Ann Surg Oncol DOI 10.1245/s10434-014-3969-y
ORIGINAL ARTICLE – PANCREATIC TUMORS
Morbidity Among Long-Term Survivors After Pancreatoduodenectomy for Pancreatic Adenocarcinoma Kathryn T. Chen, MD1, Karthik Devarajan, PhD2, and John P. Hoffman, MD3 Department of Surgery, St. Luke’s Hospital, Southcoast Health System, New Bedford, MA; 2Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA; 3Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 1
ABSTRACT Background. Because pancreatoduodenectomy for pancreatic adenocarcinoma is focused on disease-free and overall survival, morbidity among long-term survivors is not well described. This study sought to evaluate outcomes for long-term survivors of pancreatic cancer after pancreatoduodenectomy. Methods. The authors identified 29 patients from their prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy and were without evidence of disease during at least 3 years of follow-up evaluation. Demographics, treatment, and pathologic characteristics were collected for review. Data with regard to long-term sequelae also were collected, focusing on those complications requiring additional procedures and on the development of metachronous cancers. Results. The median follow-up period was 83 months, with 62 % of patients still alive. All patients received an R0 resection, and 34 % of the patients had N1 disease. For 42 % of the patients, no significant subsequent sequelae occurred. In the four remaining patients (14 %), ascites developed, requiring repeated paracentesis or Denver shunt, with a median time to development (MTD) of 63 months. Six patients (21 %) experienced a biliary stricture requiring stent placement (MTD, 56 months). One patient experienced portal venous thrombosis requiring a venous stent (MTD, 52 months), and four patients (14 %) experienced clinically significant ulcers (MTD,
Ó Society of Surgical Oncology 2014 First Received: 26 April 2014 K. T. Chen, MD e-mail: [email protected]
52 months). With regard to metachronous cancers, two patients experienced subsequent lymphomas (MTD, 92 months). Conclusions. Long-term survivors among patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can experience significant late sequelae, which often manifest more than 3 years after surgery. As such, continued follow-up evaluation and counseling are warranted.
The mortality associated with a diagnosis of pancreatic cancer continues to be grim. Fewer than 10 % of patients present with clearly resectable disease. As such, the focus for the treatment of pancreatic cancer has been on diseasefree and overall survival and on predictors for improved survival. However, long-term morbidity, more than 3 years after multimodality treatment of pancreatic cancer (chemotherapy, radiation therapy, and surgery), is not well described, although there is a definite growing cohort of long-term survivors. Currently, most high-volume institutions report a 5-years survival rate of 7–25 % for patients thought to be potentially curable who undergo surgical resection, with actual survival rates dependent on final pathologic findings.1–5 If morbidities are discussed in these reports of long-term survival, they generally are described in terms of surgical complications such pancreatic fistulas and wound infections or as wellknown physiologic changes such as delayed gastric emptying, pancreatic insufficiency, or diabetes mellitus.6,7 Postoperative complications occur for up to 50 % of patients undergoing pancreatoduodenectomy, and the management of these complications is well described.3,8 Less described are those long-term morbidities that can be the sequelae of multimodality therapy. In particular, radiation therapy is known to have late side effects, with irreversible ischemic changes occurring over a period of
K. T. Chen et al.
years. For instance, in rectal cancer, a lifelong risk beyond 10 years, with an annual rate of complications in surrounding organs and soft tissue of 10–14 % has been described.9,10 Because the length of follow-up evaluation for pancreatic cancer often is very short, these changes are not often reported. Some long-term effects attributed to irradiation of the pancreatic bed are gastrointestinal ulceration and enteritis, fistula formation, bleeding, and obstruction.11,12 As our experience in managing patients after pancreatoduodenectomy has grown, we have recognized that the development of late complications longer than 3 years after surgery requiring procedural interventions is not uncommon. It is of utmost importance to rule out the recurrence of cancer, experienced by 20 % of 5-years survivors.13,14 However, we sought to describe complications among long-term survivors of pancreatic cancer without evidence of recurrence, the management of these complications, and the possible relationships to multimodality therapy.
METHODS Under institutional review board approval, we identified 29 patients from our prospectively collected database of pancreatic adenocarcinoma patients who had undergone pancreatic head resection with curative intent (280 total patients, excluding those patients who had an R2 resection) with at least 3 years of follow-up evaluation and without evidence of disease at the last follow-up evaluation. All patients who experienced complications underwent diagnostic workups for evaluation of recurrent disease, particularly those patients with ascites or jaundice. The general workup included CA19-9, radiographic imaging such as computed tomography (CT) or magnetic resonance imaging (MRI), endoscopy or endoscopic retrograde cholangiopancreatography (ERCP) when appropriate, and evaluation of cytology or pathology for malignant cells. All the patients described in this study were thought not to have recurrent disease based on interpretation of these studies, and this was clearly documented in the follow-up clinical notes. Data regarding demographics, treatment strategies, pathologic findings, and follow-up evaluation were collected. Staging was in accordance to the American Joint Committee on Cancer (AJCC) 7th edition. Long-term complications were defined as those requiring a procedure for either diagnosis or treatment at least 1 year after the initial operation. The procedures included paracentesis, endoscopy, ERCP, percutaneous transhepatic cholangiogram, stent placement, mesenteric venous shunt placement, or a combination of these. The median time to the development (MTD) of complications was defined as the interval between surgical resection and the development of symptoms requiring an eventual procedure.
