The challenge of treating older patients with pancreaticobiliary malignancies

Curr Probl Cancer ] (2018) ]]]–]]]

Contents lists available at ScienceDirect

Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer

The challenge of treating older patients with pancreaticobiliary malignancies Lynda R. Corrigan, MB BCh*, Dara M. Bracken-Clarke, MB BCh, Anne M. Horgan, MB BCh Department of Medical Oncology, University Hospital Waterford, Ardkeen, Co Waterford, Ireland

a r t i c l e in f o Keywords: Pancreatic cancer Biliary tract cancer Older patients Surgery Chemotherapy Radiation therapy

a bs t r a c t Pancreatic and biliary tract cancers are aggressive malignancies. They commonly present with metastatic or unresectable disease. Those that do present with resectable cancer have high rates of recurrence. Despite recent advances in surgical technique, chemotherapy, and radiotherapy regimens, they are associated with poor survival outcomes. These cancers represent an exception to the trend of improved overall survival evident in most malignancies in recent decades. Depending on the goal of treatment, active management of pancreatic and biliary cancers involves surgery, chemotherapy, and radiation therapy, either alone or in combination. Both pancreatic and biliary tract cancers have a preponderance in the older population. Older patients are a heterogeneous group; although tolerability of multimodality treatment may be a challenge for some, many fit older patients may be undertreated based on their age alone. The growing field of geriatric oncology has highlighted the importance of a comprehensive assessment of these patients, and not relying on age alone as a discriminating factor for treatment. Management of older patients with pancreaticobiliary cancers is particularly challenging owing to limited prospective data in this population. As such, there is uncertainty with regard to optimal treatment approaches for these patients. In this article, we outline the therapeutic options available to patients with localized or advanced

* Correspondence to: Lynda Corrigan, Department of Medical Oncology, Specialist Registrar in Medical Oncology, University Hospital Waterford, Ardkeen, Co Waterford, Ireland. E-mail address: [email protected] (L.R. Corrigan).

https://doi.org/10.1016/j.currproblcancer.2018.01.015 0147-0272/& 2018 Elsevier Inc. All rights reserved.

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pancreatic and biliary tract cancers, and the evidence for specified treatment options in the elderly. We examine the inclusion and outcomes of elderly patients in relevant clinical trials; the morbidity that may be encountered by elderly patients receiving specified treatments and the tools that may assist the physician in selecting elderly patients for particular treatments. & 2018 Elsevier Inc. All rights reserved.

Introduction Pancreatic cancer (PC) is a disease of the elderly. The median age at diagnosis is 70 years and twothirds of those diagnosed between 2010 and 2014 in the United States were 465 years.1 Despite the preponderance of PC in the older adult, many have been excluded from large randomised trials.2 A similar trend is seen with cancers of the biliary tract (BTC) comprising carcinomas of the gallbladder (GBC), intrahepatic and extrahepatic cholangiocarcinomas (CCA). The median age of diagnosis is 67 years (intrahepatic CCA and GBC) and 72 years (extrahepatic CCA), however, the majority of trials have focused on the management of younger patients.3,4 The management of these cancers is multimodal with curative therapy based around R0 surgical resection and consideration for adjuvant therapy. There are a number of factors, however, that complicate treatment decisions in the older population. Aging is associated with a decline in the functional reserve of multiple organ systems which may impact pharmacokinetics and pharmacodynamics of chemotherapeutic agents.5,6 This has the potential to increase the risk of toxicity owing to altered drug absorption, metabolism, and excretion.6,7 Older patients are more likely to have comorbidities and functional deficits which may impact suitability for aggressive surgical, radiation, or chemotherapy approaches. In addition, poorer social supports may make compliance to treatments, particularly chemotherapy, more challenging. Therapeutic decisions in the older patient should thus consider all of these factors. Multidimensional, comprehensive clinical assessments should be used to better estimate the risks and benefits of interventions and guide treatment decisions in this population. In this article, we will review the data addressing the management of older patients with pancreaticobiliary malignancies. In addition, we will outline the clinical assessment tools that may facilitate more individualized treatment decisions for this population.

