HHS Public Access Author manuscript Author Manuscript
Ann Surg Oncol. Author manuscript; available in PMC 2016 December 01. Published in final edited form as: Ann Surg Oncol. 2016 December ; 23(13): 4156–4164. doi:10.1245/s10434-016-5457-z.
Early Recurrence and Omission of Adjuvant Therapy after Pancreaticoduodenectomy Argue against a Surgery-First Approach
Author Manuscript
Brent T. Xia, MD1, David A. Habib, BS2, Vikrom K. Dhar, MD1, Nick C. Levinsky, MD1, Young Kim, MS, MD1, Dennis J. Hanseman, PhD1, Jeffrey M. Sutton, MD1, Gregory C. Wilson, MD1, Milton Smith, MD3, Kyuran Ann Choe, MD4, Jeffrey J. Sussman, MD1, Syed A. Ahmad, MD1, and Daniel E. Abbott, MD5 1Department 2College
of Surgery, Division of Surgical Oncology, University of Cincinnati, Cincinnati, OH
of Medicine, University of Cincinnati, Cincinnati, OH
3Department
of Medicine, Division of Gastroenterology, University of Cincinnati, Cincinnati, OH
4Department
of Radiology, University of Cincinnati, Cincinnati, OH
5Department
of Surgery, Division of Surgical Oncology, University of Wisconsin, Madison, WI
Abstract Author Manuscript
Background—Sequencing therapy for patients with periampullary malignancy is controversial. Clinical trial data report high rates of adjuvant therapy completion, though contemporary, realworld rates remain incomplete. We sought to identify patients who failed to receive adjuvant therapy and those at risk for early recurrence (ER) who might benefit most from neoadjuvant therapy (NT). Methods—We retrospectively reviewed medical records of 201 patients who underwent pancreaticoduodenectomy for periampullary malignancies between 1999 and 2015; patients receiving NT were excluded. Univariate and multivariate analyses were performed to identify predictors of failure to receive adjuvant therapy and ER (within 6 months) as the primary end points.
Author Manuscript
Results—The median age at the time of surgery was 65.5 years (interquartile range 57–74 years). The majority of tumors were pancreatic ductal adenocarcinoma (76.6 %), and 71.6 % of patients received adjuvant therapy after resection. Univariate predictors of failure to undergo adjuvant therapy were advanced age, age-adjusted Charlson comorbidity index, operative transfusion, reoperation, length of stay, and 30- to 90-day readmissions (all p < 0.05). Advanced age, specifically among patients >70 years, persisted as a significant preoperative predictor on multivariate analysis (p < 0.01). Patients who failed to receive adjuvant therapy and/or developed
D. E. Abbott, MD, [email protected]. Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5457-z) contains supplementary material, which is available to authorized users. DISCLOSURE The authors declare no conflict of interest.
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ER had significantly worse overall survival rates compared to all other patients (27.8 vs. 9.7 months; p < 0.01). Conclusions—Approximately one-third of surgery-first patients undergoing pancreaticoduodenectomy at our institution did not receive adjuvant therapy and/or demonstrated ER. This substantial subset of patients may particularly benefit from NT, ensuring completion of multimodal therapy and/or avoiding futile surgical intervention. The incidence of periampullary neoplasms has risen in the past decade. Pancreatic cancer, the most common type, is projected to be responsible for 53,070 new diagnoses and 41,780 deaths in 2016.1 The closely matched incidence and mortality of this disease are reflective of its aggressive nature.
