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Efficacy and toxicity of abiraterone and docetaxel in octogenarians with metastatic castration-resistant prostate cancer

Journal of Geriatric Oncology, 1, 6, pages 23 - 28

Abstract

Objective

To assess the efficacy and toxicity of abiraterone and docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) of age > 80 compared to younger men.

Methods

Retrospective chart review of 116 men treated with abiraterone and 378 men treated with docetaxel at Princess Margaret Cancer Centre. Categorical outcome measures including PSA response rate (PSA-RR) and incidence of toxic side-effects were compared using Fisher's exact test. Overall survival (OS) and biochemical progression free survival (bPFS) were analyzed using the Kaplan–Meier method and log-rank tests.

Results

Thirty-four (29%) and 50 (13%) of the men treated with abiraterone or docetaxel, respectively, were octogenarians. For abiraterone there were no significant differences in PSA-RR (42% vs. 39%), bPFS (4.7 vs. 4.4 months) or OS (14.0 vs 20.7 months) between octogenarians and younger men, respectively. Toxicity was mild with no significant differences between age groups. For men treated with docetaxel PSA-RR and OS did not differ between age groups (40% vs. 45% and 12.0 vs. 14.1 months, respectively). However, rates of febrile neutropenia were 16% and 7% for octogenarians and younger men, respectively (p = 0.048). This difference was observed despite greater use of lower dose intensity and weekly docetaxel in the elderly cohort, with 20% of them receiving lower than standard dose during their first cycle compared to 7% of younger men (p = 0.004).

Conclusions

Treatment outcome on abiraterone and docetaxel did not differ in patients over and under the age of 80, but febrile neutropenia was more common in octogenarians treated with docetaxel despite lower dose intensity.

Abbreviations: bPFS - biochemical progression free survival, CI - confidence interval, ECOG PS - Eastern cooperative group performance status, EPR - electronic patient record, mCRPC - metastatic castration resistant prostate cancer, OS - overall survival, PM - Princess Margaret, PSA - Prostate specific antigen, PSA-RR - PSA response rate..

Keywords: Abiraterone, Docetaxel, mCRPC, Octogenarians, Toxicity, Efficacy, Prostate cancer.

1. Introduction

Prostate cancer (PC) is the second most common cancer in men in the western world and a leading cause of cancer-related death.1 and 2Increasing age is a risk factor for PC, 3 and as the life expectancy of men increases, the population of elderly men with PC is increasing.

Epidemiological studies show that compared with younger men, older men (> 75 years) are more likely to present with advanced PC, have a greater risk of death from PC despite higher death rates from competing causes, and contribute more than half of all PC deaths. 4 Additionally, as more life-prolonging treatments become available, 5 the population of very elderly men with advanced PC is increasing.

Once PC has metastasized, the goals of treatment become palliative. The initial treatment of advanced or recurrent disease is with androgen deprivation therapy (ADT) leading to a castrate level of serum testosterone, 6 but resistance to castration-therapy inevitably develops. The chemotherapeutic agent docetaxel has been the mainstay of treatment of men with metastatic castration-resistant prostate cancer (mCRPC) for over a decade. 7 Recently several new hormonal, chemotherapeutic and radionuclide agents have been approved for such men (reviewed in Sridhar et al. 5 ), thus increasing the therapeutic armamentarium. Abiraterone acetate (abiraterone), a novel hormonal agent, has been shown to increase overall survival (OS) in men with mCRPC 8 when administered both prior to and after chemotherapy8 and 9however its optimal place along the disease continuum of mCRPC is unknown.

Here we aim to compare the efficacy and toxicity of abiraterone and docetaxel in men over and under the age of 80 by performing a retrospective chart review of men with mCRPC treated with either of these two agents at Princess Margaret Cancer Centre (PM).

2. Methods

2.1. Setting, Participants, and Definitions

All men who received initial abiraterone at PM from November 2009 (first drug availability) until March 2013 were identified through the PM electronic patient records (EPR). All men who received at least one dose of docetaxel for first line chemotherapy treatment of mCRPC at PM before January 2012 were identified through pharmacy records. Men who received docetaxel in the context of neoadjuvant or adjuvant trials or as second-line chemotherapy for mCRPC were excluded. All data were extracted from the EPR. The institutional Research Ethics Board (REB) approved the study.