Pancreatic cancer Pancreatic ductal adenocarcinoma represents approximately 85% of pancreatic malignancies. It is associated with a high mortality and represents an exception to the trend of improved overall survival (OS) evident in most malignancies in recent decades. The majority of patients present with inoperable or metastatic disease. In the 15%-20% of patients who present with operable disease, the 5-year OS rate in optimally staged patients is 20%.8 Five-year OS rates for those 465 years are less than half of those who are o65 years (5.6 and 12.2%, respectively), reflecting the challenge regarding optimal management of this heterogeneous group.1 Surgery Resection of PC offers the only chance at cure. The conventional surgery for tumors of the head or uncinate process is a pancreaticoduodenectomy (Whipple procedure). Tumors in the body or tail may be resected with a partial pancreatectomy, however, these often present at a later stage when curative resection is not feasible. Despite surgery, 5-year OS rates remain poor at 15%-20%.9

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Older patients are less likely to be offered surgical resection.10,11 A large (n ¼ 9533) retrospective study evaluated trends in resection rates and operative mortality in adults aged ≥66 with locoregional PC.10 Patients were identified from the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. This demonstrated an overall resection rate of 25% for patients ≥66 years. Resection rate decreased with increasing age; 39% of those 66-70 years as compared to 4% of those ≥85 years. Increasing age also decreased the likelihood of evaluation by a surgeon (81% of those o70 vs 45% ≥85 years). Surgical evaluation and resection rates decreased with age regardless of comorbidity status. Mortality rates associated with pancreatic surgery are estimated at about 4% in high-volume centers. Approximately 40%-50% of patients will encounter operative morbidity, with complications including delayed gastric emptying, pancreatic fistula formation, wound infection, bile leak, and pancreatitis.12–15 The majority of studies examining morbidity and mortality in the older patient are retrospective in nature and single centered (Table 1). Most did not detect a difference in morbidity between older and younger patients.12,13,15,16 One large retrospective review of 2698 patients demonstrated a significant increase in morbidity in those ≥80 years compared to those o80 years.14 The findings with regard to mortality in the elderly were conflicting: some studies demonstrate a reduction in median OS,14 or an increase in 30-day mortality,16 with increased age. Others found no significant difference.12,13,15 Given the risk of complications, and low cure rates, surgical candidates need to be carefully selected. Age alone has not been demonstrated to be a reliable selection criterion for fitness for surgery.14,17 Studies have demonstrated that resection is associated with a reduction in the risk of death regardless of age,10 and that pancreaticoduodenectomy can be safely performed in the older patient, including octogenarians.14

Adjuvant therapy Owing to the high rates of systemic ( 480%) and local relapse (420%) after surgery alone, adjuvant therapies are recommended following resection of PC.18,19 Inclusion in a clinical trial is the optimal treatment for any patient; however, exclusion criteria based on age, performance status and comorbidities makes this difficult for older patients. The optimal treatment for patients in the adjuvant setting remains controversial. European guidelines favor chemotherapy alone and do not recommend the use of chemoradiotherapy outside of a clinical trial setting.18 In contrast, United States guidelines recommend chemoradiotherapy as a suitable alternative to adjuvant chemotherapy alone.19

Chemotherapy A number of clinical trials have evaluated postoperative single agent chemotherapy20–23 with favorable results compared with surveillance alone. The overall benefit persists to 10 years with an absolute survival advantage of 4%-5% at this stage.24 More recently, a doublet regimen containing gemcitabine and capecitabine has demonstrated superior median OS compared to gemcitabine alone.25 In the majority of these trials, older patients were included. Table 2 summarizes the relevant phase III clinical trials and the age cohort of the participants. ESPAC-1 did not demonstrate a difference in outcome based on age.20 However, the oldest patient enrolled in the trial was 68 years, therefore its application to an older population is unknown. In CONKO-001 age was not found to be a prognostic factor for survival: no significant difference in the primary endpoint of progression-free survival (PFS) between patients ≥65 and o65 years was demonstrated (hazard ratio [HR] ¼ 1.11, P ¼ 0.34).24 Similarly, there was no statistically significant difference in OS on multivariable analysis for age (HR ¼ 1.28, P ¼ 0.06). JASPAC 01 reported survival outcomes in those ≥65 compared to those o65, demonstrating a preserved benefit in the older group with HR of 0.57 vs 0.55 in the younger cohort.22 However, the upper age limit for inclusion was 73 years. As this was an Asian cohort, the application of these data outside of this population setting is unclear. In ESPAC-3 age was not determined to be a prognostic factor for

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Table 1 Morbidity and mortality associated with pancreatic cancer surgery in the elderly Study

Design

Age (y)

Morbidity

Mortality

Frakes et al,13 n ¼ 193

Retrospective

o70: 106 (55%)

No significant difference in morbidity between groups. Trend towards increased pancreatic leak in elderly, P ¼ 0.06

Median OS:

70-75: 35 (18%)

76-80: 26 (13.5%) 480: 26 (13.5%) Range not specified

Makary et al,14 n ¼ 2698

Retrospective

Riall et al,16 n ¼ 3736

Retrospective

o80: 2491 (92.5%) 80-89: 197 (7%) ≥90: 10 (0.5%) Range: 15-103

o60: 1780 (47.7%)

Overall morbidity rate: o80: 41.6 % 80-89: 52.8% ≥90: 50% P ¼ 0.002 Age not prognostic for morbidity on MVA Not reported