Author Manuscript
Surgical resection—pancreaticoduodenectomy (PD)—remains the only opportunity for a cure. However, given pancreatic cancer’s biology, with a 5-year survival of 15–20 % among patients with resectable disease, surgical intervention alone remains suboptimal.2,3 Randomized prospective trials have validated adjuvant therapy as an important treatment modality that improves overall survival (OS), though only 60–80 % of patients randomized to receipt of adjuvant therapy complete their treatment course.4–9 These rates are problematic, given that patients enrolled onto clinical trials are highly selected. Outside of clinical trials, postoperative complications are primarily implicated in many patients not receiving adjuvant therapy, negatively affecting their OS.10–12
Author Manuscript
Similarly, patients who develop early disease recurrence also exhibit worse OS rates13–15 Disease-free recurrence is largely dictated by tumor stage, lymph node involvement, and lymph node ratio, and these pathologic factors limit long-term survival to a select minority of patients with early-stage disease.16–20 Given these limitations of the traditional surgery-first approach, neoadjuvant therapy (NT) is an attractive option. Not only does NT ensure completion of multimodal therapy, but it also allows for improved patient selection, as patients at heightened risk for early recurrence (ER) can be spared a major operation. Outcomes and risk factors on both omission of adjuvant therapy (OAT) and ER in the same population is lacking. We sought to determine which preoperative clinical factors may be used to identify patients vulnerable to OAT and/or ER in order to identify patients who may particularly benefit most from NT.
METHODS Study Design and Data Collection
Author Manuscript
Using an institutional review board–approved pancreas database, we identified 234 patients who underwent PD with curative intent for resectable periampullary malignancies between 1999 and 2015 at the University of Cincinnati Medical Center. Patients sequenced with NT were excluded. Complete postoperative data were available for 201 patients, which comprised the final study population. A retrospective review of medical records incorporated perioperative data.
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Patient comorbidity was stratified by the age-adjusted Charlson comorbidity index (CACI).21 The comorbidity score was calculated at the time of periampullary cancer diagnosis based on clinical history. Age adjustment was factored with the addition of one point per decade past the fourth decade of life. Postoperative complications were classified according to the Clavien-Dindo system.22 Receipt of adjuvant therapy, recidivism, recurrence, and death were catalogued. OAT was defined as never receiving systemic therapy in the absence of radiographic disease. ER was defined as radiographic evidence of local progression or distant metastases within 6 months of resection. Patients who recurred before 12 weeks were excluded from analysis involving receipt of adjuvant therapy. OS was calculated from the date of surgery to the last documented follow-up or death.
Author Manuscript
Statistical Methods Continuous variables were compared using the Kruskal–Wallis H test and expressed as median (interquartile range), and Fisher’s exact test were used to compare categorical variables. Predictor variables were chosen based on their statistical significance on univariate analysis (p ≤ 0.10), or if deemed to be clinically significant. Multivariate analyses were performed with continuous and categorical variables as predictors of OAT and ER. Relative risks were expressed as odds ratios (OR) with a 95 % confidence interval (CI). Survival analysis was calculated using Kaplan–Meier curves and compared using Wilcoxon log-rank tests. An association was considered statistically significant if p < 0.05. All data analyses were performed by SAS 9.3 software (SAS Institute, Cary, NC).
RESULTS Author Manuscript
In the overall cohort, the median age at the time of surgery was 65.5 years (interquartile range 58.0–74.0 years). The majority (76.6 %) of tumors were pancreatic adenocarcinoma, and 71.6 % of patients received adjuvant therapy after resection. Patients with OAT were more likely to be older (74 vs. 63 years, p < 0.001), have a higher body-mass index (28 vs. 25 kg/m2, p = 0.034), have higher CACI scores (5 vs. 3, p < 0.001), have lower preoperative albumin levels (3.7 vs. 3.9 g/dL, p = 0.009), and have higher carbohydrate antigen 19-9 levels (178.5 vs. 76.0 U/mL, p = 0.038). Patients not receiving adjuvant therapy also had adverse perioperative characteristics, with increased severe complications (42.1 vs. 14.5 % grade III/IV, p < 0.001), length of stay (13 vs. 9 days, p < 0.001), and 30- to 90-day readmission rates (28.1 vs. 11.1 %, p = 0.005). Additional demographics and clinicopathologic characteristics are depicted in Table 1.
Author Manuscript
On univariate analysis, age (>70 vs. 10 mg/dL were associated with early 6-month recurrence. Age >70 years persisted on multivariate analysis for both postresection metrics, though there are conflicting reports on the Ann Surg Oncol. Author manuscript; available in PMC 2016 December 01.
