BRIEF COMMUNICATION

Postoperative Radiotherapy in Periampullary Cancers:A Brief Review

Amit Bahl & Tapesh Bhattacharyya & Rakesh Kapoor &

Oinam A. Singh & Tomar Parsee & Suresh C. Sharma

Published online: 28 July 2012# Springer Science+Business Media, LLC 2012

AbstractBackground The treatment of periampullary cancers is com-plex and challenging. Adjuvant therapy for resected peri-ampullary and pancreatic cancers has been the subject ofintense clinical investigations for several decades. Periam-pullary cancer management has often been clubbed withpancreatic cancers.Discussion Following surgery, adjuvant chemoradiotherapyhas been widely accepted as standard of care in the USA,although different prospective and retrospective studieshave shown conflicting results. Controversy regarding theeffectiveness of chemoradiotherapy exists in the literature,both in terms of survival as well as toxicity. However,conventional postoperative radiotherapy practice needs tobe reviewed in view of changes and developments in radiationtechniques in the last decade. In this article, we review themanagement of periampullary cancers with special emphasison the adjuvant postoperative radiotherapy.

Keywords Periampullary cancers . Treatment .

Radiotherapy

Introduction

Periampullary cancers are defined as tumors arising within1 cm of the ampulla of vater and include ampullary, pancreatic,

bile duct, and duodenal cancer [1, 2]. These tumors are usuallyclubbed with pancreatic cancers for treatment and, as such, theexact incidence of periampullary cancers may not be availablein different cancer registries. The incidence of pancreatic can-cers is however better documented with 42,470 new casesbeing recorded in the USA in 2009 [3]. The strongest etiolog-ical association of periampullary cancers is seen with cigarettesmoking, although at-risk group include patients with chronicpancreatitis, adult-onset diabetes, hereditary pancreatitis, fa-milial pancreatic cancers, and certain familial cancer syn-dromes. They are also a feature of familial adenomatouspolyposis [1, 2]. The prognosis of periampullary cancers,though better than pancreatic body cancers, still remains poor.Ampulla of vater cancers have a better survival followed bydistal common bile duct, duodenal, and pancreatic tumors [4].Their treatment involves a combination of surgery, postopera-tive radiotherapy, and chemotherapy. Though surgical treat-ment forms the first line of management, long-term results ofsurgery alone are dismal. Postoperative radiotherapy has beenused along with chemotherapy. The role of targeted therapy isnow being investigated in these tumors.

Surgery

Pancreaticoduodenectomy or Whipple’s surgery is the pre-ferred surgical technique for periampullary carcinoma man-agement [5]. The procedure involves en bloc resection of thegastric antrum and duodenum, a segment of the first portionof the jejunum, gallbladder, and distal common bile duct,the head and often neck of the pancreas, and adjacentregional lymph nodes. As a result of improved preoperativeevaluation and perioperative care, survival after potentiallycurative pancreaticoduodenectomy for periampullary andpancreatic carcinomas has improved over the past severalyears. Postoperative mortality has decreased from 20 % ormore to less than 5 % at large volume tertiary care centers.

A. Bahl (*) : T. Bhattacharyya :R. Kapoor :O. A. Singh :T. Parsee : S. C. SharmaDepartment of Radiation Oncology, Post-Graduate Instituteof Medical Education and Research (PGIMER),Chandigarh 160012, Indiae-mail: dramitbahl@yahoo.com

A. BahlRegional Cancer Center, Post-Graduate Institute of MedicalEducation and Research (PGIMER),Chandigarh 160012, India

J Gastrointest Canc (2013) 44:111–114DOI 10.1007/s12029-012-9421-2

In patients with periampullary carcinoma, a 5-year survivalrate of 30–60 % has been reported [6, 7]. This is better thanresection results for other pancreatic cancers with a 1- and 5-year survival rate of 18 and 4 %, respectively [8]. However,the most common cause of treatment failure after surgery isrecurrence in the tumor bed, regional lymph nodes, liver,and adjacent peritoneal surfaces [9–11]. Distant metastasesin the lung or peritoneal cavity are seldom seen without localtumor recurrence and are characteristic of late recurrence.Therefore, a treatment approach aiming to increase the localcontrol rate is likely to translate into better overall survival(OS) rates. Combining aggressive local and systemic adjuvanttreatment may help to increase the disease-free interval andoverall survival.

