Clin J Gastroenterol (2010) 3:186–190 DOI 10.1007/s12328-010-0157-x
Three cases of locally advanced pancreatic cancer successfully treated with chemoradiation and chemotherapy Masashi Taguchi • Yoshikuni Nagashio • Yasuyuki Kihara • Masaaki Hiura • Shintaro Abe Mitsuyoshi Yamamoto • Masaru Harada
Received: 7 January 2010 / Accepted: 18 May 2010 / Published online: 5 June 2010 Ó Springer 2010
Abstract We report three cases with unresectable locally advanced pancreatic cancer (PC) treated with a combination of chemoradiotherapy (CRT) and systemic chemotherapy, using gemcitabine (GEM) and/or S-1. All three cases were diagnosed as having locally advanced unresectable PC without distant metastatic lesions based on computed tomography, endoscopic retrograde pancreatography and/or blushing cytology. In Cases 1 and 2, we applied a so-called sandwich therapy, which consisted of induction chemotherapy before CRT and maintenance chemotherapy after CRT. The induction and maintenance chemotherapy in Cases 1 and 2 used a combination of GEM and S-1, whereas maintenance therapy with GEM or S-1 was applied in Case 3. S-1-based CRT was performed in Cases 1 and 2, and GEM-based CRT in Case 3. Survivals were 27 and 65 months, respectively, in two cases, and the disease remained stable in the other case 30 months after diagnosis. We show three cases with unresectable locally advanced PC who achieved long-term survival (27– 65 months) after treatment with a combination of CRT and systemic chemotherapy, using GEM and/or S-1. Our findings indicate that sandwich therapy might be particularly effective for locally advanced PC. Keywords Advanced pancreatic cancer (PC) Chemoradiotherapy (CRT) Chemotherapy Gemcitabine (GEM) S-1 Survival
M. Taguchi (&) Y. Nagashio Y. Kihara M. Hiura S. Abe M. Yamamoto M. Harada Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan e-mail: [email protected]
Introduction Pancreatic cancer (PC) is the fifth leading cause of death by cancer in Japan . PC remains a lethal disease; its annual incidence is approximately equal to its annual fatality rate . Surgical resection offers the only chance of a cure, but even after curative resection there is a high probability of systemic and/or local relapse. Despite surgery with curative intent, actuarial 5-year survival rates for these patients remain at about 20% . Unfortunately, at the time of diagnosis, 85% of patients with PC have unresectable locally advanced or metastatic tumors. For these patients, the overall survival (OS) ranges between 3 and 6 months . Gemcitabine (GEM) is a nucleoside analog with broad antitumor activity. When GEM was compared to 5-fluorouracil (5-FU) in a randomized phase III trial, there was a modest benefit in OS (5.6 vs. 4.4 months) as well as a clinical benefit (24 to 5%) in patients treated with GEM . S-1 is an oral fluoropyrimidine derivative that is a compound of tegafur with two modulators of 5-FU, gimeracil and oteracil potassium . Phase II studies of S-1 for advanced PC showed higher response rates and a longer time to progression than GEM . Combination therapy with GEM and S-1 was well tolerated and showed good antitumor activity in patients with PC . These two drugs are potent radiation sensitizers against cancer cells [7, 8]. The randomized trial suggested a survival benefit for patients who had received chemoradiotherapy (CRT) . However, no standard therapeutic strategy for unresectable locally advanced PC has been fully established. We report here three cases with unresectable locally advanced PC who achieved long-term survival after treatment with a combination of CRT and chemotherapy, using GEM and/or S-1.
