Original Research

According to the CDC, the medical use of opioid painkillers has increased at least 10-fold during the past 
20 years, “because of a movement toward more aggressive management of pain.”¹ Although opioid therapy is generally considered effective for the treatment of pain, long-term use (both orally and intrathecally) is associated with adverse effects (AEs) such as constipation, fatigue, nausea, sleep disturbances, depression, sexual dysfunction, and hypogonadism.^2,3Opioid-induced androgen deficiency (OPIAD), as defined by Smith and Elliot, is a clinical syndrome characterized by inappropriately low concentrations of gonadotropins (specifically, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), which leads to inadequate production of sex hormones, including estradiol and testosterone.⁴

Related: Testosterone Replacement Therapy: Playing Catch-up With Patients

The mechanism behind this phenomenon is initiated by either endogenous or exogenous opioids acting on opioid receptors in the hypothalamus, which causes a decrease in the release of gonadotropin-
releasing hormone (GnRH). This decrease in GnRH causes a reduction in the release of LH and FSH from the pituitary gland as well as testosterone or estradiol from the gonads.^4,5 Various guidelines report different cutoffs for the lower limit of normal total testosterone: The Endocrine Society recommends 300 ng/dL, the American Association of Clinical Endocrinologists suggests 200 ng/dL, and various other organizations suggest 230 ng/dL.^6-8 Hypotestosteronism can result in patients presenting with a broad spectrum of clinical symptoms, including reduced libido, erectile dysfunction (ED), fatigue, hot flashes, depression, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis.⁴ Women with low testosterone levels can experience irregular menstrual periods, oligomenorrhea, or amenorrhea.⁹ Opioid-induced androgen deficiency often goes unrecognized and untreated. The reported prevalence of opioid-induced hypogonadism ranges from 21% to 86%.^4,9 Given the growing number of patients on chronic opioid therapy, OPIAD warrants further investigation to identify the prevalence in the veteran population to appropriately monitor and manage this deficiency.

The objective of this retrospective review was to identify the presence of secondary hypogonadism in chronic opioid users among a cohort of veterans receiving chronic opioids for nonmalignant pain. In addition to identifying the presence of secondary hypogonadism, the relationship between testosterone concentrations and total daily morphine equivalent doses (MEDs) was reviewed. These data along with the new information recently published on testosterone replacement therapy (TRT) and cardiovascular (CV) risk were then used to evaluate current practices at the West Palm Beach VAMC for OPIAD monitoring and management and to modify and update the local Criteria for Use (CFU) for TRT.

Methods

Patient data from the West Palm Beach VAMC in Florida from January 2013 to December 2013 were reviewed to identify patients who had a total testosterone (TT) level measured. All patient appointments for evaluation and treatment by the clinical pharmacy specialist in pain management were reviewed for data collection. This retrospective review was approved by the scientific advisory committee as part of the facility’s ongoing performance improvement efforts as defined by VHA Handbook 1058.05 and did not require written patient consent.¹⁰

Several distinct TT level data were collected. The descriptive data included patient age; gender; type of treated pain; testosterone level(s) drawn, including TT level before opioid therapy, TT level before/during/after TRT, and current total testosterone level; total daily MED of opioid therapy; duration of chronic opioid therapy; symptoms of exhibited hypogonadism; TRT formulation, dose, and duration; TRT prescriber; symptom change (if any); and laboratory tests ordered for TRT monitoring (lipid profile, liver profile, complete blood count, LH/FSH, and prostate specific antigen [PSA] panel).^5,11,12

Related: Combination Treatment Relieves Opioid-Induced Constipation

Daily MED of opioid therapy was calculated using the VA/DoD opioid conversion table for patients on oxycodone, hydromorphone, or hydrocodone.¹³ For those on the fentanyl patch or methadone, conversion factors of 1:2 (fentanyl [µg/h]:morphine [mg/d]) and 1:3 (methadone:morphine) were used to convert to the MED.¹⁴ For patients on the buprenorphine patch, the package insert was used to convert to the corresponding MED.¹⁵ Combination therapies used the applicable conversions to calculate the total daily MED.

Once the data were collected, descriptive statistics were used to analyze the data. In addition, 4 graphs were generated to review potential relationships. The correlation coefficient was calculated using the Alcula Online Statistics Calculator (http://www.alcula.com; Correlation Coefficient Calculator).

Results

A total of 316 unique veteran patients were seen by the clinical pharmacy specialist in pain management from January 1, 2013, through December 31, 2013. Of these, 73 patients (23.1%) had at least 1 TT level drawn in 2013. Three patients with testosterone levels drawn (4.1%) were excluded from the data analysis for the following reasons: 1 patient did not have testosterone levels on file before receiving testosterone replacement from a non-VA source, 
1 patient received opioids from a non-VA source (MED and duration of opioid therapy could not be calculated), and 1 patient inconsistently received opioids and MED used at the time of testosterone level draw. Per the local TRT CFU, a TT level > 350 ng/dL
does not require treatment, whereas levels < 230 ng/dL (with symptoms) may require TRT, and 
< 200 ng/dL should be treated as 
hypogonadal (interpretation based on local laboratory’s reference range for TT).16 Of the 70 patients included in the analysis, 34 (48.6%) had a TT level < 230 ng/dL and would be considered eligible for TRT if they presented with symptoms 
of low testosterone. Of these 34 patients with a low testosterone level, 28 (40%) were being treated or had been treated with TRT (Figure 1).

The average age of the male patients with a testosterone level drawn was 58.3 years, which was not significantly different from the calculated median age of 60 years. No female patients had a testosterone level drawn. On average, the TT level was normal before starting opioids (reference range per local laboratory: 175-781 ng/dL). Once opioids were initiated, patients were treated for an average duration of 52.5 months (calculated through December 2013) with an average daily dose of 126.8 MED (Table). Fifty of the 70 patients (71.4%) with testosterone levels drawn in 2013 received TRT. The most common symptoms reported by patients related to low testosterone included ED, decreased libido, depression, chronic fatigue, generalized weakness, and hot flashes or night sweats.

The average TT level prior to TRT was 145.3, and the average 
testosterone level after initiation of or 
during treatment with TRT was 292.4, which is within the normal TT level range. Most patients receiving TRT were treated with testosterone cypionate injections, and this was also the formulation used for the longest periods, likely due to the local CFU. In addition to testosterone cypionate injections, patients were also treated with testosterone enanthate injections, testosterone patches, and testosterone gel.

Figure 1 compares current testosterone level and testosterone level before TRT with total daily MEDs. Figure 2 compares current testosterone level and testosterone level before TRT with length of opioid therapy. The 2 figures use data from all patients included in the analysis and indicate a potential inverse relationship between the total daily MED and duration of therapy with the testosterone level, although none of the calculated correlation coefficients indicate that a strong relationship was present.

