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Pain Predicts Overall Survival in Men With Metastatic Castration-Refractory Prostate Cancer

Susan Halabi, Nicholas J. Vogelzang, Alice B. Kornblith, San-San Ou, Philip W. Kantoff, Nancy A. Dawson, Eric J. Small

From the Department of Biostatistics and Bioinformatics, Duke University, and Cancer and Leukemia Group B Statistical Center, Durham, NC; Dana Farber Cancer Institute, Boston, MA; Georgetown University, Washington, DC; Nevada Cancer Institute, Las Vegas, NV; and University of California at San Francisco, San Francisco, CA

Corresponding author: Susan Halabi, PhD, Department of Biostatistics and Bioinformatics, Duke University Medical Center, 2424 Erwin Rd, Durham, NC 27705; e-mail: susan.halabi{at}duke.edu

	ABSTRACT

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Purpose Pain from castration-refractory prostate cancer (CRPC) bone metastases is a common event. Although it is assumed that pain represents an adverse prognostic factor, this variable has not been extensively evaluated. The objective of this study was to determine whether men with CRPC who had higher pain interference scores at baseline had worse clinical outcomes compared with men who had lower pain scores.

Patients and Methods Data from three randomized phase III multicenter trials conducted by the Cancer and Leukemia Group B from 1992 to 1998 were combined. Eligible patients had progressive CRPC adenocarcinoma of the prostate, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic functions. Seven items from the Brief Pain Inventory were used to assess the impact of pain on a range of daily activities and quality of life, each rated on a scale from 0 to 10.

Results In 599 men, the median pain interference scores was 17 (interquartile range, 4 to 34), and 38% of the men had opioid analgesic use at baseline. There was a statistically significant association between pain interference scores and risk of death. The median survival times were 17.6 months (95% CI, 16.1 to 19.1 months) and 10.2 months (95% CI, 8.6 to 11.3 months; P < .001) in men with low (< 17) and high ( 17) pain scores, respectively. Pain was inversely associated with likelihood of prostate-specific antigen decline, objective response, and time to bone progression.

Conclusion This analysis demonstrates that pain is a statistically significant predictor of overall survival in men with metastatic CRPC. These results need to be validated prospectively in future phase III trials.

	INTRODUCTION

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The American Cancer Society has estimated that 186,320 men in the United States will be diagnosed with prostate cancer during 2008, and that 28,660 men will die from this disease.¹ In virtually all cases, death from this disease occurs in the setting of the development of castration-refractory prostate cancer (CRPC).² More than 90% of men with CRPC have bone metastases, and many experience debilitating bone pain.³ Currently, there are few treatment options for men with metastatic CRPC. Docetaxel was approved for first-line chemotherapy in men with CRPC based on two trials (TAX 327⁴ and Southwest Oncology Group 9916⁵) that demonstrated superior survival and palliation. The median time to disease progression, however, is 6 months,⁵ response duration is short, and many patients go on to require second-line chemotherapy and additional palliative care. Of interest, in TAX 327, a similar hazard ratio in favor of docetaxel over mitoxantrone was observed in men with and without pain,⁴ suggesting that the benefits of docetaxel were accrued independent of the presence of pain.

Although it is assumed that pain represents an adverse prognostic factor, this variable has been evaluated in only one prior CRPC study.⁴ As a result, there is a paucity of data on the impact of pain interference at baseline in predicting overall survival (OS) and clinical outcomes in men with advanced prostate cancer. The objective of this study was to determine whether men with CRPC who had higher pain interference scores at baseline had worse clinical outcomes compared with men who had lower pain scores.

	PATIENTS AND METHODS

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Study Population
Data from 768 men with CRPC who were treated on three Cancer and Leukemia Group B (CALGB) multi-institutional phase III trials from 1992 to 1998 were evaluated. CALGB 9181 was a phase III trial where 149 men were randomly assigned to either low-dose (160 mg/d) or high-dose (640 mg/d) megestrol acetate. CALGB 9182 was a phase III trial where 242 men were randomly assigned to hydrocortisone alone (dose of 30 mg in the morning plus 10 mg in the evening) or hydrocortisone with mitoxantrone (intravenous injection at a dose of 14 mg/m² every 3 weeks). CALGB 9480 was a phase III trial where 390 patients were randomly assigned to low- (3.192 g/m²), intermediate- (5.320 g/m²), or high-dose suramin (7.661 g/m²). Eligible patients on these trials were men with prostate cancer that had progressed during androgen-deprivation therapy (despite castrate levels of testosterone). Patients who had received prior treatment with chemotherapy, immunotherapy, or other nonhormonal therapy were excluded from these trials. In addition, an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate hematologic, renal, and hepatic functions were required. Additional details regarding these trials have been published elsewhere.^6-8 Each participant signed an institutional review board–approved, informed consent document in accordance with federal and institutional guidelines.