Adjuvant Therapy in Periampullary Cancer

Results of treatment of periampullary cancers have often beenreported with pancreatic cancers. Nonpancreatic perimapullarycancers yield a better survival than pancreatic cancers becauseof their early detection and adjuvant treatments can improvelocal control and survival in this subgroup of patients. Adju-vant therapy in periampullary cancers also needs to bereviewed in view of availability of advanced radiotherapytechniques, better chemotherapy, and targeted therapy agents.The GITSG trial demonstrated the superiority of adjuvantchemoradiotherapy treatment in pancreatic cancer with splitcourse radiotherapy of 40 Gy. A 2-year survival rate of 43versus 18 % (p00.03) was observed to favor adjuvant chemo-radiotherapy. This trial demonstrated that increased survivalwas possible with adjuvant treatment after surgical resection ofpancreatic cancer [12]. The European Organisation for Re-search and treatment of Cancer—in a phase III randomized,controlled trial—examined the role of adjuvant chemoradio-therapy for the treatment of pancreatic and periampullarycancers. Majority of the patients (93 %) in this study receiveda radiation dose of only 40 Gy and that too with a plannedinterruption. This trial failed to show any benefit of the adju-vant treatment [13]. The statistical methods adopted in thisstudy have also been questioned by Garofalo et al. [14]. Theradiation dose of 40Gy used in the cited trials appears to be toolow to prevent local recurrence and provide effective adjuvantmanagement for periampullary cancers. In a retrospectiveanalysis, Krishnan et al. have shown higher primary tumorstage (T3, T4) to be an independent adverse risk factor inampulla of vater carcinomas. These patients showed an im-proved overall survival (median 35.2 vs 16.5 months, p00.06)with adjuvant chemoradiotherapy [15]. In the Mayo clinicreview, 472 patients underwent an R0 resection for invasivecarcinoma of the pancreas. Median overall survival after adju-vant radiochemotherapywas 2.1 vs. 1.6 years for surgery alone(p00.001), with a radiotherapy dose of 50.4 Gy. The 2-year

OS was 50 vs. 39 % and the 5-year OS was 28 vs. 17 %,respectively. Adverse prognostic factors identified includedpositive lymph nodes and high histologic grade [16].

In a retrospective analysis of 118 patients with carcinomaof the ampulla of vater, Kim et al. showed that adjuvantchemoradiation may enhance locoregional control and over-all survival after curative resection, especially in those withnodal involvement [17].

Willett et al. [18] reported their experience with 41patients with ampullary carcinomas, 12 of whom were con-sidered of high risk and received adjuvant radiotherapy (40–50.4 Gy), some with radiosensitizing 5-FU chemotherapy.In this study, high-risk features were defined as pancreaticinvasion, high tumor grade, positive nodes, and positivemargins. The high-risk patients who received adjuvant ther-apy exhibited better 5-year actuarial local control comparedwith 17 high-risk patients who underwent resection alone(83 vs. 50 %). Distant failure (liver, peritoneum, and pleura)was the predominant pattern of recurrence. No difference inoverall survival was noted. Poultsides et al. have empha-sized the need for evaluating adjuvant treatment protocols induodenal cancers. Lymph nodal involvement was the majoradverse prognostic factor in their analysis, which againhighlights the need for effective adjuvant chemoradiother-apy [19]. Beltran et al. evaluated adjuvant radiotherapy to adose of 50–60 Gy in extra-hepatic biliary duct cancers. Afive-year actuarial locoregional control rate of 48.3 % wasobserved by them. They advocated newer trials for radiationdose escalation along with newer adjuvant chemotherapyregimens [20]. Horqan et al., in a metanalysis of adjuvanttreatment in biliary tract cancers, found benefit of radiother-apy and chemotherapy in node positive disease [21]. In areview for adjuvant treatment for biliary tract cancers, Ceredaet al. have also stressed the need for newer trials to evaluateadjuvant modalities [22].

Though the GITSG study [12] showed a benefit foradjuvant chemoradiotherapy, it was not clear from that trialwhether the benefit seen was due to adjuvant chemoradio-therapy or maintainence chemotherapy given in that trial.The European Study Group for Pancreatic Cancer undertooka study to evaluate the impact of adjuvant radiochemother-apy in pancreatic cancers. This study reported poor resultswith adjuvant chemoradiotherapy [23]. However, this trialhas been criticized for its quality control, radiation therapydelivery, and performance status deficits in the arms con-taining radiation therapy.

