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Patient and Treatment Factors Associated With Complications After Prostate Brachytherapy

Aileen B. Chen, Anthony V. D’Amico, Bridget A. Neville, Craig C. Earle

From the Harvard Radiation Oncology Program, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA

Address reprint requests to Craig C. Earle, MD, MSc, FRCPC, Center for Outcomes and Policy Research, Dana-Farber Cancer Center, 44 Binney St, 454-STE 21-24, Boston, MA 02115; e-mail: craig_earle{at}dfci.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose: To assess the prevalence and predictors of complications after prostate brachytherapy in a population-based sample of older men.

Patients and Methods: We analyzed claims for Medicare-enrolled men older than age 65 years living in Surveillance, Epidemiology, and End Results (SEER) surveillance areas diagnosed with prostate cancer from 1991 to 1999 who underwent brachytherapy as initial treatment.

Results: There were 5,621 men who had brachytherapy with at least 2 years of follow-up. A complication diagnosis or invasive procedure occurred in 54.5% of men within 2 years, with 14.1% undergoing an invasive procedure. Urinary, bowel, and erectile morbidity rates were 33.8%, 21.0%, and 16.7%, respectively, and invasive procedure rates were 10.3%, 0.8%, and 4.0%, respectively. On multivariable analysis, combined urinary diagnoses and invasive procedures (obstruction, incontinence, bleeding, fistula) were associated with older age (P < .01), nonwhite race (odds ratio [OR], 1.30; P = .01), low income (OR, 1.74; P < .01), external-beam radiotherapy (EBRT; OR, 0.85; P = .01), androgen deprivation (OR, 1.31; P < .01), later year of brachytherapy (OR, 1.03/yr; P = .02), higher Charlson comorbidity score (P < .01), and prior transurethral resection of the prostate (OR, 1.65; P < .01). Bowel morbidity (bleeding/proctitis, injury) was associated with older age (P = .04), EBRT (OR, 1.46; P < .01), later year (OR, 1.04/yr; P < .01), higher Charlson score (P = .01), and inflammatory bowel disease (OR, 2.60; P < .01). Erectile morbidity was associated with younger age (P < .01), nonwhite race (OR, 1.37; P < .01), AD (OR, 1.18; P = .04), and later year (OR, 1.08/yr; P < .01). Invasive procedure rates declined with later year of brachytherapy (OR, 0.93/yr; P < .01).

Conclusion: Morbidity after prostate brachytherapy was common, though invasive procedures were required infrequently. Invasive procedures for complications declined during the 1990s, suggesting technical improvement with experience.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Prostate cancer is the most common nonskin malignancy and the third leading cause of cancer death in men.¹ Primary treatment options for men with localized disease include radical prostatectomy and radiation therapy (external beam and/or brachytherapy).

Disease-free survival, overall survival, and biochemical control rates in patients with low-risk prostate cancer treated with brachytherapy are high^2,3 and comparable to other treatment modalities.⁴ Therefore, the choice of treatment is often based on the complication profiles for each option, as well as patient characteristics and preferences.

Prostate brachytherapy offers several potential advantages over other modalities, including faster recovery times than radical surgery and a shorter duration of treatment compared with external-beam radiotherapy (EBRT).⁵ In addition, because of the rapid dose fall-off in surrounding normal tissues, brachytherapy might result in lower complication rates than EBRT.

With the increasing use of prostate-specific antigen (PSA) to screen for prostate cancer, the number of patients with low-risk disease who are potentially eligible for brachytherapy has increased. During the 1990s, the proportion of men treated with brachytherapy for localized prostate cancer increased substantially, with a concomitant decrease in rates of EBRT and radical prostatectomy.^6-10 Though the utilization of radical prostatectomy has been declining, it remains the most common treatment for younger men with localized cancer.¹¹ Radiation therapy is more often used in older men with medical comorbidities.^9,11

