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Role of Adjuvant Chemoradiotherapy for Ampulla of Vater Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 2, pp. 436–441, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.11.067
CLINICAL INVESTIGATION
Ampulla of Vater
ROLE OF ADJUVANT CHEMORADIOTHERAPY FOR AMPULLA OF VATER CANCER KYUBO KIM, M.D.,* EUI KYU CHIE, M.D.,* JIN-YOUNG JANG, M.D.,y SUN WHE KIM, M.D.,y DO-YOUN OH, M.D.,z SEOCK-AH IM, M.D.,z TAE-YOU KIM, M.D.,z YUNG-JUE BANG, M.D.,z x AND SUNG W. HA, M.D.* Departments of *Radiation Oncology, y Surgery, and z Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; and x Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea Purpose: To evaluate the role of adjuvant chemoradiotherapy for ampulla of Vater cancer. Methods and Materials: Between January 1991 and December 2002, 118 patients with ampulla of Vater cancer underwent en bloc resection. Forty-one patients received adjuvant chemoradiotherapy [RT(+) group], and 77 did not [RT(-) group]. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes, for a total dose of up to 40 Gy delivered in 2-Gy fractions, with a planned 2-week rest period halfway through the treatment period. Intravenous 5-fluorouracil (500 mg/m2/day) was given on Days 1 to 3 of each split course. The median follow-up was 65 months. Results: The 5-year overall survival rate in the RT(-) and RT(+) groups was 66.9% and 52.8%, respectively (p = 0.2225). The 5-year locoregional relapse–free survival rate in the RT(-) and RT(+) groups was 79.9% and 80.2%, respectively (p = 0.9582). When age, type of operation, T stage, N stage, histologic differentiation, and the use of adjuvant chemoradiotherapy were incorporated into the Cox proportional hazard model, there was an improvement in the locoregional relapse–free survival rate (p = 0.0050) and a trend toward a longer overall survival (p = 0.0762) associated with the use of adjuvant chemoradiotherapy. Improved overall survival (p = 0.0235) and locoregional relapse–free survival (p = 0.0095) were also evident in patients with nodal metastasis. In contrast, enhanced locoregional control (p = 0.0319) did not result in longer survival in patients with locally advanced disease (p = 0.4544). Conclusions: Adjuvant chemoradiotherapy may enhance locoregional control and overall survival in patients with ampulla of Vater cancer after curative resection, especially in those with nodal involvement. Ó 2009 Elsevier Inc. Ampulla of Vater cancer, Adjuvant chemoradiotherapy.
with the cancer (9–13). A further problem with these studies is that the findings have been inconclusive. There is thus a need to further examine the role of adjuvant chemoradiotherapy in ampulla of Vater cancer. In this study, we retrospectively examined the findings in a relatively large series (n = 118) of patients with ampulla of Vater cancer treated with curative intent at a single center and also examined the role of adjuvant chemoradiotherapy, with the hope that more conclusive findings would be yielded regarding the role of this treatment in this cancer.
INTRODUCTION The prognosis for patients with ampulla of Vater cancer is better than that for patients with other periampullary malignancies, such as pancreatic and/or bile duct cancers (1, 2). This is because these tumors generally produce symptoms earlier than tumors in other locations, and thus these tumors are diagnosed at an earlier stage. Nevertheless, the 5-year overall survival rate in patients who undergo curative resection, which is the current standard treatment for this cancer, is rather unsatisfactory, ranging from 30% to 60% (3–7). To further improve the treatment outcome, many clinicians now treat patients with this cancer with adjuvant chemoradiotherapy in a manner similar to that used in patients with pancreatic cancer (8). However, because of the rarity of the disease and the difficulties in differentiating ampulla of Vater cancer from other periampullary cancers, there have been only a few studies evaluating the role of adjuvant chemoradiotherapy in patients
METHODS AND MATERIALS Between January 1991 and December 2002, 131 patients with ampullary adenocarcinoma underwent en bloc resection. Of these 131 patients, 13 were excluded from the study: 6 because they had undergone adjuvant radiotherapy at an outside institution and were lost to follow-up, 2 because they died of postoperative Presented at the 14th European Cancer Conference, September 23–27, 2007, Barcelona, Spain. Conflict of interest: none. Received Sept 1, 2008, and in revised form Oct 18, 2008. Accepted for publication Nov 6, 2008.
Reprint requests to: Eui Kyu Chie, M.D., Department of Radiation Oncology, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 110-744, Republic of Korea. Tel: (+82) 2-2072-3705; Fax: (+82) 2-765-3317; E-mail: [email protected] 436
Chemoradiotherapy for ampulla of Vater cancer d K. KIM et al.
complications, 2 because they did not complete adjuvant chemoradiotherapy, 2 because they had synchronous metastases at presentation, and 1 because of a synchronous primary malignancy at presentation. This left 118 patients, who formed the study population for this retrospective analysis. Referral for adjuvant chemoradiotherapy was done at the discretion of the attending surgeon. It was offered primarily to patients with T2 or higher disease and/or with nodal involvement. However, patients were only allowed to undergo adjuvant treatment after informed consent was obtained, because evidence in favor of adjuvant treatment was lacking at the time of treatment. Patients underwent external-beam radiotherapy using megavoltage equipment (6–10-MV X-ray). The planning target volume encompassed the tumor bed and regional lymph nodes (LNs), including the portocaval, retrocaval, and aortocaval LNs. All patients underwent individualized computer-based treatment planning. The total dose of 40 Gy was delivered in 2-Gy fractions for 5 days per week, with 2 weeks of planned rest after delivery of the first 20 Gy. Five-fluorouracil (5-FU; 500 mg/m2/day given in an i.v. bolus) was administered concomitantly on the first 3 days of each 2 weeks of radiotherapy. Overall survival was calculated from the date of surgical resection. The actuarial survival rates were calculated using the Kaplan-Meier method (14), and statistical significance was evaluated with the Wilcoxon test. The Cox proportional hazard model was used for multivariate analysis. Statistical analysis was done using SPSS software (release 12.0.1; SPSS, Chicago, IL).