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perioperative outcomes of elderly patients after PD35–38 Age is often intimately associated with a patient’s performance status, affecting a clinician and patient’s decision for administration of adjuvant therapy. Receipt of adjuvant therapy among elderly patients is important, having demonstrated a protective effect on 2-year survival.39 In addition to age, a total bilirubin >10 mg/dL increased the likelihood of ER. This may reflect advanced disease, and may be considered a surrogate for patients with worse tumor biology. In addition, hyperbilirubinemia may also affect the performance status of the patient before and after surgery, influencing recovery and completion of adjuvant therapy. Previous studies have implicated jaundice as an independent prognostic factor of early mortality in pancreatic ductal adenocarcinoma.40,41
Author Manuscript
It is of interest that CACI did not achieve significance along with age on multivariate analysis. In addition, we found no significant interaction between age and CACI on multivariate analysis. This may be attributed to the comparable baseline comorbidities in our study population, when age is not factored in. Dias-Santos et al. reported that CACI is a useful tool in predicting length of stay, postoperative complications, and 1-year mortality.42 However, their findings on CACI cannot be extrapolated to OAT, as their study included patients who received NT, and who underwent distal pancreatectomy and total pancreatectomy in addition to PD. Furthermore, Dale et al. report the use of preoperative geriatric assessment to predict postoperative outcomes and identify older patients at risk for complications.43 In their study, patients with “exhaustion” within the Fried’s model of frailty were fourfold more likely to experience a major complication. Although this study primarily measured complications and 30-day readmission, it would be of interest to see if preoperative assessment of biologic age can predict receipt and completion rate adjuvant therapy.
Author Manuscript
Even less is known about the effect of timeliness to adjuvant therapy. On our univariate and multivariate analysis, patients over 70 were more likely to experience a delay in therapy. However, we found that a delay in adjuvant therapy did not affect OS compared to patients who received their therapy before that cutoff point. This is comparable to the most recent follow-up of the ESPAC-3 treatment arm population, in which completion of chemotherapy, rather than time to initiation, was an independent prognostic factor in terms of disease free and OS.44
Author Manuscript
Although no convincing data exist on the use of NT for nonpancreatic periampullary cancers, the ESPAC-3 trial validated the role of multimodal therapy in these malignancies. Our study was inclusive of nonpancreatic periampullary cancers in order to comprehensively address the population of patients at risk for OAT. The findings of Valle et al. reinforce the concept that patients should not initiate adjuvant therapy until they have recovered sufficiently, and those who experience a prolonged postoperative recovery should not be discouraged from multimodal therapy.44 Yet these recent finding alone cannot answer for the significant portion of surgery-first patients who do not receive adjuvant therapy at all, as reasons are multifactorial. The limitations of this study are related to its retrospective nature. First, patients with incomplete data on receipt of adjuvant therapy were omitted from analysis (n = 33). Second,
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we were unable to control for the adjuvant therapy regimen, duration, and completion during the time period of this study. Third, some patients with ER may not have been captured due to incomplete follow-up; as a tertiary care referral center, patients who originate from outside our geographic region may choose to receive nonoperative care outside of our facility. Last, we would expect that with larger study numbers, more univariate results would have persistent statistical significance on multivariate analyses, strengthening our results.