60-69: 887 (23.7%) 70-79: 855 (22.9%) ≥80: 214 (5.7%) Range not specified

Brozzetti et al,12 n ¼ 166

Retrospective

Ito et al,15 n ¼ 98

Prospective

o70: 109 (66%) ≥70: 57 (34%) Range: 25-85 o75: 67 (68.3%) ≥75: 31 (31.6%) Range not specified

Overall morbidity rate: o70: 42.2% ≥70: 43.8% P ¼ 0.86 Overall morbidity rate: o75: 46.3% ≥75: 54.8% P ¼ 0.43

o70: 23 mo

70-75: 23.4 mo 76-80: 16.1 mo 480: 18.7 mo, P ¼ 0.62 Age not prognostic for survival on MVA Median OS: o80: 40 mo 80-89: 19 mo ≥90: 15 mo P o 0.05 Age not prognostic for survival on MVA 30 day mortality rates: o60: 2.4% 60-69: 5.8% 70-79: 7.4% ≥80: 11.4% P o 0.0001 Age independent predictor of mortality on MVA 30 d mortality rates: o70: 3.7% ≥70: 10.5% P ¼ 0.09 3-y OS: o75: 65.9% ≥75: 84.8% P ¼ 0.10

MVA, multivariate analysis.

survival.23 Subgroup analysis in ESPAC-4 demonstrated similar HRs for death in the younger (o65 years) and older cohorts at 0.82 (HR ¼ 0.64-1.06) and 0.81 (HR ¼ 0.62-1.06), respectively.25 Another important consideration is the toxicity profiles associated with the adjuvant regimens. Single agent chemotherapy regimens such as gemcitabine and 5-flourouracil (5-FU)/leucovorin are generally well tolerated, as demonstrated by the toxicity profile reported in the adjuvant trials.23–25 In ESPAC-3, there were significantly higher rates of serious adverse events in the 5-FU arm (14%) vs the gemcitabine arm (7.5%).23 Grade 3 or 4 stomatitis and diarrhea were more common in the 5-FU arm, whereas hematological toxicities were more common in the gemcitabine arm. In ESPAC-4 there was no significant difference in the rate of adverse events in either arm (26% for gemcitabine and 24% for gemcitabine or capecitabine, P 4 0.05).25 However, more patients on the combination arm

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Table 2 Outcomes for the elderly in randomised controlled trials for metastatic pancreatic cancer Clinical trial

Protocol

Chemotherapy ESPAC-1,20 n ¼ 541 FU/LV vs surveillance

CONKO-001,21 n ¼ 368

Gemcitabine vs surveillance

JASPAC 01,22 n ¼ 377

Gemcitabine vs S-1

ESPAC-3,23 n¼ 1088

FU/LV vs gemcitabine

ESPAC- 4,25 n¼ 730 Gemcitabine/capecitabine vs gemcitabine

Chemoradiotherapy GITSG26 n¼ 43

EORTC,27 n¼ 207

ESPAC- 1,20 n¼541

Concurrent EBRT (40 Gy) plus bolus FU vs surveillance (Terminated owing to poor accrual) Concurrent EBRT (40 Gy) plus infusional FU vs surveillance Concurrent EBRT (20 Gy) plus bolus FU vs surveillance

Primary endpoint

Age (y)

OS: 19.7 vs 14 mo Age 460: 285 (53%) Age ≤60: 256 (47%) P ¼ 0.0005 Range: 51-68 PFS: 13.4 vs Age ≥65: 219 (62%) 6.7 mo Age o65: 135 (38%) P o 0.001 Range: 34-82 OS: 26 vs 47 mo Age ≥65: 227 (60%) (noninferiority) Age o65: 150 (40%) P o 0.0001 Range: 59-73 OS: 23.0 vs 23.6 Age breakdown not mo specified P ¼ 0.39 Range: 31-85 OS: 28.0 vs 25.5 Age ≥65: 348 (48%) mo Age o65: 382(52%) P ¼ 0.032 Range: 37-81 OS: 20 vs 11 mo

Age ≥61: 25 (58%)

P ¼ 0.03 OS: 24.5 vs 19.0 mo P ¼ 0.208 OS: 15.5 vs 16.1 mo P ¼ 0.24

Age ≤60: 18 (42%) Age breakdown not specified Range: 24-80 Age 4 60: 285 (53%) Age ≤ 60: 256 (47%) Range: 51-68

EBRT: external beam radiation therapy; FU/LV, fluorouracil/leucovorin.

required dose reduction as demonstrated by a median dose intensity of 93% of the planned protocol for the gemcitabine group vs 83% and 78% for gemcitabine and capecitabine, respectively in the gemcitabine and capecitabine group. Grade 3 or higher neutropenia and hand-foot syndrome were more prominent in the combination arm at 38% (vs 24% in gemcitabine arm, P ¼ 0.0001) of patients and 7% (vs 0% in gemcitabine arm, P o 0.0001), respectively.

