|Year : 2015 | Volume
| Issue : 2 | Page : 433-437
Adjuvant chemoradiotherapy in periampullary cancers - Where does it stand with conformal radiotherapy: A single institution experience
Rakesh Kapoor, Amit Bahl, Tapesh Bhattacharyya, Rajesh Gupta, Arun S Oinam
Department of Radiation Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India
|Date of Web Publication||7-Jul-2015|
Department of Radiation Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012, Punjab
Source of Support: A preliminary report of this study was presented in the 15th ESMO GI cancers in Barcelona and the abstract had been published in Annals of Oncology 24;2013 suppl 4: P81. The authors have updated the full results with more number of patients till 2012 (2007–2012) that is, for 5 years., Conflict of Interest: None
Background: Treatment of periampullary cancer involves Whipple surgery, followed by adjuvant radiotherapy and chemotherapy. Postoperative radiotherapy is particularly useful in managing high-risk patients (tumors involving the pancreas, poorly differentiated histology, involved lymph nodes and positive margins). Here, we review our results of treatment of 84 patients treated by surgery and adjuvant radiotherapy and chemotherapy.
Material and Methods: A retrospective analysis of 84 patients of periampullary cancers treated in our department between January 2007 and December 2012 was carried out. All patients underwent Whipples surgery followed by postoperative radiotherapy 45-50 Gy/25-28 number in those presenting with high-risk features. Radiotherapy was delivered using three-dimensional conformal technique with 6 MV photons using three field treatment plans. Chemotherapy was given for 6 cycles using gemcitabine and oxaliplatin regimen repeated 2 weekly.
Results: Eighty four postoperative patients with high-risk features were available for the final analysis. There were 69 males and 15 female patients. There were 34.5% stage I, 57.1% stage II and 8.3% stage III patients. At end of adjuvant treatment with radiotherapy and chemotherapy 70% patients had a complete response, 7.5% had residual disease, 15% showed progressive disease, 5% were dead and 2.5% defaulted the treatment. The mean number of chemotherapy cycles received was 2.6. At 1 year follow-up the probability of disease free survival was 80% for node-negative patients versus 73% for node-positive disease (P = 0.27). Patients with stage up to IIA had a 1 year disease free survival of 83% versus 40% for patients with stage beyond IIA (P = 0.024).
Conclusions: Our results showed a trend favoring lymph node negative status with disease free survival. With computed tomography based planning, adequate delineation of draining nodes is possible, and radiation toxicity has significantly decreased. Adequate coverage of nodal basins during radiotherapy planning is important, and stage of the disease seems to be an important prognostic factor.
Keywords: Chemotherapy, periampullary cancer, radiotherapy
|How to cite this article:|
Kapoor R, Bahl A, Bhattacharyya T, Gupta R, Oinam AS. Adjuvant chemoradiotherapy in periampullary cancers - Where does it stand with conformal radiotherapy: A single institution experience. J Can Res Ther 2015;11:433-7
|How to cite this URL:|
Kapoor R, Bahl A, Bhattacharyya T, Gupta R, Oinam AS. Adjuvant chemoradiotherapy in periampullary cancers - Where does it stand with conformal radiotherapy: A single institution experience. J Can Res Ther [serial online] 2015 [cited 2020 May 28];11:433-7. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/433/144353
| > Introduction|| |
Periampullary cancers are defined as tumors arising within 1 cm of ampulla of vater and include ampullary, pancreatic head, bile duct and duodenal cancer. Surgery is the mainstay of curative treatment in periampullary cancer. With the advancement of surgical techniques, the perioperative morbidity has been reduced significantly. The 5 years overall survival rate in patients who undergo curative resection, is unsatisfactory, ranging from 30% to 60%. Even after radical surgery around 70% developed distant metastasis, and 50% of the patients fail locoregionally and the prognosis of these patients remains poor. Therefore combining aggressive local and systemic adjuvant therapy may help to increase the treatment outcome. However, there are contradictory results of adjuvant chemo radiotherapy in the treatment of periampullary cancer and which subset of patients are going to be benefitted from adjuvant therapy is not yet clear. Keeping this view in mind, we have conducted a retrospective analysis to find out where does adjuvant chemoradiation stand in our patients and which subset of patients should be considered under high-risk category so that they can benefit most with adjuvant chemo radiotherapy.