CONCLUSIONS
Author Manuscript
Our findings indicate that elderly patients, especially past their seventh decade, are most at risk for OAT and ER after PD. This results in a striking survival disadvantage. We submit that elderly patients over the age of 70 years are at elevated risk for OAT and/or ER; they should be considered for NT, rather than a surgery-first approach, based on the associated benefit of completion of multimodal therapy and improved survival.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66:7–30. [PubMed: 26742998] 2. Kennedy EP, Yeo CJ. The case for routine use of adjuvant therapy in pancreatic cancer. J Surg Oncol. 2007; 95:597–603. [PubMed: 17230543] 3. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas—616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000; 4:567–579. [PubMed: 11307091] 4. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007; 297:267–277. [PubMed: 17227978] 5. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008; 299:1019–1026. [PubMed: 18319412] 6. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010; 304:1073–1081. [PubMed: 20823433] 7. Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA. 2012; 308:147–156. [PubMed: 22782416] 8. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013; 310:1473–1481. [PubMed: 24104372] 9. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. a prospective, single-institution experience. Ann Surg. 1997; 225:621–633. [PubMed: 9193189] 10. Merkow RP, Bilimoria KY, Tomlinson JS, et al. Postoperative complications reduce adjuvant chemotherapy use in resectable pancreatic cancer. Ann Surg. 2014; 260:372–377. [PubMed: 24374509]
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11. Bilimoria KY, Bentrem DJ, Lillemoe KD, Talamonti MS, Ko CY. Pancreatic cancer quality indicator development expert panel, American College of surgeons. assessment of pancreatic cancer care in the United States based on formally developed quality indicators. J Natl Cancer Inst. 2009; 101:848–859. [PubMed: 19509366] 12. Simons JP, Ng SC, McDade TP, Zhou Z, Earle CC, Tseng JF. Progress for resectable pancreatic [corrected] cancer? A population- based assessment of US practices. Cancer. 2010; 116:1681– 1690. [PubMed: 20143432] 13. Mehta VK, Fisher GA, Ford JM, et al. Adjuvant chemoradiotherapy for “unfavorable” carcinoma of the ampulla of Vater: preliminary report. Arch Surg. 2001; 136:65–69. [PubMed: 11146780] 14. Howe JR, Klimstra DS, Moccia RD, Conlon KC, Brennan MF. Factors predictive of survival in ampullary carcinoma. Ann Surg. 1998; 228:87–94. [PubMed: 9671071] 15. Hsu HP, Shan YS, Hsieh YH, Yang TM, Lin PW. Predictors of recurrence after pancreaticoduodenectomy in ampullary cancer: comparison between non-, early and late recurrence. J Formos Med Assoc. 2007; 106:432–443. [PubMed: 17588836] 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; 198:722–731. [PubMed: 15110805] 17. 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. [PubMed: 7826162] 18. Riediger H, Keck T, Wellner U, et al. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest Surg. 2009; 13:1337–1344. [PubMed: 19418101] 19. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg. 2006; 10:1199–1210. [PubMed: 17114007] 20. Pawlik TM, Gleisner AL, Cameron JL, et al. Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery. 2007; 141:610–618. [PubMed: 17462460] 21. 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; 40:373–383. [PubMed: 3558716] 22. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: 5-year experience. Ann Surg. 2009; 250:187–196. [PubMed: 19638912] 23. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999; 341:2061–2067. [PubMed: 10615079] 24. Du L, DeFoe M, Ruzinova MB, Olsen JR, Wang-Gillam A. Perioperative therapy for surgically resectable pancreatic adenocarcinoma. Hematol Oncol Clin North Am. 2015; 29:717–726. [PubMed: 26226906] 25. Mayo SC, Gilson MM, Herman JM, et al. Management of patients with pancreatic adenocarcinoma: national trends in patient selection, operative management, and use of adjuvant therapy. J Am Coll Surg. 2012; 214:33–45. [PubMed: 22055585] 26. Wu W, He J, Cameron JL, et al. The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy for adenocarcinoma. Ann Surg Oncol. 2014; 21:2873–2881. [PubMed: 24770680] 27. Nussbaum DP, Adam MA, Youngwirth LM, et al. Minimally invasive pancreaticoduodenectomy does not improve use or time to initiation of adjuvant chemotherapy for patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2016; 23:1026–1033. [PubMed: 26542590] 28. Papalezova KT, Tyler DS, Blazer DG 3rd, et al. Does preoperative therapy optimize outcomes in patients with resectable pancreatic cancer? J Surg Oncol. 2012; 106:111–118. [PubMed: 22311829] 29. Cooper AB, Holmes HM, Bordes JK, et al. Role of neoadjuvant therapy in the multimodality treatment of older patients with pancreatic cancer. J Am Coll Surg. 2014; 219:111–120. [PubMed: 24856952]