Identifying predictors of complications may help to select appropriate patients for brachytherapy and to identify ways to improve delivery of care. Prior studies on complications after prostate brachytherapy have typically reported single-institution experiences, often in highly selected populations.^12-15 Our study assessed the prevalence and predictors of complications after prostate brachytherapy in a population-based sample of men older than age 65 years.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Sources of Data
We used data from the National Cancer Institute’s (National Institutes of Health, Bethesda, MD) Surveillance, Epidemiology, and End Results (SEER) cancer registries linked to Medicare claims data. The 11 tumor registries that participate in the SEER program capture approximately 97% of the incident cancer cases for these regions¹⁶ and include a nearly representative sample of approximately 14% of the United States population.¹⁷ SEER registries collect data on patient age, sex, race, ethnicity, cancer site, stage, histology, and dates of death and diagnosis. Medicare claims, both inpatient and outpatient, have been linked to SEER for patients older than age 65 years.¹⁸ The Medicare data set included claims from January 1, 1991, through December 31, 2001, and was linked to SEER data for cases diagnosed from January 1, 1991, through December 31, 1999.

Study Cohort
Our study cohort included Medicare-enrolled men older than age 65 years who were diagnosed with prostate cancer while living in SEER surveillance areas between 1991 and 1999 and underwent brachytherapy as initial treatment. Subjects were continuously enrolled in both Part A and B of Medicare and not in a health-management organization (HMO) during the study period. Men with T4 disease or distant metastases at diagnosis were excluded.¹⁹

Identification of Brachytherapy Cases
Brachytherapy cases were identified from Medicare hospital claims using International Classification of Diseases, ninth revision, Clinical Modification (ICD-9-CM) codes, Medicare physician and outpatient claims using ICD-9-CM, Current Procedural Terminology (CPT) and Health Care Financing Administration Common Procedure Coding System (HCPCS) codes, and SEER data. Because SEER may include men for whom brachytherapy was planned, but who did not actually receive it, SEER-identified cases were included only if at least one brachytherapy-associated claim could also be identified in the Medicare data. To limit the analysis to patients having brachytherapy as initial therapy, we excluded cases with prior prostatectomy or with EBRT more than 1 year before brachytherapy.

Definition of Explanatory Variables
Demographic variables, including age, race, geographic area, marital status, and low-income status were studied. Patients were defined as low-income if the state buy-in variable on the Medicare enrollment data indicated that the person was eligible for state assistance with Medicare premiums and copayments. This variable is specific, though not sensitive, for low-income status.²⁰ Age was categorized into 5-year intervals. Race was categorized as white, black, or other for univariable analysis, but these were grouped into white and nonwhite for multivariable analysis. SEER registries were grouped into West (San Francisco, Hawaii, New Mexico, Seattle, Utah, San Jose, Los Angeles), Midwest (Michigan, Iowa), South (Georgia, rural Georgia), and Northeast (Connecticut) regions to define geographic areas. Marital status was defined as currently married versus not married.

Tumor-related variables, including grade, tumor stage, lymph node status, and PSA status were identified from SEER data. Grade was categorized as low (Gleason score of 2 to 4), intermediate (Gleason score of 5 to 7), or high (Gleason score of 8+) in the SEER data. We categorized tumor stage as T1, T2, or T3. Lymph node status could be defined from clinical and/or pathologic data and was categorized as positive, negative, or unknown/not evaluated. PSA status at diagnosis was categorized in SEER as elevated, normal, or not available based on laboratory-specific determinations of normal range. SEER did not collect PSA data before 1998.

Treatment variables including concomitant EBRT and initial androgen deprivation (AD) with a luteinizing hormone–releasing hormone (LHRH) agonist were defined from Medicare claims. EBRT could occur before or within 1 year following brachytherapy, and initial AD could be initiated at any time beginning 6 months before brachytherapy until 1 year after brachytherapy. Identification of AD from Medicare claims has been validated previously.²¹ Year of brachytherapy was analyzed as a continuous variable.