Data Analysis
The primary end point considered was OS, which was defined as the time from the date of randomization to the date of death. The effect of baseline pain interference scores on OS was evaluated. In addition, the effect of baseline pain interference scores on other end points, such as progression-free survival (PFS), time to biochemical failure (prostate-specific antigen [PSA] PFS), 50% decline in PSA, and objective (bidimensionally measurable) response proportion in men with measurable disease, was explored. PFS was defined as the time from the date of randomization to the date of first progression: PSA, clinical, bone, or death, whichever occurred first. PSA values were collected every 3 to 4 weeks. PSA PFS was defined as the interval from the date of randomization to the date of first biochemical progression using the PSA consensus criteria or death, whichever occurred first.⁹ Although PSA Consensus Criteria were not developed at the time these trials were designed, standard consensus criteria for a PSA response ( 50% decline in PSA from baseline confirmed by a second determination at least 2 weeks later) were used for retrospective analysis of the data.⁹

Seven items from the Wisconsin Brief Pain Inventory (BPI) scale were used to assess the impact of pain on daily activities in CALGB 9181 and 9182.¹⁰ Patients at baseline were asked to rate, on a scale from 0 to 10, the impact that their pain had on activities that include general activity, mood, sleep, walking ability, normal work, enjoyment of life, and relations with other people. The entire BPI scale was used to assess pain in CALGB 9480. The last question (consisting of the seven items) of the BPI instrument corresponded to the seven items of the BPI scale that were collected in the 9181 and 9182 studies. Therefore, we pooled data across the three trials for the seven items. Data were available for 599 of 768 patients.

We compared the baseline characteristics of men who completed the BPI scale with the 169 men who did not complete the BPI instrument at baseline. With the exception of race, men who completed the BPI scale at baseline had similar characteristics to men who did not complete a pain inventory. Of men who completed the BPI scale at baseline 82% were white. Among those who did not complete the BPI scale at baseline, 91% were white.

The Kaplan-Meier product-limit¹¹ method was used to estimate the OS, PFS, bone PFS, and PSA PFS distributions by the median pain interference scores at baseline. The proportional hazards model¹² was used to assess the prognostic significance of pain scores in predicting clinical outcomes and was used for stratifying by protocol. In addition, we investigated which of the seven pain items predicted overall survival. Furthermore, the logistic regression method was used to assess the prognostic significance of pain interference in predicting the probability of experiencing an objective (bidimensional mass) response rate and the probability of at least 50% decline in PSA.

Known and potential prognostic variables,^13,14 including age, race, performance status, Gleason score, hemoglobin, testosterone, PSA, alkaline phosphatase, lactate dehydrogenase (LDH), presence of visceral disease, treatment with mitoxantrone, prior treatment with radiotherapy, and years since diagnosis, were included in the multivariable models. LDH, years since diagnosis, alkaline phosphatase, and PSA were modeled using the restricted cubic spline function as they had skewed distributions. S-plus (Version 3.3; Statistical Sciences, Seattle, WA) statistical software was used for the data analyses, and all statistical tests were two-sided.

	RESULTS

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Baseline Characteristics
The baseline clinical and laboratory characteristics of 599 patients are listed in Table 1. The median pain interference score at baseline was 17 (interquartile range [IQR], 4 to 34), and this cut point (median) was used to dichotomize the patients into two groups: low and high pain. There were statistically significant differences in race, performance status, and laboratory values by the two pain groups. Men who had pain interference scores 17 had worse performance status, lower levels of hemoglobin, and higher PSA, LDH, and alkaline phosphatase levels than men with pain interference scores less than 17. There were no differences in sociodemographic factors between the two groups. The majority of men were married (80%), were not full-time employed (92%), and had college or postgraduate educational level (53%).

