Comorbidity, age and overall survival in patients with advanced pancreatic cancer – Results from NCIC CTG PA.3: A phase III trial of gemcitabine plus erlotinib or placebo

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Abstract

Background

The effect of comorbidity, age and performance status (PS) on treatment of advanced pancreatic cancer is poorly understood. We examined these factors as predictors of outcome in advanced pancreatic cancer patients treated with gemcitabine +/– erlotinib.

Patients and methods

Comorbidity was evaluated by two physicians using the Charlson Comorbidity Index (CCI) and correlated with clinical outcome data from the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial.

Results

Five hundred and sixty-nine patients were included; 47% were aged ⩾65 years old, 36% had comorbidity (CCI > 0). In multivariate analysis, neither age (p = 0.22) nor comorbidity (p = 0.21) was associated with overall survival. The baseline presence of better PS and lower pain intensity scores was associated with better overall survival (p < 0.0001 and p = 0.01, respectively). An improvement in survival with the addition of erlotinib therapy was seen in patients age <65 (adjusted hazard ratio (HR) 0.73, p = 0.01) or in the presence of comorbidity (adjusted HR 0.72, p = 0.03). However, neither age nor CCI score was predictive of erlotinib benefit after test for interaction. Patients treated with gemcitabine plus erlotinib who were ⩾65 years of age or those with comorbidity had a higher rate of infections ⩾grade 3.

Conclusion

Low baseline pain intensity and better PS were associated with improved overall survival, while age and comorbidity were not independent prognostic factors for patients treated with gemcitabine-based therapy.

Introduction

Pancreatic cancer is a significant problem worldwide. It ranks ninth versus seventh in incidence, and fourth versus fifth in cancer-related mortality in the United States1 and Europe,2 respectively. Despite efforts to improve therapeutic strategies, prognosis is dismal with a 5 year overall survival (OS) of 5.5%.3 Over the past decade, pancreatic cancer incidence has increased for both sexes and 53% of patients have metastatic disease at presentation.3 Primarily a disease of the elderly, the median age at diagnosis is 72 years and 68% of patients are ⩾65 years of age.3 With an aging population, pancreatic cancer incidence is expected to increase by 55% over the next 20 years.4

Despite their predominance among cancer patients generally, the elderly remain underrepresented in clinical trials.5, 6 Evidence suggests that patients aged ⩾65 years of age can benefit from experimental treatments and do not experience greater treatment-related mortality.5, 6 Though information is limited regarding the benefit and tolerance of chemotherapy in elderly patients with pancreatic cancer, small retrospective studies suggest that the elderly derive benefit from gemcitabine and do not experience greater toxicity.7, 8, 9 In addition to advanced age, the influence of comorbidity on treatment effects is poorly understood. Elderly patients have a higher incidence of comorbidities, yet elderly patients included in clinical trials are generally free of significant comorbidity and therefore may not be representative of the wider population with cancer.10

Although various methods exist to measure comorbidity in cancer patients, the Charlson Comorbidity Index (CCI) is the most widely recognised and has been shown to have prognostic value in breast, head and neck, prostate, lung and colorectal cancers.11, 12, 13, 14, 15 The index includes 19 medical conditions with weighted scores (1–6), which is based on the relative risk of death within 12 months. The total comorbidity score is represented by the sum of these weighted scores.14 In pancreatic cancer, there has been little investigation into the interaction between comorbidity and outcome in patients receiving chemotherapy. Aside from the association between performance status (PS) and outcome, little is known about prognostic factors in advanced pancreatic cancer.16, 17, 18, 19, 20

The independent ability of age, comorbidity and PS to predict outcome in pancreatic cancer is poorly understood, but of clinical importance. Herein we explore this relationship in the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial.

Section snippets

Patients

Five hundred and sixty-nine patients with locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine plus either erlotinib or a matched placebo as previously described.21 Prior chemotherapy was not permitted, except for fluorouracil or gemcitabine given concurrently as a radiosensitiser with radiotherapy for local disease. Other eligibility included histologic or cytologic evidence of adenocarcinoma of the pancreas, measurable or evaluable disease,

Baseline age and comorbidity scoring

Of the 569 patients, 47% (N = 268) were aged ⩾65 years old and 36% (N = 202) had comorbidities (Table 1, Table 2). 31.1% had a CCI = 1 and 4.2% had a CCI = 2. Only one patient included in the analysis had a CCI > 2. The two physician reviewers differed in CCI scoring 51 patient charts and consensus scores were reached after review of these charts.

Baseline diabetes, metformin therapy, insulin therapy and statin therapy

Thirty percent (N = 175) of patients had a baseline diagnosis of diabetes mellitus, 26% (N = 46) were using metformin and 46% (N = 81) were using insulin therapy (

Discussion

Since the relationship between advancing age, PS and comorbidity has not been adequately investigated in advanced pancreatic cancer, we undertook a retrospective analysis of the NCIC CTG PA.3 clinical trial to determine the role played by each of these factors as predictors of outcome. Our analysis revealed that in the total patient population on this trial, PS and baseline pain intensity were significantly correlated with survival, while neither age nor comorbidity was an independent

Disclosure

Presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 2010. This project was supported by funding through the CAMO/CIHR/Rx&D Research Fellowship Programme.

Conflict of interest statement

Michael Vickers, none; John Hilton, none; Wendy Parulekar, none; Chris O’Callaghan, none; Dongsheng Tu, none; Erin Powell, honoraria – Roche, Pfizer; Timothy Asmis, Consultant, Research funding, Honoraria – Roche; Derek Jonker, Consultant (unremunerated) – Roche; Malcolm Moore, Consultant – OSI Pharma.

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