TABLE 1 Patient demographics, treatment characteristics, and pathology n (%) Median age at diagnosis (years)
71
Male gender
15 (52)
Location of tumor Head Head/body
25 (86) 4 (14)
Median CA19-9 at diagnosis: n (range)
62.7 (0–3,940)
Receipt of neoadjuvant chemoradiation Receipt of neoadjuvant chemotherapy before/after neoadjuvant chemoradiation
12 (41) 3 (10)
Type of surgery Whipple (with antrectomy)
21 (72)
Pancreatoduodenectomy
8 (28)
Required vein resection
3 (10)
Pathologic stage 0
8 (28)
1a
3 (10)
1b
1 (3)
2a
7 (24)
2b Node positivity
10 (34) 10 (34)
R0 margin
29 (100)
Adjuvant chemoradiation
12 (41)
Adjuvant chemotherapy
4 (14)
Median follow-up period (months)
83
Median overall survival (months)
100
We performed univariate analyses to identify variables associated with long-term complications requiring procedural intervention. In our analyses, the variables considered included gender, age, location of tumor (head, body, or tail), receipt of neoadjuvant chemoradiation, type of surgery (classic Whipple with antrectomy vs pyloruspreserving pancreatoduodenectomy), venous resection at the time of surgery, pathologic response to chemoradiation (major, moderate, or minor), receipt of postoperative chemoradiation, and receipt of postoperative chemotherapy. RESULTS Demographics and Treatment Characteristics The study identified 29 patients without evidence of recurrence who had received at least 3 years of follow-up evaluation (Table 1). The median age at diagnosis was 71 years, and 52 % of the patients were men. The majority of the patients (86 %) had tumors located in the head of the pancreas. The median CA19-9 at diagnosis (uncorrected for bilirubin) was 62.7 (range, 0–3,940).
Morbidity Among Long-Term Survivors
Of the 29 patients, 27 were found to have invasive cancer, and 2 were found to have carcinoma in situ at the final pathology. The latter two patients both had ductal carcinoma in situ (DCIS) arising in intraductal papillary mucinous neoplasms (IPMNs). With regard to treatment, 24 patients (82 %) received chemoradiation. Half of these patients received their treatment in the neoadjuvant setting, and the remaining half received it postoperatively. Chemoradiation consisted of gemcitabine or 5-FU given concurrently with 50.4 Gy of radiation in 28 fractions. Of the 12 patients who received neoadjuvant chemoradiation, 3 went on to receive additional chemotherapy (gemcitabine, gemcitabine-pxaliplatin, or gemcitabine-erlotinib) before surgery. Three patients (10 %) received adjuvant gemcitabine or 5-FU alone, and three patients received adjuvant gemcitabine after receipt of neoadjuvant chemoradiation. Two patients (7 %) had only carcinoma in situ at the final pathology and did not receive any additional therapy other than surgery. For treatment, 72 % of the patients underwent a classic Whipple procedure with antrectomy, and 28 % underwent a pylorus-preserving pancreatoduodenectomy. Three patients required portal vein or superior mesenteric vein (SMV) reconstruction. All the patients received an R0 resection. Six patients (50 % of those receiving neoadjuvant chemoradiation) had a pathologic complete response to neoadjuvant therapy. Overall, 50 % had pathologic stage 0 or 1 disease, and a total of 67 % of the patients had node-negative disease. Somewhat surprisingly, 34 % of our long-term survivors were found to have node-positive disease. After definitive surgical resection, eight immediate postoperative complications occurred (28 % overall). Reoperations were performed for three patients: two for jejunal loop problems and one for blood within the drains (nothing found at exploration). These three patients had no late complications. Other complications included one wound infection, one atrial fibrillation, and one case of Clostridium difficile infection. Three patients had type A fistulas. Two of these patients recovered without futher complications and were not diabetics at the last follow-up evaluation. The remaining patient needed a perioperative reoperation for obstruction of the retrocolic gastrojejunostomy. This patient had been diabetic for more than a decade before Whipple and remained diabetic postoperatively. Two of these three patients had no late complications. The remaining patient experienced portal vein and SMV thrombosis at 52 months. Late Complications At the last follow-up evaluation, 34 % of the patients were receiving medications for diabetes, and 73 % of the patients were taking pancreatic enzyme supplements routinely for varying degrees of pancreatic insufficiency,
TABLE 2 Late sequelae and metachronous cancers n (%)
Median time to development (months)
Ascites
5 (17)
63
Biliary stricture Ulcer
6 (21) 4 (14)
56 52
Major late sequelae
Incisional hernias
2 (7)
29
Bile reflux
1 (3)
60
Radiation enteritis and development of jejunalcolic fistula
1 (3)
15 (fistula, 92)
1 (3)
52
Portal vein thrombosis Reoperation (any) Metachronous cancers Lymphoma
5 (17) 2 (7)
92
Colon
1 (3)
3
Bladder dysplasia
1 (3)
63
whereas 42 % of the patients experienced no late adverse events from pancreatoduodenectomy. The more common late sequelae included ascites, ulcer disease, and biliary stricture (Table 2). Five patients (17 %) experienced ascites, with a MTD of 63 months. None of these patients had undergone portal vein or SMV reconstruction at the time of the original operation. Three of these five patients required multiple repeat paracentesis for symptomatic relief, and two eventually underwent Denver shunt placement. The etiology for ascites was not always apparent, but cytologic interpretation of multiple samples of the ascites showed no neoplasia. Four of the five patients were thought to have cryptogenic cirrhosis. The remaining patient was thought to have biliary cirrhosis with a concurrent biliary stricture requiring repeated dilation. In terms of biliary strictures, six patients (21 %) underwent repeated procedures for treatment, with an MTD of 56 months. Some presented initially with cholangitis. Three patients had concurrent stones and sludge shown on a cholangiogram. One patient with biliary stenosis originally underwent an emergent Whipple procedure for a biliary-portal fistula and had concomitant SMV and bile duct narrowing. Another patient had multiple strictures within the intra- and extrahepatic biliary tree, with a secondary sclerosing pattern. The patients were typically managed with stent placement, via either percutaneous transhepatic cholangiography or endoscopic means. Regardless, repeated procedures were typically required for stent exchange or for persistent stricturing after balloon dilation. Only one patient was able eventually to have the stent permanently removed.