Clin J Gastroenterol (2010) 3:186–190
Case report Case 1 A 59-year-old Japanese woman was referred to our hospital because of episodic back and epigastric pains accompanied by an elevated serum amylase level. On clinical examination at first admission there was no palpable mass in the abdomen and no palpable lymph nodes. Laboratory tests showed elevated pancreatic enzyme levels and tumor markers (Table 1). Contrast-enhanced computed tomography (CT) demonstrated a low-density mass in the body and tail of the pancreas, measuring 6.8 9 3.1 cm, with tumor encasement of the celiac trunk without metastasis (Fig. 1a). Endoscopic retrograde pancreatography (ERP) revealed an obstruction of the main pancreatic duct (MPD) in the pancreatic body (Fig. 1b). Blushing cytology from the MPD showed class V adenocarcinoma. Therefore, she was diagnosed as having locally advanced PC without a distant metastatic lesion. We applied 60 mg/m2 of S-1 daily for 14 consecutive days followed by a one-week break. We administered 1000 mg/m2 GEM in a 30-min intravenous infusion on days 8 and 15 of each cycle. The cycle was repeated every 21 days . Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. A partial response was obtained for 8 months (Fig. 1c). However, 6 months after the initiation Table 1 Laboratory tests at first admission
of first-line chemotherapy, tumor marker levels began to elevate (from 2,500 to 2,800 U/ml). We then gave CRT using S-1 with concurrent radiotherapy (50.4 Gy). We administered 40 mg/m2 of S-1 orally after breakfast and dinner on the day of irradiation (Monday to Friday). A total dose of 50.4 Gy was delivered in 28 fractions over 5.5 weeks. Tumor marker levels decreased remarkably after the CRT (Fig. 2). Combination chemotherapy with GEM and S-1 was then resumed. However, tumor marker levels eventually began to increase again, and her Eastern Cooperative Oncology Group (ECOG) performance status gradually became worse. She survived for 27 months after the diagnosis of locally advanced PC. Case 2 A 58-year-old Japanese man was referred to our hospital because of a pancreatic tumor and elevated tumor marker levels. On clinical examination at first admission there was no palpable mass in the abdomen and no palpable lymph nodes. Laboratory tests showed glucose intolerance and elevated tumor markers (Table 1). Contrast-enhanced CT demonstrated a low-density mass in the tail of the pancreas, measuring 3.1 9 2.7 cm, with direct invasion of the tumor into the stomach and retroperitoneal cavity. ERP revealed an obstruction of the MPD in the body of the pancreas. Blushing cytology from the MPD showed class V adenocarcinoma. Therefore, he was diagnosed with locally advanced PC without distant metastatic lesion. Combination chemotherapy with GEM and S-1, using the same protocol described above, was started . His disease stabilized in 7 months. Then we applied CRT for 1 month (from 8 to 9 months) using the same protocol described above. Thereafter, tumor marker levels decreased remarkably (Fig. 2). After the CRT, combination chemotherapy with GEM and S-1 was resumed. The patient’s condition remains good and his disease continues to be stable 30 months after the diagnosis of locally advanced PC.