Suspected risk factors for complications, including history of transurethral resection of the prostate (TURP) and inflammatory bowel disease (IBD), were defined from all Medicare claims before brachytherapy. TURP was also defined from SEER records. We calculated a comorbidity index for the 12 months before prostate cancer diagnosis using Deyo’s implementation²² of the Charlson score²³ applied to both inpatient and outpatient claims, as suggested by Klabunde.^23,24 Because some men had less than 12 months of claims preceding diagnosis, we performed a separate analysis, limiting the cohort to men older than age 66 years who were diagnosed in 1992 or later. The results did not differ substantially and are not reported.

Complications
The outcome of interest was defined as complications occurring within the 2 years after brachytherapy. Two sets of outcome variables were created to assess the occurrence of (1) complications that may or may not have required an invasive procedure (combined diagnoses and invasive procedures) and (2) complications requiring invasive procedures. This latter group would presumably constitute more severe complications. To identify complications that required invasive procedures, we used ICD-9-CM procedure codes, as well as CPT codes from the time of brachytherapy through 2 years of follow-up. To identify complications that may or may not have required invasive procedures, we used the same ICD-9-CM procedure and CPT codes with the addition of ICD-9-CM diagnosis codes.

Urinary, bowel, and erectile complications were considered both separately and in aggregate. Urinary diagnoses and invasive procedures included incontinence, obstruction, irradiation cystitis, bladder hemorrhage, and urinary fistulas. Because most men experience acute urinary symptoms after brachytherapy that often resolve spontaneously, we also considered late (occurring > 6 months after brachytherapy) urinary complications separately. Results did not differ substantially and are not reported. Bowel diagnoses and invasive procedures included rectal hemorrhage, ulcers, fistulas, hyperbaric oxygen therapy, and rectal repairs. Erectile diagnoses and invasive procedures included impotence, penile prostheses, and intracavernosal injections. Medicare codes used to define urinary, bowel, and erectile complications are listed in Table A1 (online only) and are categorized as diagnosis codes or invasive procedure codes.

Statistical Methods
Univariable logistic regression models were used to identify factors associated with urinary, rectal, and erectile complication diagnoses and invasive procedures after brachytherapy. Covariates examined included demographic, prostate cancer, treatment, and risk factor variables, as described. Variables that were found to be significantly associated (P < .05) with complications on at least one univariable model were included in multivariable logistic models to predict the probability of complications following brachytherapy. Odds ratios (ORs) and 95% CIs were calculated. All P values were two sided.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Descriptive Statistics of the Study Cohort
We identified 6,747 men older than age 65 years at diagnosis who had brachytherapy as initial treatment for T1 to T3 prostate cancer; 5,621 had at least 2 years of follow-up and constitute the study population. The median age at the time of brachytherapy was 72 years (range, 65 to 91 years), and the median time from diagnosis to brachytherapy was 120 days (range, 0 to 2,951 days). Table 1 summarizes the demographic, tumor, treatment, and comorbidity characteristics of our cohort. Of note, most patients had combined-modality therapy: EBRT was used with brachytherapy in 59.9% of men, 35.5% of men received an LHRH agonist, and 21.8% received both additional treatments.

Urinary obstruction was identified in 30.0% of men within 2 years, and 7.5% of men had urinary incontinence. Overall, 10.2% and 0.2%, respectively required invasive procedures.

Rates of urinary, bowel, and erectile complications were 32.7% versus 35.4% (P = .03), 23.2% versus 17.7% (P < .01), and 17.2% versus 16.4% (P = .44), respectively in patients who received EBRT compared with those who did not. In patients who received initial AD compared with those who did not, rates of urinary, bowel, and erectile complications were 38.4% versus 31.2% (P < .01), 21.8% versus 20.5% (P = .27), and 19.0% versus 15.5% (P < .01), respectively.

Table 1 presents crude rates of combined complication diagnoses and invasive procedures for each of the demographic, tumor, treatment, and risk-factor variables.