K. T. Chen et al.
Although all our patients continue to receive a proton pump inhibitor or H2 blocker after surgery, four patients (14 %) experienced ulcer disease, with an MTD of 52 months. Two patients presented with perforated gastrojejunal anastomotic ulcers, and two patients had a diagnosis of duodenal ulcers. Two additional patients experienced diffuse gastritis. The patients who presented with nonperforated ulcers and gastritis were managed medically with antacid therapy. Both of the patients who experienced perforated anastomotic ulcers received an antrectomy with pancreatoduodenectomy. One had been managed initially with a proton pump inhibitor for gastritis but had stopped medication 3 months before presentation. The remaining patient experienced perforation while receiving medication for gastritis, and a vagotomy was performed at the time of exploration. Other major complications included incisional hernias (2 patients, MTD 29 months), bile reflux gastritis (1 patient, MTD 60 months), radiation enteritis with repeated bowel obstruction and eventual development of jejunocolic fistula (1 patient, MTD of enteritis 15 months and MTD of fistula 92 months), and SMV/portal vein thrombosis (1 patient, MTD 52 months). Five patients (17 %) had multiple late complications with combinations of the aforementioned complications. During our relatively short follow-up period, metachronous cancers were uncommon (3 of 28). Two patients experienced lymphoma (7 %, MTD 93 months). Both were non-Hodgkin’s B cell lymphomas. One was a mantle cell lymphoma, and the other was a diffuse large B-cell lymphoma. Colon cancer was diagnosed for one patient shortly after surgical resection for pancreatic cancer (MTD 3 months). Using univariate analysis, we attempted to identify predictors of major complications requiring procedural intervention. None of the complications were significantly associated with a predictor (gender, age, location of tumor [head or body]), receipt of neoadjuvant chemoradiation, type of surgery (classic Whipple with antrectomy vs pancreatoduodenectomy), venous resection at the time of surgery, pathologic response to chemoradiation (major, moderate, or minor), receipt of postoperative chemoradiation, or receipt of postoperative chemotherapy. The analysis was limited by the small number of patients in our study and the relatively large number of potential variables. DISCUSSION Most studies evaluating the morbidity of pancreatoduodenectomy focus on immediate postoperative complications (pancreatic fistula, delayed gastric emptying) or the sequelae related to loss of pancreatic function such as diabetes or steatorrhea. Only a handful of studies have evaluated patients with long-term survival after resection for
pancreatic malignancy, and none have described long-term complications requiring intervention as we have. Of our 29 patients, 12 (42 %) were without significant sequelae. We were unable to identify any predictors for specific complications, either due to small sample size or truly a lack of association. Patients who received multimodality therapy with chemoradiation and surgery appeared as likely to experience significant complications as those without such therapy. Two patients in our group did not receive chemotherapy or radiation. One of these patients had no further complications, and the other patient experienced a perforated marginal ulcer. With regard to biliary strictures, all the patients in our study who experienced biliary strictures requiring repeated interventions received either neoadjuvant (n = 3, 50 %) or adjuvant (n = 3, 50 %) external beam radiation. However, an association between radiation and stricture formation has never been proved in the literature. House et al.15 reported on the incidence of biliary stricture formation after pancreatoduodenectomy for both benign and malignant disease. They found an MTD of 13 months (range, 1– 106 months), without association with postoperative chemoradiotherapy. The incidence reported was only 2.6 % among patients with malignant disease, although the median follow-up time was only 27 months. Similarly, another review of 122 patients who underwent pancreatoduodenectomy for benign diseases showed a 5- and 10-year cumulative probability of biliary stricture of 8 % and 13 %, respectively.16 The causes of biliary strictures are thus considered more likely related to ischemia or reflux of enteric contents into the biliary system with cholangitis than to prior radiotherapy.15–17 In our study, we also had one patient whose an ischemic stricture likely developed after an emergent Whipple for biliary-portal fistula. The bile duct was quite scarred at the time. With regard to ulcer development, radiation therapy is recognized as causing mucosal ulceration and ischemia in the gastrointestinal tract, which can alternately present as enteritis.12,18 However, the etiology also can be attributed to a lack of reflux of basic biliopancreatic secretions and a lack of vagotomy, as suggested by some studies showing increased rates of marginal ulceration in patients undergoing Roux-en-Y reconstruction versus a jejunal loop.19,20 In our study, two patients presented with perforation, both after undergoing a classic Whipple with a jejunal loop reconstruction. Two additional patients were found to have post-anastomotic ulcers and were managed medically. Thus, we believe it is prudent for all patients to continue receiving long-term acid-suppressing medications after pancreatoduodenectomy but cannot recommend any specific type of gastrectomy or reconstruction based on these findings.
