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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Gastrointest Surg. Author manuscript; available in PMC Mar 18, 2013.
Published in final edited form as:
PMCID: PMC3600849
NIHMSID: NIHMS435783
Young Patients Undergoing Resection of Pancreatic Cancer Fare Better than their Older Counterparts
Jin He, Barish H. Edil, John L. Cameron, Richard D. Schulick, Ralph H. Hruban, Joseph M. Herman, Lei Zheng, Christine Iacobuzio-Donahue, Nita Ahuja, Timothy M. Pawlik, and Christopher L. Wolfgangcorresponding author
Jin He, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA;
corresponding authorCorresponding author.
Christopher L. Wolfgang: cwolfga2/at/jhmi.edu
Background
The median age of pancreatic ductal adenocarcinoma (PDAC) patients is 71 years. PDAC rarely affects individuals under the age of 45. We investigated features of PDAC occurring in young patients (≤45 years) who underwent surgical resection in order to determine if any difference exists in comparison to elderly patients (≥70 years).
Methods
A retrospective analysis of patients with PDAC who were ≤45 years on the date of surgery between 1975 and 2009 was performed. This cohort was compared with PDAC patients whose ages were over 70 years on the date of surgery over the same time interval. Information reviewed included demographics, Charlson Age–Comorbidity Index (CACI), pathological staging, surgical management, and death or last follow-up.
Results
Seventy five patients with PDAC of age ≤45 years at surgery were identified. The reference group consisted of 870 patients with a median age of 75. The most common symptoms of young patients were jaundice (45 %), abdominal pain (32 %), or weight loss (33 %). This did not differ significantly from older patients. Among the younger patients, 7 (9 %) underwent total pancreatectomy, 60 (80 %) underwent pancreaticoduodenectomy, and 8 (11 %) had distal pancreatectomy. The distribution of type of surgery was similar between two groups. Fifty-two of the young patients (69 %) had an R0 resection and this did not differ from the older age group (n=616; 71 %). The rate of lymph node positivity was 68 % for younger patients and 74 % for older patients (p=0.27). Of the younger patients, 11, 13, 49, and 2 were classified as stage I, IIA, IIB, and III, respectively, and did not differ from the older age group. The median overall survival for the young patients cohort was 19 months (95 % CI 15–22 months) which is longer than 16 months (95 % CI 14–17 months) of the older group (p=0.007). The actual 5- and 10- year survival in young age group (24 and 17 %) was longer than that in old age group (11 and 3 %) (p<0.05). The median CACI of the younger patients was 0.5 and was lower than 4.1 of the older patients (p<0.0001).
Conclusions
The demographic, pathologic, and treatment characteristics of PDAC patients younger than 45 years were similar to those older than 70 years. Younger patients had fewer complications after curative resections. The better survival among younger patients is likely related to fewer comorbidities in this group. These findings will be useful in counseling young patients with resectable pancreatic cancer.
Keywords: Pancreas surgery, Morbidity, Mortality, Outcomes
Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is a highly lethal disease that is characterized by early systemic spread and rapid progression following diagnosis. It is the fourth leading cause of cancer deaths in the US1 with 43,920 new cases and 37,390 deaths estimated to have occurred in 2012 (http://seer.cancer.gov/statfacts/html/pancreas.html). Both the advanced stage at presentation and lack of effective systemic therapy contribute to the poor prognosis of this disease. Resection of localized disease offers the only chance for long-term survival. Prognostic factors following the resection of PDAC include tumor size, histologic grade, lymph node status, and margin status. Patients who undergo an R0 resection for PDAC with favorable tumor characteristic that include size less than 3 cm, well-differentiated tumors, and absence of nodal metastasis have a 5-year survival rate of approximately 40 %.24
The median age of diagnosis of PDAC in the USA is 71 years. Less than 3 % of patients diagnosed with PDAC are under the age of 45 years (accessed at July 12, 2012, http://seer.cancer.gov/statfacts/html/pancreas.html). Whether the age of onset affects long-term survival for patients with PDAC is not well-defined. Very little data exist regarding the clinicopathological features and treatment response of young patients with PDAC.58 Age of onset was not found to be a prognostic factor in several large cohort studies.2,9 In contrast, a population-based study using the SEER registry from 1988 through 2002 showed that younger patients (defined as less than age 49) with PDAC were more likely to undergo surgical treatment and had an associated higher 2-year survival rate as compared with patients age 80 years or older (36 vs. 10 %).10 Similarly, Duffy et al. reported a cohort of 35 young patients with PDAC who underwent curative resections achieved an impressive median overall survival of 41.8 months.6
In light of the potential differences in young patients who develop pancreatic cancers in comparison to a more typical age group, we sought to evaluate clinical and pathological features in these patients. The goal of this study was to characterize the outcome after curative surgery in young patients with PDAC. We performed a retrospective review of our pancreatic resection database, which covers a 34-year period, to characterize our experience with regard to the treatment of PDAC in a younger patient population.