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30. Miura JT, Krepline AN, George B, et al. Use of neoadjuvant therapy in patients 75 years of age and older with pancreatic cancer. Surgery. 2015; 158:1545–1555. [PubMed: 26243342] 31. Abbott DE, Tzeng CW, Merkow RP, et al. The cost-effectiveness of neoadjuvant chemoradiation is superior to a surgery-first approach in the treatment of pancreatic head adenocarcinoma. Ann Surg Oncol. 2013; 20(Suppl 3):S500–S508. [PubMed: 23397153] 32. Christians KK, Heimler JW, George B, et al. Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. Surgery. 2016; 159:893–900. [PubMed: 26602840] 33. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008; 26:3496– 3502. [PubMed: 18640930] 34. Sutton JM, Abbott DE. Neoadjuvant therapy for pancreas cancer: past lessons and future therapies. World J Gastroenterol. 2014; 20:15564–15579. [PubMed: 25400440] 35. Watanabe J, Hanaki T, Arai Y, et al. Perioperative outcomes after pancreaticoduodenectomy in elderly patients. Hepatogastroenterology. 2015; 62:590–594. [PubMed: 26897934] 36. Sukharamwala P, Thoens J, Szuchmacher M, Smith J, DeVito P. Advanced age is a risk factor for post-operative complications and mortality after a pancreaticoduodenectomy: a meta-analysis and systematic review. HPB (Oxford). 2012; 14:649–657. [PubMed: 22954000] 37. Suzuki S, Kaji S, Koike N, Harada N, Suzuki M. Pancreaticoduodenectomy can be safely performed in the elderly. Surg Today. 2013; 43:620–624. [PubMed: 23104552] 38. Hayman TJ, Strom T, Springett GM, et al. Outcomes of resected pancreatic cancer in patients age >/=70. J Gastrointest Oncol. 2015; 6:498–504. [PubMed: 26487943] 39. Horowitz DP, Hsu CC, Wang J, et al. Adjuvant chemoradiation therapy after pancreaticoduodenectomy in elderly patients with pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2011; 80:1391–1397. [PubMed: 20643511] 40. Sauvanet A, Boher JM, Paye F, et al. Severe jaundice increases early severe morbidity and decreases long-term survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. J Am Coll Surg. 2015; 221:380–389. [PubMed: 26206638] 41. Strasberg SM, Gao F, Sanford D, et al. Jaundice: an important, poorly recognized risk factor for diminished survival in patients with adenocarcinoma of the head of the pancreas. HPB (Oxford). 2014; 16:150–156. [PubMed: 23600768] 42. Dias-Santos D, Ferrone CR, Zheng H, Lillemoe KD, Fernandez-Del Castillo C. The Charlson age comorbidity index predicts early mortality after surgery for pancreatic cancer. Surgery. 2015; 157:881–887. [PubMed: 25704415] 43. Dale W, Hemmerich J, Kamm A, et al. Geriatric assessment improves prediction of surgical outcomes in older adults undergoing pancreaticoduodenectomy: a prospective cohort study. Ann Surg. 2014; 259:960–965. [PubMed: 24096757] 44. Valle JW, Palmer D, Jackson R, et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol. 2014; 32:504–512. [PubMed: 24419109]
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FIG. 1.
Kaplan-Meier curves of patients with periampullary malignancies after resection according to a receipt of adjuvant therapy, demonstrating survival advantage for patients who received adjuvant therapy (p < 0.01); b timing of disease recurrence, demonstrating survival disadvantage for patients with early 6-month recurrence (p < 0.01); and c omission of adjuvant therapy and/or early recurrence (ER), demonstrating a survival disadvantage for patients who did not receive adjuvant therapy and/or had ER (p < 0.01)
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TABLE 1
Author Manuscript
Demographic and clinicopathologic characteristics stratified by receipt of adjuvant therapy Variable
Without adjuvant therapy (n = 57)
With adjuvant therapy (n = 144)
74.0 (67.2–77.9)
63.0 (55.8–71.0)
33:24
75:69
p
Preoperative demographics Age, y Gender (M:F) Race
Ann Surg Oncol. Author manuscript; available in PMC 2016 December 01. Published in final edited form as: Ann Surg Oncol. 2016 December ; 23(13): 4156–4164. doi:10.1245/s10434-016-5457-z.