PSA response was defined as ≥ 50% decline of PSA compared with baseline maintained for at least 3 weeks. Men with a rise in PSA within the first 12 weeks of chemotherapy treatment were considered as PSA responders if subsequent values of PSA satisfied the above criterion, as recommended by the Prostate Cancer Working group 2 (PCWG2). 10

Biochemical progression-free survival (bPFS) was defined as the time between drug initiation and PSA progression according to (PCWG2) criteria. 10 As most men were not treated under trial setting, radiological assessment was not performed at pre-determined intervals and radiological PFS could not be determined consistently. Overall survival (OS) was defined as the time between treatment initiation and death from any cause. Men who were alive or lost to follow-up were censored on their last day of contact.

Co-morbidities were defined as the pre-existing conditions of hypertension, dyslipidemia, active smoking, cardio-vascular disease, diabetes mellitus, COPD or any other significant disease (including other malignancies aside for non-melanoma skin cancer). Co-morbidities were collected from the initial patient visit with his treating oncologist, in which they were detailed in length as part of the medical note, and updated if more accumulated over time. The total number of co-morbidities was calculated for each patient at start of treatment with either abiraterone or docetaxel.

2.2. Outcome Measurements and Statistical Analysis

The primary outcome was PSA-RR. Secondary outcomes of interest were toxicity as well as bPFS (for men treated with abiraterone) and OS. PFS was not defined as an endpoint for docetaxel as many patients stopped treatment upon the completion of a set amount of cycles without progressive disease.

Monthly PSA measurements were performed during the first 3 months of abiraterone treatment, and thereafter every 1–3 months according to physicians' discretion. Continuous variables were reported as medians with range (for age) or interquartile range (for laboratory parameters). Categorical variables were described as counts and/or proportions and compared using Fisher's exact test. OS and bPFS were estimated by the Kaplan–Meier method and compared using log-rank tests. All p-values were 2-sided and considered significant if < 0.05. No correction was made for multiple significance testing. Data analysis was performed using Statistical Analysis Software (SAS) Version 9.2 (SAS Institute, Inc., Cary, NC) or SPSS Version 20 (IBM Corp).

3. Results

3.1. Abiraterone

Of 116 men treated with abiraterone, 34 were octogenarians (29%). Baseline characteristics show that a higher percentage of octogenarians had more than one concurrent co-morbid condition, slightly lower hemoglobin and albumin levels than younger men and an Eastern Cooperative Group (ECOG) Performance Status (PS) of 2 or higher ( Table 1 ). Octogenarians were more likely to be prescribed abiraterone at a reduced dose with a high-fat meal than at full-dose in the fasting state ( Table 2 ), based on data showing similar pharmacokinetics of these two dosing regimens. 11 In these men, upfront dose reduction was not performed for medical reasons but because abiraterone was not reimbursed in Ontario for those who had not received prior docetaxel, mandating these men to purchase the drug out-of-pocket.

Table 1 Baseline characteristics of patients treated with abiraterone.

  Young (≤ 80 years) Octogenarian (> 80 years)
N = 82 N = 34
Age, years (median, range) 70 (50–79) 85 (80–91)
 
ECOG PS, N (%)
0 or 1 67 (82) 20 (61)
2 or 3 15 (18) 13 (39)
 
Comorbidities, N (%)
0–1 46 (57) 15 (45)
> 1 35 (43) 18 (55)
 
Extent of disease, N (%) a
Bone 60 (75) 23 (74)
Lymph nodes (LN) 35 (44) 10 (33)
Visceral 11 (14) 7 (23)
     
Hemoglobin, g/dL, median (IQR) 119 (109–129) 115 (107–130)
Albumin, g/L, median (IQR) 39 (37–42) 37 (36–39)

a The different subgroups are not mutually exclusive.

ECOG PS, Eastern Cooperative Group Performance Status; IQR, interquartile range.

Table 2 Dosing and toxicity of abiraterone.