A prospectively maintained database of patients undergoing pancreatic resection at the Johns Hopkins Hospital was reviewed to identify patients who underwent resection for a pathologically confirmed PDAC between 1975 and 2009. Patients with PDAC who were younger than 45 years or older than 70 years on the date of surgery were grouped into two cohorts. International patients who were not followed long-term after resection were excluded. Other common pathologic subtypes of pancreatic tumors in young patients including solid-pseudopapillary neoplasm, acinar cell carcinoma, neuroendocrine tumor, and pancreatoblastoma were excluded.
Patient demographics, Charlson Age–Comorbidity Index (CACI), tumor pathological staging, and surgical treatment-related variables were retrieved from the database and confirmed by chart review. Follow-up was obtained through office records and the social security death index. Patient factors evaluated included age, gender, and medical comorbidities. Treatment factors included the date of operation, type of operation, the estimated blood loss, length of stay (LOS), status at last follow-up, and whether adjuvant therapy was administered. Pathologic factors evaluated included tumor, nodes, and metastases stage, margin (positive or negative), and differentiation (well, moderate, or poor). Margins assessed included the pancreatic resection margin, biliary margin, bowel margins, and uncinate margin. Maximal tumor size was determined and defined as the maximum diameter at pathological analysis.
CACI is a measure of comorbidity to standardize the evaluation of surgical patient and has been used to predict post-op mortality of patients undergoing surgery in many studies.11 CACI score was calculated by weighing each preoperative comorbid disease separately and adding to the age factor as described by Charlson.12 One point for each decade over the age of 50 was added.
Overall survival was computed from the time of operative resection to the date of last follow-up. Statistical Package for the Social Sciences software (SPSS V.16) was used to analyze data. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Continuous variables were expressed as median±standard deviation and were compared using Mann–Whitney test. Categorical variables were compared using a χ2 test (or Fisher’s exact test). Overall survival was computed from the time of operative resection to the date of last follow-up. A p value of less than 0.05 was considered significant. The institutional internal review board approved this study.
Demographic Data
Data for patients with PDAC in each age group are presented in Table 1. At total of 945 patients were included in the study, 75 of whom were of age less than 45 years at surgery and 870 were older than 70 years. The median age of the young group was 41 years (range, 31–45). The median age of the old group was 75 years (range, 70–93). Patient demographics, including gender and race, were comparable between the two groups (Table 1). The percentage of patients with smoking history was similar between two groups. Other possible risk factors for PDAC, such as family history of pancreatic cancer13 and previous radiation exposure, were not investigated in this study.
Table 1
Table 1
Demographic and treatment data
The most common symptoms of young patients were jaundice (45 %), abdominal pain (32 %), or weight loss (33 %). This did not differ significantly from older patients (p=0.46).
The median CACI score was 0.5 (range, 0–2) for the younger group and 4.2 (range, 3–14) for the older group. Young patients had significant less preoperative comorbidities (p<0.0001).
Operative Data and Complications
In the younger cohort, 7 (9 %) underwent total pancreatectomy, 60 (80 %) underwent pancreaticoduodenectomy, and 8 (11 %) had distal pancreatectomy. Among these pancreatic operations, four (5 %) involved vein resection. This included three SMV resection and one portal vein resection. The type of pancreatic resection performed in young patients was not significantly different from those done in the older patient group. Fifty-two patients (69 %) in the young patient group underwent an R0 resection and this did not differ from the older age group (n=616; 71 %).
Delayed gastric emptying, pancreatic fistula, and wound infection are the most common complication after pancreatic surgery. Young patients had significantly lower incidence of postoperative pancreatic fistula (0 vs. 8 %; p=0.013) and delayed gastric emptying (5 vs. 15 %; p=0.017) in comparison to the older age group. The Clavien classification system has been widely used to grade surgical complications.14,15 In this system, grade III complication was defined as those requiring surgical, endoscopic, or radiological intervention. Fifteen of 75 (20 %) young patients had complications; five of them (33 %) were grade III or above. Two hundred seventy-one of 870 (31 %) old patients had complications, 111 of them (41 %) were grade III or above. The incidence of complication with grade III or above was not significantly different between young and old groups.
The median LOS was not significant different between two groups (9 vs. 9 days). Both groups had low perioperative mortality (young, 0 vs. old, 2 %).