Clinical Outcomes
Overall survival. Of 599 men, 99% had died by the time of this analysis, and the median follow-up time among surviving patients was 39.4 months (95% CI, 3.47 to 56.9 months). There was a statistically significant difference in survival times by pain interference. The median survival times were 17.6 months (95% CI, 16.1 to 19.1 months) and 10.2 months (95% CI, 8.6 to 11.3 months) for men with pain scores less than 17 and for men with pain scores 17, respectively (P < .001; Fig 1).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier survival curves by pain interference scores at baseline.

PFS, bone PFS, and PSA PFS. The median times to first progression observed (clinical progression, bone progression, PSA progression, or death) were 2.5 months (95% CI, 2.2 to 2.7 months) for men with pain interference scores less than 17 and 1.8 months (95% CI, 1.6 to 2.1 months) for men with pain scores 17 (P < .001; Fig 2). In multivariable analysis, pain was not a statistically significant predictor of PFS. The HR for progression was 1.2 (95% CI, 1.0 to 1.4; P = .071) for men with pain interference scores 17 as compared with men with scores less than 17 (Table 3).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier progression-free survival curves by pain interference scores at baseline.

The median times to PSA progression were 4.0 months (95% CI, 3.0 to 4.5) for men with pain interference scores less than 17 and 2.9 months (95% CI, 2.4 to 3.5; P < .001) for men with pain scores 17. The adjusted HR for biochemical progression was 1.16 (95% CI, 0.95 to 1.41; P = .149) for men with pain scores 17 as compared with men with pain scores less than 17.

Objective response and post therapy changes in PSA. The association between pain interference scores and objective response was also explored in men with measurable disease. Men with pain interference scores 17 had a lower objective response rate compared with men with scores less than 17 (2.2% v 10.4%; P = .034). In multivariable logistic regression, the odds ratio for objective response was 0.19 (95% CI, 0.04 to 0.96; P = .044) for men with pain scores 17 compared with men with scores less than 17.

There was also an association between pain interference and post-therapy changes in PSA. A lower proportion of men experienced 50% decline in PSA in men with scores 17 compared with men with pain interference scores less than 17. In multivariable logistic regression, the odds ratio for PSA decline of 50% was 0.65 (95% CI, 0.44 to 0.95; P = .027) for men with pain scores 17 compared with men with scores less than 17.

	DISCUSSION

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Debilitating pain is one of the most common morbidities experienced by men with metastatic CRPC, and there is emerging evidence that pain is an important predictor of clinical outcome in men with CRPC. Nevertheless, the presence of pain has not been incorporated into prognostic models in this disease state, and only in a few studies of prostate cancer has it been evaluated.^15-17 For example, in an analysis of 85 patients with CRPC, Berry et al¹⁵ identified severe bone pain as predictive of short survival duration. Because of the limited sample size, the analysis was based on a univariate model. More recently, using data from the TAX 327 trial, Armstrong et al¹⁸ identified pain as a statistically significant prognostic factor of overall survival. The adjusted HR for men who had pain at baseline was 1.48 (95% CI, 1.23 to 1.79) and was among the strongest predictors in the multivariable model.

There are a number of studies that have reported that quality of life is predictive of OS in patients with advanced cancer. Physical well-being with symptoms is a well-recognized domain in quality-of-life evaluations in patients with cancer. Pain, however, has not consistently been shown to be a prognostic factor of overall survival.^19-23 In a CALGB trial of 206 patients with non–small-cell lung cancer, Herndon et al²⁴ showed that pain is a predictor of OS. Increases of 20, 30, and 40 units in the European Organisation for Research and Treatment of Cancer pain scores were associated, respectively, with increases of 13%, 20%, and 27% in the hazard of death in these patients.²⁴

The analysis undertaken as part of this study confirms previous reports suggesting that pain interference score is an important prognostic factor of OS in CRPC and furthermore suggests that it has an impact on other clinical outcomes, including PFS and response proportion. In the present study, men with CRPC and with an elevated pain interference score had shorter survival duration than men with lower pain interference scores. Among those men who had pain interference scores greater than the median (17), they were at 43% increased risk of death compared with men with pain scores less than 17. When pain was evaluated as a continuous variable in the model, there was an 11% increased risk of death for each 10-unit increase in pain interference scores.