Factors Associated With Urinary Complications
Factors associated with increased rates of combined urinary diagnoses and invasive procedures on multivariable analysis included age group at brachytherapy (P < .01), nonwhite race (OR, 1.30; P < .01), low income status (OR, 1.74; P < .01), initial EBRT (OR, 0.85; P = .01), initial AD (OR, 1.31; P < .01), later year of brachytherapy (OR, 1.03; P = .02), higher Charlson comorbidity score (P < .01), and history of TURP (OR, 1.65; P < .01). Predictors for invasive urinary procedures were similar, although the effect of nonwhite race was only of borderline significance, and there was no significant association with initial EBRT. Earlier year of brachytherapy was associated with an increased risk for invasive procedures (OR, 1.11; P < .01).

Factors Associated With Bowel Complications
Factors associated with rates of combined bowel diagnoses and invasive procedures on multivariable analysis included older age group at brachytherapy (P = .04), use of initial EBRT (OR, 1.46; P < .01), later year of brachytherapy (OR, 1.04; P < .01), higher Charlson score (P = .01), and history of IBD (OR, 2.60; P < .01). There was an insufficient number of invasive bowel procedures for separate analysis.

Factors Associated With Erectile Complications
Factors associated with rates of combined erectile diagnoses and invasive procedures included younger age group (P < .01), nonwhite race (OR, 1.38; P < .01), initial AD (OR, 1.18, P = .04), and later year of brachytherapy (OR, 1.08; P < .01). Younger age group was associated with increased invasive procedures for erectile dysfunction (P = .01).

Table 2 gives the full results of the multivariable analysis for combined complication diagnoses and invasive procedures, and Table 3 gives the results of the analysis for invasive complication procedures. On univariable analysis, T stage, PSA status, tumor grade, nodal status, and urban residence were not found to be significant predictors for any of the complication outcomes, so were not included in the multivariable analysis.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

Prior studies on patient complications following prostate brachytherapy have typically reported single-institution experiences in often highly selected patients treated by the most experienced providers. They have varied in the definitions of complication end point, length of follow-up, and characteristics of the patient population. The vast majority of men have some obstructive symptoms after treatment, with most spontaneously resolving over several months. Rates of obstruction requiring TURP or dilation have been reported to be of 5% to 15%,^12,13,25,26 urinary incontinence 0% to 6%,^12,13,25,26 and rectal toxicities 1% to 39%.^14,26,27 Reported rates of erectile dysfunction occurring after brachytherapy have ranged from 4% to more than 66%.^12,26,28-31

We defined urinary, bowel, and erectile complications by using Medicare billing codes and found that a significant proportion of men had billing codes associated with rectal, urinary, or erectile morbidity following brachytherapy, though most did not require invasive procedures for treatment. In a more limited study using Medicare claims data of men having brachytherapy in 1991, 6.6% had a diagnosis of urinary incontinence, 5.5% rectal injury, and 8.4% erectile dysfunction.³²

Previous studies have shown that the use of TURP, prostate size, and poor preimplantation urinary function are associated with higher rates of urinary toxicity.^12,13,25 Predictors of rectal complications have included EBRT, higher clinical stage, and white race.^27,30 Age, preimplantation function, and prostate dose have been linked to higher rates of erectile dysfunction after brachytherapy.^29-31 With respect to treatment factors, prior studies have found that postimplantation dosimetry, including dose to the prostate, urethra, neurovascular bundle, penile bulb, and anterior rectum are associated with postimplantation morbidity.^33,34

Although T stage, PSA, and Gleason score are known to be important prognostic factors for prostate cancer, we found that they were not associated with increased rates of urinary, bowel, or erectile morbidity following brachytherapy. Consistent with prior studies, we found that prior TURP was associated with increased rates of urinary morbidity and that use of EBRT was associated with increased rectal morbidity after brachytherapy. Also, nonwhite race and low income men had higher rates of combined complication diagnoses and invasive procedures. This could be caused by a combination of factors, including access to experienced providers or differences in cancer presentation. We observed that AD was associated with increased rates of urinary and erectile morbidity, as well as increased rates of invasive procedures for treatment of complications. LHRH agonists are known to affect libido and also have metabolic and physiologic effects, which may increase the incidence and severity of complications. Furthermore, use of LHRH agonists may be associated with larger prostate size, which is associated with urinary morbidity. We also found that a history of IBD was associated with a greater rate of combined bowel diagnoses and invasive procedures. IBD is commonly believed to increase the risk of bowel complications after pelvic EBRT,³⁵ although this had not been previously documented for prostate brachytherapy.³⁶