Morbidity Among Long-Term Survivors
Finally, there are very few data on metachronous cancers after treatment for pancreatic cancer given the overall poor prognosis for pancreatic cancer. However, it is interesting to note that among our long-term survivors, a 7 % incidence of non-Hodgkin’s lymphoma was identified (2 patients). One of these two patients died of mantle cell lymphoma. CONCLUSIONS As we begin to accumulate an increasing number of longterm survivors after multimodality treatment of pancreatic cancer, it is important to recognize that late sequelae can, and often do, occur. Many complications manifest 4 years after definitive surgery. Although reoperation is uncommon, interventional procedures are often required. Although we could not verify the cause of death in all of our patients, it is worth noting that several patients were thought to have deaths related to their late complications. Thus, long-term follow-up evaluation with a pancreatic surgeon is warranted, which helps to ensure prompt recognition of complications requiring intervention. We recommend that patients receive appropriate counseling before undergoing surgery and throughout their surveillance periods. Unfortunately, we did not identify any specific risk factors for the development of late complications, and as such, all patients should continue long-term surveillance. It would be interesting to compare our findings with those of other institutions. The effect of minimally invasive surgery on late sequelae, as it evolves in the future, is another area for investigation. REFERENCES 1. Cameron JL, Crist DW, Sitzmann JV, et al. Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am J Surg. 1991;161:120–4; discussion 124–5. 2. Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas: is it really improving? Ann Surg. 1995;221:59–66. 3. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg. 1997;226:248–57; discussion 257–60. 4. Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma: clinicopathologic analysis of 5-year survivors. Ann Surg. 1996;223:273–9.
5. Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg. 2003;27:324–9. 6. Bock EA, Hurtuk MG, Shoup M, Aranha GV. Late complications after pancreaticoduodenectomy with pancreaticogastrostomy. J Gastrointest Surg. 2012;16:914–9. 7. Yamaguchi K, Tanaka M, Chijiiwa K, Nagakawa T, Imamura M, Takada T. Early and late complications of pylorus-preserving pancreatoduodenectomy in Japan 1998. J Hepatobiliary Pancreat Surg. 1999;6:303–11. 8. Halloran CM, Ghaneh P, Bosonnet L, Hartley MN, Sutton R, Neoptolemos JP. Complications of pancreatic cancer resection. Dig Surg. 2002;19:138–46. 9. Jung H, Beck-Bornholdt HP, Svoboda V, Alberti W, Herrmann T. Quantification of late complications after radiation therapy. Radiother Oncol. 2001;61:233–46. 10. Svoboda V, Beck-Bornholdt HP, Herrmann T, Alberti W, Jung H. Late complications after a combined pre- and postoperative (sandwich) radiotherapy for rectal cancer. Radiother Oncol. 1999;53:177–87. 11. Shimizu Y, Yasui K, Fuwa N, Arai Y, Yamao K. Late complication in patients undergoing pancreatic resection with intraoperative radiation therapy: gastrointestinal bleeding with occlusion of the portal system. J Gastroenterol Hepatol. 2005;20:1235–40. 12. Coia LR, Myerson RJ, Tepper JE. Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys. 1995;31:1213–36. 13. Jacobs NL, Que FG, Miller RC, Vege SS, Farnell MB, Jatoi A. Cumulative morbidity and late mortality in long-term survivors of exocrine pancreas cancer. J Gastrointest Cancer. 2009;40: 46–50. 14. Katz MH, Wang H, Fleming JB, et al. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009;16:836–47. 15. House MG, Cameron JL, Schulick RD, et al. Incidence and outcome of biliary strictures after pancreaticoduodenectomy. Ann Surg. 2006;243:571–6; discussion 576–8. 16. Reid-Lombardo KM, Ramos-Medina A, Thomsen K, Harmsen WS, Farnell MB. Long-term anastomotic complications after pancreaticoduodenectomy for benign diseases. J Gastrointest Surg. 2007;11:1704–11. 17. Ammori BJ, Joseph S, Attia M, Lodge JP. Biliary strictures complicating pancreaticoduodenectomy. Int J Pancreatol. 2000;28:15–21; discussion 21–22. 18. McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2001;19:4202–8. 19. Wu JM, Tsai MK, Hu RH, Chang KJ, Lee PH, Tien YW. Reflux esophagitis and marginal ulcer after pancreaticoduodenectomy. J Gastrointest Surg. 2011;15:824–8. 20. Sakaguchi T, Nakamura S, Suzuki S, et al. Marginal ulceration after pylorus-preserving pancreaticoduodenectomy. J Hepatobiliary Pancreat Surg. 2000;7:193–7.