Chemoradiotherapy The data to support combined chemoradiotherapy in the adjuvant setting are conflicting. The early GITSG (Gastrointestinal Tumor Study Group) clinical trial was a small study (n ¼ 43) which was closed early secondary to poor accrual.26 Outcomes based on age have not been reported for GITSG or for the European Organization for Research and Treatment of Cancer (EORTC) trial.27 A number of retrospective studies have examined the uptake of adjuvant therapy in the older patient. A retrospective review of 10,505 patients ≥66 years, with locoregional disease, demonstrated that only 11% received combined surgery and chemotherapy.28 Of those that received adjuvant chemotherapy, 80% also received radiotherapy. Nagrial et al29 assessed the use and efficacy of adjuvant chemotherapy in patients aged ≥70 compared to those o70 years. A total of 439 were included (261 o70 and 178 ≥70 years). Older patients were less likely to receive adjuvant chemotherapy (29.8% vs 51.5%; P o 0.0001). Older patients also had a worse outcome when adjuvant therapy was not delivered with a HR for death of 1.89 (95% CI: 1.27-2.78, P ¼ 0.002). Although it is encouraging to see the inclusion of older patients in these trials, there are some limitations to applying these findings to the older population as a whole. None of the trials stratify patients by age from the outset. Exclusion criteria for the trials are more likely to exclude older patients, given the increased likelihood of comorbidity in this cohort. Therefore, the older

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population in clinical trials tend to be a more select group and not wholly representative of the realworld population. None of the aforementioned trials present subset analysis for toxicity, an important consideration in the older patient, as they may be vulnerable to increased toxicity compared to their younger counterparts. Taking this into account, there are some conclusions that can be drawn from these pivotal trials. Age has not been determined to be an independent prognostic factor for survival in more than 1 study and should not be used in isolation to determine a patient’s suitability for treatment. The toxicity profile may favor single agent gemcitabine, however, patients up to the age of 81 were treated in ESPAC-4 and it may be an option for the fitter older patient.

Metastatic disease Approximately 40%-50% of patients present with metastatic disease, with 5-year OS in the region of 2%-3%. An additional 30%-40% present with locally advanced, inoperable disease.1 Recent treatment developments with doublet or triplet regimens have conferred a small survival benefit but the median OS remains dismal, between 9 and 12 months.30,31 The proportion of older patients treated with palliative chemotherapy varies in the literature. Oberstein et al32 examined the use of single agent gemcitabine in 3231 patients 465 years, identified from the SEER database, between 1998 and 2005. Approximately 54% of older patients were treated with chemotherapy. More recently, Li et al33 demonstrated higher treatment rates (n ¼ 237), with 83% of patients aged ≥75 years receiving chemotherapy in their institution. In a review of the Veterans Affairs Central Cancer Registry only 13% of patients aged ≥80 years received any systemic chemotherapy.34 When compared to their younger counterparts, older patients are less likely to receive chemotherapy.32,35,36 Sehgal et al35 examined the likelihood of receiving chemotherapy based on age in over 16,000 patients. 38% of patients 470 years received chemotherapy compared to 69% of patients o50 years. The treatment options for metastatic disease have improved in the last decade. Single agent gemcitabine represented the standard of care. More recently gemcitabine and abraxane has demonstrated superior OS compared to gemcitabine alone in the MPACT trial (median OS of 8.5 vs 6.7 months, respectively, HR for death, 0.72; 95% CI: 0.62-0.83; P o 0.001).30 ACCORD-11 compared FOLFIRINOX to gemcitabine, with a significant improvement OS in the combination arm (median OS 11.1 vs 6.8 months, respectively, HR for death, 0.57; 95% CI: 0.45-0.73; P o 0.001).31 The MPACT trial included older patients; 42% were ≥65 years (range: 27-88 years). HRs for survival favoured the gemcitabine or abraxane arm in both younger (o65) and older (≥65) patients but a greater benefit was seen in the younger cohort (HR is 0.65 and 0.81, respectively). Furthermore, 29% patients accrued to ACCORD-11 were 4 65 years. However, the trial had an upper age limit of 75. A benefit to treatment with FOLFIRINOX was illustrated in the older cohort with a HR of 0.48 in those 465 compared to 0.61 in those ≤65 years. ACCORD-11 did identify age 465 as an independent adverse prognostic factor for survival. This was not the case in the MPACT study and other randomised control trials have not demonstrated age to be a prognostic factor for survival.30,37-39 None of these clinical trials outline toxicity rates based on age. The grade 3 or higher toxicities associated with the combination of gemcitabine and abraxane were higher than those of gemcitabine alone and included neutropenia, fatigue, and peripheral neuropathy. There was no significant difference in the rate of serious AEs between the 2 groups. Grade 3 or higher peripheral neuropathy was evident in 17% in the combination arm as opposed to 1% in the gemcitabine arm. This may be a factor to consider in elderly patients who may have premorbid impaired mobility or functional deficits that could deteriorate with peripheral neuropathy. FOLFIRINOX is associated with a significantly higher incidence of neutropenia, febrile neutropenia, diarrhea, and peripheral neuropathy than gemcitabine. Grade 3 or higher febrile neutropenia was seen in 5.4% of patients in the FOLFIRINOX arm as opposed to 1.2% in the gemcitabine arm (P ¼ 0.03). Filgrastim was required by 42.5% of patients receiving FOLFIRINOX compared to 5.3% of those on gemcitabine.