RESULTS Of the 118 patients in the study, 69 were male and 49 were female. The median age of the patients was 57 years (range, 28–78 years). Forty patients underwent Whipple’s operation, and 78 patients underwent pylorus-preserving pancreaticoduodenectomy. All patients but 3 underwent LN dissection. Stage was determined according to the American Joint Committee on Cancer staging system (15). With regard to T stage, 43 patients had T1 disease, 35 patients had T2 disease, 37 patients had T3 disease, and 3 patients had T4 disease. Thirty-eight patients had LN metastasis, and 80 patients did not. The degree of histologic differentiation was as follows: the tumor was well differentiated in 51 patients, moderately differentiated in 56 patients, and poorly differentiated in 9 patients. The degree of differentiation was not noted in the records of 2 patients. Forty-one patients received adjuvant chemoradiotherapy [RT(+) group], and 77 did not [RT(-) group]. When the characteristics of patients in each group [i.e., RT(+) and RT(-) groups] were compared using the c2 test or Fisher’s exact test, this revealed that some of the potential prognostic factors were not distributed equally between the groups. In particular, the pathologic features (i.e., T stage, N stage, and histologic differentiation) were more advanced in the RT(+) group than in the RT(-) group (p = 0.0012, 0.0013, and 0.0472, respectively). In addition, patients aged #60 years were more likely to receive adjuvant treatment than were patients aged >60 years (p = 0.0036; Table 1). Thirty-six patients underwent maintenance chemotherapy after the completion of concurrent chemoradiotherapy; 27 patients
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Table 1. Patient characteristics Patients, n (%) Characteristic Age (y) #60 >60 Type of operation Whipple’s operation PPPD T stage 1 2 3 4 N stage 0 1 Differentiationy W/D M/D P/D
RT(+) (n = 41) RT(-) (n = 77)
p
33 (80.5) 8 (19.5)
41 (53.2) 36 (46.8)
0.0036
16 (39.0) 25 (61.0)
24 (31.2) 53 (68.8)
0.3907
6 (14.6) 15 (36.6) 19 (46.3) 1 (2.4)
37 (48.1) 20 (26.0) 18 (23.4) 2 (2.6)
0.0012
20 (48.8) 21 (51.2)
60* (77.9) 17 (22.1)
0.0013
12 (29.3) 24 (58.5) 5 (12.2)
39 (52.0) 32 (42.7) 4 (5.3)
0.0472
Abbreviations: RT = radiotherapy; PPPD = pylorus-preserving pancreaticoduodenectomy; W/D = well differentiated; M/D = moderately differentiated; P/D = poorly differentiated. * Three patients did not have lymph node dissection. y In 2 patients in the RT(-) group, the histologic differentiation was not available.
received 5-FU every 4 weeks (500 mg/m2/day for 5 days), 3 patients received 5-FU once weekly (500 mg/m2/day), and 1 patient received enteric coated tegafur-uracil. The following combination chemotherapies were given in 1 patient each: 5-FU, leucovorin, and mitomycin-C; enteric coated tegafur-uracil, leucovorin, and mitomycin-C; and gemcitabine and capecitabine. Information on the chemotherapeutic agent used was not available for 2 patients who received maintenance chemotherapy at the outside institution. Two patients who did not undergo chemoradiotherapy received adjuvant chemotherapy (monthly 5-FU treatments) without radiotherapy. The scheduled duration of maintenance chemotherapy was 12 months. At the median follow-up period of 65 months, treatment failed in 41 patients. Local recurrence occurred in 9 patients, regional recurrence occurred in 11 patients, and local and regional recurrence occurred in 2 patients. Distant metastases developed in 34 patients, 15 of whom had locoregional recurrence as well. The most frequent site of distant metastasis was the liver. Detailed patterns of failure by treatment modality are shown in Table 2. Of the 21 patients with treatment failure in the RT(-) group, 15 had locoregional recurrence as a component of failure. In contrast, only 7 of the 20 patients in the RT(+) group showed locoregional treatment failure. The 5-year overall, locoregional relapse–free, and distant metastasis–free survival rates in all patients were 61.9%, 80.0%, and 71.5%, respectively (Fig. 1). When broken down by treatment modality, the 5-year overall survival rate in the RT(-) and RT(+) groups was 66.9% and 52.8%, respectively (p = 0.2225). The 5-year locoregional relapse–free
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Table 2. Patterns of failure according to treatment modality
Table 3. Univariate analysis for OS and LRRFS
Patients (n) Parameter
RT(+) (n = 41)
Total no. of treatment failures Locoregional Local Regional Local and regional Locoregional + distant Distant
Variable
RT(-) (n = 77)
20 4 1 2 1 3 13
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21 3 1 1 1 12 6
Abbreviation as in Table 1.