Hb (g/dl) Plt (mm-3)
11.1 19.9 9 104
13.5 20.2 9 104
12.4 18 9 104
An 81-year-old Japanese woman was referred to our hospital after the detection of a dilatation of the MPD and elevated tumor marker levels. On clinical examination at first admission there was no palpable mass in the abdomen and no palpable lymph nodes. Laboratory tests showed glucose intolerance and elevation of tumor markers (Table 1). Contrast-enhanced CT demonstrated a low-density mass in the head of the pancreas that measured 2.5 9 2.6 cm with an encasement of the superior mesenteric artery. ERP revealed a stenosis of the MPD in the pancreatic head and a
Blood chemistry Alb (g/dl) T-bil (mg/dl)
FPG (mg/dl) HbA1c (%)
Clin J Gastroenterol (2010) 3:186–190
Fig. 1 a Abdominal CT scans of Case 1 at first admission revealed a low-density mass in the body and tail of the pancreas that measured 6.8 9 3.1 cm (arrowheads) with tumor encasement of the celiac trunk. b ERP of Case 1 revealed an obstruction of the main pancreatic duct (MPD) in the body. Blushing cytology from MPD showed class V adenocarcinoma. c Abdominal CT scans of Case 1 after CRT. The size of the low-density mass in the body and tail of the pancreas decreased
dilatation of the MPD in the pancreatic tail. The result of the blushing cytology from the MPD was class III. Therefore, she was diagnosed with locally advanced PC without a distant metastatic lesion. We immediately performed CRT, using GEM with concurrent radiotherapy (50.4 Gy). We gave 50 mg of GEM intravenously twice a week (on Monday and Wednesday). A total dose of 61.2 Gy was delivered in 34 fractions over six weeks. Tumor marker levels decreased remarkably. We next administered systemic chemotherapy, using GEM. A partial response was obtained for 45 months. However, at that point tumor marker levels began to increase again. We changed the systemic chemotherapy from GEM to S-1 monotherapy, and her disease stabilized for another 8 months. Thereafter her tumor marker levels again started to rise, and her ECOG performance status gradually worsened. She survived for 65 months after the diagnosis of advanced PC (Fig. 2). Autopsy specimens revealed a poorly differentiated ductal adenocarcinoma of the pancreatic head (6 9 6 cm) with duodenum, liver, lung, lymph node, and lumbar vertebrae metastases.
Discussion We report here three patients with unresectable locally advanced PC who achieved long-term survival after
treatment with a combination therapy consisting of CRT and chemotherapy, using GEM and/or S-1. We suggest that CRT is the key therapy in locally advanced PC. Recently, two randomized trials have been completed that compared chemotherapy alone and CRT, using GEM [10, 11]. Patients were treated with GEM alone, or with radiation (total dose 60 Gy) and concurrent 5-FU and cisplatin followed by GEM. The median survival in the group receiving GEM alone was 14.3 months, and that in the CRT group was 9.1 months . On the other hand, ECOG-4201 was designed to compare GEM with radiation (total 50.4 Gy) followed by weekly GEM versus similar doses of GEM alone. A median survival benefit was seen in the CRT arm compared to the GEM-alone arm (11.0 vs. 9.2 months) . Severe adverse events of CRT arms were more frequent compared with the GEM arm [10, 11]. We reluctantly decreased the dose of GEM for neutropenia during systemic chemotherapy in all three cases, but there were no adverse events during CRT in all three cases. Because of these results, the efficacy of CRT in locally advanced PC remains controversial. However, an important concern when administering CRT as the first-line treatment in patients with locally advanced PC is that some of them may have occult metastatic disease at diagnosis, and such patients will not clearly benefit from such a locoregional treatment.
Clin J Gastroenterol (2010) 3:186–190
Fig. 2 Clinical courses and tumor marker levels for Cases 1, 2, and 3. CRT, Chemoradiotherapy, using S-1 in Cases 1 and 2 and GEM in Case 3. GS, Combination therapy of GEM and S-1. GEM, Monotherapy of GEM. S-1, Monotherapy of S-1