An interesting observation was that the rates of invasive procedures after brachytherapy declined for men undergoing treatment in more recent years, although the rates of combined diagnoses and invasive procedures increased slightly during the same period. There are several possible explanations. Because of external pressures, physicians could have become increasingly assiduous about documenting diagnoses of morbidity in billing records, even though the number of serious complications requiring invasive procedures was declining as a result of growing experience with the procedure. Alternatively, the 1990s was a period of rapid adoption of prostate brachytherapy by new providers, and consequently the rate of minor complications could have increased with greater adoption of brachytherapy by inexperienced providers, yet better patient selection, implantation techniques, and postimplantation management could result in lower rates of complications requiring invasive procedures.

There are several limitations to our study. The SEER-Medicare data are based on hospital and physician claims rather than on clinical data, and the presence of complications must be inferred from physician and hospital bills. Therefore, this approach is likely to underestimate complication rates, particularly since in the past Medicare typically did not reimburse for oral medications. Also, complications that affect patients’ quality of life but for which they do not seek medical attention are not captured when complications are defined from Medicare bills. Surveys of patients typically show higher rates of post-treatment morbidity than clinicians appreciate.³⁷ In addition, erectile complications, in particular, may continue to develop beyond the 2-year follow-up period.^30,31 In our cohort, for men who had at least 4 years follow-up, approximately one third of combined erectile diagnoses and invasive procedures occurred 3 to 4 years after implant. For these reasons, our results likely represent a lower bound for morbidity following treatment. On the other hand, although we assumed that diagnosis and invasive procedure codes related to urinary, bowel, and erectile morbidity resulted from brachytherapy, there may be other reasons for the use of these codes, possibly leading to overestimation of complications. Differences in rates of complications may partly be caused by differences in diagnosis and management practices. In addition, our study was limited to men age 65 years or older living in SEER surveillance areas and diagnosed from 1991 to 1999, so the results may not be generalizable to other populations. Although invasive procedure rates for complications declined during the 1990s, improvements in and wider availability of modern brachytherapy techniques could reduce these rates even further in men currently having prostate implants. Finally, there were several variables that are likely to be associated with morbidity after brachytherapy that we could not control for in our analysis, such as implantation technique, prostate size, radiation dose, and preimplantation function. For example, several studies have found that postimplantation dosimetric factors are associated with increased rates of urinary, rectal, and erectile morbidity after brachytherapy.^33,34

We found that urinary, bowel, and erectile morbidity after prostate brachytherapy were common in a relatively unselected, population-based sample of older men, although invasive procedures were not frequently required. We identified demographic, tumor-related, treatment, and comorbid factors that may increase the risk of complications after treatment. This information may be used by patients and physicians to identify those patients most appropriate for brachytherapy and may serve as a starting point to address possible reasons for worse outcomes in certain groups. Finally, we observed that the rate of complications requiring invasive procedures for management declined during the 1990s, possibly suggesting improvement in technical factors over time as physicians have gained more familiarity with the procedure.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Aileen B. Chen, Anthony V. D’Amico, Craig C. Earle Financial support: Craig C. Earle Collection and assembly of data: Bridget A. Neville Data analysis and interpretation: Aileen B. Chen, Anthony V. D’Amico, Bridget A. Neville, Craig C. Earle Manuscript writing: Aileen B. Chen, Anthony V. D’Amico, Craig C. Earle Final approval of manuscript: Aileen B. Chen, Anthony V. D’Amico, Bridget A. Neville, Craig C. Earle

 

	NOTES

 
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted June 22, 2006; accepted September 11, 2006.

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chen, A. B. Articles by Earle, C. C. Search for Related Content PubMed PubMed Citation Articles by Chen, A. B. Articles by Earle, C. C.