survival rate in the RT(-) and RT(+) groups was 79.9% and 80.2%, respectively (p = 0.9582). The 5-year distant metastasis–free survival rate in the RT(-) and RT(+) groups was 77.5% and 60.6%, respectively (p = 0.0661). Univariate analysis showed that advanced T stage, nodal involvement, and poor histologic differentiation were all adverse prognostic factors affecting overall survival. Tumor stage, N stage, and histologic differentiation were significant prognostic factors for locoregional relapse–free survival (Table 3). When age, type of operation, T stage, N stage, histologic differentiation, and the use of adjuvant chemoradiotherapy were incorporated into the Cox proportional hazard model, there was an improvement in locoregional relapse–free survival (p = 0.0050) and a trend toward better overall survival (p = 0.0762) associated with the use of adjuvant chemoradiotherapy (Table 4). However, the impact of adjuvant chemoradiotherapy on distant metastasis–free survival was not significant (p = 0.8362). Subgroup analysis was conducted to identify which group of patients would benefit from adjuvant chemoradiotherapy. For patients with nodal involvement (n = 38), the use of chemoradiotherapy was correlated with increased overall and locoregional relapse–free survival on multivariate analysis (p = 0.0235 and 0.0095, respectively) (Fig. 2). However, the benefit of adjuvant chemoradiotherapy was significant in terms of locoregional relapse–free survival (p = 0.0319) but not of overall survival (p = 0.4544) in patients with T3/T4
p
5-y OS (%)
Age (y) #60 >60 Operation Whipple’s operation PPPD T stage T1 T2 T3 T4 N stage N0 N1 Differentiation W/D M/D P/D RT Yes No
p
5-y LRRFS
0.1354 64.0 58.6
0.3473 76.8 85.6
0.1625 51.4 67.3
0.6209 77.8 81.2
0.0022 76.3 62.5 46.8 33.3
0.0037 89.5 83.7 65.8 50.0
<0.0001 75.6 33.3
0.0028 86.4 65.0
<0.0001 81.6 47.9 27.8
0.0006 91.5 73.9 21.4
0.2225 52.8 66.9
0.9582 80.2 79.9
Abbreviations: OS = overall survival; LRRFS = locoregional relapse–free survival. Other abbreviations as in Table 1.
disease (n = 40) (Fig. 3). Subgroup analysis was not performed for patients with poorly differentiated histology because of the small number of patients involved (n = 9). Acute radiation morbidity was evaluated using Radiation Therapy Oncology Group criteria (16). During chemoradiotherapy, the most common toxicity was nausea or vomiting, with Grade 2 nausea and vomiting developing in 19 patients. Grade 2 diarrhea was recorded in 3 patients and Grade 2 abdominal pain in 1 patient. No patient experienced Grade 3 or 4 toxicity. According to World Health Organization criteria (17), Grade 2 hematologic toxicity developed in 7 patients during concurrent chemoradiotherapy and in 12 patients during maintenance chemotherapy. Grade 3 hematologic toxicity was observed in 2 patients during maintenance chemotherapy. With regard to late radiation morbidity, 2 patients had an intestinal obstruction; 1 patient was treated with conservative management, and the other patient was treated with surgery.
100
Probability (%)
80
Table 4. Multivariate analysis for overall and locoregional relapse-free survival
60
OS
40
LRRFS DMFS OS
20 0
0
12
24
36
48
60
Months from surgery
Fig. 1. Overall survival (OS), locoregional relapse–free survival (LRRFS), and distant metastasis–free survival (DMFS) curves of all patients.
LRRFS
Variable
Risk ratio
p
Risk ratio
p
Age Operation T stage N stage Differentiation RT
1.290 0.628 1.294 2.806 2.051 0.523
0.4018 0.1207 0.1658 0.0018 0.0104 0.0762
0.383 0.764 1.801 3.495 3.167 0.192
0.0603 0.5774 0.0312 0.0121 0.0129 0.0050
Abbreviations as in Tables 1 and 3.
Chemoradiotherapy for ampulla of Vater cancer d K. KIM et al.
(a)
(a)
100
100 RT (+) (N=21)
60 RT (-) (N=17)
40
0
0
12
24
60 RT (-) (N=20)
40 P = 0.0319
20
P = 0.0095
20
RT (+) (N=20)
80
LRRFS (%)
LRRFS (%)
80
36
48
0
60
0
12
24
36
48
60
Months from surgery
Months from surgery
(b)
(b) 100
100
80
80
60
OS (%)
OS (%)
439
RT (+) (N=21)
40
RT (-) (N=20)
60 40
RT (+) (N=20) P = 0.0235
20 0
0
12
24
36
RT (-) (N=17)
48
20
60
Months from surgery
0
P = 0.4544
0
12
24
36
48
60
Months from surgery
Fig. 2. (a) Locoregional relapse–free survival (LRRFS) curves according to treatment modality in patients with nodal involvement. (b) Overall survival (OS) curves according to treatment modality in patients with nodal involvement. RT = adjuvant chemoradiotherapy.
Fig. 3. (a) Locoregional relapse-free survival (LRRFS) curves according to treatment modality in patients with T3/4 disease. (b) Overall survival (OS) curves according to treatment modality in patients with T3/4 disease. RT = adjuvant chemoradiotherapy.
One patient suffered from choledochojejunostomy stricture and was treated with balloon dilatation.