| > Materials and methods|| |
A retrospective analysis of 84 patients of periampullary cancers treated in our department between 2007 and 2012 was carried out. All patients underwent detailed pretreatment workup, which included complete history and physical examination, routine blood investigations comprising complete hemogram, liver function tests, kidney function tests, chest X-ray, contrast-enhanced computed tomography (CT) of abdomen and pelvis, biopsy and CA 19.9. A multidisciplinary team of surgeons, gastroenterologists, radiologists and radiation oncologists evaluated all the patients. Patients with outside pathology diagnosis had their pathology slides reviewed at our institution.
All patients underwent Whipple surgery followed by postoperative radiotherapy 45-50 Gy/25-28 number in those presenting with high-risk features. Radiotherapy was delivered using conformal technique with 6 MV photons using three field treatment plans [Figure 1] and [Figure 2]. Planning CT scans films were taken for the patients with proper immobilization using a multislice CT scanner with slice thickness of 2.5 mm using a multislice CT scanner (GE Healthcare Technologies, Wankesha, WI, USA). The images were transferred to Eclipse TM treatment planning system (version 8.6, Varian Associates, Palo Alto, CA, USA). Patients were planned for postoperative radiation initially with departmental protocol and subsequently using radiation therapy oncology group (RTOG) guidelines for tumor bed and nodal stations delineation after taking contrast-enhanced CT scan on Eclipse planning system [Figure 3] and [Figure 4]. Each plan was evaluated by using dose volume histogram for bilateral kidneys, liver, stomach, spinal cord and dose to a small intestine. Chemotherapy was given for 6 cycles using gemcitabine and oxaliplatin (GEMOX) regimen with a dose of gemcitabine 1 g/m 2 and Oxaliplatin 100 mg/m 2 repeated 2 weekly. For statistical analysis SPSS version 18 was used. A P < 0.05 were considered as significant. Kaplan-Meir analysis was used for disease free survival evaluation.
|Figure 1: Three field three-dimensional conformal radiotherapy treatment plan|
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| > Results|| |
Of the total 84 patients 69 were males and 15 were females. The median age of presentation was 59 years (range: 27-78 years). According to American Joint Committee on Cancer staging majority of the patients presented with T2 (45.2%) and T3 (42.9%) disease. Twenty-nine patients had lymph node metastasis on imaging. Most of the patients (57.1%) belonged to stage II disease [Table 1].
All patients underwent Whipple surgical procedure. All patients had pathological diagnosis of adenocarcinoma. Sixty-nine (82.1%) patients had pathological tumor size of <3 cm, followed by tumor size of 4-6 cm in 11 (13.1%) patients. Tumor size of >6 cm was seen in four cases. Margins were positive in only 4 (4.8%) patients and most patients had clear margins. Mean number of lymph nodes dissected was 5.85. Lymphovascular space invasion (LVSI) was positive in 9.5% of cases. Perineural invasion (PNI) was seen in six cases [Table 2].
Patients with high-risk features were taken up for sequential chemo radiation. Patients were treated with radiation dose of 45-50.4 Gy delivered over 25-28 fractions. All patients (79/84) except 2 were treated with three-dimensional (3D) conformal radiotherapy. These two patients were treated with intensity-modulated radiotherapy. Three patients did not receive any adjuvant radiotherapy. Three patients did not get any radiotherapy. Two of these patients were referred in our department after more than 8 months of surgery because they had delayed wound healing due to wound dehiscence. One a patient was having Karnofsky performance status <50 and had persistent symptoms of subacute intestinal obstruction.