Figures 3 and 4 include data only for patients who had both a testosterone level collected before opioids (baseline testosterone level) and a current testosterone level. Figure 3 trends the data using total daily MED, and Figure 4 uses the duration of opioid therapy. The correlation for Figure 4 is slightly stronger; the strongest negative correlations were identified between total daily MED and testosterone level before opioid therapy (r = -0.273) and duration of opioid therapy and testosterone level prior to opioid therapy (r = -0.396). The trends indicate that most patients had a normal TT level before opioid treatment and that patients treated with higher MEDs and for longer durations of time were more likely to have lower total testosterone levels.

Discussion

Low testosterone levels can adversely affect patients’ quality of life (QOL) and add to patients’ medication burden with the initiation of TRT. Given new data analyzing the potential effects of TRT on CV event risk, the use of TRT should be carefully considered, as it may carry significant risks and may not be suitable for all patients.

In November 2013, a study was published regarding TRT and 
increased CV risk.¹⁷ This was a retrospective cohort study of men with low testosterone levels (< 300 ng/dL) who had undergone coronary angiography in the VA system between 2005 and 2011 (average age in testosterone group was 60.6 years). The results were significant for an absolute rate of events (all-cause mortality, myocardial infarction [MI], and ischemic stroke) of 19.9% in the no testosterone group and 25.7% in the TRT group, an absolute risk difference of 5.8% at 3 years after coronary angiography. Kaplan-Meier survival curves demonstrated that testosterone use was associated with increased risk of death, MI, and stroke. This result was unchanged when adjusted for the presence of coronary artery disease (CAD). In 
addition, no significant difference was found between the groups in terms of systolic blood pressure, low-
density lipoprotein cholesterol level, or in the use of beta-blocker and statin medications. What is important to note is that in this cohort, 20% had a prior history of MI and heart failure, and more than 50% had confirmed obstructive CAD on angiography. In addition, as this was an observational study, confounding or bias may exist, and given the study population, 
generalizability may be limited to a veteran population.

Related: A Multidisciplinary Chronic Pain Management Clinic in an Indian Health Service Facility

Another retrospective cohort study assessed the risk of acute nonfatal MI following an initial TRT prescription in a large health care database (average age based on TRT prescription was 54.4 years).¹⁸ In men aged ≥ 65 years, a 2-fold increase in the risk of MI in the immediate 90 days after filling an initial TRT prescription declined to baseline after 91 to 180 days among those who did not refill their prescription. Younger men with a history of heart disease had a 2- to 3-fold increased risk of MI in the 90 days following initial TRT prescription. No excess risk was observed in the younger men without such a history. Again, this study has its limitations related to the retrospective design and use of a health care database as opposed to a randomized controlled trial.

In February 2014, a VA National Pharmacy Benefits Management (PBM) bulletin addressed 2 recent studies that had identified a possible risk of increased CV events in men receiving TRT. The bulletin noted that these studies had prompted the FDA to reassess the CV safety of TRT.¹⁹ The TRT CFU was updated by VISN 8 to ensure that the patients receive appropriate treatment and are monitored accordingly.

One of the major changes to the CFU was defining the reference ranges for TRT (interpretation based on a local laboratory’s reference range for total testosterone): serum TT < 200 ng/dL be “treated as 
hypogonadal, those with TT 
> 400 ng/dL be considered normal and those with TT 200-400 ng/dL be treated based on their clinical presentation if symptomatic; TT levels 
> 350 ng/dL do not require treatment, and levels below 230 ng/dL (with symptoms) may require testosterone replacement therapy.”¹⁶ Other important updates included revision of the exclusion criteria as well as 
highlighting special considerations related to TRT, including the use of free testosterone levels rather than TT levels in patients with suspected protein-binding issues, role in fertility treatments, limited use in patients on spironolactone therapy (due to spironolactone’s anti-androgen effects), and potential association with mood and behavior.¹⁶

As chronic opioid therapy is associated with OPIAD, the renewed interest in TRT and its potential AEs provides yet another reason to reconsider opioid therapy. This is especially valid when opioids are the potential cause of hypogonadism and the reaction is treating the AEs of opioids (as opposed to considering elimination of the causative agent) with a therapy that can potentially increase the risk for CV events so that opioids can be continued. Outside the potential CV risk with TRT, opioids carry the innate risk for substance abuse and addiction.

The Opioid Safety Initiative Requirements was released as a memorandum in April 2014 and is the VHA’s effort to “reduce harm from unsafe medications and/or excessive doses while adequately controlling pain in Veterans.”²⁰ Although it does not discuss the risk of OPIAD, it does highlight the need to identify and mitigate high-risk patients as well as high-risk opioid regimens. All these factors, including the possibility of hypogonadism, should be considered before starting opioid therapy and at the time of opioid renewal, as it is known that opioid therapy is not without risks.

At the West Palm Beach VAMC, the primary care providers (PCPs) are responsible for the management of TRT, including the workup, renewal, and monitoring. The Chronic Nonmalignant Pain Management Clinic (CNMPMC) orders testosterone levels on patients who report symptoms of low testosterone, such as hot flashes, depression, and low energy level and refers them to their PCP as indicated. The authors believe that this is most appropriate for a number of reasons: (1) the CNMPMC is a consult service, and patients are not followed indefinitely; (2) patients should be fully evaluated for appropriateness of TRT (including assessment of CV risk) before starting therapy; and (3) the necessary monitoring parameters (laboratory testing, digital rectal exam, and osteoporosis screening) are not typically within the VA pain clinic provider’s scope of practice or expertise. A consideration for future practice would be to incorporate the use of a standardized questionnaire for OPIAD monitoring in patients receiving ≥ 100 mg of morphine daily (eg, the Aging Males’ Symptoms scale).²¹ It should, however, be at the forefront of the pain specialist’s and PCP’s minds that all patients on chronic opioid therapy or considering chronic opioid therapy should be counseled on the risk for OPIAD. If OPIAD is identified, the patient should be carefully considered for an opioid dose reduction as an initial management strategy.