ORIGINAL ARTICLE – PANCREATIC TUMORS
Morbidity Among Long-Term Survivors After Pancreatoduodenectomy for Pancreatic Adenocarcinoma Kathryn T. Chen, MD1, Karthik Devarajan, PhD2, and John P. Hoffman, MD3 Department of Surgery, St. Luke’s Hospital, Southcoast Health System, New Bedford, MA; 2Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA; 3Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 1
ABSTRACT Background. Because pancreatoduodenectomy for pancreatic adenocarcinoma is focused on disease-free and overall survival, morbidity among long-term survivors is not well described. This study sought to evaluate outcomes for long-term survivors of pancreatic cancer after pancreatoduodenectomy. Methods. The authors identified 29 patients from their prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy and were without evidence of disease during at least 3 years of follow-up evaluation. Demographics, treatment, and pathologic characteristics were collected for review. Data with regard to long-term sequelae also were collected, focusing on those complications requiring additional procedures and on the development of metachronous cancers. Results. The median follow-up period was 83 months, with 62 % of patients still alive. All patients received an R0 resection, and 34 % of the patients had N1 disease. For 42 % of the patients, no significant subsequent sequelae occurred. In the four remaining patients (14 %), ascites developed, requiring repeated paracentesis or Denver shunt, with a median time to development (MTD) of 63 months. Six patients (21 %) experienced a biliary stricture requiring stent placement (MTD, 56 months). One patient experienced portal venous thrombosis requiring a venous stent (MTD, 52 months), and four patients (14 %) experienced clinically significant ulcers (MTD,
Ó Society of Surgical Oncology 2014 First Received: 26 April 2014 K. T. Chen, MD e-mail: [email protected]
52 months). With regard to metachronous cancers, two patients experienced subsequent lymphomas (MTD, 92 months). Conclusions. Long-term survivors among patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can experience significant late sequelae, which often manifest more than 3 years after surgery. As such, continued follow-up evaluation and counseling are warranted.
The mortality associated with a diagnosis of pancreatic cancer continues to be grim. Fewer than 10 % of patients present with clearly resectable disease. As such, the focus for the treatment of pancreatic cancer has been on diseasefree and overall survival and on predictors for improved survival. However, long-term morbidity, more than 3 years after multimodality treatment of pancreatic cancer (chemotherapy, radiation therapy, and surgery), is not well described, although there is a definite growing cohort of long-term survivors. Currently, most high-volume institutions report a 5-years survival rate of 7–25 % for patients thought to be potentially curable who undergo surgical resection, with actual survival rates dependent on final pathologic findings.1–5 If morbidities are discussed in these reports of long-term survival, they generally are described in terms of surgical complications such pancreatic fistulas and wound infections or as wellknown physiologic changes such as delayed gastric emptying, pancreatic insufficiency, or diabetes mellitus.6,7 Postoperative complications occur for up to 50 % of patients undergoing pancreatoduodenectomy, and the management of these complications is well described.3,8 Less described are those long-term morbidities that can be the sequelae of multimodality therapy. In particular, radiation therapy is known to have late side effects, with irreversible ischemic changes occurring over a period of
K. T. Chen et al.
years. For instance, in rectal cancer, a lifelong risk beyond 10 years, with an annual rate of complications in surrounding organs and soft tissue of 10–14 % has been described.9,10 Because the length of follow-up evaluation for pancreatic cancer often is very short, these changes are not often reported. Some long-term effects attributed to irradiation of the pancreatic bed are gastrointestinal ulceration and enteritis, fistula formation, bleeding, and obstruction.11,12 As our experience in managing patients after pancreatoduodenectomy has grown, we have recognized that the development of late complications longer than 3 years after surgery requiring procedural interventions is not uncommon. It is of utmost importance to rule out the recurrence of cancer, experienced by 20 % of 5-years survivors.13,14 However, we sought to describe complications among long-term survivors of pancreatic cancer without evidence of recurrence, the management of these complications, and the possible relationships to multimodality therapy.
METHODS Under institutional review board approval, we identified 29 patients from our prospectively collected database of pancreatic adenocarcinoma patients who had undergone pancreatic head resection with curative intent (280 total patients, excluding those patients who had an R2 resection) with at least 3 years of follow-up evaluation and without evidence of disease at the last follow-up evaluation. All patients who experienced complications underwent diagnostic workups for evaluation of recurrent disease, particularly those patients with ascites or jaundice. The general workup included CA19-9, radiographic imaging such as computed tomography (CT) or magnetic resonance imaging (MRI), endoscopy or endoscopic retrograde cholangiopancreatography (ERCP) when appropriate, and evaluation of cytology or pathology for malignant cells. All the patients described in this study were thought not to have recurrent disease based on interpretation of these studies, and this was clearly documented in the follow-up clinical notes. Data regarding demographics, treatment strategies, pathologic findings, and follow-up evaluation were collected. Staging was in accordance to the American Joint Committee on Cancer (AJCC) 7th edition. Long-term complications were defined as those requiring a procedure for either diagnosis or treatment at least 1 year after the initial operation. The procedures included paracentesis, endoscopy, ERCP, percutaneous transhepatic cholangiogram, stent placement, mesenteric venous shunt placement, or a combination of these. The median time to the development (MTD) of complications was defined as the interval between surgical resection and the development of symptoms requiring an eventual procedure.