Dosing Young (≤ 80 years) Octogenarian (> 80 years) p-Value
N = 82 N = 34
Baseline reduced dose, N (%) 10 (12) 10 (29) 0.03
Dose reduction due to toxicity, N (%) 2 (2) a 0 0.36
Drug discontinuation due to toxicity, N (%) 1 (1) b 3 (9) c 0.07

a Hepatotoxicity in both patients.

b Diarrhea.

c Rash; cardiac failure; peripheral edema.

The PSA-RR was similar for the two age groups: 42% (95% confidence interval [CI] 26–60%) in octogenarians and 39% (95% CI 28–50%) in younger men (p = 0.8). Similarly, there were no significant differences in median bPFS: 4.7 (95% CI 1.8–6.4) and 4.4 (95% CI 3.0–5.7) months for octogenarians and younger men, respectively (p = 0.8). There were no significant differences in median OS: 14.0 (95% CI 9.5–18.8) and 20.7 (95% CI 16.5–23.6) months for octogenarians and younger men, respectively (p = 0.1), although the median OS for octogenarians was numerically lower than for younger men.

Abiraterone was well tolerated in both age groups with uncommon and known side-effects of hypokalemia, hypertension, fluid retention and mild liver toxicity, without significant differences between the age groups. Toxicity-related dose reductions or discontinuations were uncommon, although there was a non-significant trend to more frequent toxicity-related drug discontinuation in the octogenarians (9% vs. 1%, p = 0.07; Table 2 ). There were no drug-associated deaths in either age groups.

3.2. Docetaxel

A total of 378 men were treated with docetaxel, of which 50 (13%) were octogenarians. Patient characteristics are shown in Table 3 . Most men in both age groups had an ECOG PS of 0 or 1, with 56% of the older patients having more than one co-morbid condition vs. 34% of the younger patients. Median hemoglobin and albumin levels were slightly lower in octogenarians. There were significant differences in the dosing regimens of docetaxel between octogenarians and younger men: more octogenarians received weekly docetaxel (16% vs. 4%, p = 0.003), based on results from the TAX-327 trial showing better tolerability of the weekly regimen in older men. 7 Upfront dose-reductions were also more common and overall dose-intensity was lower ( Table 4 ). None of the patients in both age groups received prophylactic support with stem-cell factor (such as G-CSF) upfront.

Table 3 Baseline characteristics of patients treated with docetaxel.

  Young (≤ 80 years) Octogenarian (> 80 years)
N = 328 N = 50
Age (years; median, range) 70 (43–79) 82.(80–90)
 
ECOG PS, N (%)
0 or 1 212 (74) 31 (66)
2 or 3 77 (23) 16 (32)
 
Comorbidities, N (%)
0–1 216 (66) 22 (44)
> 1 112 (34) 28 (56)
 
Extent of disease, N (%) a
Bones 286 (88) 56 (92)
Lymph nodes 174 (53) 26 (52)
Visceral 63 (19) 12 (26)
     
Hemoglobin, g/dL, median (IQR) 11.8 (10.6–12.9) 11.7 (10.4–13.1)
Albumin, g/L, median (IQR) 40 (38–42) 38 (37–41)

a The different subgroups are not mutually exclusive.

ECOG PS, Eastern Cooperative Group Performance Status; IQR, interquartile range.

Table 4 Schedule, dose, and toxicity in patients treated with docetaxel.

  Young

(≤ 80y)
Octogenarian

(> 80y)
p-Value
N = 328 N = 50
Schedule, N (%)
Weekly 13 (4) 8 (16) 0.003
Three-weekly 315 (96) 42 (84)  
 
Dosing, N (%)
Dose reduction ≤ 80% in first cycle 22 (7) 10 (20) 0.004
Dose reduction to ≤ 80% by cycle 6 58 (18) 18 (36) 0.004
Dose intensity (IQR) 0.95 (0.93–1) 0.88 (0.78–0.99) 0.03
 
Reason for stopping treatment, N (%)
Toxicity 67 (20) 16 (32) 0.04
Treatment completed 100 (31) 8 (16)  
Disease progression 121 (37) 16 (32)  
Other 24 (7) 8 (16)  
Death within 30 days of last dose 16 (5) 2 (4)  
 
Adverse events, N (%)
Febrile neutropenia, N (%, 95% CI) 23 (7;4–10) 8 (16; 5–27) 0.048

PSA-RR for octogenarians and younger men were 40% (95% CI 25–54%) and 45% (95% CI 40–50), respectively (p = 0.5) and Median OS was 12.0 months (95% CI 8.3–15.7) and 14.1 months (95% CI 12.3–15.9) in octogenarians and younger men, respectively (p = 0.3).