Pathology Data
The rate of lymph node positivity was 68 % for younger patients and 74 % for older patients (p=0.27). Lymph node ratio (defined as ratio between positive lymph nodes and total excised lymph nodes) was also not significantly different between the two groups (0.14 vs. 0.14, p=0.78). Microvascular invasion was observed in 32 % of younger patients and 42 % of older patients (p=0.1). Perineural invasion was observed in 64 % of younger patients and 73 % of older patients (p=0.09). According to AJCC staging (seventh edition), 11 (15 %), 13 (17 %), 49 (65 %), and 2 (3 %) patients in young age group were in stage I, IIA, IIB, and III, respectively. This staging distribution did not differ from that in the older age group (p=0.27) (Fig. 1).
Fig. 1
Fig. 1
Staging by age
Survival Analysis
Most studies of patients undergoing resection for pancreatic adenocarcinoma reported estimated (actuarial) 5-year survival rates. Actual 5-year survival is rarely described. So we reported both estimated and actual survival data in this study.
The estimated median overall survival for the young patients cohort was 19 months (95 % CI: 15–22 months) which was significantly longer than that for the older group (16 months, 95 % CI: 14–17 months) (p=0.007) (Fig. 2). Subgroup analysis of patients with stage I/IIA disease showed the estimated median overall survival for the young patients cohort (n=24) was 27 months (95 % CI: 0–106 months) which was same as that for the older group (27 months, 95 % CI: 20–34 months) (p=0.1). However, for patients with stage IIB/IIIA disease, the estimated median overall survival for the young cohort (n=51) was 16 months (95 % CI: 12–21 months) which was significantly longer than that for the older group (14 months, 95 % CI: 13–15 months) (p=0.046).
Fig. 2
Fig. 2
Estimated overall survival by age, from time of first surgery. Deaths within 30 days of surgery were excluded
Similarly, the actual 5- and 10-year survivals in young age group (24 and 17 %) were also significantly longer than those in old age group (11 and 3 %) (p=0.005 and p<0.001, respectively) (Table 1).
Stage I or IIA was strongly associated with 5-year actual survival rate in both age groups as compared to stage IIB and III (42 vs. 16 % in the young age group, p=0.014; 20 vs. 7 % in the old age group; p<0.0001) (Table 2).
Table 2
Table 2
Five-year actual survival analysis
Except for prostate cancer,14 younger patients diagnosed with other common cancers tend to have higher survival rates than older patients in age-specific relative survival studies. (http://info.cancerresearchuk.org/cancerstats/survival/age/, accessed on October 22, 2012.) However, very little information is available regarding PDAC in young patients. Our hypothesis was that young patients with PDAC might have worse overall outcome comparing to the older patients even after curative surgery. However, our data showed the opposite. Young patients with PDAC actually do better in survival than their older counterparts.
Lüttges et al. analyzed the pathologic characteristics of six young patients with PDAC derived from a population of 439 reviewed.7 In this study, no difference in the expression of p53, MLH1, MSH2, and c-Erb-B2 were identified between young and older patients. Moreover, no unique immunohistochemical characteristics were found in younger patients. In addition, no familial component was identified by family history. However, literature review by Lüttges et al showed PDACs in patients with the age <40 years were commonly associated with risk factors such as Peutz-Jeghers syndrome, hereditary pancreatic cancer syndrome, and preceding radiotherapy.7 Similarly, Bergmann et al. studied the pathologic characteristics of seven patients with PDAC under the age of 40 (age range 35–40).5 The tumor grade, p53, Smad4, EGFR expression levels were comparable between young and older patients.
Most large series of resected PDAC have reported 5-year survival rates of 12–19 %,2,1517 and the factors associated with 5-year survival have been typically stage-related. Ferrone et al. reported that their patients resected for pancreatic adenocarcinoma experienced an actual 5-year survival of 12 % and a 10-year survival of 5 %.9 The median age in that study was 68 years. The factors found to be associated with survival endpoint were the stage of disease at presentation and the resection margin status. Our data are consistent with the literature. In this study, the actual 5- and 10-year survival rates for older age group (median age 75 years) were 11 and 3 %, respectively. In both age groups, stage I or IIA is associated with more actual 5-year survival as compared to stage IIB and III (Table 2).