local control or overall survival. On the other hand, several recent reports affirmed the positive effect of adjuvant chemoradiotherapy on overall survival, but not on local control, in patients with high-risk factors (10, 13). The European Organization for Research and Treatment of Cancer (EORTC) conducted a Phase III randomized, controlled trial that examined the role of adjuvant chemoradiotherapy for the treatment of pancreatic and periampullary cancers, but this study failed to show any benefit of the treatment. However, it is difficult to draw conclusions regarding the effectiveness of the therapy in patients with pure ampulla of Vater cancer, because these patients accounted for only a small portion of the study population (8). In the present study, the 5-year locoregional relapse-free and overall survival rates were comparable in the RT(-) and RT(+) groups. However, this was due to the skewed distribution of the risk factors, all of which have been confirmed to be significant prognostic factors by a number of investigators (3, 5, 21). After adjusting for confounding factors using a multivariate analysis, however, better overall survival and locoregional relapse–free survival rates were then seen in the RT(+) group than in the RT(-) group. In the subgroup analysis done to identify the optimal indications for adjuvant chemoradiotherapy, a significant improvement in overall survival was seen in patients with nodal involvement treated with the
DISCUSSION Radical surgical resection is the only means of effective cure in patients with ampulla of Vater cancer, with a 5-year overall survival rate of 30–60% in these patients (3–7). Although this is a more favorable outcome compared with the outcomes in patients with other periampullary cancers, there is still room for improvement in the outcome. Although little has been known about patterns of failure after resection for ampulla of Vater cancer, it has been shown that locoregional relapse occurs as a single event or as a component of failure in 25–75% of patients (18–20). Given these observations, the combination of adjuvant radiotherapy and surgical resection seems to be a reasonable way to improve treatment outcome. In this regard, Willet et al. (9) reported improved local control, but not improved overall survival, in association with the receipt of adjuvant chemoradiotherapy after surgical resection. Several retrospective studies done after the study of Willet et al. yielded conflicting findings, however. For example, Sikora et al. (12) evaluated the effect of concurrent chemoradiotherapy followed by maintenance chemotherapy and noted no benefit from adjuvant treatment in terms of either
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I. J. Radiation Oncology d Biology d Physics
therapy, a finding that was identical to that made at the Mayo Clinic in patients with ampullary carcinomas (13). The radiotherapy schedule used in the patients in our study was a rather conventional one: radiotherapy up to 40 Gy was delivered with a 2-week planned rest period halfway through the treatment course. Such split-course radiotherapy has been used in several randomized, controlled trials conducted in patients with pancreaticobiliary malignancies, including the aforementioned EORTC trial (8). Considering the possible detrimental effect of treatment interruption on local control, however, further improvement in outcome could be expected in response to uninterrupted higher-dose radiotherapy. A need for fortified systemic therapy was suggested by our finding of similar 5-year distant metastasis–free survival rates in the RT(-) and RT(+) groups, even though most patients in the RT(+) group received maintenance chemotherapy. In our patterns-of-failure analysis, we found, not surprisingly, that the majority of treatment failures in the RT(+) group occurred at distant sites. Specifically, the proportion of patients with these metastases in the RT(-) group was only 29% (6 of 21), whereas it was 65% (13 of 20) in the RT(+) group. This finding is likely due to the fact that, although radiotherapy conferred better locoregional control in the RT(+) group, it had a limited effect on the control of micrometastases. Instead, these metastases reflected the failure of 5-FU–based chemotherapy and not radiotherapy. Thus, more effective chemotherapy is needed for further improvement in treatment outcome. Recently, gemcitabine has shown promise in the treatment of unresectable and/or metastatic biliary tract cancer, including ampulla of Vater cancer, both alone (22) and in combination with oxaliplatin (23), capecitabine (24), or cisplatin (25). Thus, clinical trials of effective chemotherapeutic
Volume 75, Number 2, 2009
agents for adjuvant therapy in this cancer are warranted to reduce the incidence of distant metastases. One strength of our study was the inclusion of age in the analysis of overall survival as a prognostic factor. Other series to date have included only pathologic findings as confounding factors. The inclusion of age is important because the delivery of adjuvant therapy is based on not only tumor characteristics but also on patient characteristics. For example, with regard to age, in general, young patients with a good performance status are more frequently given adjuvant therapy than are older patients with a poor performance status. This was borne out in the present study, in which we found that patients aged #60 years were more likely to receive adjuvant chemoradiotherapy than were patients aged >60 years; this might therefore have confounded the results in favor of chemoradiotherapy. For this reason, we controlled the age factor as well as other pathologic risk factors using a multivariate analysis, although age did not have any impact on either locoregional control or overall survival on univariate analysis. One further limitation of our study was its retrospective design and the relatively small number of patients, though the number was relatively large considering the rarity of ampulla of Vater cancer. In addition, there might be selection biases other than age (e.g., performance and nutritional status) that may have contributed to the improved overall survival seen in the RT(+) group. This further points up the need for a randomized, controlled trial to elucidate the role of adjuvant chemoradiotherapy in ampulla of Vater cancer. We conclude from our study findings that adjuvant chemoradiotherapy may improve locoregional control, and possibly overall survival, in patients with ampulla of Vater cancer after curative resection, especially in those with nodal involvement.
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9. Willett CG, Warshaw AL, Convery K, et al. Patterns of failure after pancreaticoduodenectomy for ampullary carcinoma. Surg Gynecol Obstet 1993;176:33–38. 10. Lee JH, Whittington R, Williams NN, et al. Outcome of pancreaticoduodenectomy and impact of adjuvant therapy for ampullary carcinomas. Int J Radiat Oncol Biol Phys 2000; 47(4):945–953. 11. Mehta VK, Fisher GA, Ford JM, et al. Adjuvant chemoradiotherapy for ‘‘unfavorable’’ carcinoma of the ampulla of Vater. Arch Surg 2001;136:65–69. 12. Sikora SS, Balachandran P, Dimri K, et al. Adjuvant chemoradiotherapy in ampullary cancers. Eur J Surg Oncol 2005; 31:158–163. 13. Bhatia S, Miller RC, Haddock MG, et al. Adjuvant therapy for ampullary carcinomas: The Mayo Clinic experience. Int J Radiat Oncol Biol Phys 2006;66:514–519. 14. Kaplan EL, Meier PI. A nonparametric estimation from incomplete observations. J Am Statics Assoc 1958;53:457–481. 15. American Joint Committee on Cancer. Cancer staging handbook. 6th ed. New York: Springer- Verlag; 2002. p. 107–112. 16. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. 17. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47:207–214.