Limitations

A limitation of this review is the lack of consistency or adequacy of serum testosterone sampling, noting that valid testosterone levels need to be drawn in the morning and not obtained during a time of acute illness. In addition, testosterone levels need to be drawn at an appropriate interval while on TRT (eg, at the midpoint between testosterone injections).¹⁶ Although the time of the sample collection is documented in the Computerized Patient Record System (CPRS), it is unknown whether the patient was acutely ill on the day of the sampling unless a progress note is entered, and it is difficult to determine whether the level timing was accurate based on the testosterone replacement formulation. Another limitation is that the average decline in serum testosterone levels with aging in men is 1% to 2% per year. A significant fraction of older men have levels below the lower limit of the normal range for healthy young men, so in older men it can be more difficult to determine whether low testosterone is related to chronic opioid use or to older age.^5,16

As this was a retrospective review, additional limitations included the inability to measure subclinical OPIAD, and the data collection related to symptoms of hypogonadism was restricted by documentation in the CPRS progress notes. The lack of data for females does not contribute to the literature on OPIAD in women. Finally, as the total daily MED does not distinguish between short-acting and long-acting opioid therapy, no differences between the impacts of short-acting vs long-
acting opioid therapy on risk for 
hypogonadism can be inferred. There is evidence to suggest that long-acting opioids are associated with a significantly higher risk for OPIAD compared with short-acting opioids, although the mechanism behind this is not well established.^22,23

Conclusions

The average age of the patients 
on chronic opioid therapy with a 
testosterone level drawn in this cohort was 58.3 years, which is younger than originally anticipated. The median age of 60 years is not significantly different from the average age, indicating that outliers did not impact this calculation. On average, the TT level was normal before starting opioids. Once opioids were started, patients were treated for an average duration of 52.5 months with an average daily dose of 126.8 mg MED. In this veteran cohort, 48.6% of patients met the criteria for TRT based on TT level alone, which is within the reported prevalence range of opioid-induced hypogonadism already published.^4,9 These results are in line with the original hypothesis that chronic opioid use can adversely impact testosterone levels and can have a poor effect on a patient’s QOL due to symptoms of low testosterone. In addition to TRT, possible and suggested (but not proven) treatment options for OPIAD include discontinuation of opioid therapy, opioid rotation, or conversion to buprenorphine.²¹ The approach used should account for multiple patient-specific factors and should be individualized.

Based on the data, there is a trend toward lower testosterone levels in veterans treated with higher MED and for longer periods with chronic opioids. Given recent data that infer that TRT carries increased CV risk as well as the VHA’s Opioid Safety Initiative, it is imperative that providers closely evaluate the appropriateness of starting TRT and/or continuing chronic opioid therapy. All patients generally should have failed non-
opioid management prior to opioid therapy for chronic nonmalignant pain, and this should be documented accordingly. It is also crucial to have the “opioid talk” with patients from time to time and discuss the risks vs benefits, the potential for addiction, overdose, dependence, tolerance, constipation, and OPIAD so patients can continue to be an active and informed participants in their care.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

According to the CDC, the medical use of opioid painkillers has increased at least 10-fold during the past 
20 years, “because of a movement toward more aggressive management of pain.”¹ Although opioid therapy is generally considered effective for the treatment of pain, long-term use (both orally and intrathecally) is associated with adverse effects (AEs) such as constipation, fatigue, nausea, sleep disturbances, depression, sexual dysfunction, and hypogonadism.^2,3Opioid-induced androgen deficiency (OPIAD), as defined by Smith and Elliot, is a clinical syndrome characterized by inappropriately low concentrations of gonadotropins (specifically, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), which leads to inadequate production of sex hormones, including estradiol and testosterone.⁴

Related: Testosterone Replacement Therapy: Playing Catch-up With Patients

The mechanism behind this phenomenon is initiated by either endogenous or exogenous opioids acting on opioid receptors in the hypothalamus, which causes a decrease in the release of gonadotropin-
releasing hormone (GnRH). This decrease in GnRH causes a reduction in the release of LH and FSH from the pituitary gland as well as testosterone or estradiol from the gonads.^4,5 Various guidelines report different cutoffs for the lower limit of normal total testosterone: The Endocrine Society recommends 300 ng/dL, the American Association of Clinical Endocrinologists suggests 200 ng/dL, and various other organizations suggest 230 ng/dL.^6-8 Hypotestosteronism can result in patients presenting with a broad spectrum of clinical symptoms, including reduced libido, erectile dysfunction (ED), fatigue, hot flashes, depression, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis.⁴ Women with low testosterone levels can experience irregular menstrual periods, oligomenorrhea, or amenorrhea.⁹ Opioid-induced androgen deficiency often goes unrecognized and untreated. The reported prevalence of opioid-induced hypogonadism ranges from 21% to 86%.^4,9 Given the growing number of patients on chronic opioid therapy, OPIAD warrants further investigation to identify the prevalence in the veteran population to appropriately monitor and manage this deficiency.

The objective of this retrospective review was to identify the presence of secondary hypogonadism in chronic opioid users among a cohort of veterans receiving chronic opioids for nonmalignant pain. In addition to identifying the presence of secondary hypogonadism, the relationship between testosterone concentrations and total daily morphine equivalent doses (MEDs) was reviewed. These data along with the new information recently published on testosterone replacement therapy (TRT) and cardiovascular (CV) risk were then used to evaluate current practices at the West Palm Beach VAMC for OPIAD monitoring and management and to modify and update the local Criteria for Use (CFU) for TRT.

Methods

Patient data from the West Palm Beach VAMC in Florida from January 2013 to December 2013 were reviewed to identify patients who had a total testosterone (TT) level measured. All patient appointments for evaluation and treatment by the clinical pharmacy specialist in pain management were reviewed for data collection. This retrospective review was approved by the scientific advisory committee as part of the facility’s ongoing performance improvement efforts as defined by VHA Handbook 1058.05 and did not require written patient consent.¹⁰

Several distinct TT level data were collected. The descriptive data included patient age; gender; type of treated pain; testosterone level(s) drawn, including TT level before opioid therapy, TT level before/during/after TRT, and current total testosterone level; total daily MED of opioid therapy; duration of chronic opioid therapy; symptoms of exhibited hypogonadism; TRT formulation, dose, and duration; TRT prescriber; symptom change (if any); and laboratory tests ordered for TRT monitoring (lipid profile, liver profile, complete blood count, LH/FSH, and prostate specific antigen [PSA] panel).^5,11,12

Related: Combination Treatment Relieves Opioid-Induced Constipation

Daily MED of opioid therapy was calculated using the VA/DoD opioid conversion table for patients on oxycodone, hydromorphone, or hydrocodone.¹³ For those on the fentanyl patch or methadone, conversion factors of 1:2 (fentanyl [µg/h]:morphine [mg/d]) and 1:3 (methadone:morphine) were used to convert to the MED.¹⁴ For patients on the buprenorphine patch, the package insert was used to convert to the corresponding MED.¹⁵ Combination therapies used the applicable conversions to calculate the total daily MED.

Once the data were collected, descriptive statistics were used to analyze the data. In addition, 4 graphs were generated to review potential relationships. The correlation coefficient was calculated using the Alcula Online Statistics Calculator (http://www.alcula.com; Correlation Coefficient Calculator).