Early Recurrence and Omission of Adjuvant Therapy after Pancreaticoduodenectomy Argue against a Surgery-First Approach
Author Manuscript
Brent T. Xia, MD1, David A. Habib, BS2, Vikrom K. Dhar, MD1, Nick C. Levinsky, MD1, Young Kim, MS, MD1, Dennis J. Hanseman, PhD1, Jeffrey M. Sutton, MD1, Gregory C. Wilson, MD1, Milton Smith, MD3, Kyuran Ann Choe, MD4, Jeffrey J. Sussman, MD1, Syed A. Ahmad, MD1, and Daniel E. Abbott, MD5 1Department 2College
of Surgery, Division of Surgical Oncology, University of Cincinnati, Cincinnati, OH
of Medicine, University of Cincinnati, Cincinnati, OH
3Department
of Medicine, Division of Gastroenterology, University of Cincinnati, Cincinnati, OH
4Department
of Radiology, University of Cincinnati, Cincinnati, OH
5Department
of Surgery, Division of Surgical Oncology, University of Wisconsin, Madison, WI
Abstract Author Manuscript
Background—Sequencing therapy for patients with periampullary malignancy is controversial. Clinical trial data report high rates of adjuvant therapy completion, though contemporary, realworld rates remain incomplete. We sought to identify patients who failed to receive adjuvant therapy and those at risk for early recurrence (ER) who might benefit most from neoadjuvant therapy (NT). Methods—We retrospectively reviewed medical records of 201 patients who underwent pancreaticoduodenectomy for periampullary malignancies between 1999 and 2015; patients receiving NT were excluded. Univariate and multivariate analyses were performed to identify predictors of failure to receive adjuvant therapy and ER (within 6 months) as the primary end points.
Author Manuscript
Results—The median age at the time of surgery was 65.5 years (interquartile range 57–74 years). The majority of tumors were pancreatic ductal adenocarcinoma (76.6 %), and 71.6 % of patients received adjuvant therapy after resection. Univariate predictors of failure to undergo adjuvant therapy were advanced age, age-adjusted Charlson comorbidity index, operative transfusion, reoperation, length of stay, and 30- to 90-day readmissions (all p < 0.05). Advanced age, specifically among patients >70 years, persisted as a significant preoperative predictor on multivariate analysis (p < 0.01). Patients who failed to receive adjuvant therapy and/or developed
D. E. Abbott, MD, [email protected]. Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5457-z) contains supplementary material, which is available to authorized users. DISCLOSURE The authors declare no conflict of interest.
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ER had significantly worse overall survival rates compared to all other patients (27.8 vs. 9.7 months; p < 0.01). Conclusions—Approximately one-third of surgery-first patients undergoing pancreaticoduodenectomy at our institution did not receive adjuvant therapy and/or demonstrated ER. This substantial subset of patients may particularly benefit from NT, ensuring completion of multimodal therapy and/or avoiding futile surgical intervention. The incidence of periampullary neoplasms has risen in the past decade. Pancreatic cancer, the most common type, is projected to be responsible for 53,070 new diagnoses and 41,780 deaths in 2016.1 The closely matched incidence and mortality of this disease are reflective of its aggressive nature.
Author Manuscript
Surgical resection—pancreaticoduodenectomy (PD)—remains the only opportunity for a cure. However, given pancreatic cancer’s biology, with a 5-year survival of 15–20 % among patients with resectable disease, surgical intervention alone remains suboptimal.2,3 Randomized prospective trials have validated adjuvant therapy as an important treatment modality that improves overall survival (OS), though only 60–80 % of patients randomized to receipt of adjuvant therapy complete their treatment course.4–9 These rates are problematic, given that patients enrolled onto clinical trials are highly selected. Outside of clinical trials, postoperative complications are primarily implicated in many patients not receiving adjuvant therapy, negatively affecting their OS.10–12
Author Manuscript
Similarly, patients who develop early disease recurrence also exhibit worse OS rates13–15 Disease-free recurrence is largely dictated by tumor stage, lymph node involvement, and lymph node ratio, and these pathologic factors limit long-term survival to a select minority of patients with early-stage disease.16–20 Given these limitations of the traditional surgery-first approach, neoadjuvant therapy (NT) is an attractive option. Not only does NT ensure completion of multimodal therapy, but it also allows for improved patient selection, as patients at heightened risk for early recurrence (ER) can be spared a major operation. Outcomes and risk factors on both omission of adjuvant therapy (OAT) and ER in the same population is lacking. We sought to determine which preoperative clinical factors may be used to identify patients vulnerable to OAT and/or ER in order to identify patients who may particularly benefit most from NT.