Postoperative Radiotherapy Practices in PeriampullaryCancers

Delivery of adequate radiation dose to the periampullarytumor bed using conventional radiotherapy techniques with

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two or three field portals has been limited by the presence ofmultiple organs at risk as these surround the periampullaryregion. These include the kidneys, small intestine, stomach,liver, and spinal cord. Hence, the use of postoperative ra-diotherapy in periampullary carcinomas has been quite con-servative. The use of inadequate radiation dose, plannedtreatment interruptions, and the ineffective method of radiosensitization have been the major drawbacks. A medianradiotherapy dose of 40 Gy has generally been used withplanned breaks midway in the treatment. Such a low dose isunlikely to impact local control. Modern radiation therapytechniques like intensity-modulated radiotherapy (IMRT)thus have a major role in such a setting to limit the dosesto the organs at risk and practice dose escalation. IMRT hasbeen implemented successfully in other areas of the bodywhere such complex anatomy exists between the tumor andnormal structures. The superiority of dose distribution pro-duced by IMRT over conventional techniques has beendemonstrated in sites such as the head and neck and theprostate. The implementation of IMRT in periampullary andpancreatic cancer however has been limited.

Landry et al. [24] evaluated the influence of IMRT withinverse treatment planning on the dose–volume histogramsof normal tissue compared with standard 3D conformalradiation treatment (3D-CRT) in ten patients with pancreaticcancer. Doses of 61.2 Gy to the gross tumor volume and45 Gy to the clinical treatment volume were evaluated. Theyfound IMRT plans to be more conformal than 3D-CRTplans. The median volume of small bowel exceeding 50and 60 Gy was 19.2, 12.5, and 19.8 % for IMRT and31 % for 3D-CRT, respectively. The normal tissue compli-cation probability model predicted a small bowel complica-tion probability of 9.3 % with IMRT compared with 24.4 %with 3D-CRT (p00.021). Yovino et al. analyzed the use ofIMRT in pancreatic and ampullary cancers with radiothera-py doses ranging from 54 to 59.4 Gy and found a significantdecrease in upper and lower gastrointestinal toxicity withIMRT [25]. Adjuvant IMRT has not been associated with anincrease in local recurrences in pancreatic cancers treatedwith a median dose of 50.4 Gy [26].

Conclusion

The optimal curative management of periampullary carci-noma is still evolving. Surgery followed by adjuvant radio-chemotherapy seems to be a feasible treatment option. Localcontrol can be improved by the use of adjuvant radiotherapy.A postoperative radiotherapy dose of 40 Gy may not beadequate in high-risk cases. Postoperative radiation doseneeds to be escalated using advanced radiation techniqueslike intensity-modulated radiotherapy and further trials arerequired to study dose escalation.

Conflict of Interest The authors declare no conflict of interest.

References

1. Offerhaus GJ, Giardiello FM, Krush AJ, Booker SV, TersmetteAC, Kelley NC, et al. The risk of upper gastrointestinal cancer infamilial adenomatous polyposis. Gastroenterology. 1992;102:1980–2.

2. Jagelman DG, DeCosse JJ, Bussey HJ. Upper gastrointestinalcancer in familial adenomatous polyposis. Lancet. 1988;1:1149–51.

3. Jemal A, Siegal R, Ward E, Hao Y, Xu J, Thun MJ. Cancerstatistics 2009. CA Cancer J Clin. 2009;59:225–49.

4. Kim K, Chie EK, Jang JY, Kim SW, Han SW, Oh DY. Prognosticsignificance of tumour location after adjuvant chemoradiotherapyfor periampullary adenocarcinoma. Clin Transl Oncol. 2012;14:391–5.

5. Crist DW, Cameron JL. The current status of the Whipple opera-tion for periampullary carcinoma. Adv Surg. 1992;25:21–49.

6. Chakravarthy A, Abrams RA, Yeo CJ, Korman LT, DonehowerRC, Hruban RH, et al. Intensified adjuvant combined modalitytherapy for resected periampullary adenocarcinoma: acceptabletoxicity and suggestion of improved 1 year disease free survival.Int J Radiat Oncol Biol Phys. 2000;48:1089–96.