Results

A total of 316 unique veteran patients were seen by the clinical pharmacy specialist in pain management from January 1, 2013, through December 31, 2013. Of these, 73 patients (23.1%) had at least 1 TT level drawn in 2013. Three patients with testosterone levels drawn (4.1%) were excluded from the data analysis for the following reasons: 1 patient did not have testosterone levels on file before receiving testosterone replacement from a non-VA source, 
1 patient received opioids from a non-VA source (MED and duration of opioid therapy could not be calculated), and 1 patient inconsistently received opioids and MED used at the time of testosterone level draw. Per the local TRT CFU, a TT level > 350 ng/dL
does not require treatment, whereas levels < 230 ng/dL (with symptoms) may require TRT, and 
< 200 ng/dL should be treated as 
hypogonadal (interpretation based on local laboratory’s reference range for TT).16 Of the 70 patients included in the analysis, 34 (48.6%) had a TT level < 230 ng/dL and would be considered eligible for TRT if they presented with symptoms 
of low testosterone. Of these 34 patients with a low testosterone level, 28 (40%) were being treated or had been treated with TRT (Figure 1).

The average age of the male patients with a testosterone level drawn was 58.3 years, which was not significantly different from the calculated median age of 60 years. No female patients had a testosterone level drawn. On average, the TT level was normal before starting opioids (reference range per local laboratory: 175-781 ng/dL). Once opioids were initiated, patients were treated for an average duration of 52.5 months (calculated through December 2013) with an average daily dose of 126.8 MED (Table). Fifty of the 70 patients (71.4%) with testosterone levels drawn in 2013 received TRT. The most common symptoms reported by patients related to low testosterone included ED, decreased libido, depression, chronic fatigue, generalized weakness, and hot flashes or night sweats.

The average TT level prior to TRT was 145.3, and the average 
testosterone level after initiation of or 
during treatment with TRT was 292.4, which is within the normal TT level range. Most patients receiving TRT were treated with testosterone cypionate injections, and this was also the formulation used for the longest periods, likely due to the local CFU. In addition to testosterone cypionate injections, patients were also treated with testosterone enanthate injections, testosterone patches, and testosterone gel.

Figure 1 compares current testosterone level and testosterone level before TRT with total daily MEDs. Figure 2 compares current testosterone level and testosterone level before TRT with length of opioid therapy. The 2 figures use data from all patients included in the analysis and indicate a potential inverse relationship between the total daily MED and duration of therapy with the testosterone level, although none of the calculated correlation coefficients indicate that a strong relationship was present.

Figures 3 and 4 include data only for patients who had both a testosterone level collected before opioids (baseline testosterone level) and a current testosterone level. Figure 3 trends the data using total daily MED, and Figure 4 uses the duration of opioid therapy. The correlation for Figure 4 is slightly stronger; the strongest negative correlations were identified between total daily MED and testosterone level before opioid therapy (r = -0.273) and duration of opioid therapy and testosterone level prior to opioid therapy (r = -0.396). The trends indicate that most patients had a normal TT level before opioid treatment and that patients treated with higher MEDs and for longer durations of time were more likely to have lower total testosterone levels.

Discussion

Low testosterone levels can adversely affect patients’ quality of life (QOL) and add to patients’ medication burden with the initiation of TRT. Given new data analyzing the potential effects of TRT on CV event risk, the use of TRT should be carefully considered, as it may carry significant risks and may not be suitable for all patients.

In November 2013, a study was published regarding TRT and 
increased CV risk.¹⁷ This was a retrospective cohort study of men with low testosterone levels (< 300 ng/dL) who had undergone coronary angiography in the VA system between 2005 and 2011 (average age in testosterone group was 60.6 years). The results were significant for an absolute rate of events (all-cause mortality, myocardial infarction [MI], and ischemic stroke) of 19.9% in the no testosterone group and 25.7% in the TRT group, an absolute risk difference of 5.8% at 3 years after coronary angiography. Kaplan-Meier survival curves demonstrated that testosterone use was associated with increased risk of death, MI, and stroke. This result was unchanged when adjusted for the presence of coronary artery disease (CAD). In 
addition, no significant difference was found between the groups in terms of systolic blood pressure, low-
density lipoprotein cholesterol level, or in the use of beta-blocker and statin medications. What is important to note is that in this cohort, 20% had a prior history of MI and heart failure, and more than 50% had confirmed obstructive CAD on angiography. In addition, as this was an observational study, confounding or bias may exist, and given the study population, 
generalizability may be limited to a veteran population.

Related: A Multidisciplinary Chronic Pain Management Clinic in an Indian Health Service Facility

Another retrospective cohort study assessed the risk of acute nonfatal MI following an initial TRT prescription in a large health care database (average age based on TRT prescription was 54.4 years).¹⁸ In men aged ≥ 65 years, a 2-fold increase in the risk of MI in the immediate 90 days after filling an initial TRT prescription declined to baseline after 91 to 180 days among those who did not refill their prescription. Younger men with a history of heart disease had a 2- to 3-fold increased risk of MI in the 90 days following initial TRT prescription. No excess risk was observed in the younger men without such a history. Again, this study has its limitations related to the retrospective design and use of a health care database as opposed to a randomized controlled trial.

In February 2014, a VA National Pharmacy Benefits Management (PBM) bulletin addressed 2 recent studies that had identified a possible risk of increased CV events in men receiving TRT. The bulletin noted that these studies had prompted the FDA to reassess the CV safety of TRT.¹⁹ The TRT CFU was updated by VISN 8 to ensure that the patients receive appropriate treatment and are monitored accordingly.

One of the major changes to the CFU was defining the reference ranges for TRT (interpretation based on a local laboratory’s reference range for total testosterone): serum TT < 200 ng/dL be “treated as 
hypogonadal, those with TT 
> 400 ng/dL be considered normal and those with TT 200-400 ng/dL be treated based on their clinical presentation if symptomatic; TT levels 
> 350 ng/dL do not require treatment, and levels below 230 ng/dL (with symptoms) may require testosterone replacement therapy.”¹⁶ Other important updates included revision of the exclusion criteria as well as 
highlighting special considerations related to TRT, including the use of free testosterone levels rather than TT levels in patients with suspected protein-binding issues, role in fertility treatments, limited use in patients on spironolactone therapy (due to spironolactone’s anti-androgen effects), and potential association with mood and behavior.¹⁶

As chronic opioid therapy is associated with OPIAD, the renewed interest in TRT and its potential AEs provides yet another reason to reconsider opioid therapy. This is especially valid when opioids are the potential cause of hypogonadism and the reaction is treating the AEs of opioids (as opposed to considering elimination of the causative agent) with a therapy that can potentially increase the risk for CV events so that opioids can be continued. Outside the potential CV risk with TRT, opioids carry the innate risk for substance abuse and addiction.