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18. Barton RM, Copeland EM III. Carcinoma of the ampulla of Vater. Surg Gynecol Obstet 1983;156:297–301. 19. Kopelson G. Curative surgery for adenocarcinoma of the pancreas/ampulla of Vater: The role of adjuvant pre or postoperative radiation therapy. Int J Radiat Oncol Biol Phys 1983;9: 911–915. 20. Todoroki T, Koike N, Morishita Y, et al. Patterns and predictors of failure after curative resections of carcinoma of the ampulla of Vater. Ann Surg Oncol 2003;10:1176–1183. 21. Beger HG, Treitschke F, Gansauge F, et al. Tumor of the ampulla of Vater: Experience with local or radical resection in 171 consecutively treated patients. Arch Surg 1999;134: 526–532.
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22. Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Semin Oncol 2002;29(Suppl. 20):40–45. 23. Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: A GERCOR study. Ann Oncol 2004;15: 1339–1343. 24. Cho JY, Paik YH, Chang YS, et al. Capecitabine combined with gemcitabine as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer 2005; 104:2753–2758. 25. Kim ST, Park JO, Lee J, et al. A phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer 2006;106: 1339–1346.
doi:10.1016/j.ijrobp.2008.11.067
CLINICAL INVESTIGATION
Ampulla of Vater
ROLE OF ADJUVANT CHEMORADIOTHERAPY FOR AMPULLA OF VATER CANCER KYUBO KIM, M.D.,* EUI KYU CHIE, M.D.,* JIN-YOUNG JANG, M.D.,y SUN WHE KIM, M.D.,y DO-YOUN OH, M.D.,z SEOCK-AH IM, M.D.,z TAE-YOU KIM, M.D.,z YUNG-JUE BANG, M.D.,z x AND SUNG W. HA, M.D.* Departments of *Radiation Oncology, y Surgery, and z Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; and x Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea Purpose: To evaluate the role of adjuvant chemoradiotherapy for ampulla of Vater cancer. Methods and Materials: Between January 1991 and December 2002, 118 patients with ampulla of Vater cancer underwent en bloc resection. Forty-one patients received adjuvant chemoradiotherapy [RT(+) group], and 77 did not [RT(-) group]. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes, for a total dose of up to 40 Gy delivered in 2-Gy fractions, with a planned 2-week rest period halfway through the treatment period. Intravenous 5-fluorouracil (500 mg/m2/day) was given on Days 1 to 3 of each split course. The median follow-up was 65 months. Results: The 5-year overall survival rate in the RT(-) and RT(+) groups was 66.9% and 52.8%, respectively (p = 0.2225). The 5-year locoregional relapse–free survival rate in the RT(-) and RT(+) groups was 79.9% and 80.2%, respectively (p = 0.9582). When age, type of operation, T stage, N stage, histologic differentiation, and the use of adjuvant chemoradiotherapy were incorporated into the Cox proportional hazard model, there was an improvement in the locoregional relapse–free survival rate (p = 0.0050) and a trend toward a longer overall survival (p = 0.0762) associated with the use of adjuvant chemoradiotherapy. Improved overall survival (p = 0.0235) and locoregional relapse–free survival (p = 0.0095) were also evident in patients with nodal metastasis. In contrast, enhanced locoregional control (p = 0.0319) did not result in longer survival in patients with locally advanced disease (p = 0.4544). Conclusions: Adjuvant chemoradiotherapy may enhance locoregional control and overall survival in patients with ampulla of Vater cancer after curative resection, especially in those with nodal involvement. Ó 2009 Elsevier Inc. Ampulla of Vater cancer, Adjuvant chemoradiotherapy.
with the cancer (9–13). A further problem with these studies is that the findings have been inconclusive. There is thus a need to further examine the role of adjuvant chemoradiotherapy in ampulla of Vater cancer. In this study, we retrospectively examined the findings in a relatively large series (n = 118) of patients with ampulla of Vater cancer treated with curative intent at a single center and also examined the role of adjuvant chemoradiotherapy, with the hope that more conclusive findings would be yielded regarding the role of this treatment in this cancer.
INTRODUCTION The prognosis for patients with ampulla of Vater cancer is better than that for patients with other periampullary malignancies, such as pancreatic and/or bile duct cancers (1, 2). This is because these tumors generally produce symptoms earlier than tumors in other locations, and thus these tumors are diagnosed at an earlier stage. Nevertheless, the 5-year overall survival rate in patients who undergo curative resection, which is the current standard treatment for this cancer, is rather unsatisfactory, ranging from 30% to 60% (3–7). To further improve the treatment outcome, many clinicians now treat patients with this cancer with adjuvant chemoradiotherapy in a manner similar to that used in patients with pancreatic cancer (8). However, because of the rarity of the disease and the difficulties in differentiating ampulla of Vater cancer from other periampullary cancers, there have been only a few studies evaluating the role of adjuvant chemoradiotherapy in patients
METHODS AND MATERIALS Between January 1991 and December 2002, 131 patients with ampullary adenocarcinoma underwent en bloc resection. Of these 131 patients, 13 were excluded from the study: 6 because they had undergone adjuvant radiotherapy at an outside institution and were lost to follow-up, 2 because they died of postoperative Presented at the 14th European Cancer Conference, September 23–27, 2007, Barcelona, Spain. Conflict of interest: none. Received Sept 1, 2008, and in revised form Oct 18, 2008. Accepted for publication Nov 6, 2008.