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Several retrospective studies have demonstrated safety of gemcitabine single agent in the older population.40,41 There is less data with respect to the combination regimens. One retrospective review of 52 patients aged ≥70, with pancreatic or colorectal cancer, treated with FOLFIRINOX demonstrated similar rates of grade 3/4 hematological toxicity to the ACCORD-11 clinical trial (neutropenia 33%) and slightly higher rates of grade 3/4 diarrhea at 25%.42 A total of 39% of patients on this study discontinued treatment secondary to toxicity. It is encouraging to see the inclusion of older patients in some of the more recent clinical trials in the metastatic setting, however, there is a lack of level 1 evidence to inform a robust treatment paradigm for these patients. Nevertheless, it is clear that many older patients benefit from combination chemotherapy and should not be excluded from this based on age alone. FOLFIRINOX should be reserved for patients with a performance status of 0-1 and for those with few comorbidities. The authors would be reluctant to administer this regimen in patients aged 475 given its toxicity profile and the exclusion of these older patients from the landmark clinical trial. Gemcitabine or Abraxane is a more attractive combination in the older patient, owing to its proven efficacy in this cohort and its more favorable side effect profile. Single agent gemcitabine remains a reasonable alternative for patients deemed fit for systemic chemotherapy but with concerns regarding comorbidity burden and frailty.

Biliary tract cancer BTC encompasses malignant neoplasms arising from the epithelium of the biliary tract, incorporating the intrahepatic and extrahepatic bile ducts and gallbladder. Complete resection remains the only potentially curative therapy for BTC. However, patients commonly present with unresectable or metastatic disease, and recurrence rates remain high after complete resection. As a result, the prognosis of BTC remains dismal, with a 5-year survival rate of 10%-20%43-45 and a median survival of less than 1 year for unresectable or metastatic disease.46,47 BTC is primarily a disease of the older population with median age of diagnosis (SEER data, 2008-2012) being 67 years for intrahepatic CCA and 72 years for GBC and other BTCs.3,4 Surgery Curative surgery for BTCs may include major liver resection, biliary reconstruction, or pancreaticoduodenectomy. Resectability is determined by disease isolated to the liver or biliary tract with no distant metastases, no evidence of peritoneal disease and no nodal deposits beyond the porta hepatis. Multifocal liver disease is generally seen as a contraindication. Although definitive surgery for BTCs is frequently extensive and morbid, data do not identify age alone as a major contraindication. A multi-institution study by Vitale et al48 reported on the outcomes of liver resection for 584 patients, 129 of who were 470 years, with intrahepatic CCA. Complication rates were higher in older as compared to younger patients (53% vs 43%, P ¼ 0.03). There was a nonstatistically significant trend to improved 5-year OS and disease-free survival (DFS), in youngers older patients respectively, OS 24.4% vs 13.3%; and DFS 12.0% vs 7.3% (P 4 0.05). Similar surgical outcomes in GBC were noted in a small series (n ¼ 22) by Chen et al,49 with neither age nor liver involvement being adverse prognosticators if R0 resection could be achieved. OS was similar in the both cohorts. Higher postoperative complication rates in older patients appear to be associated with a greater burden of comorbidities. Zhang et al50 assessed 289 older patients (60-102 years, mean: 73.9 ± 8.9) between 2013 and 2016 with biliary tract disease, predominantly benign, and managed both operatively and nonoperatively. Mortality was 2.9% in the surgical group. Further analysis of these data suggest that hypertension, chronic pulmonary disease, and chronic kidney disease were among the main drivers of postoperative complications. Despite the paucity of data on surgical outcomes in older patients with BTC, outcome data from large institutions indicate that surgery is being offered to well-selected patients independent of age and that it is both safe and appropriate.49,51,52