All patients received GEMOX based chemotherapy. Mean number of chemotherapy cycles received by our patients was 2.6.
Acute radiation morbidity was evaluated using RTOG criteria. The most common toxicity observed was nausea or vomiting with grade 1 nausea and vomiting seen in nine patients. Grade 2 nausea and vomiting was seen in four patients. Grade 2 abdominal pain was seen in three patients. Three patients suffered from grade 2 diarrhea.
At the end of adjuvant treatment 70% had a complete response, partial response and stable disease were seen in 7.5% of patients and 15% had progressive disease. Three patients were lost to follow-up. Four patients expired after a short period after the completion of adjuvant therapy. At a median follow-up period of 1 year 51 patients (60.7%) were disease free, 14 patients (16.7%) had residual disease and disease progression was seen in 15 patients (17.9%).
Our patients had 1 year disease free survival of around 70% [Figure 3]. On subset analysis, it was found that at 1 year follow-up the probability of disease free survival was 80% for node-negative patients versus 73% for node-positive disease (P = 0.27) [Figure 4]. Patients with stage up to IIA had a 1 year disease free survival of 83% versus 40% for patients with stage beyond IIA (P = 0.024) [Figure 5]. Age, sex, margin status, pathological tumor size, LVSI, PNI did not have any significant impact on disease free survival.
| > Discussion|| |
Treating periampullary cancer is a significant therapeutic challenge. The prognosis of this disease is poor and most of the patients after radical resection recur primarily within the abdominal cavity; most recurrences are locoregional and in the liver. Therefore, combining local and systemic adjuvant treatment in pereiampullaary cancers seems promising. Adjuvant chemotherapy and radiation for pancreatic cancer has been the subject of debate for a long period. Our study suggests a role for selective treatment of patients with advanced primary tumor stage with adjuvant chemoradiation therapy.
In the present study, the median age of presentation is 59 years (range: 27-78 years) that is quite similar to western figures. Kim et al.  reported median age of presentation was 57 years. In a study by Yovino et al.  the median age was 62 years. Lee et al.  reported a slightly higher median age of 65 years (range: 42-78 years). Male to female ratio is significantly higher (4.6:1) as compared to other studies. ,,
With comprehensive staging evaluation and careful patient selection Whipple procedure was performed in our patients. Only four patients had positive margins and margin status were unknown in two patients. No patient had gross residual disease. Most studies report high resectability rates in nonpancreatic periampullary cancers. ,
Mean number of lymph nodes dissected in our study was 5.85 which was far inferior from the standard. Most of our patients underwent inadequate lymph node dissection which prompted us to give adjuvant treatment in almost all the patients. Lymph node positivity was seen in only 32 (38.1%) patients. On subset analysis of our study, it was found that at 1 year follow-up the probability of disease free survival was 80% for node negative patients versus 73% for node-positive disease (P = 0.27). Krishnan et al.  showed that nodal status was prognostic for poor local control (P = 0.03) but not distant control or overall survival. Lee et al.  found that positive nodes were a significant adverse factor (P = 0.001) and adjuvant therapy should be advocated in those cases. Bhatia et al.  in their studies concluded that postoperative adjuvant 5 FU based chemoradiation might improve overall survival in patients with pathologically node positive disease.
Willet et al.  reported their experience with 41 patients with ampullary carcinomas, 12 of them were considered high risk and received adjuvant radiation (40-50.4 Gy), some with radiosensitizing 5 FU chemotherapy. In that study high-risk features identified were the pancreatic invasion, high tumor grade, positive nodes and positive margins. Those high-risk patients who received adjuvant therapy exhibited better 5 years locoregional control as compared with high-risk patients who underwent resection alone, although this trend was not statistically significant. There was no difference in overall survival and distant failure (liver, peritoneum and pleura) was the predominant pattern of relapse.