METHODS Study Design and Data Collection
Author Manuscript
Using an institutional review board–approved pancreas database, we identified 234 patients who underwent PD with curative intent for resectable periampullary malignancies between 1999 and 2015 at the University of Cincinnati Medical Center. Patients sequenced with NT were excluded. Complete postoperative data were available for 201 patients, which comprised the final study population. A retrospective review of medical records incorporated perioperative data.
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Patient comorbidity was stratified by the age-adjusted Charlson comorbidity index (CACI).21 The comorbidity score was calculated at the time of periampullary cancer diagnosis based on clinical history. Age adjustment was factored with the addition of one point per decade past the fourth decade of life. Postoperative complications were classified according to the Clavien-Dindo system.22 Receipt of adjuvant therapy, recidivism, recurrence, and death were catalogued. OAT was defined as never receiving systemic therapy in the absence of radiographic disease. ER was defined as radiographic evidence of local progression or distant metastases within 6 months of resection. Patients who recurred before 12 weeks were excluded from analysis involving receipt of adjuvant therapy. OS was calculated from the date of surgery to the last documented follow-up or death.
Author Manuscript
Statistical Methods Continuous variables were compared using the Kruskal–Wallis H test and expressed as median (interquartile range), and Fisher’s exact test were used to compare categorical variables. Predictor variables were chosen based on their statistical significance on univariate analysis (p ≤ 0.10), or if deemed to be clinically significant. Multivariate analyses were performed with continuous and categorical variables as predictors of OAT and ER. Relative risks were expressed as odds ratios (OR) with a 95 % confidence interval (CI). Survival analysis was calculated using Kaplan–Meier curves and compared using Wilcoxon log-rank tests. An association was considered statistically significant if p < 0.05. All data analyses were performed by SAS 9.3 software (SAS Institute, Cary, NC).
RESULTS Author Manuscript
In the overall cohort, the median age at the time of surgery was 65.5 years (interquartile range 58.0–74.0 years). The majority (76.6 %) of tumors were pancreatic adenocarcinoma, and 71.6 % of patients received adjuvant therapy after resection. Patients with OAT were more likely to be older (74 vs. 63 years, p < 0.001), have a higher body-mass index (28 vs. 25 kg/m2, p = 0.034), have higher CACI scores (5 vs. 3, p < 0.001), have lower preoperative albumin levels (3.7 vs. 3.9 g/dL, p = 0.009), and have higher carbohydrate antigen 19-9 levels (178.5 vs. 76.0 U/mL, p = 0.038). Patients not receiving adjuvant therapy also had adverse perioperative characteristics, with increased severe complications (42.1 vs. 14.5 % grade III/IV, p < 0.001), length of stay (13 vs. 9 days, p < 0.001), and 30- to 90-day readmission rates (28.1 vs. 11.1 %, p = 0.005). Additional demographics and clinicopathologic characteristics are depicted in Table 1.
Author Manuscript
On univariate analysis, age (>70 vs. 10 mg/dL were associated with early 6-month recurrence. Age >70 years persisted on multivariate analysis for both postresection metrics, though there are conflicting reports on the Ann Surg Oncol. Author manuscript; available in PMC 2016 December 01.