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These data, though limited, support radical surgical intervention in potentially resectable patients regardless of age. However comprehensive medical or geriatric assessment to select appropriate patients and medical optimization should be pursued prior to radical surgery. Adjuvant therapy Adjuvant therapy for BTCs has been controversial in the absence of randomized data. A metaanalysis of studies published between 1960 and 2010 including 6712 patients showed a nonsignificant improvement in OS with any adjuvant therapy compared with surgery alone (pooled odds ratio, OR ¼ 0.74; P ¼ 0.06). The greatest benefit for adjuvant therapy was in those with lymph node positive disease (OR ¼ 0.49; P ¼ 0.004) and R1 disease (OR ¼ 0.36; P ¼ 0.002).53 More recently, the phase III PRODIGE-12 trial failed to demonstrate any significant benefit in DFS. PRODIGE-12 randomised 196 patients with R0 or R1 resected BTC (all subtypes) to either observation or gemcitabine or oxaliplatin for 12 cycles.54 DFS was 30.4 vs 22.0 months in the treatment vs observation arms with HR of 0.83 (P ¼ 0.31). Quality of life outcomes were not significantly different. This was a reasonably well-tolerated regimen with total grade 3 toxicities of 57.5% vs 22.2% and total grade 4 toxicities of 17.0% vs 9.1% in the treatment and observation arms, respectively. The most frequent of these toxicities were peripheral neuropathy and neutropenia with rates of 50% and 22.3%, respectively in the treatment arm. In contrast, the BILCAP study confirmed a benefit with adjuvant chemotherapy (n ¼ 447).55 BILCAP randomised 447 patients postresected BTC to either capecitabine for 8 cycles or observation alone. Both arms were appropriately matched with an overall significant preponderance of higherrisk disease: R1 resection 38%, node-positive status: 54%; median age was 63 years (range: 55-69 years). Results favoured the treatment arm with RFS of 25 vs 18 months and OS of 51 vs 36 months, HR ¼ 0.80; P ¼ 0.097.55 Based on these data, capecitabine is an accepted standard-of-care in the adjuvant setting. This was well-tolerated regimen, with plantar-palmar erythema (grade 3/4: 20.7%), fatigue (grade 3/4: 7.5%), and diarrhea (grade 3/4: 7.5%) being the most commonly reported toxicities in the treatment arm. Although the BILCAP trial primarily assessed younger BTC patients (o69 years) it is reasonable to extrapolate tolerability of this regimen from other studies of capecitabine use in the elderly.56-58 Few trials have directly assessed adjuvant chemotherapy in the older population. Horgan et al analyzed all BTCs in a large Canadian center from 1987-2013 (n ¼ 913, 321 470 years). In this series surgery rates were similar, 39% vs 38% between the older and younger cohorts, respectively. However, adjuvant therapy rates were 25% (chemotherapy) and 6% (chemoradiotherapy) for the younger cohort as opposed to 14% (chemotherapy) and 6% (chemoradiotherapy) for the older cohort (P ¼ 0.08).51 Lee et al reviewed 531 elderly patients with BTCs in a large Korean center from 20032001. In this analysis, there was a significantly lower rate of both chemotherapy and radiotherapy administration in the older cohort, however, the proportion of adjuvant to palliative therapies was similar in both groups.52 Systemic therapy was associated with better OS, undifferentiated between the adjuvant and palliative setting. There is a benefit to capecitabine-based adjuvant therapy in BTCs and, based on prior studies in other disease types, this agent is both safe and well tolerated in the older population.56,59 Based on age-related changes in absorption, hand-foot syndrome appears to be less frequent in the elderly with capecitabine.57,58 The decision for adjuvant treatment must be based on overall performance status, comorbidities, and frailty rather than age alone. Table 3 outlines the major published randomised trials in thecadjuvant and metastatic setting in biliary tract cancers. Metastatic disease Most patients with BTC present with either locally advanced or unresectable or metastatic disease and a significant proportion of those treated with curative intent ultimately relapse. The standard of care for unresectable or metastatic disease is cisplatin or gemcitabine, based on the ABC02 study.60 This trial compared cisplatin and gemcitabine with gemcitabine alone in recurrent,

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Table 3 Randomized trials in biliary tract cancer Clinical trial Adjuvant PRODIGE 12 ¼ ACCORD 1854 n ¼ 196 Phase III BILCAP55 n ¼ 447 Phase III Metastatic ABC-0260 n ¼ 410 Phase III

Protocol

Primary endpoint

Median age (y)

Gemcitabine/oxaliplatin vs surveillance

HR (for relapse): 0.83, P ¼ 0.31

63, range: 33-83

Capecitabine vs surveillance

HR (for survival) : 0.80, P ¼ 0.097 HR (for relapse) : 0.75, P ¼ 0.028

63, IQR : 53, 69

Cisplatin/gemcitabine vs gemcitabine

OS: 11.7 vs 8.1 months, P o 0.001

63 range: 23-85 y

IQR, interquartile range.