Lee et al.  reported their experience of 39 patients with resected ampullary cancer. Thirteen patients received adjuvant chemoradiation. Radiation therapy was delivered to the surgical bed and regional lymph nodes to a median dose of 48.6 Gy with concurrent 5 FU. Patients with nodal metastasis or T3 disease were at high risk for relapse and use of adjuvant chemoradiotherapy might improve long-term disease control in these patients.
Kim et al.  shared their experience of adjuvant chemoradiation in 118 patients with resected ampulla of vater cancer. Forty-one patients received adjuvant chemoradiotherapy. Postoperative radiotherapy dose was 40 Gy delivered in 2 Gy/fraction, with a planned 2 weeks gap halfway through the treatment period. Intravenous 5 FU was given on day 1-3 of each split course. Adjuvant chemoradiation might enhance locoregional control and overall survival in patients with ampulla of vater cancer after curative resection, especially in those with nodal involvement.
Several other studies , reported the positive impact of adjuvant chemoradiotherapy on overall survival in patients with high-risk features.
Lymphovascular invasion and PNI was seen in 9.5% and 7.1% of patients respectively, and they did not have any significant impact on disease free survival. Similar findings are showed in a study by Krishnan et al.  where LVSI or PNI were not significantly associated with local control, distant control or overall survival. However, Mehta et al.  showed neurovascular invasion as one of the determinants of poor prognosis.
Our patients had 1 year disease free survival of around 70% [Figure 3]. Chakravarthy et al.  in their study reported disease free survival at 12 months was 66%. The median survival was not yet reached but was >17 months. For pancreas patients, a 1-year disease free survival was 52%, and the median disease free survival was 12.4 months. For nonpancreatic periampullary patients at 12 month's disease, free survival was 90%. Abrams et al.  reported a median disease free survival of 8.3 months of all patients and 8.5 months for patients with pancreatic cancer. Lee et al. showed disease free survival of 52% at 3 years. Patients with stage up to IIA had a 1 year disease free survival of 83% versus 40% for patients with stage beyond IIA (P = 0.024). Krishnan et al.  found higher tumor stage (T3/T4) as an independent adverse risk factor for poorer treatment outcome. Lee et al.  also showed higher pathological stage as poor prognostic determinant of 3 years disease free survival. The current study identified nodal involvement and stage of the disease as important prognostic factors which have an impact on disease free survival, and those patients can be benefitted from adjuvant chemotherapy and radiation.
In contrast to those studies supporting the use of adjuvant therapy, there are studies that have showed no definite benefit to the addition of adjuvant therapy. Sikora et al.  evaluated the effect of concurrent chemoradiation, followed by maintenance chemotherapy in ampullary cancer and showed no benefit of adjuvant therapy in local control or survival. Czito et al.  showed improved local control from adjuvant therapy with resection in patients with advanced disease but there was no overall survival benefit. Phase III trial conducted by European Organisation for Research and Treatment of Cancer (EORTC)  examined the role of adjuvant chemoradiotherapy for the treatment of pancreatic and periampullary cancers, but this study failed to show any benefit of adjuvant treatment. However, the use of inadequate radiation dose, planned treatment interruptions and the ineffective method of radiosensitization have been a major draw backs of many of these negative studies. The European Study Group for Pancreatic Cancer-1 study,  which had shown detrimental results of radiotherapy was also criticized for its quality control, the manner in which radiation therapy was delivered and also regarding potential performance status deficits in the arm containing radiotherapy.
In the current study, all patients received postoperative radiotherapy. Concurrent chemoradiation was not given to our patients because of their unsatisfactory general condition and poor nutritional status. Instead of concurrent chemo radiation we preferred sequential chemoradiation with GEMOX that our patients tolerated well. Only three patients suffered from grade 2 diarrhea and four patients suffered from grade 2 nausea and vomiting which were managed conservatively.