Reprint requests to: Eui Kyu Chie, M.D., Department of Radiation Oncology, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 110-744, Republic of Korea. Tel: (+82) 2-2072-3705; Fax: (+82) 2-765-3317; E-mail: [email protected] 436
Chemoradiotherapy for ampulla of Vater cancer d K. KIM et al.
complications, 2 because they did not complete adjuvant chemoradiotherapy, 2 because they had synchronous metastases at presentation, and 1 because of a synchronous primary malignancy at presentation. This left 118 patients, who formed the study population for this retrospective analysis. Referral for adjuvant chemoradiotherapy was done at the discretion of the attending surgeon. It was offered primarily to patients with T2 or higher disease and/or with nodal involvement. However, patients were only allowed to undergo adjuvant treatment after informed consent was obtained, because evidence in favor of adjuvant treatment was lacking at the time of treatment. Patients underwent external-beam radiotherapy using megavoltage equipment (6–10-MV X-ray). The planning target volume encompassed the tumor bed and regional lymph nodes (LNs), including the portocaval, retrocaval, and aortocaval LNs. All patients underwent individualized computer-based treatment planning. The total dose of 40 Gy was delivered in 2-Gy fractions for 5 days per week, with 2 weeks of planned rest after delivery of the first 20 Gy. Five-fluorouracil (5-FU; 500 mg/m2/day given in an i.v. bolus) was administered concomitantly on the first 3 days of each 2 weeks of radiotherapy. Overall survival was calculated from the date of surgical resection. The actuarial survival rates were calculated using the Kaplan-Meier method (14), and statistical significance was evaluated with the Wilcoxon test. The Cox proportional hazard model was used for multivariate analysis. Statistical analysis was done using SPSS software (release 12.0.1; SPSS, Chicago, IL).
RESULTS Of the 118 patients in the study, 69 were male and 49 were female. The median age of the patients was 57 years (range, 28–78 years). Forty patients underwent Whipple’s operation, and 78 patients underwent pylorus-preserving pancreaticoduodenectomy. All patients but 3 underwent LN dissection. Stage was determined according to the American Joint Committee on Cancer staging system (15). With regard to T stage, 43 patients had T1 disease, 35 patients had T2 disease, 37 patients had T3 disease, and 3 patients had T4 disease. Thirty-eight patients had LN metastasis, and 80 patients did not. The degree of histologic differentiation was as follows: the tumor was well differentiated in 51 patients, moderately differentiated in 56 patients, and poorly differentiated in 9 patients. The degree of differentiation was not noted in the records of 2 patients. Forty-one patients received adjuvant chemoradiotherapy [RT(+) group], and 77 did not [RT(-) group]. When the characteristics of patients in each group [i.e., RT(+) and RT(-) groups] were compared using the c2 test or Fisher’s exact test, this revealed that some of the potential prognostic factors were not distributed equally between the groups. In particular, the pathologic features (i.e., T stage, N stage, and histologic differentiation) were more advanced in the RT(+) group than in the RT(-) group (p = 0.0012, 0.0013, and 0.0472, respectively). In addition, patients aged #60 years were more likely to receive adjuvant treatment than were patients aged >60 years (p = 0.0036; Table 1). Thirty-six patients underwent maintenance chemotherapy after the completion of concurrent chemoradiotherapy; 27 patients
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Table 1. Patient characteristics Patients, n (%) Characteristic Age (y) #60 >60 Type of operation Whipple’s operation PPPD T stage 1 2 3 4 N stage 0 1 Differentiationy W/D M/D P/D
RT(+) (n = 41) RT(-) (n = 77)
p
33 (80.5) 8 (19.5)
41 (53.2) 36 (46.8)
0.0036
16 (39.0) 25 (61.0)
24 (31.2) 53 (68.8)
0.3907
6 (14.6) 15 (36.6) 19 (46.3) 1 (2.4)
37 (48.1) 20 (26.0) 18 (23.4) 2 (2.6)
0.0012
20 (48.8) 21 (51.2)
60* (77.9) 17 (22.1)
0.0013
12 (29.3) 24 (58.5) 5 (12.2)
39 (52.0) 32 (42.7) 4 (5.3)
0.0472
Abbreviations: RT = radiotherapy; PPPD = pylorus-preserving pancreaticoduodenectomy; W/D = well differentiated; M/D = moderately differentiated; P/D = poorly differentiated. * Three patients did not have lymph node dissection. y In 2 patients in the RT(-) group, the histologic differentiation was not available.
received 5-FU every 4 weeks (500 mg/m2/day for 5 days), 3 patients received 5-FU once weekly (500 mg/m2/day), and 1 patient received enteric coated tegafur-uracil. The following combination chemotherapies were given in 1 patient each: 5-FU, leucovorin, and mitomycin-C; enteric coated tegafur-uracil, leucovorin, and mitomycin-C; and gemcitabine and capecitabine. Information on the chemotherapeutic agent used was not available for 2 patients who received maintenance chemotherapy at the outside institution. Two patients who did not undergo chemoradiotherapy received adjuvant chemotherapy (monthly 5-FU treatments) without radiotherapy. The scheduled duration of maintenance chemotherapy was 12 months. At the median follow-up period of 65 months, treatment failed in 41 patients. Local recurrence occurred in 9 patients, regional recurrence occurred in 11 patients, and local and regional recurrence occurred in 2 patients. Distant metastases developed in 34 patients, 15 of whom had locoregional recurrence as well. The most frequent site of distant metastasis was the liver. Detailed patterns of failure by treatment modality are shown in Table 2. Of the 21 patients with treatment failure in the RT(-) group, 15 had locoregional recurrence as a component of failure. In contrast, only 7 of the 20 patients in the RT(+) group showed locoregional treatment failure. The 5-year overall, locoregional relapse–free, and distant metastasis–free survival rates in all patients were 61.9%, 80.0%, and 71.5%, respectively (Fig. 1). When broken down by treatment modality, the 5-year overall survival rate in the RT(-) and RT(+) groups was 66.9% and 52.8%, respectively (p = 0.2225). The 5-year locoregional relapse–free
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Table 2. Patterns of failure according to treatment modality
Table 3. Univariate analysis for OS and LRRFS
Patients (n) Parameter
RT(+) (n = 41)
Total no. of treatment failures Locoregional Local Regional Local and regional Locoregional + distant Distant
Variable
RT(-) (n = 77)
20 4 1 2 1 3 13
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21 3 1 1 1 12 6
Abbreviation as in Table 1.