TABLE 1 Patient demographics, treatment characteristics, and pathology n (%) Median age at diagnosis (years)
71
Male gender
15 (52)
Location of tumor Head Head/body
25 (86) 4 (14)
Median CA19-9 at diagnosis: n (range)
62.7 (0–3,940)
Receipt of neoadjuvant chemoradiation Receipt of neoadjuvant chemotherapy before/after neoadjuvant chemoradiation
12 (41) 3 (10)
Type of surgery Whipple (with antrectomy)
21 (72)
Pancreatoduodenectomy
8 (28)
Required vein resection
3 (10)
Pathologic stage 0
8 (28)
1a
3 (10)
1b
1 (3)
2a
7 (24)
2b Node positivity
10 (34) 10 (34)
R0 margin
29 (100)
Adjuvant chemoradiation
12 (41)
Adjuvant chemotherapy
4 (14)
Median follow-up period (months)
83
Median overall survival (months)
100
We performed univariate analyses to identify variables associated with long-term complications requiring procedural intervention. In our analyses, the variables considered included gender, age, location of tumor (head, body, or tail), receipt of neoadjuvant chemoradiation, type of surgery (classic Whipple with antrectomy vs pyloruspreserving pancreatoduodenectomy), venous resection at the time of surgery, pathologic response to chemoradiation (major, moderate, or minor), receipt of postoperative chemoradiation, and receipt of postoperative chemotherapy. RESULTS Demographics and Treatment Characteristics The study identified 29 patients without evidence of recurrence who had received at least 3 years of follow-up evaluation (Table 1). The median age at diagnosis was 71 years, and 52 % of the patients were men. The majority of the patients (86 %) had tumors located in the head of the pancreas. The median CA19-9 at diagnosis (uncorrected for bilirubin) was 62.7 (range, 0–3,940).
Morbidity Among Long-Term Survivors
Of the 29 patients, 27 were found to have invasive cancer, and 2 were found to have carcinoma in situ at the final pathology. The latter two patients both had ductal carcinoma in situ (DCIS) arising in intraductal papillary mucinous neoplasms (IPMNs). With regard to treatment, 24 patients (82 %) received chemoradiation. Half of these patients received their treatment in the neoadjuvant setting, and the remaining half received it postoperatively. Chemoradiation consisted of gemcitabine or 5-FU given concurrently with 50.4 Gy of radiation in 28 fractions. Of the 12 patients who received neoadjuvant chemoradiation, 3 went on to receive additional chemotherapy (gemcitabine, gemcitabine-pxaliplatin, or gemcitabine-erlotinib) before surgery. Three patients (10 %) received adjuvant gemcitabine or 5-FU alone, and three patients received adjuvant gemcitabine after receipt of neoadjuvant chemoradiation. Two patients (7 %) had only carcinoma in situ at the final pathology and did not receive any additional therapy other than surgery. For treatment, 72 % of the patients underwent a classic Whipple procedure with antrectomy, and 28 % underwent a pylorus-preserving pancreatoduodenectomy. Three patients required portal vein or superior mesenteric vein (SMV) reconstruction. All the patients received an R0 resection. Six patients (50 % of those receiving neoadjuvant chemoradiation) had a pathologic complete response to neoadjuvant therapy. Overall, 50 % had pathologic stage 0 or 1 disease, and a total of 67 % of the patients had node-negative disease. Somewhat surprisingly, 34 % of our long-term survivors were found to have node-positive disease. After definitive surgical resection, eight immediate postoperative complications occurred (28 % overall). Reoperations were performed for three patients: two for jejunal loop problems and one for blood within the drains (nothing found at exploration). These three patients had no late complications. Other complications included one wound infection, one atrial fibrillation, and one case of Clostridium difficile infection. Three patients had type A fistulas. Two of these patients recovered without futher complications and were not diabetics at the last follow-up evaluation. The remaining patient needed a perioperative reoperation for obstruction of the retrocolic gastrojejunostomy. This patient had been diabetic for more than a decade before Whipple and remained diabetic postoperatively. Two of these three patients had no late complications. The remaining patient experienced portal vein and SMV thrombosis at 52 months. Late Complications At the last follow-up evaluation, 34 % of the patients were receiving medications for diabetes, and 73 % of the patients were taking pancreatic enzyme supplements routinely for varying degrees of pancreatic insufficiency,
TABLE 2 Late sequelae and metachronous cancers n (%)
Median time to development (months)
Ascites
5 (17)
63
Biliary stricture Ulcer
6 (21) 4 (14)
56 52
Major late sequelae
Incisional hernias
2 (7)
29
Bile reflux
1 (3)
60
Radiation enteritis and development of jejunalcolic fistula
1 (3)
15 (fistula, 92)
1 (3)
52
Portal vein thrombosis Reoperation (any) Metachronous cancers Lymphoma
5 (17) 2 (7)
92
Colon
1 (3)
3
Bladder dysplasia
1 (3)
63
whereas 42 % of the patients experienced no late adverse events from pancreatoduodenectomy. The more common late sequelae included ascites, ulcer disease, and biliary stricture (Table 2). Five patients (17 %) experienced ascites, with a MTD of 63 months. None of these patients had undergone portal vein or SMV reconstruction at the time of the original operation. Three of these five patients required multiple repeat paracentesis for symptomatic relief, and two eventually underwent Denver shunt placement. The etiology for ascites was not always apparent, but cytologic interpretation of multiple samples of the ascites showed no neoplasia. Four of the five patients were thought to have cryptogenic cirrhosis. The remaining patient was thought to have biliary cirrhosis with a concurrent biliary stricture requiring repeated dilation. In terms of biliary strictures, six patients (21 %) underwent repeated procedures for treatment, with an MTD of 56 months. Some presented initially with cholangitis. Three patients had concurrent stones and sludge shown on a cholangiogram. One patient with biliary stenosis originally underwent an emergent Whipple procedure for a biliary-portal fistula and had concomitant SMV and bile duct narrowing. Another patient had multiple strictures within the intra- and extrahepatic biliary tree, with a secondary sclerosing pattern. The patients were typically managed with stent placement, via either percutaneous transhepatic cholangiography or endoscopic means. Regardless, repeated procedures were typically required for stent exchange or for persistent stricturing after balloon dilation. Only one patient was able eventually to have the stent permanently removed.