Despite the use of lower dose-intensity of docetaxel in octogenarians, toxicity-related drug cessation was significantly more common in this age group (32% vs. 20% in older and younger men, respectively, p = 0.04). In addition, febrile neutropenia was more frequent in octogenarians than in younger men, occurring in 16% vs. 7% of patients, respectively (p = 0.048, Table 4 ) and was even higher (19%) in octogenarians receiving docetaxel every 3 weeks. Death within 30 days of last docetaxel dose was uncommon, without significant differences between the two age groups ( Table 4 ).

4. Discussion

With an aging population and several new treatment options for mCRPC there are important questions relating to optimal drug usage and sequencing. These questions are particularly important for very elderly men with mCRPC, who may not receive all available therapeutic lines due to competing co-morbidities or declining performance status.

Here we assessed retrospectively the efficacy and tolerability of abiraterone and docetaxel in octogenarians with mCRPC. Almost all men received these drugs outside of a clinical trial, so that our results reflect ‘real life’ experience. 12 Our data show that both drugs are effective in men over and under the age of 80: there was no significant difference in PSA-RR for either of the drugs and no significant difference in PFS on abiraterone or OS in octogenarians treated with either of the drugs when compared to their younger counterparts. Of note, the median OS on abiraterone was numerically (albeit not statistically significant) lower in octogenarians than in younger men. Our efficacy results are in line with a recently published post-hoc subgroup analysis of the COU-AA-301 study, showing that abiraterone is as effective in men over the age of 75 as in younger men. 13 It is also consistent with a post-hoc analysis of the pivotal TAX-327 study, showing that efficacy of docetaxel is similar below and above age 75. 14

The toxicity profile of abiraterone in elderly men has not been studied extensively. Mulders et al. report an overall similar rate of adverse events in men treated with abiraterone over and under the age of 75, with a higher rate of peripheral edema in abiraterone-treated elderly men. 13 Notably, this report shows that the rates of cardiac disorders were slightly higher in the elderly population in the abiraterone plus prednisone arm compared with the placebo plus prednisone arm, whereas these adverse events were similar across treatment groups in younger men.

There were no significant differences in the incidence of abiraterone-related adverse events between octogenarians and younger men in our cohort, although the small number of subjects would not have allowed for small yet potentially clinically significant effects to be detected. There was a trend for higher toxicity-related treatment discontinuations in the elderly. The only documented heart failure on abiraterone in our cohort occurred in an 87-year-old man with a history of congestive heart failure. The potential interaction between old age and cardiac toxicity on abiraterone warrants further investigation. Moreover, thought should be given to poly-pharmacy, compliance with treatment and dosing mistakes on abiraterone in very elderly, as it is an oral drug that is taken by patients alone at their residence. These issues could not be addressed within this research due to its retrospective nature.

Docetaxel has been widely used for the treatment of PC as well as other solid malignancies and more experience regarding its toxicity in the very elderly has accumulated. Men of age > 65 treated with docetaxel at a dose of 75 mg/m2every 3 weeks (i.e. the standard regimen used for the treatment of mCRPC) have been shown to experience grade 4 neutropenia and febrile neutropenia more commonly than younger men, although this did not reach statistical significance. 15 No significant differences were found in chemotherapy tolerance and toxicity in a Dutch retrospective analysis of men treated with docetaxel for mCRPC up to the age of 80 years. 16 However, when compared to younger men, men aged 80 years or above experienced grade 3/4 toxicity more frequently and were five times less likely to complete the first three treatment cycles at the intended dose. 16 Tolerability and efficacy of 3-weekly docetaxel in TAX-327 appear less favorable with advancing age, 17 especially in regards to infection and weight loss.