survival rate in the RT(-) and RT(+) groups was 79.9% and 80.2%, respectively (p = 0.9582). The 5-year distant metastasis–free survival rate in the RT(-) and RT(+) groups was 77.5% and 60.6%, respectively (p = 0.0661). Univariate analysis showed that advanced T stage, nodal involvement, and poor histologic differentiation were all adverse prognostic factors affecting overall survival. Tumor stage, N stage, and histologic differentiation were significant prognostic factors for locoregional relapse–free survival (Table 3). When age, type of operation, T stage, N stage, histologic differentiation, and the use of adjuvant chemoradiotherapy were incorporated into the Cox proportional hazard model, there was an improvement in locoregional relapse–free survival (p = 0.0050) and a trend toward better overall survival (p = 0.0762) associated with the use of adjuvant chemoradiotherapy (Table 4). However, the impact of adjuvant chemoradiotherapy on distant metastasis–free survival was not significant (p = 0.8362). Subgroup analysis was conducted to identify which group of patients would benefit from adjuvant chemoradiotherapy. For patients with nodal involvement (n = 38), the use of chemoradiotherapy was correlated with increased overall and locoregional relapse–free survival on multivariate analysis (p = 0.0235 and 0.0095, respectively) (Fig. 2). However, the benefit of adjuvant chemoradiotherapy was significant in terms of locoregional relapse–free survival (p = 0.0319) but not of overall survival (p = 0.4544) in patients with T3/T4
p
5-y OS (%)
Age (y) #60 >60 Operation Whipple’s operation PPPD T stage T1 T2 T3 T4 N stage N0 N1 Differentiation W/D M/D P/D RT Yes No
p
5-y LRRFS
0.1354 64.0 58.6
0.3473 76.8 85.6
0.1625 51.4 67.3
0.6209 77.8 81.2
0.0022 76.3 62.5 46.8 33.3
0.0037 89.5 83.7 65.8 50.0
<0.0001 75.6 33.3
0.0028 86.4 65.0
<0.0001 81.6 47.9 27.8
0.0006 91.5 73.9 21.4
0.2225 52.8 66.9
0.9582 80.2 79.9
Abbreviations: OS = overall survival; LRRFS = locoregional relapse–free survival. Other abbreviations as in Table 1.
disease (n = 40) (Fig. 3). Subgroup analysis was not performed for patients with poorly differentiated histology because of the small number of patients involved (n = 9). Acute radiation morbidity was evaluated using Radiation Therapy Oncology Group criteria (16). During chemoradiotherapy, the most common toxicity was nausea or vomiting, with Grade 2 nausea and vomiting developing in 19 patients. Grade 2 diarrhea was recorded in 3 patients and Grade 2 abdominal pain in 1 patient. No patient experienced Grade 3 or 4 toxicity. According to World Health Organization criteria (17), Grade 2 hematologic toxicity developed in 7 patients during concurrent chemoradiotherapy and in 12 patients during maintenance chemotherapy. Grade 3 hematologic toxicity was observed in 2 patients during maintenance chemotherapy. With regard to late radiation morbidity, 2 patients had an intestinal obstruction; 1 patient was treated with conservative management, and the other patient was treated with surgery.
100
Probability (%)
80
Table 4. Multivariate analysis for overall and locoregional relapse-free survival
60
OS
40
LRRFS DMFS OS
20 0
0
12
24
36
48
60
Months from surgery
Fig. 1. Overall survival (OS), locoregional relapse–free survival (LRRFS), and distant metastasis–free survival (DMFS) curves of all patients.
LRRFS
Variable
Risk ratio
p
Risk ratio
p
Age Operation T stage N stage Differentiation RT
1.290 0.628 1.294 2.806 2.051 0.523
0.4018 0.1207 0.1658 0.0018 0.0104 0.0762
0.383 0.764 1.801 3.495 3.167 0.192
0.0603 0.5774 0.0312 0.0121 0.0129 0.0050
Abbreviations as in Tables 1 and 3.
Chemoradiotherapy for ampulla of Vater cancer d K. KIM et al.
(a)
(a)
100
100 RT (+) (N=21)
60 RT (-) (N=17)
40
0
0
12
24
60 RT (-) (N=20)
40 P = 0.0319
20
P = 0.0095
20
RT (+) (N=20)
80
LRRFS (%)
LRRFS (%)
80
36
48
0
60
0
12
24
36
48
60
Months from surgery
Months from surgery
(b)
(b) 100
100
80
80
60
OS (%)
OS (%)
439
RT (+) (N=21)
40
RT (-) (N=20)
60 40
RT (+) (N=20) P = 0.0235
20 0
0
12
24
36
RT (-) (N=17)
48
20
60
Months from surgery
0
P = 0.4544
0
12
24
36
48
60
Months from surgery
Fig. 2. (a) Locoregional relapse–free survival (LRRFS) curves according to treatment modality in patients with nodal involvement. (b) Overall survival (OS) curves according to treatment modality in patients with nodal involvement. RT = adjuvant chemoradiotherapy.