unresectable, or metastatic patients. A total of 410 patients were recruited with a median age of 69.2 and 69.9 years for the gemcitabine and cisplatin or gemcitabine arms, respectively (range: 23.4-84.8 years). OS was superior in the combination arm at 11.7 months vs 8.1 months in the gemcitabine arm (P o 0.001). Specific trials of chemotherapy in older patients with BTC are not extensive with many data derived from single-center results or subgroup analyses. Horgan et al demonstrated a significantly increased rate of best supportive care rather than palliative chemotherapy in their older cohort (470 years) of BTC cases treated between 1987 and 2013 in the Princess Margaret Cancer Center, Canada, with 34% (n ¼ 68) of older vs 57% of younger (n ¼ 206, P ¼ 0.0007) patients receiving palliative chemotherapy. Older age was associated with greater comorbidity (Charlson Comorbidity Index 41: 21% vs 6%, P ¼ 0.003) and inferior ECOG PS (ECOG PS 41: 16% vs 5%, P ¼ 0.009). Despite this, improvements in both OS and PFS were similar in both the older and younger cohorts; median OS of best supportive care: 6.8 vs 5 months, respectively; median OS of palliative chemotherapy: 14.3 vs 13.8 months for the younger vs older cohorts, respectively.51 Toxicity data for the older cohort specifically are limited by the paucity of trials specific to this cohort. ABC-02 demonstrated overall grade 3/4 toxicity rates of 68.8% and 70.7% for the gemcitabine vs cisplatin or gemcitabine arms. The most frequent grade 3 þ toxicities were: neutropenia (16.6% vs 25.3%), abnormal liver function (19.6% vs 13.1%), and fatigue (16.6% vs 18.7%); infection rates were similar. Cisplatin or gemcitabine was a well-tolerated regimen with 73.5% of patients completing the planned 3 months therapy (vs 66.5% for gemcitabine single-agent) in the ABC-02 cohort.60 Age was not a specified subgroup in the ABC-02 trial and toxicity data from the older population alone are not available. Retrospective data from the Netherlands and Romania assessing cisplatin and cisplatin doublets in the older population (admittedly primarily in lung cancer) suggest that these regimens are tolerable and safe in the older cohort with similar toxicity rates to younger patients but a potentially higher discontinuation rate.61,62 Lee et al52 reported demonstrated benefit of palliative and radical therapies in both their older and younger cohorts. In this series, 531 cases of BTCs were identified in Seoul National University Hospital between 2003 and 2011 of whom 326 were ≥65 years. Of this cohort 97% vs 91% (younger vs older) had ECOG PS o2 and 12% vs 21% had moderate and 2% vs 5% had severe comorbidity scores Subsequent univariate and multivariate analyses demonstrated surgery and chemotherapy alone as positive predictors of outcome with stage, lower baseline serum albumin, and greater comorbidity predictive of inferior survival; age alone was not associated with inferior outcome (P ¼ 0.33). The largest series is from McNamara et al63 who analyzed the results of 13 international trials (11 first line, 2 with a targeted agent added), ultimately including 1163 patients, recruited from 19972013. This included 260 patients (22%) 470 and 18 (2%) 480 years with a median age of 63. Patients were divided into 4 age groups: o40 years vs ≥40 years and nonelderly ( o70 years) vs

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elderly (≥70 years). Primary analysis demonstrated PFS for the o70 and ≥70 years cohort of: 6.0 vs 5.0 months, (P ¼ 0.53), respectively. OS was 10.2 vs 8.8 months (P ¼ 0.08) for the o70 and ≥70 cohorts, respectively. Subsequent multivariate analysis of these data demonstrated no association between age and either PFS or OS. No evidence of an interaction between age and tumor location or treatment type (monotherapy vs combination therapy) in terms of both PFS and OS was demonstrated, thus favouring maximal therapy independent of age. Based on the aforementioned data, age alone should not disqualify a patient from palliative therapy. BTCs are tumors of the older population and, although limited, the data demonstrate the efficacy of doublet therapy independent of age.