To our knowledge, our study is the largest cohort of young patients undergoing resection for PDAC reported. We show that the actuarial overall survival and actual survival of the young cohort of patients was significantly better than those of their older counterpart (Table 1 and Fig. 2). Except for the lower incidence of postoperative pancreatic fistula and delayed gastric emptying in the young age group, the clinical characteristics of PDAC in both groups after resection were similar. Patients of both groups had similar demographic characteristics including gender, race, and smoking history. Their pathology results showed similar cancer staging and lymph node metastasis. They received similar pancreatic resection with similar rate of R0 resection, median LOS, and perioperative mortality. Taken together, the improved survival rate in the young group may reflect an overall better state of health and relative lower rate of comorbidities. This is supported by the significant difference of CACI between two groups.
These finding are useful in counseling young patients undergoing pancreatectomy for PDAC in that they have a better chance of survival than the most of the current reports available in the literature which are based on populations with an older median survival.
The major limitation of our study is the lack the data regarding disease-specific survival. This is of great importance for the cohort of old patients, where some long-term surviving patients might be dying from etiologies other than PDAC.
Footnotes
This paper was presented at the Pancreas club 2011, Chicago.
Contributor Information
Jin He, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Barish H. Edil, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
John L. Cameron, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Richard D. Schulick, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Ralph H. Hruban, Department of Pathology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Joseph M. Herman, Department of Radiation Oncology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Lei Zheng, Department of Medical Oncology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Christine Iacobuzio-Donahue, Department of Pathology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Nita Ahuja, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Timothy M. Pawlik, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
Christopher L. Wolfgang, Department of Surgery, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 600 N Wolfe St, Osler 624, Baltimore, MD 21287, USA.
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277–300. [PubMed]
2. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg. 2006 Nov;10(9):1199–1210. discussion 1210-1191. [PubMed]
3. Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg. 2006 Jul;244 (1):10–15. [PubMed]
4. de Jong MC, Li F, Cameron JL, et al. Re-evaluating the impact of tumor size on survival following pancreaticoduodenectomy for pancreatic adenocarcinoma. J Surg Oncol. 2011 Jun 1;103 (7):656–662. [PMC free article] [PubMed]
5. Bergmann F, Aulmann S, Wente MN, et al. Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40. J Clin Pathol. 2006 Jun;59(6):580–584. [PMC free article] [PubMed]
6. Duffy A, Capanu M, Allen P, et al. Pancreatic adenocarcinoma in a young patient population—12-year experience at Memorial Sloan Kettering Cancer Center. J Surg Oncol. 2009 Jul 1;100 (1):8–12. [PubMed]
7. Luttges J, Stigge C, Pacena M, Kloppel G. Rare ductal adenocarcinoma of the pancreas in patients younger than age 40 years. Cancer. 2004 Jan 1;100(1):173–182. [PubMed]
8. Soliman AS, El-Ghawalby N, Ezzat F, et al. Unusually high rate of young-onset pancreatic cancer in the East Nile Delta region of Egypt. Int J Gastrointest Cancer. 2002;32(2–3):143–151. [PubMed]
9. Ferrone CR, Brennan MF, Gonen M, et al. Pancreatic adenocarcinoma: the actual 5-year survivors. J Gastrointest Surg. 2008 Apr;12(4):701–706. [PubMed]
10. Baxter NN, Whitson BA, Tuttle TM. Trends in the treatment and outcome of pancreatic cancer in the United States. Ann Surg Oncol. 2007 Apr;14(4):1320–1326. [PubMed]
11. Ouellette JR, Small DG, Termuhlen PM. Evaluation of Charlson-Age Comorbidity Index as predictor of morbidity and mortality in patients with colorectal carcinoma. J Gastrointest Surg. 2004 Dec;8(8):1061–1067. [PubMed]
12. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40 (5):373–383. [PubMed]
13. Hruban RH, Canto MI, Goggins M, Schulick R, Klein AP. Update on familial pancreatic cancer. Adv Surg. 2010;44:293–311. [PMC free article] [PubMed]
14. Wingo PA, Ries LA, Rosenberg HM, Miller DS, Edwards BK. Cancer incidence and mortality, 1973–1995: a report card for the U.S. Cancer. 1998 Mar 15;82(6):1197–1207. [PubMed]
15. Ahmad NA, Lewis JD, Ginsberg GG, et al. Long term survival after pancreatic resection for pancreatic adenocarcinoma. Am J Gastroenterol. 2001 Sep;96(9):2609–2615. [PubMed]
16. Cleary SP, Gryfe R, Guindi M, et al. Prognostic factors in resected pancreatic adenocarcinoma: analysis of actual 5-year survivors. J Am Coll Surg. 2004 May;198(5):722–731. [PubMed]
17. Han SS, Jang JY, Kim SW, Kim WH, Lee KU, Park YH. Analysis of long-term survivors after surgical resection for pancreatic cancer. Pancreas. 2006 Apr;32(3):271–275. [PubMed]