The Opioid Safety Initiative Requirements was released as a memorandum in April 2014 and is the VHA’s effort to “reduce harm from unsafe medications and/or excessive doses while adequately controlling pain in Veterans.”²⁰ Although it does not discuss the risk of OPIAD, it does highlight the need to identify and mitigate high-risk patients as well as high-risk opioid regimens. All these factors, including the possibility of hypogonadism, should be considered before starting opioid therapy and at the time of opioid renewal, as it is known that opioid therapy is not without risks.

At the West Palm Beach VAMC, the primary care providers (PCPs) are responsible for the management of TRT, including the workup, renewal, and monitoring. The Chronic Nonmalignant Pain Management Clinic (CNMPMC) orders testosterone levels on patients who report symptoms of low testosterone, such as hot flashes, depression, and low energy level and refers them to their PCP as indicated. The authors believe that this is most appropriate for a number of reasons: (1) the CNMPMC is a consult service, and patients are not followed indefinitely; (2) patients should be fully evaluated for appropriateness of TRT (including assessment of CV risk) before starting therapy; and (3) the necessary monitoring parameters (laboratory testing, digital rectal exam, and osteoporosis screening) are not typically within the VA pain clinic provider’s scope of practice or expertise. A consideration for future practice would be to incorporate the use of a standardized questionnaire for OPIAD monitoring in patients receiving ≥ 100 mg of morphine daily (eg, the Aging Males’ Symptoms scale).²¹ It should, however, be at the forefront of the pain specialist’s and PCP’s minds that all patients on chronic opioid therapy or considering chronic opioid therapy should be counseled on the risk for OPIAD. If OPIAD is identified, the patient should be carefully considered for an opioid dose reduction as an initial management strategy.

Limitations

A limitation of this review is the lack of consistency or adequacy of serum testosterone sampling, noting that valid testosterone levels need to be drawn in the morning and not obtained during a time of acute illness. In addition, testosterone levels need to be drawn at an appropriate interval while on TRT (eg, at the midpoint between testosterone injections).¹⁶ Although the time of the sample collection is documented in the Computerized Patient Record System (CPRS), it is unknown whether the patient was acutely ill on the day of the sampling unless a progress note is entered, and it is difficult to determine whether the level timing was accurate based on the testosterone replacement formulation. Another limitation is that the average decline in serum testosterone levels with aging in men is 1% to 2% per year. A significant fraction of older men have levels below the lower limit of the normal range for healthy young men, so in older men it can be more difficult to determine whether low testosterone is related to chronic opioid use or to older age.^5,16

As this was a retrospective review, additional limitations included the inability to measure subclinical OPIAD, and the data collection related to symptoms of hypogonadism was restricted by documentation in the CPRS progress notes. The lack of data for females does not contribute to the literature on OPIAD in women. Finally, as the total daily MED does not distinguish between short-acting and long-acting opioid therapy, no differences between the impacts of short-acting vs long-
acting opioid therapy on risk for 
hypogonadism can be inferred. There is evidence to suggest that long-acting opioids are associated with a significantly higher risk for OPIAD compared with short-acting opioids, although the mechanism behind this is not well established.^22,23

Conclusions

The average age of the patients 
on chronic opioid therapy with a 
testosterone level drawn in this cohort was 58.3 years, which is younger than originally anticipated. The median age of 60 years is not significantly different from the average age, indicating that outliers did not impact this calculation. On average, the TT level was normal before starting opioids. Once opioids were started, patients were treated for an average duration of 52.5 months with an average daily dose of 126.8 mg MED. In this veteran cohort, 48.6% of patients met the criteria for TRT based on TT level alone, which is within the reported prevalence range of opioid-induced hypogonadism already published.^4,9 These results are in line with the original hypothesis that chronic opioid use can adversely impact testosterone levels and can have a poor effect on a patient’s QOL due to symptoms of low testosterone. In addition to TRT, possible and suggested (but not proven) treatment options for OPIAD include discontinuation of opioid therapy, opioid rotation, or conversion to buprenorphine.²¹ The approach used should account for multiple patient-specific factors and should be individualized.

Based on the data, there is a trend toward lower testosterone levels in veterans treated with higher MED and for longer periods with chronic opioids. Given recent data that infer that TRT carries increased CV risk as well as the VHA’s Opioid Safety Initiative, it is imperative that providers closely evaluate the appropriateness of starting TRT and/or continuing chronic opioid therapy. All patients generally should have failed non-
opioid management prior to opioid therapy for chronic nonmalignant pain, and this should be documented accordingly. It is also crucial to have the “opioid talk” with patients from time to time and discuss the risks vs benefits, the potential for addiction, overdose, dependence, tolerance, constipation, and OPIAD so patients can continue to be an active and informed participants in their care.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

According to the CDC, the medical use of opioid painkillers has increased at least 10-fold during the past 
20 years, “because of a movement toward more aggressive management of pain.”¹ Although opioid therapy is generally considered effective for the treatment of pain, long-term use (both orally and intrathecally) is associated with adverse effects (AEs) such as constipation, fatigue, nausea, sleep disturbances, depression, sexual dysfunction, and hypogonadism.^2,3Opioid-induced androgen deficiency (OPIAD), as defined by Smith and Elliot, is a clinical syndrome characterized by inappropriately low concentrations of gonadotropins (specifically, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), which leads to inadequate production of sex hormones, including estradiol and testosterone.⁴

Related: Testosterone Replacement Therapy: Playing Catch-up With Patients

The mechanism behind this phenomenon is initiated by either endogenous or exogenous opioids acting on opioid receptors in the hypothalamus, which causes a decrease in the release of gonadotropin-
releasing hormone (GnRH). This decrease in GnRH causes a reduction in the release of LH and FSH from the pituitary gland as well as testosterone or estradiol from the gonads.^4,5 Various guidelines report different cutoffs for the lower limit of normal total testosterone: The Endocrine Society recommends 300 ng/dL, the American Association of Clinical Endocrinologists suggests 200 ng/dL, and various other organizations suggest 230 ng/dL.^6-8 Hypotestosteronism can result in patients presenting with a broad spectrum of clinical symptoms, including reduced libido, erectile dysfunction (ED), fatigue, hot flashes, depression, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis.⁴ Women with low testosterone levels can experience irregular menstrual periods, oligomenorrhea, or amenorrhea.⁹ Opioid-induced androgen deficiency often goes unrecognized and untreated. The reported prevalence of opioid-induced hypogonadism ranges from 21% to 86%.^4,9 Given the growing number of patients on chronic opioid therapy, OPIAD warrants further investigation to identify the prevalence in the veteran population to appropriately monitor and manage this deficiency.