Fig. 3. (a) Locoregional relapse-free survival (LRRFS) curves according to treatment modality in patients with T3/4 disease. (b) Overall survival (OS) curves according to treatment modality in patients with T3/4 disease. RT = adjuvant chemoradiotherapy.
One patient suffered from choledochojejunostomy stricture and was treated with balloon dilatation.
local control or overall survival. On the other hand, several recent reports affirmed the positive effect of adjuvant chemoradiotherapy on overall survival, but not on local control, in patients with high-risk factors (10, 13). The European Organization for Research and Treatment of Cancer (EORTC) conducted a Phase III randomized, controlled trial that examined the role of adjuvant chemoradiotherapy for the treatment of pancreatic and periampullary cancers, but this study failed to show any benefit of the treatment. However, it is difficult to draw conclusions regarding the effectiveness of the therapy in patients with pure ampulla of Vater cancer, because these patients accounted for only a small portion of the study population (8). In the present study, the 5-year locoregional relapse-free and overall survival rates were comparable in the RT(-) and RT(+) groups. However, this was due to the skewed distribution of the risk factors, all of which have been confirmed to be significant prognostic factors by a number of investigators (3, 5, 21). After adjusting for confounding factors using a multivariate analysis, however, better overall survival and locoregional relapse–free survival rates were then seen in the RT(+) group than in the RT(-) group. In the subgroup analysis done to identify the optimal indications for adjuvant chemoradiotherapy, a significant improvement in overall survival was seen in patients with nodal involvement treated with the
DISCUSSION Radical surgical resection is the only means of effective cure in patients with ampulla of Vater cancer, with a 5-year overall survival rate of 30–60% in these patients (3–7). Although this is a more favorable outcome compared with the outcomes in patients with other periampullary cancers, there is still room for improvement in the outcome. Although little has been known about patterns of failure after resection for ampulla of Vater cancer, it has been shown that locoregional relapse occurs as a single event or as a component of failure in 25–75% of patients (18–20). Given these observations, the combination of adjuvant radiotherapy and surgical resection seems to be a reasonable way to improve treatment outcome. In this regard, Willet et al. (9) reported improved local control, but not improved overall survival, in association with the receipt of adjuvant chemoradiotherapy after surgical resection. Several retrospective studies done after the study of Willet et al. yielded conflicting findings, however. For example, Sikora et al. (12) evaluated the effect of concurrent chemoradiotherapy followed by maintenance chemotherapy and noted no benefit from adjuvant treatment in terms of either
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I. J. Radiation Oncology d Biology d Physics
therapy, a finding that was identical to that made at the Mayo Clinic in patients with ampullary carcinomas (13). The radiotherapy schedule used in the patients in our study was a rather conventional one: radiotherapy up to 40 Gy was delivered with a 2-week planned rest period halfway through the treatment course. Such split-course radiotherapy has been used in several randomized, controlled trials conducted in patients with pancreaticobiliary malignancies, including the aforementioned EORTC trial (8). Considering the possible detrimental effect of treatment interruption on local control, however, further improvement in outcome could be expected in response to uninterrupted higher-dose radiotherapy. A need for fortified systemic therapy was suggested by our finding of similar 5-year distant metastasis–free survival rates in the RT(-) and RT(+) groups, even though most patients in the RT(+) group received maintenance chemotherapy. In our patterns-of-failure analysis, we found, not surprisingly, that the majority of treatment failures in the RT(+) group occurred at distant sites. Specifically, the proportion of patients with these metastases in the RT(-) group was only 29% (6 of 21), whereas it was 65% (13 of 20) in the RT(+) group. This finding is likely due to the fact that, although radiotherapy conferred better locoregional control in the RT(+) group, it had a limited effect on the control of micrometastases. Instead, these metastases reflected the failure of 5-FU–based chemotherapy and not radiotherapy. Thus, more effective chemotherapy is needed for further improvement in treatment outcome. Recently, gemcitabine has shown promise in the treatment of unresectable and/or metastatic biliary tract cancer, including ampulla of Vater cancer, both alone (22) and in combination with oxaliplatin (23), capecitabine (24), or cisplatin (25). Thus, clinical trials of effective chemotherapeutic
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agents for adjuvant therapy in this cancer are warranted to reduce the incidence of distant metastases. One strength of our study was the inclusion of age in the analysis of overall survival as a prognostic factor. Other series to date have included only pathologic findings as confounding factors. The inclusion of age is important because the delivery of adjuvant therapy is based on not only tumor characteristics but also on patient characteristics. For example, with regard to age, in general, young patients with a good performance status are more frequently given adjuvant therapy than are older patients with a poor performance status. This was borne out in the present study, in which we found that patients aged #60 years were more likely to receive adjuvant chemoradiotherapy than were patients aged >60 years; this might therefore have confounded the results in favor of chemoradiotherapy. For this reason, we controlled the age factor as well as other pathologic risk factors using a multivariate analysis, although age did not have any impact on either locoregional control or overall survival on univariate analysis. One further limitation of our study was its retrospective design and the relatively small number of patients, though the number was relatively large considering the rarity of ampulla of Vater cancer. In addition, there might be selection biases other than age (e.g., performance and nutritional status) that may have contributed to the improved overall survival seen in the RT(+) group. This further points up the need for a randomized, controlled trial to elucidate the role of adjuvant chemoradiotherapy in ampulla of Vater cancer. We conclude from our study findings that adjuvant chemoradiotherapy may improve locoregional control, and possibly overall survival, in patients with ampulla of Vater cancer after curative resection, especially in those with nodal involvement.
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