Patient selection Chronological age alone is a poor predictor of cancer treatment outcomes and toxicities. Thus, a major focus in recent years has been the development of clinical assessment tools that facilitate a more individualized treatment approach for older patients. Comprehensive geriatric assessment A comprehensive geriatric assessment (CGA) is a multidisciplinary review of an older person addressing the domains of physical, functional, nutritional, cognitive, and psychosocial status in addition to comorbidities and polypharmacy.64 In terms of systemic therapies, it may better identify patients that are fit for standard therapy, those that are vulnerable and require intervention, and those that are frail and best served by supportive care alone.65 Ongoing research will further define the best use of a CGA in the oncological setting and how to implement changes based on its findings. The International Society of Geriatric Oncology and the National Comprehensive Cancer Network advise consideration of CGA for patients aged ≥65 years.66,67 However, performing a CGA is timeconsuming and resources limit its widespread use. As such, a number of screening tools have been developed that may assist in identifying vulnerable older patients who may benefit from a CGA. The Vulnerable Elders Survey 13 (VES-13) is a 13 item self-administered questionnaire aimed to identify an increased risk of death or functional decline in elderly patients.68 The G-8 screening tool is an 8-item questionnaire administered by a healthcare professional designed specifically for oncology patients.69 It recommends a CGA if a score highlights impairments in one or more domains of the mininutritional assessment and also incorporates age. Surgery Current data indicate that a large number of older surgical cancer patients are frail or prefrail, that frailty can be identified based on a geriatric assessment, and that frailty is a predictor of negative surgical outcomes, including 30-day postoperative morbidity and mortality along with long-term mortality.70 Therefore, frailty should be assessed routinely in older patients being considered for surgery. Screening tools as mentioned in section 3.1 may help identify those who would benefit from a CGA preoperatively. The ability of a CGA to predict the risk of postoperative complications has been examined in other disease types. Fagard et al71 demonstrated that in patients undergoing surgery for colorectal cancer, an abnormal G8 score was associated with 30 day postoperative complications on univariate analysis. Ragulin-Coyne et al have developed a scoring system specific to those patients undergoing pancreatectomy. Its aim is to identify in-hospital mortality rate and it incorporates age into an algorithm, along with comorbidity (based on the Charlson Index) and hospital volume of resection.72 Those who are identified as at risk from specific geriatric assessment or general screening tools may be considered for preoperative rehabilitation programmes, which have been demonstrated to improve function and physical capacity postoperatively.73

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Chemotherapy Although chemotherapy improves outcomes for older patients with pancreaticobiliary cancers, they are also more likely to experience toxicities than younger patients. A number of models have been developed to predict the likelihood of chemotherapy toxicity and are based on certain elements assessed in a CGA. The CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) model, was developed to predict grade 4 hematological toxicity and grade 3 or 4 nonhaematological toxicity.74 The CARG (Cancer and Aging Research Group) score is an 11-item model that includes the following risk factors: age, cancer type, standard chemotherapy dosing, polychemotherapy, anemia, creatinine clearance, hearing problems, falls, help taking medication, limited ability to walk, and decreased social activity.75 These tools can help inform the decision-making process regarding chemotherapy in older patients. Additionally, in the metastatic setting it is pertinent to it is important to discuss goals of care with elderly patients. Quality of life has been demonstrated to be of greater importance than survival in older patients.76 Increasing the evidence base Older patients are underrepresented in clinical trials.2,77,78 This is not solely as a result of an age limit for trial entry, rather, elderly patients are likely to be excluded from clinical trials owing to comorbidity, physician′s perception, and poorer performance status.78,79 In order to improve the care we offer our older patient, we need better evidence to inform the treatment paradigm. This does not extend solely to the inclusion of a greater number of elderly patients in disease-specific clinical trials, but also to the development of elderly specific clinical trials and to the inclusion of CGA into trials which recruit elderly patients. The U-13 conference has published guidelines for the design and implementation of therapeutic clinical trials for older or frail adults.80 The American Society of Clinical Oncology have also published recommendations to improve evidence generation in the elderly group.81 The increasing awareness of the need for elderly participation in clinical trials is promising and if translated into practice will lead to more informed decision-making in the future across all cancer types.

Conclusion The management of pancreaticobiliary malignancies in the older population is challenging, with limited trial data in this cohort. However, older age should not be considered a contraindication to either palliative or radical surgical or systemic treatment approaches. Combination therapy can be delivered in the well older patient and remains effective. This review of data confirms the need to expand clinical trials to include older populations and adapt eligibility criteria to ensure recruitment of representative patients. Extrapolating efficacy in the older population based primarily on results in younger patients is necessarily limited. Determination of the patient′s physiological age through comprehensive assessments and better prediction of toxicities from cytotoxic therapies using available models, can result in a more tailored approach to the management of these patients. References: 1. National Cancer Institute Surveillance Epidemiology and End Results Program. SEER Cancer Statistics Review (CSR) 19752014. 2017 [cited 2017 30 July]; Available from: https://seer.cancer.gov/. 2. 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(27):2061–2067. 3. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. The Oncologist 2016;21(5):594–599. 4. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol 2014;6:99–109. 5. Balducci L, Extermann M. Cancer and aging. An evolving panorama. Hematol Oncol Clin North Am 2000;14(1):1–16.

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