The objective of this retrospective review was to identify the presence of secondary hypogonadism in chronic opioid users among a cohort of veterans receiving chronic opioids for nonmalignant pain. In addition to identifying the presence of secondary hypogonadism, the relationship between testosterone concentrations and total daily morphine equivalent doses (MEDs) was reviewed. These data along with the new information recently published on testosterone replacement therapy (TRT) and cardiovascular (CV) risk were then used to evaluate current practices at the West Palm Beach VAMC for OPIAD monitoring and management and to modify and update the local Criteria for Use (CFU) for TRT.

Methods

Patient data from the West Palm Beach VAMC in Florida from January 2013 to December 2013 were reviewed to identify patients who had a total testosterone (TT) level measured. All patient appointments for evaluation and treatment by the clinical pharmacy specialist in pain management were reviewed for data collection. This retrospective review was approved by the scientific advisory committee as part of the facility’s ongoing performance improvement efforts as defined by VHA Handbook 1058.05 and did not require written patient consent.¹⁰

Several distinct TT level data were collected. The descriptive data included patient age; gender; type of treated pain; testosterone level(s) drawn, including TT level before opioid therapy, TT level before/during/after TRT, and current total testosterone level; total daily MED of opioid therapy; duration of chronic opioid therapy; symptoms of exhibited hypogonadism; TRT formulation, dose, and duration; TRT prescriber; symptom change (if any); and laboratory tests ordered for TRT monitoring (lipid profile, liver profile, complete blood count, LH/FSH, and prostate specific antigen [PSA] panel).^5,11,12

Related: Combination Treatment Relieves Opioid-Induced Constipation

Daily MED of opioid therapy was calculated using the VA/DoD opioid conversion table for patients on oxycodone, hydromorphone, or hydrocodone.¹³ For those on the fentanyl patch or methadone, conversion factors of 1:2 (fentanyl [µg/h]:morphine [mg/d]) and 1:3 (methadone:morphine) were used to convert to the MED.¹⁴ For patients on the buprenorphine patch, the package insert was used to convert to the corresponding MED.¹⁵ Combination therapies used the applicable conversions to calculate the total daily MED.

Once the data were collected, descriptive statistics were used to analyze the data. In addition, 4 graphs were generated to review potential relationships. The correlation coefficient was calculated using the Alcula Online Statistics Calculator (http://www.alcula.com; Correlation Coefficient Calculator).

Results

A total of 316 unique veteran patients were seen by the clinical pharmacy specialist in pain management from January 1, 2013, through December 31, 2013. Of these, 73 patients (23.1%) had at least 1 TT level drawn in 2013. Three patients with testosterone levels drawn (4.1%) were excluded from the data analysis for the following reasons: 1 patient did not have testosterone levels on file before receiving testosterone replacement from a non-VA source, 
1 patient received opioids from a non-VA source (MED and duration of opioid therapy could not be calculated), and 1 patient inconsistently received opioids and MED used at the time of testosterone level draw. Per the local TRT CFU, a TT level > 350 ng/dL
does not require treatment, whereas levels < 230 ng/dL (with symptoms) may require TRT, and 
< 200 ng/dL should be treated as 
hypogonadal (interpretation based on local laboratory’s reference range for TT).16 Of the 70 patients included in the analysis, 34 (48.6%) had a TT level < 230 ng/dL and would be considered eligible for TRT if they presented with symptoms 
of low testosterone. Of these 34 patients with a low testosterone level, 28 (40%) were being treated or had been treated with TRT (Figure 1).

The average age of the male patients with a testosterone level drawn was 58.3 years, which was not significantly different from the calculated median age of 60 years. No female patients had a testosterone level drawn. On average, the TT level was normal before starting opioids (reference range per local laboratory: 175-781 ng/dL). Once opioids were initiated, patients were treated for an average duration of 52.5 months (calculated through December 2013) with an average daily dose of 126.8 MED (Table). Fifty of the 70 patients (71.4%) with testosterone levels drawn in 2013 received TRT. The most common symptoms reported by patients related to low testosterone included ED, decreased libido, depression, chronic fatigue, generalized weakness, and hot flashes or night sweats.

The average TT level prior to TRT was 145.3, and the average 
testosterone level after initiation of or 
during treatment with TRT was 292.4, which is within the normal TT level range. Most patients receiving TRT were treated with testosterone cypionate injections, and this was also the formulation used for the longest periods, likely due to the local CFU. In addition to testosterone cypionate injections, patients were also treated with testosterone enanthate injections, testosterone patches, and testosterone gel.

Figure 1 compares current testosterone level and testosterone level before TRT with total daily MEDs. Figure 2 compares current testosterone level and testosterone level before TRT with length of opioid therapy. The 2 figures use data from all patients included in the analysis and indicate a potential inverse relationship between the total daily MED and duration of therapy with the testosterone level, although none of the calculated correlation coefficients indicate that a strong relationship was present.

Figures 3 and 4 include data only for patients who had both a testosterone level collected before opioids (baseline testosterone level) and a current testosterone level. Figure 3 trends the data using total daily MED, and Figure 4 uses the duration of opioid therapy. The correlation for Figure 4 is slightly stronger; the strongest negative correlations were identified between total daily MED and testosterone level before opioid therapy (r = -0.273) and duration of opioid therapy and testosterone level prior to opioid therapy (r = -0.396). The trends indicate that most patients had a normal TT level before opioid treatment and that patients treated with higher MEDs and for longer durations of time were more likely to have lower total testosterone levels.

Discussion

Low testosterone levels can adversely affect patients’ quality of life (QOL) and add to patients’ medication burden with the initiation of TRT. Given new data analyzing the potential effects of TRT on CV event risk, the use of TRT should be carefully considered, as it may carry significant risks and may not be suitable for all patients.

In November 2013, a study was published regarding TRT and 
increased CV risk.¹⁷ This was a retrospective cohort study of men with low testosterone levels (< 300 ng/dL) who had undergone coronary angiography in the VA system between 2005 and 2011 (average age in testosterone group was 60.6 years). The results were significant for an absolute rate of events (all-cause mortality, myocardial infarction [MI], and ischemic stroke) of 19.9% in the no testosterone group and 25.7% in the TRT group, an absolute risk difference of 5.8% at 3 years after coronary angiography. Kaplan-Meier survival curves demonstrated that testosterone use was associated with increased risk of death, MI, and stroke. This result was unchanged when adjusted for the presence of coronary artery disease (CAD). In 
addition, no significant difference was found between the groups in terms of systolic blood pressure, low-
density lipoprotein cholesterol level, or in the use of beta-blocker and statin medications. What is important to note is that in this cohort, 20% had a prior history of MI and heart failure, and more than 50% had confirmed obstructive CAD on angiography. In addition, as this was an observational study, confounding or bias may exist, and given the study population, 
generalizability may be limited to a veteran population.