In Cases 1 and 2 we used a so-called sandwich therapy, consisting of combined induction chemotherapy before CRT together with maintenance chemotherapy after CRT. This therapeutic strategy is potentially effective for a select subgroup of patients without early metastasis who are eligible to receive CRT. This approach of introducing systemic treatment (chemotherapy) prior to locoregional treatment (surgery or radiotherapy) has been investigated in other gastrointestinal cancers, such as esophageal, gastric, and rectal cancers, with varying degrees of success [12–15]. Several studies evaluated the benefit not only of neoadjuvant chemotherapy before surgery in resectable PC, but also of induction chemotherapy before concurrent CRT in locally advanced PC [16–18]. In our Cases 1 and 2, administration of induction chemotherapy provided 6– 8 months to confirm the absence of detectable metastases. Tumor marker levels fell even further when CRT was applied after the induction chemotherapy. Moreover, we confirmed that our three cases had no distant metastasis with CT and no tumor marker rises during CRT. In locally advanced PC, it remains controversial as to whether
locoregional control (like CRT) is superior to systemic control with GEM and/or S-1. We believe that CRT may be an important therapeutic option, and that induction chemotherapy should be combined with CRT for greatest effect. We believe that locally advanced PC requires the use of multidisciplinary therapies like our sandwich therapy. There are other theoretical advantages to our sandwich therapy other than the eradication of micrometastatic disease and predicted biologic behavior of tumors in response to chemotherapy. In Cases 1 and 2, we were able to successfully perform maintenance chemotherapy using the same regimen as with the induction chemotherapy. The response to induction chemotherapy may guide the choice of chemotherapy regimen used either with radiotherapy and/or subsequent chemotherapy. We chose combination therapy with GEM and S-1 as the systemic chemotherapy. Although each drug has been reported to have many clinical benefits in advanced PC [4, 5], there are few systematic studies of combination chemotherapy with GEM and S-1 [6, 19]. In a phase II study of combination chemotherapy with GEM and S-1, the response rate (32–48%) was much higher than that observed for GEM combined with 5-FU (19%), or for GEM combined with capecitabine (19%) or UFT (16%), which is another oral prodrug of 5-FU [6, 19–22]. Although a reduction in the administration of GEM was required in two-thirds of the patients due to myelosuppression, the median survival was favorable (8.4–12.5 months) [6, 19]. In Case 3, we did not perform this combination chemotherapy as the induction chemotherapy; we immediately performed CRT because of her advanced age. The multicenter prospective randomized control study comparing GEM vs. S-1 vs. GEM and S-1 in advanced PC is now ongoing. The results of this study may clarify the efficacy of combination chemotherapy with GEM and S-1 for locally advanced PC. We chose GEM in Case 3, and S-1 in Cases 1 and 2, as the radiosensitizer. There has been only one small randomized study that has evaluated the effect of radiosensitizers in locally advanced PC . Thirty-four patients with locally advanced PC were randomized to receive GEM-based (600 mg/m2 weekly every 14 days, total 50.4–61.2 Gy) or 5-FU-based (500 mg/m2 daily for 3 days, with equivalent dose of radiation) CRT. The objective response rates to GEM-based and 5-FU-based CRT were 50 and 13%, respectively. Moreover, median survivals with GEM-based and 5-FU-based CRT were 14.5 and 6.7 months, respectively. These results must be interpreted with caution because of the limited accrual, and the poor results in the 5-FU arm. GEM is probably only modestly better than 5-FU when used with radiotherapy . Gastrointestinal and hematologic toxicities
(30–50% of patients of grade 3 or 4) were reported using GEM-based CRT . On the other hand, there are no systematic studies evaluating S-1-based CRT in locally advanced PC. In a phase II study of S-1-based CRT, the response rate and the median survival were 24% and 12.9 months, respectively . The most common grade 3 hematologic toxicity was thrombocytopenia (4%). There was no grade 4 toxicity. Therefore, we chose S-1-based CRT in Cases 1 and 2 because of the good median survival and low toxicity associated with it. Our cases demonstrated that S-1-based CRT as well as GEM-based CRT for advanced PC show long-term progression and are well tolerated with no severe toxicity. In conclusion, we present three cases with unresectable locally advanced PC who achieved long-term survival (27– 65 months) by treatment with a combination therapy consisting of CRT and systemic chemotherapy, using GEM and/or S-1. Additional prospective randomized control studies are required to confirm these promising results.