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perioperative outcomes of elderly patients after PD35–38 Age is often intimately associated with a patient’s performance status, affecting a clinician and patient’s decision for administration of adjuvant therapy. Receipt of adjuvant therapy among elderly patients is important, having demonstrated a protective effect on 2-year survival.39 In addition to age, a total bilirubin >10 mg/dL increased the likelihood of ER. This may reflect advanced disease, and may be considered a surrogate for patients with worse tumor biology. In addition, hyperbilirubinemia may also affect the performance status of the patient before and after surgery, influencing recovery and completion of adjuvant therapy. Previous studies have implicated jaundice as an independent prognostic factor of early mortality in pancreatic ductal adenocarcinoma.40,41
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It is of interest that CACI did not achieve significance along with age on multivariate analysis. In addition, we found no significant interaction between age and CACI on multivariate analysis. This may be attributed to the comparable baseline comorbidities in our study population, when age is not factored in. Dias-Santos et al. reported that CACI is a useful tool in predicting length of stay, postoperative complications, and 1-year mortality.42 However, their findings on CACI cannot be extrapolated to OAT, as their study included patients who received NT, and who underwent distal pancreatectomy and total pancreatectomy in addition to PD. Furthermore, Dale et al. report the use of preoperative geriatric assessment to predict postoperative outcomes and identify older patients at risk for complications.43 In their study, patients with “exhaustion” within the Fried’s model of frailty were fourfold more likely to experience a major complication. Although this study primarily measured complications and 30-day readmission, it would be of interest to see if preoperative assessment of biologic age can predict receipt and completion rate adjuvant therapy.
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Even less is known about the effect of timeliness to adjuvant therapy. On our univariate and multivariate analysis, patients over 70 were more likely to experience a delay in therapy. However, we found that a delay in adjuvant therapy did not affect OS compared to patients who received their therapy before that cutoff point. This is comparable to the most recent follow-up of the ESPAC-3 treatment arm population, in which completion of chemotherapy, rather than time to initiation, was an independent prognostic factor in terms of disease free and OS.44
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Although no convincing data exist on the use of NT for nonpancreatic periampullary cancers, the ESPAC-3 trial validated the role of multimodal therapy in these malignancies. Our study was inclusive of nonpancreatic periampullary cancers in order to comprehensively address the population of patients at risk for OAT. The findings of Valle et al. reinforce the concept that patients should not initiate adjuvant therapy until they have recovered sufficiently, and those who experience a prolonged postoperative recovery should not be discouraged from multimodal therapy.44 Yet these recent finding alone cannot answer for the significant portion of surgery-first patients who do not receive adjuvant therapy at all, as reasons are multifactorial. The limitations of this study are related to its retrospective nature. First, patients with incomplete data on receipt of adjuvant therapy were omitted from analysis (n = 33). Second,
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we were unable to control for the adjuvant therapy regimen, duration, and completion during the time period of this study. Third, some patients with ER may not have been captured due to incomplete follow-up; as a tertiary care referral center, patients who originate from outside our geographic region may choose to receive nonoperative care outside of our facility. Last, we would expect that with larger study numbers, more univariate results would have persistent statistical significance on multivariate analyses, strengthening our results.
CONCLUSIONS
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Our findings indicate that elderly patients, especially past their seventh decade, are most at risk for OAT and ER after PD. This results in a striking survival disadvantage. We submit that elderly patients over the age of 70 years are at elevated risk for OAT and/or ER; they should be considered for NT, rather than a surgery-first approach, based on the associated benefit of completion of multimodal therapy and improved survival.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
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FIG. 1.
Kaplan-Meier curves of patients with periampullary malignancies after resection according to a receipt of adjuvant therapy, demonstrating survival advantage for patients who received adjuvant therapy (p < 0.01); b timing of disease recurrence, demonstrating survival disadvantage for patients with early 6-month recurrence (p < 0.01); and c omission of adjuvant therapy and/or early recurrence (ER), demonstrating a survival disadvantage for patients who did not receive adjuvant therapy and/or had ER (p < 0.01)
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TABLE 1
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Demographic and clinicopathologic characteristics stratified by receipt of adjuvant therapy Variable
Without adjuvant therapy (n = 57)
With adjuvant therapy (n = 144)
74.0 (67.2–77.9)
63.0 (55.8–71.0)
33:24
75:69
p
Preoperative demographics Age, y Gender (M:F) Race