When we analyzed each of the seven items in the BPI for the effect of pain on physical functioning and psychological state, each was a statistically significant predictor of overall survival. More importantly, however, in multivariable analysis, only the "enjoyment of life" item predicted overall survival. Serlin et al²⁵ demonstrated a nonlinear relationship between pain severity and pain interference in metastatic patients with cancer pain from four countries, including the United States. This suggests that when pain interference is high, not only does it affect quality of life, but it is a harbinger of advanced disease and serves as the best indicator for survival duration.

There are a couple of reports suggesting that bone metastases are a significant predictor of OS in patients with CRPC.^26,27 The finding of severe pain as a prognostic variable is more likely to be true, as increased pain interference may have reflected more extensive bone metastases. In univariate analysis, bone metastases as a binary variable predicted PFS and OS. In multivariable analysis, however, it neither predicted PFS nor OS. This could be due to the fact that 90% of the men had bone metastases and that there was a high association of this variable with other baseline variables in the model, such as performance status, opioid analgesic use, and alkaline phosphatase.

This study also demonstrated that men with high pain interference scores were less likely to experience a PSA response or an objective bidimensional response (as measured by Response Evaluation Criteria in Solid Tumors). Unlike previous reports,^15,17,18 we also evaluated the impact of pain in predicting other clinical outcomes. Men who had pain scores 17 were at 22% increased risk of bone progression compared with men with pain scores less than 17. Although it is important to collect and analyze further data on the survival of those men with severe pain, these data and the lung cancer trial of the CALGB suggest that severity of pain data could be routinely incorporated into clinical decision making for these two solid tumors.

Although not statistically significant, there was a trend for a higher hazard of disease and biochemical progression in men with elevated pain interference scores compared with men with lower pain scores. A possible explanation is that in our data set, more than one half of the progression events were due to biochemical progression. In the discrete disease progression model in CRPC, we have assumed that the biochemical progression happens much earlier than bone progression and, consequently, precedes the manifestation of symptoms such as pain (Fig 3). These data support that model, but further data are needed to understand the timing and relationship of PSA progression to pain progression.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Castration-refractory prostate cancer progression model.

One of the main criticisms of using pain interference as a prognostic variable is its subjective nature, and certainly, the importance of measuring pain interference reliably cannot be overemphasized. In this pooled analysis of three trials, the brief pain inventory was used to measure pain interference. This scale is a validated scale and has been used extensively in recent oncology trials.

In summary, the findings from the present analysis suggest that pain interference is an adverse prognostic factor of clinical outcomes in men with CRPC, although prospective confirmation is required. The inverse association between pain interference scores and response proportion could indicate that pain serves to identify a subset of men with either more advanced disease or that is more likely to be refractory to therapy. Alternatively, it could indicate a disease that simply progresses rapidly before clinical benefit can be accrued from therapy. Standardized pain instruments should be administered as part of trials in men with CRPC, and results should be incorporated into future prognostic models.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Susan Halabi, GPC Biotech (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Susan Halabi, Nicholas J. Vogelzang, Eric J. Small

Provision of study materials or patients: Nicholas J. Vogelzang

Collection and assembly of data: Nicholas J. Vogelzang, Philip W. Kantoff, Nancy A. Dawson, Eric J. Small

Data analysis and interpretation: Susan Halabi, Nicholas J. Vogelzang, Alice B. Kornblith, San-San Ou, Philip W. Kantoff, Nancy A. Dawson, Eric J. Small

Manuscript writing: Susan Halabi, Nicholas J. Vogelzang, Alice B. Kornblith, Eric J. Small

Final approval of manuscript: Susan Halabi, Nicholas J. Vogelzang, Alice B. Kornblith, San-San Ou, Philip W. Kantoff, Nancy A. Dawson, Eric J. Small

	Appendix

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	NOTES

 
Supported in part by grants from the United States Department of Defense (Grants No. DAMD 17-03-1-0112 and W81XWH-06-1-0032) and the National Cancer Institute (Grant No. CA 36601).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted October 30, 2007; accepted February 5, 2008.

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