K. T. Chen et al.
Although all our patients continue to receive a proton pump inhibitor or H2 blocker after surgery, four patients (14 %) experienced ulcer disease, with an MTD of 52 months. Two patients presented with perforated gastrojejunal anastomotic ulcers, and two patients had a diagnosis of duodenal ulcers. Two additional patients experienced diffuse gastritis. The patients who presented with nonperforated ulcers and gastritis were managed medically with antacid therapy. Both of the patients who experienced perforated anastomotic ulcers received an antrectomy with pancreatoduodenectomy. One had been managed initially with a proton pump inhibitor for gastritis but had stopped medication 3 months before presentation. The remaining patient experienced perforation while receiving medication for gastritis, and a vagotomy was performed at the time of exploration. Other major complications included incisional hernias (2 patients, MTD 29 months), bile reflux gastritis (1 patient, MTD 60 months), radiation enteritis with repeated bowel obstruction and eventual development of jejunocolic fistula (1 patient, MTD of enteritis 15 months and MTD of fistula 92 months), and SMV/portal vein thrombosis (1 patient, MTD 52 months). Five patients (17 %) had multiple late complications with combinations of the aforementioned complications. During our relatively short follow-up period, metachronous cancers were uncommon (3 of 28). Two patients experienced lymphoma (7 %, MTD 93 months). Both were non-Hodgkin’s B cell lymphomas. One was a mantle cell lymphoma, and the other was a diffuse large B-cell lymphoma. Colon cancer was diagnosed for one patient shortly after surgical resection for pancreatic cancer (MTD 3 months). Using univariate analysis, we attempted to identify predictors of major complications requiring procedural intervention. None of the complications were significantly associated with a predictor (gender, age, location of tumor [head or body]), receipt of neoadjuvant chemoradiation, type of surgery (classic Whipple with antrectomy vs pancreatoduodenectomy), venous resection at the time of surgery, pathologic response to chemoradiation (major, moderate, or minor), receipt of postoperative chemoradiation, or receipt of postoperative chemotherapy. The analysis was limited by the small number of patients in our study and the relatively large number of potential variables. DISCUSSION Most studies evaluating the morbidity of pancreatoduodenectomy focus on immediate postoperative complications (pancreatic fistula, delayed gastric emptying) or the sequelae related to loss of pancreatic function such as diabetes or steatorrhea. Only a handful of studies have evaluated patients with long-term survival after resection for
pancreatic malignancy, and none have described long-term complications requiring intervention as we have. Of our 29 patients, 12 (42 %) were without significant sequelae. We were unable to identify any predictors for specific complications, either due to small sample size or truly a lack of association. Patients who received multimodality therapy with chemoradiation and surgery appeared as likely to experience significant complications as those without such therapy. Two patients in our group did not receive chemotherapy or radiation. One of these patients had no further complications, and the other patient experienced a perforated marginal ulcer. With regard to biliary strictures, all the patients in our study who experienced biliary strictures requiring repeated interventions received either neoadjuvant (n = 3, 50 %) or adjuvant (n = 3, 50 %) external beam radiation. However, an association between radiation and stricture formation has never been proved in the literature. House et al.15 reported on the incidence of biliary stricture formation after pancreatoduodenectomy for both benign and malignant disease. They found an MTD of 13 months (range, 1– 106 months), without association with postoperative chemoradiotherapy. The incidence reported was only 2.6 % among patients with malignant disease, although the median follow-up time was only 27 months. Similarly, another review of 122 patients who underwent pancreatoduodenectomy for benign diseases showed a 5- and 10-year cumulative probability of biliary stricture of 8 % and 13 %, respectively.16 The causes of biliary strictures are thus considered more likely related to ischemia or reflux of enteric contents into the biliary system with cholangitis than to prior radiotherapy.15–17 In our study, we also had one patient whose an ischemic stricture likely developed after an emergent Whipple for biliary-portal fistula. The bile duct was quite scarred at the time. With regard to ulcer development, radiation therapy is recognized as causing mucosal ulceration and ischemia in the gastrointestinal tract, which can alternately present as enteritis.12,18 However, the etiology also can be attributed to a lack of reflux of basic biliopancreatic secretions and a lack of vagotomy, as suggested by some studies showing increased rates of marginal ulceration in patients undergoing Roux-en-Y reconstruction versus a jejunal loop.19,20 In our study, two patients presented with perforation, both after undergoing a classic Whipple with a jejunal loop reconstruction. Two additional patients were found to have post-anastomotic ulcers and were managed medically. Thus, we believe it is prudent for all patients to continue receiving long-term acid-suppressing medications after pancreatoduodenectomy but cannot recommend any specific type of gastrectomy or reconstruction based on these findings.