One of the strengths of our study is that we could deliver the radiation dose up to 45-50.4 Gy without any preplanned gap like EORTC trial  or study by Kim et al.  The impact of radiotherapy quality on local control and its potentially associated impact on survival in the adjuvant setting has already been assessed prospectively in RTOG 9704 study. The present day RTOG contouring guidelines along with 3D conformal dose delivery as highlighted in this study has shown definite improvement in patient outcome both terms of local control and disease free survival.  With CT based planning, adequate delineation of draining nodes is possible, and radiation toxicity has significantly decreased thus preventing interruption in chemo radiation. Our results showed a trend favoring lymph node negative status with disease free survival. Adequate coverage of nodal basins during radiotherapy planning is important, and stage of the disease seems to be an important prognostic factor in management of periampullary cancers. This study highlights the stage of the disease is an important prognostic factor, which can be considered as one of the high-risk features in periampullary cancers. On the other hand, limitations of our study are small sample size and its retrospective nature.
| > References|| |
Kim K, Chie EK, Jang JY, Kim SW, Oh DY, Im SA, et al.
Role of adjuvant chemoradiotherapy for ampulla of Vater cancer. Int J Radiat Oncol Biol Phys 2009;75:436-41.
Yovino S, Poppe M, Jabbour S, David V, Garofalo M, Pandya N, et al.
Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys 2011;79:158-62.
Lee JH, Whittington R, Williams NN, Berry MF, Vaughn DJ, Haller DG, et al.
Outcome of pancreaticoduodenectomy and impact of adjuvant therapy for ampullary carcinomas. Int J Radiat Oncol Biol Phys 2000;47:945-53.
Barton RM, Copeland EM 3 rd
. Carcinoma of the ampulla of Vater. Surg Gynecol Obstet 1983;156:297-301.
Talamini MA, Moesinger RC, Pitt HA, Sohn TA, Hruban RH, Lillemoe KD, et al.
Adenocarcinoma of the ampulla of Vater. A 28-year experience. Ann Surg 1997;225:590-9.
Krishnan S, Rana V, Evans DB, Varadhachary G, Das P, Bhatia S, et al.
Role of adjuvant chemoradiation therapy in adenocarcinomas of the ampulla of vater. Int J Radiat Oncol Biol Phys 2008;70:735-43.
Bhatia S, Miller RC, Haddock MG, Donohue JH, Krishnan S. Adjuvant therapy for ampullary carcinomas: The mayo clinic experience. Int J Radiat Oncol Biol Phys 2006;66:514-9.
Willett CG, Warshaw AL, Convery K, Compton CC. Patterns of failure after pancreaticoduodenectomy for ampullary carcinoma. Surg Gynecol Obstet 1993;176:33-8.
Mehta VK, Fisher GA, Ford JM, Poen JC, Vierra MA, Oberhelman HA, et al.
Adjuvant chemoradiotherapy for "unfavorable" carcinoma of the ampulla of vater: Preliminary report. Arch Surg 2001;136:65-9.
Sikora SS, Balachandran P, Dimri K, Rastogi N, Kumar A, Saxena R, et al.
Adjuvant chemo-radiotherapy in ampullary cancers. Eur J Surg Oncol 2005;31:158-63.
Chakravarthy A, Abrams RA, Yeo CJ, Korman LT, Donehower RC, Hruban RH, et al.
Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: Acceptable toxicity and suggestion of improved 1-year disease-free survival. Int J Radiat Oncol Biol Phys 2000;48:1089-96.
Abrams RA, Grochow LB, Chakravarthy A, Sohn TA, Zahurak ML, Haulk TL, et al.
Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: Survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels. Int J Radiat Oncol Biol Phys 1999;44:1039-46.
Czito BG, Clough R, Pappas T. Carcinoma of the ampulla of vater: Patterns of failure after resection and possible benefit of adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 2005;63:S166-7.
Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, 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;230:776-82.
Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al.
A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-10.
Abrams RA, Winter KA, Regine WF, Safran H, Hoffman JP, Lustig R, et al.
Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704: A phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 2012;82:809-16.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]