Clin J Gastroenterol (2010) 3:186–190
References 16. 1. Lowenfels AB, Maisonneuve P. Epidemiology and prevention of pancreatic cancer. Jpn J Clin Oncol. 2004;34:238–44. 2. Lockhart AC, Rothenberg ML, Berlin JD. Treatment for pancreatic cancer: current therapy and continued progress. Gastroenterology. 2005;128:1642–54. 3. Cubiella J, Castells A, Fondevila C, Sans M, Sabater L, Navarro S, et al. Prognostic factors in nonresectable pancreatic adenocarcinoma: a rationale to design therapeutic trials. Am J Gastroenterol. 1999;94:1271–8. 4. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, 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. 5. Ueno H, Okusaka T, Ikeda M, Takezako Y. Morizane C An early phase II study of S-1 in patients with metastatic pancreatic cancer. Oncology. 2005;68:171–8. 6. Nakamura K, Yamaguchi T, Ishihara T, Sudo K, Kato H, Saisho H. Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer. Br J Cancer. 2006;94:1575–9. 7. Crane CH, Varadhachary G, Settle SH, Fleming JB, Evans DB, Wolff RA. The integration of chemoradiation in the care of patient with localized pancreatic cancer. Cancer Radiother. 2009;13:123–43. 8. Harada K, Kawaguchi S, Supriatno, Kawashima Y, Yoshida H, Sato M. S-1, an oral fluoropyrimidine anti-cancer agent, enhanced radiosensitivity in a human oral cancer cell line in vivo and in vitro: involvement possibility of inhibition of survival signal, Akt/PKB. Cancer Lett. 2005;226:161–8. 9. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: comparison of combinedmodality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst. 1988;80:751–5. 10. Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouche O, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU, intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine
alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study. Ann Oncol. 2008;19:1592–9. Loehrer PPM, Cardenes H, Wagner L, Brell J, Ramanathan R, Crane CH, Alberts SR, Benson AB. Eastern Cooperative Oncology Group: A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized unresectable pancreatic cancer. J Clin Oncol. 2008;26:4506. Ajani JA, Komaki R, Putnam JB, Walsh G, Nesbitt J, Pisters PW, et al. A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction. Cancer. 2001;92:279–86. Ajani JA, Walsh G, Komaki R, Morris J, Swisher SG, Putnam JB Jr, et al. Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction. Cancer. 2004;100:2347–54. Calvo FA, Serrano FJ, Diaz-Gonzalez JA, Gomez-Espi M, Lozano E, Garcia R, et al. Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol. 2006;17:1103–10. Swisher SG, Ajani JA, Komaki R, Nesbitt JC, Correa AM, Cox JD, et al. Long-term outcome of phase II trial evaluating chemotherapy, chemoradiotherapy, and surgery for locoregionally advanced esophageal cancer. Int J Radiat Oncol Biol Phys. 2003;57:120–7. Huguet F, Andre T, Hammel P, Artru P, Balosso J, Selle F, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol. 2007;25:326–31. Krishnan S, Rana V, Janjan NA, Varadhachary GR, Abbruzzese JL, Das P, et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer. 2007;110:47–55. Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007;14:2088–96. Oh DY, Y Cha, IS Choi, SY Yoon, IK Choi, JH Kim, et al. A multicenter phase II study of gemcitabine and S-1 combination chemotherapy in patients with unresectable pancreatic cancer. Cancer Chemother Pharmacol, 2009;65:527–36. Feliu J, Lopez Alvarez MP, Jaraiz MA, Constenla M, Vicent JM, Belon J, et al. Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. The ONCOPAZ Cooperative Group. Cancer. 2000;89:1706–13. Hess V, Salzberg M, Borner M, Morant R, Roth AD, Ludwig C, et al. Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial. J Clin Oncol. 2003;21:66–8. Hidalgo M, Castellano D, Paz-Ares L, Gravalos C, Diaz-Puente M, Hitt R, et al. Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol. 1999;17:585–92. Li CP, Chao Y, Chi KH, Chan WK, Teng HC, Lee RC, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys. 2003;57:98–104. Kim HM, Bang S, Park JY, Seong J, Song SY, Chung JB, et al. Phase II trial of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2009;63:535–41.