Related: A Multidisciplinary Chronic Pain Management Clinic in an Indian Health Service Facility

Another retrospective cohort study assessed the risk of acute nonfatal MI following an initial TRT prescription in a large health care database (average age based on TRT prescription was 54.4 years).¹⁸ In men aged ≥ 65 years, a 2-fold increase in the risk of MI in the immediate 90 days after filling an initial TRT prescription declined to baseline after 91 to 180 days among those who did not refill their prescription. Younger men with a history of heart disease had a 2- to 3-fold increased risk of MI in the 90 days following initial TRT prescription. No excess risk was observed in the younger men without such a history. Again, this study has its limitations related to the retrospective design and use of a health care database as opposed to a randomized controlled trial.

In February 2014, a VA National Pharmacy Benefits Management (PBM) bulletin addressed 2 recent studies that had identified a possible risk of increased CV events in men receiving TRT. The bulletin noted that these studies had prompted the FDA to reassess the CV safety of TRT.¹⁹ The TRT CFU was updated by VISN 8 to ensure that the patients receive appropriate treatment and are monitored accordingly.

One of the major changes to the CFU was defining the reference ranges for TRT (interpretation based on a local laboratory’s reference range for total testosterone): serum TT < 200 ng/dL be “treated as 
hypogonadal, those with TT 
> 400 ng/dL be considered normal and those with TT 200-400 ng/dL be treated based on their clinical presentation if symptomatic; TT levels 
> 350 ng/dL do not require treatment, and levels below 230 ng/dL (with symptoms) may require testosterone replacement therapy.”¹⁶ Other important updates included revision of the exclusion criteria as well as 
highlighting special considerations related to TRT, including the use of free testosterone levels rather than TT levels in patients with suspected protein-binding issues, role in fertility treatments, limited use in patients on spironolactone therapy (due to spironolactone’s anti-androgen effects), and potential association with mood and behavior.¹⁶

As chronic opioid therapy is associated with OPIAD, the renewed interest in TRT and its potential AEs provides yet another reason to reconsider opioid therapy. This is especially valid when opioids are the potential cause of hypogonadism and the reaction is treating the AEs of opioids (as opposed to considering elimination of the causative agent) with a therapy that can potentially increase the risk for CV events so that opioids can be continued. Outside the potential CV risk with TRT, opioids carry the innate risk for substance abuse and addiction.

The Opioid Safety Initiative Requirements was released as a memorandum in April 2014 and is the VHA’s effort to “reduce harm from unsafe medications and/or excessive doses while adequately controlling pain in Veterans.”²⁰ Although it does not discuss the risk of OPIAD, it does highlight the need to identify and mitigate high-risk patients as well as high-risk opioid regimens. All these factors, including the possibility of hypogonadism, should be considered before starting opioid therapy and at the time of opioid renewal, as it is known that opioid therapy is not without risks.

At the West Palm Beach VAMC, the primary care providers (PCPs) are responsible for the management of TRT, including the workup, renewal, and monitoring. The Chronic Nonmalignant Pain Management Clinic (CNMPMC) orders testosterone levels on patients who report symptoms of low testosterone, such as hot flashes, depression, and low energy level and refers them to their PCP as indicated. The authors believe that this is most appropriate for a number of reasons: (1) the CNMPMC is a consult service, and patients are not followed indefinitely; (2) patients should be fully evaluated for appropriateness of TRT (including assessment of CV risk) before starting therapy; and (3) the necessary monitoring parameters (laboratory testing, digital rectal exam, and osteoporosis screening) are not typically within the VA pain clinic provider’s scope of practice or expertise. A consideration for future practice would be to incorporate the use of a standardized questionnaire for OPIAD monitoring in patients receiving ≥ 100 mg of morphine daily (eg, the Aging Males’ Symptoms scale).²¹ It should, however, be at the forefront of the pain specialist’s and PCP’s minds that all patients on chronic opioid therapy or considering chronic opioid therapy should be counseled on the risk for OPIAD. If OPIAD is identified, the patient should be carefully considered for an opioid dose reduction as an initial management strategy.

Limitations

A limitation of this review is the lack of consistency or adequacy of serum testosterone sampling, noting that valid testosterone levels need to be drawn in the morning and not obtained during a time of acute illness. In addition, testosterone levels need to be drawn at an appropriate interval while on TRT (eg, at the midpoint between testosterone injections).¹⁶ Although the time of the sample collection is documented in the Computerized Patient Record System (CPRS), it is unknown whether the patient was acutely ill on the day of the sampling unless a progress note is entered, and it is difficult to determine whether the level timing was accurate based on the testosterone replacement formulation. Another limitation is that the average decline in serum testosterone levels with aging in men is 1% to 2% per year. A significant fraction of older men have levels below the lower limit of the normal range for healthy young men, so in older men it can be more difficult to determine whether low testosterone is related to chronic opioid use or to older age.^5,16

As this was a retrospective review, additional limitations included the inability to measure subclinical OPIAD, and the data collection related to symptoms of hypogonadism was restricted by documentation in the CPRS progress notes. The lack of data for females does not contribute to the literature on OPIAD in women. Finally, as the total daily MED does not distinguish between short-acting and long-acting opioid therapy, no differences between the impacts of short-acting vs long-
acting opioid therapy on risk for 
hypogonadism can be inferred. There is evidence to suggest that long-acting opioids are associated with a significantly higher risk for OPIAD compared with short-acting opioids, although the mechanism behind this is not well established.^22,23

Conclusions

The average age of the patients 
on chronic opioid therapy with a 
testosterone level drawn in this cohort was 58.3 years, which is younger than originally anticipated. The median age of 60 years is not significantly different from the average age, indicating that outliers did not impact this calculation. On average, the TT level was normal before starting opioids. Once opioids were started, patients were treated for an average duration of 52.5 months with an average daily dose of 126.8 mg MED. In this veteran cohort, 48.6% of patients met the criteria for TRT based on TT level alone, which is within the reported prevalence range of opioid-induced hypogonadism already published.^4,9 These results are in line with the original hypothesis that chronic opioid use can adversely impact testosterone levels and can have a poor effect on a patient’s QOL due to symptoms of low testosterone. In addition to TRT, possible and suggested (but not proven) treatment options for OPIAD include discontinuation of opioid therapy, opioid rotation, or conversion to buprenorphine.²¹ The approach used should account for multiple patient-specific factors and should be individualized.

