on days 1 to 38; IV administration of cisplatin, 30 mg/m2, for 60 minutes on days 1, 8, 15, 22, 29, and 36 (6 doses); (4) subcutaneous administration of interferon-␣ 2b, 3,000,000 U 3 times/wk, on days 1 to 38 (17 total doses); (5) continuous administration of 5-FU, 200/mg/m2/d, on days 64 to 101 and days 120 to 161. Study arm B: Folinic acid (D-L form), 20 mg/m2 IV bolus injection, followed by 5-FU IV bolus injection, 425 mg/m2/d, given on 5 consecutive days every 28 days for 6 cycles, ie, for 24 weeks.
Fig. 2. Mechanism of interferon-␣ alone and in combination with chemotherapy and radiotherapy. 5-FU, cisplatin, and interferon-␣ are radiosensitizers [1]. Interferon-␣ is also a chemosensitizer [1]. Interferon-␣ enhances NK cell–mediated cytotoxicity and, to a lesser extent, CD8 cell proliferation. Interferon-␣ acts antiangiogenically and enhances leukocyte– endothelium interactions [3]. Treatment with interferon-␣ induces the switch to the immunoproteasome, resulting in increased immunogenicity. Cisplatin induces rapid cell regrowth, and this could be prevented by interferon-␣ [5]. Chemotherapy as well as radiotherapy induces NF-B, known to promote growth of pancreatic carcinoma. Interferon-␣ inhibits NF-B upregulation or even downregulates NF-B [6]. 5-FU makes pancreatic tumor cells more susceptible to interferon-␣–triggered NK cell attacks [7]. Interferon-␣ induces upregulation of Fas, thus resulting in increased NK cell cytotoxicity [8].
animals. Furthermore, more leukocytes roll and stick to the endothelium, which is the first step before infiltration into the tumor. Chemotherapy alone decreased the numbers of attaching leukocytes [23]. This is in accordance with the observations made in parallel to the CapRI study. One day after interferon-␣ injection, patients in the multimodality treatment arm showed a significant increase in spontaneous NK cell– mediated cytotoxicity; however, this effect faded after repeated injections. Five days after the first interferon-␣ injection, interleukin-12 and tumor-necrosis factor (TNF)–␣ serum levels peaked. A significant increase of monocytes, peripheral dendritic cells, CD40⫹ cells, central and effector memory T-cells, and CD8 cells was observed; however, CD4 cells decreased during therapy. Furthermore, immune cells releasing Granzyme B after stimulation with the tumor
antigens CA 19.9 and MUC-1 protein increased during therapy. All of these effects were observed only after radiochemoimmunotherapy, and none of them were noted after chemotherapy alone [20]. Discussion Adjuvant therapy in potentially curatively resected adenocarcinoma of the pancreas has become standard treatment in recent years. As the first, large multicenter randomized controlled trial (RCT), the ESPAC-1 trial clearly favored adjuvant chemotherapy over best supportive care [1]. Preliminary data from the CONKO 001 trial confirmed this observation [2]. Furthermore, ESPAC-1 showed that adjuvant chemotherapy is superior to postoperative chemoradiation [1]. However, the quality of the radiochemotherapeutic
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regimen in the ESPAC-1 trial has been disputed. The EORTC trial, comparing chemoradiation with best supportive care, recently confirmed with a follow-up of 10 years the conclusion that routine use of adjuvant radiochemotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region [3,4]. Because the data from phase III RCTs regarding radiochemotherapy are not encouraging, the confirmed data for radiochemoimmunotherapy are urgently needed. The Virginia Mason study group in Seattle, WA, published promising data in a phase II study involving immunotherapy and chemoradiation in the adjuvant setting [5]. The reliability of the data has been intensively discussed, and source data verification has been performed by the National Cancer Institute). In the current setting with a reference adjuvant treatment from an RCT and promising data from a phase II trial, there is the ideal basis for a controlled trial comparing the 2 most current and successful regimens. Jaffee et al [24] investigated a different approach for radiochemoimmunotherapy. They treated patients with a gene-modified granulocyte/macrophage/colony–stimulating factor—secreting allogeneic pancreatic cancer cell vaccine in combination with radiochemotherapy. This approach showed safety in a phase I trial with 14 patients which indicated also a clinical benefit, especially in patients showing an immune response [24]. They focused in the immunomonitoring on the pancreatic tumor antigen mesothelin. Mesothelin is a transmembrane glycoprotein and derives from a larger protein, called mesothelin/megakaryocyte potentiating factor, overexpressed by most pancreatic tumors [25–27]. In 2005 a phase II trial with 60 patients completed enrollment; first reported data with a 2-year survival of 70% appears very encouraging [28]. In the accompanying immunomonitoring of this study, again mesothelin-specific lymphocytes were identified in subjects who demonstrated evidence of immune and clinical responses. It is clearly too early to draw any final conclusion from 2 phase II trials dealing with radiochemoimmunotherapy, but these data cannot be ignored. The only possible way to deal with them is to test them in a phase III RCT, such as the CapRI trial. In addition to the primary objective of determining overall survival, CapRI has a broad accompanying scientific component. So far, only trials including immunotherapy have attempted to shed light on the underlying mechanisms as well as define predictive markers far behind the classical ones as age, resection margins, and others. Translational research might help to answer the question why radiochemoimmunotherapy might be so effective when radiochemotherapy is, at best, as good as chemotherapy. The data from the Jaffee group, the in vitro and in vivo data investigating interferon-␣, and the observations made in the CapRI patients might help to answer this question. At present, in our opinion everything points toward a major impact of the immunotherapeutic aspect in this multimodality treatment. However, it must be emphasized that immunotherapy should be combined with chemotherapy or radiochemotherapy because a complex interacting network is needed to control pancreatic carcinoma. The results of the CapRI trial will definitely advance clinical and scientific knowledge on the adjuvant treatment of pancreatic carcinoma because it may confirm
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