A retrospective analysis of docetaxel pattern of usage and toxicity profile across 7 French tertiary oncology centers compared the standard 3 weekly regimen to an adapted regimen, defined either as weekly dosing or a dose-reduced 3-weekly regimen. Both neutropenia and febrile neutropenia were significantly more common with the standard dosing regimen, 18 providing the experimental basis to our practice of prescribing weekly or low-dose docetaxel in elderly or frail men.

In our cohort, older age was associated with a significantly higher risk of febrile neutropenia despite more up-front dose-reduction and prescription of weekly chemotherapy and despite the fact that the majority of octogenarians that received docetaxel had a baseline ECOG PS of 0 or 1. More octogenarians stopped treatment due to toxicity, despite receiving it at significantly lower dose intensity. Our results suggest that amelioration or prevention of chemotherapy-induced-toxicity is difficult in octogenarians even with modification of dose and schedule, and that even awareness and careful vigilance of treating physicians cannot mitigate toxicity altogether. Our results may also imply that the clinical tool of performance status according to the ECOG scale, which is widely used in oncology daily practice, is not sensitive enough to predict toxicity of chemotherapy in this very elderly population. The guidelines for treatment of older men with prostate cancer, published by the international society of geriatric oncology (SIOG), emphasize the importance of meticulous characterization of co-morbidity and health status in the elderly. 19 A complete geriatric assessment may also help to better characterize general health status of elderly patients and direct them towards the most appropriate treatment accordingly.

Our current analysis did not compare the efficacy and toxicity of abiraterone treatment with that of docetaxel treatment, nor did it compare the effectiveness of either one given after the other, and cannot therefore be used for making decisions about drug sequencing in elderly men with mCRPC. Nonetheless, our results are in line with previous observational studies and post-hoc analyses, and we suggest that docetaxel should be used cautiously in octogenarians. Limitations of our work include its retrospective nature and the small cohort size of octogenarians treated with abiraterone, potentially masking less frequent yet clinically important side effects in this population. Differences in outcome that have not reached statistical significance in this work may become significant with larger patient cohorts. Another potential limitation of our data is potential underreporting of co-morbidities, as these were collected from patient records retrospectively. Additionally, the retrospective nature of this work did not allow assessments of other important endpoints to elderly patients with cancer, such as quality of life, independence and functional status. Clearly formal assessments of these outcomes on abiraterone and docetaxel in very elderly patients are urgently needed in order to improve our decision-making processes in this growing patient population.

Disclosures and Conflict of Interest Statements

The authors report no conflicts of interest.

Author Contributions

R Leibowitz-Amit and AJ Templeton equally contributed to all aspects of this manuscript.

Study concept and design: R Leibowitz-Amit, AJ Templeton, IF Tannock, AM Joshua

Data acquisition: R Leibowitz-Amit, AJ Templeton, JJ Knox, SS Sridhar, IF Tannock, AM Joshua

Quality control of data and algorithms: R Leibowitz-Amit, AJ Templeton, SM Alibhai, IF Tannock, AM Joshua

Data analysis and interpretation: R Leibowitz-Amit and AJ Templeton (equal contribution)

Statistical analysis: R Leibowitz-Amit and AJ Templeton (equal contribution)

Manuscript preparation: R Leibowitz-Amit and AJ Templeton

Manuscript editing: R Leibowitz-Amit, AJ Templeton, SM Alibhai, IF Tannock, AM Joshua

Manuscript review: All authors

Acknowledgment

We thank Mr. Eshetu Atenafu from the Department of Biostatistics at the Princess Margaret Cancer Centre for his kind and professional assistance in biostatistical analysis.

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Footnotes

a Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada

b Department of Medicine, University Health Network, Toronto, ON M5G 2M9, Canada

lowast Corresponding author at: Department of Medical Oncology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5G 2M9, Canada. Tel.: + 1 416 946 4501; fax: + 1 416 946 6546.

1 Equal contribution.