Morbidity Among Long-Term Survivors
Finally, there are very few data on metachronous cancers after treatment for pancreatic cancer given the overall poor prognosis for pancreatic cancer. However, it is interesting to note that among our long-term survivors, a 7 % incidence of non-Hodgkin’s lymphoma was identified (2 patients). One of these two patients died of mantle cell lymphoma. CONCLUSIONS As we begin to accumulate an increasing number of longterm survivors after multimodality treatment of pancreatic cancer, it is important to recognize that late sequelae can, and often do, occur. Many complications manifest 4 years after definitive surgery. Although reoperation is uncommon, interventional procedures are often required. Although we could not verify the cause of death in all of our patients, it is worth noting that several patients were thought to have deaths related to their late complications. Thus, long-term follow-up evaluation with a pancreatic surgeon is warranted, which helps to ensure prompt recognition of complications requiring intervention. We recommend that patients receive appropriate counseling before undergoing surgery and throughout their surveillance periods. Unfortunately, we did not identify any specific risk factors for the development of late complications, and as such, all patients should continue long-term surveillance. It would be interesting to compare our findings with those of other institutions. The effect of minimally invasive surgery on late sequelae, as it evolves in the future, is another area for investigation. REFERENCES 1. Cameron JL, Crist DW, Sitzmann JV, et al. Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am J Surg. 1991;161:120–4; discussion 124–5. 2. Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas: is it really improving? Ann Surg. 1995;221:59–66. 3. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg. 1997;226:248–57; discussion 257–60. 4. Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma: clinicopathologic analysis of 5-year survivors. Ann Surg. 1996;223:273–9.
5. Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg. 2003;27:324–9. 6. Bock EA, Hurtuk MG, Shoup M, Aranha GV. Late complications after pancreaticoduodenectomy with pancreaticogastrostomy. J Gastrointest Surg. 2012;16:914–9. 7. Yamaguchi K, Tanaka M, Chijiiwa K, Nagakawa T, Imamura M, Takada T. Early and late complications of pylorus-preserving pancreatoduodenectomy in Japan 1998. J Hepatobiliary Pancreat Surg. 1999;6:303–11. 8. Halloran CM, Ghaneh P, Bosonnet L, Hartley MN, Sutton R, Neoptolemos JP. Complications of pancreatic cancer resection. Dig Surg. 2002;19:138–46. 9. Jung H, Beck-Bornholdt HP, Svoboda V, Alberti W, Herrmann T. Quantification of late complications after radiation therapy. Radiother Oncol. 2001;61:233–46. 10. Svoboda V, Beck-Bornholdt HP, Herrmann T, Alberti W, Jung H. Late complications after a combined pre- and postoperative (sandwich) radiotherapy for rectal cancer. Radiother Oncol. 1999;53:177–87. 11. Shimizu Y, Yasui K, Fuwa N, Arai Y, Yamao K. Late complication in patients undergoing pancreatic resection with intraoperative radiation therapy: gastrointestinal bleeding with occlusion of the portal system. J Gastroenterol Hepatol. 2005;20:1235–40. 12. Coia LR, Myerson RJ, Tepper JE. Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys. 1995;31:1213–36. 13. Jacobs NL, Que FG, Miller RC, Vege SS, Farnell MB, Jatoi A. Cumulative morbidity and late mortality in long-term survivors of exocrine pancreas cancer. J Gastrointest Cancer. 2009;40: 46–50. 14. Katz MH, Wang H, Fleming JB, et al. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009;16:836–47. 15. House MG, Cameron JL, Schulick RD, et al. Incidence and outcome of biliary strictures after pancreaticoduodenectomy. Ann Surg. 2006;243:571–6; discussion 576–8. 16. Reid-Lombardo KM, Ramos-Medina A, Thomsen K, Harmsen WS, Farnell MB. Long-term anastomotic complications after pancreaticoduodenectomy for benign diseases. J Gastrointest Surg. 2007;11:1704–11. 17. Ammori BJ, Joseph S, Attia M, Lodge JP. Biliary strictures complicating pancreaticoduodenectomy. Int J Pancreatol. 2000;28:15–21; discussion 21–22. 18. McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2001;19:4202–8. 19. Wu JM, Tsai MK, Hu RH, Chang KJ, Lee PH, Tien YW. Reflux esophagitis and marginal ulcer after pancreaticoduodenectomy. J Gastrointest Surg. 2011;15:824–8. 20. Sakaguchi T, Nakamura S, Suzuki S, et al. Marginal ulceration after pylorus-preserving pancreaticoduodenectomy. J Hepatobiliary Pancreat Surg. 2000;7:193–7.