7. Trede M. The surgical treatment of pancreatic carcinoma. Surgery.1985;97:28–35.

8. Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, TalaminiMA, et al. Six hundred fifty consecutive pancraeticoduodenecto-mies in the 1990s: pathology, complications and outcomes. AnnSurg. 1997;226:248–57.

9. Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH,Goodman SN, et al. Pancreaticoduodenectomy for cancer ofthe head of the pancreas: 201 patients. Ann Surg. 1995;221:721–33.

10. Bluemke DA, Abrams RA, Yeo CJ, Cameron JL, FishmanEK. Recurrent pancreatic adenocarcinoma: spiral CT evalua-tion following the Whipple procedure. Radiographics. 1997;17:303–13.

11. Griffin JF, Smalley SR, Jewel W, Paradelo JC, Reymond RD,Hassenein RES, et al. Patterns of failure after curative resectionof pancreatic carcinoma. Cancer. 1990;66:56–61.

12. Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combinedradiation and chemotherapy following curative resection. ArchSurg. 1985;120:899–03.

13. Klinkenbijl JH, Jeekel J, Sahmoud T, Pel RV, Couvreur ML,Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil aftercurative resection of cancer of the pancreas and periampullaryregion: phase III trial of the EORTC Gastrointestinal Tract CancerCooperative Group. Ann Surg. 1999;230:776–82.

14. Garofalo MC, Regine WF, Tan MT. On statistical reanalysis, theEORTC trial is a positive for adjuvant chemoradiation in pancre-atic cancer. Ann Surg. 2006;244:332–3.

15. Krishnan S, Rana V, Evans DB, Varadhachary G, Das P, Bhatia S,et al. Role of adjuvant chemoradiation therapy in adenocarcinomasof the ampulla of vater. Int J Radiation Oncol Biol Phys.2008;70:735–43.

16. Miller RC, Iott MJ, Corsini M. Review of adjuvant radiochemo-therapy for resected pancreatic cancer and results from Mayo clinicfor the 5th JUCTS symposium. Int J Radiat Oncol Biol Phys.2009;75:364–8.

17. Kim K, Chie EU, Jang JY, Kim SW, Oh DY, Im SA, et al. Role ofadjuvant chemoradiotherapy for ampulla of vater cancer. Int JRadiat Oncol Biol Phys. 2009;75:436–41.

J Gastrointest Canc (2013) 44:111–114 113

18. Willet CG, Warshaw AL, Convery K, et al. Patterns of failure afterpancreaticoduodenectomy for ampullary carcinoma. Surg GynecolObstet. 1993;176:33–8.

19. Poultsides GA, Huang LC, Cameron JL, Tuli R, Lan L, Hruban RH,et al. Duodenal adenocarcinoma: clinicopathologic analysis andimplications for treatment. Ann Surg Oncol. 2012;19(6):1928–35.

20. Beltran MB, Roth AD, Mentha G, Allal AS. Adjuvant radio-chemotherapy for extrahepatic biliary tract cancers. BMC cancer.2011;11:267–72.

21. Horqan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in thetreatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30(16):1934–40.

22. Cereda S, Belli C, ReniM. Adjuvant treatment in biliary tract cancer:to treat or not to treat? World J Gastroenterol. 2012;18:2591–6.

23. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, HickeyH, et al. A randomized trial of chemoradiotherapy and chemotherapy

after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–10.

24. Landry JC, Yang GY, Ting JY, Staley CA, Torres W, Esiashvili N, etal. Treatment of pancreatic cancer tumors with intensity-modulatedradiation therapy (IMRT) using the volume at risk approach (VARA):employing dose–volume histogram (DVH) and normal tissue com-plication probability (NTCP) to evaluate small bowel toxicity. MedDosim. 2002;27:121–9.

25. Yovino S, Poppe M, Jabbour S, David V, Garofalo M, Pandya N, etal. Intensity modulated radiation therapy significantly improvesacute gastrointestinal toxicity in pancreatic and ampullary cancers.Int J Radiat Oncol Biol Phys. 2011;79:158–62.

26. Yovino S, Maidment BW, Herman JM, Pandya N, Goloubeva O,Wolfgang C, et al. Analysis of local control in patients receivingIMRT for resected pancreatic cancers. Int J Radiat Oncol BiolPhys. 2012;83:916–20.

114 J Gastrointest Canc (2013) 44:111–114