Based on the data, there is a trend toward lower testosterone levels in veterans treated with higher MED and for longer periods with chronic opioids. Given recent data that infer that TRT carries increased CV risk as well as the VHA’s Opioid Safety Initiative, it is imperative that providers closely evaluate the appropriateness of starting TRT and/or continuing chronic opioid therapy. All patients generally should have failed non-
opioid management prior to opioid therapy for chronic nonmalignant pain, and this should be documented accordingly. It is also crucial to have the “opioid talk” with patients from time to time and discuss the risks vs benefits, the potential for addiction, overdose, dependence, tolerance, constipation, and OPIAD so patients can continue to be an active and informed participants in their care.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Since the 1980s, patients with a single intracranial metastatic lesion traditionally have been treated with surgery followed by whole brain radiation therapy (WBRT). However, there is growing concern about the debilitating cognitive effects associated with WBRT in long-term survivors.

Limbrick and colleagues studied the outcomes of surgery followed by stereotactic radiosurgery (SRS) instead of WBRT and found that the less invasive surgical resection (SR) followed by SRS was an equally effective therapeutic option for the treatment of patients with limited metastatic disease to the brain.¹ Median overall survival (OS) was 20 months and was 
22 and 13 months for Classes 1 and 2 recursive partitioning analysis (RPA) patients, respectively. Recursive partitioning analysis refers to 3 prognostic classes based on a database of 
3 trial studies and 1,200 patients (Table 1).² According to RPA, the best survival was observed in Class 1 patients, and the worst survival was seen in Class 3 patients. Limbrick and colleagues found that survival outcome was equivalent to or greater than that reported by other studies using surgery plus WBRT or SRS plus WBRT.¹ The WBRT was not used and was reserved as salvage therapy in cases of initial failure such as disease progression of brain metastasis.

Radiation Therapies

Stereotactic radiosurgery is not a surgical procedure but a newly developed radiotherapy technique. It is a highly precise, intensive form of radiation therapy, focused on the tumor, with the goal of protecting the surrounding normal brain tissue as much as possible. Radiosurgery was initially introduced with the Gamma Knife by Lars Leksell several decades ago in order to deliver an intense radiation dose to a small, well-defined, single focal point using extreme precision. Stereotactic radiosurgery delivers efficient and focused radiation treatment to the tumor lesion.

There are 2 practical and commercially available radiation delivery systems for SRS: linear accelerator (LINAC)-based radiosurgery and Gamma Knife systems. Use of the Gamma Knife is limited largely to treatment of central nervous system (CNS) malignancies and certain head and neck cancers. Linear 
accelerator-based SRS is applicable to neoplasms in any organ system of the body (Table 2).

Proton therapy is yet another evolving and completely different mode of radiation therapy. There are currently 14 proton therapy centers in operation in the U.S., and 11 more centers are now under construction. Proton therapy uses charged heavy-particle therapy using proton beams, whereas conventional LINAC-based radiotherapy is X-ray radiotherapy, which uses high energy photon beams. Because of their relatively large mass, protons have little scatter of radiation to surrounding normal structures and can remain sharply focused on the tumor lesion. Accordingly, proton therapy delivers negligible radiation doses beyond tumor lesions, and much of the surrounding normal tissues can be saved from excessive and unnecessary radiation doses.

Related: Bone Metastasis: A Concise Overview

A single proton beam produces a narrow Bragg peak dose distribution at depth, and multiple consecutive stepwise series of different energies of proton beams are needed to administer complete coverage of the target tumor volume. The accumulation of these beam energies produces a uniform radiation dose distribution covering the entire tumor volume (Figure 1). In spite of the theoretical beneficial effects of proton beam therapy, more clinical experience is needed for it to be validated. Even then, the significantly higher costs of proton therapy represent another barrier to its wider implementation. Proton beam radiosurgery is still, in large part, an evolving technology, not widely and uniformly available.

Role of Radiosurgery

Photon (X-ray)-based radiosurgery can be an alternative to craniotomy. Patients can return to their activities immediately after treatment. The ideal candidate for radiosurgery should have a small tumor (1-3 cm is best) with a well-defined margin. Retrospective studies reported no significant difference in therapy outcomes between the 2 therapies.^3,4 Additional benefits of radiosurgery include low morbidity and mortality. Furthermore, radiosurgery can be applied to tumors near critical structures, such as the thalamus, basal ganglia, and brainstem, that are otherwise surgically inaccessible.

Most brain metastases are well defined and spherical, so they are ideally treated using SRS (Figure 1). Additionally, the brain is encased in the bony skull, which prevents significant intrafraction motion and provides a reproducible fidulial for accurate setup. Radiosurgery can tailor the radiation dose in order to precisely concentrate radiation distribution to the tumor lesion with a rapid dose falloff beyond the margin of the tumor bed, so surrounding normal brain tissues are spared from high-dose radiation. In sharp contrast, WBRT indiscriminately irradiates the entire brain without sparing the adjacent normal brain tissue (Figure 2). However, because of its limited dose distribution, radiosurgery offers no protection elsewhere in the brain from future metastasis, which is a benefit of whole brain radiation.

Future Use of SBRT

Based on successful experience with intracranial lesions, stereotactic techniques have been expanded to additional anatomical body sites other than the brain. Stereotactic body radiation therapy (SBRT), also called stereotactic body ablative radiotherapy, is progressively gaining acceptance and is being applied to various extracranial tumors, especially lung cancers and hepatic malignancies. Dosimetric studies and early phase clinical trials have clearly established the feasibility, safety, and efficacy of SBRT for certain tumor sites, such as lung, liver, kidney, spine, and paraspinal tumors. Additionally, SBRT may reduce treatment time and therapy costs and thus provide increased convenience to patients.

Effectiveness of SRS

Stafinski and colleagues conducted a meta-analysis of randomized trials to study the effectiveness of SRS in improving the survival as well as the quality of life (QOL) and functional status following SRS of patients with brain metastasis.⁵ This study found that SRS plus WBRT increased OS for patients with single brain metastasis compared with WBRT alone. Although no significant difference in OS was found in patients with multiple brain metastases, the addition of SRS to WBRT improved the local control and functional independence of this group of patients.

Related: Palliative Radiotherapy for the Management of Metastatic Cancer

Kondziolka and colleagues reported a local failure rate at 1 year of merely 8% following SRS boost therapy after WBRT compared with 100% without SRS.⁶ There was also a remarkable difference in median time to local failure—36 months vs 6 months, respectively. A randomized study designed to assess the possible benefit of SRS for the treatment of brain metastasis found a survival gain for patients with a single brain metastasis with a median survival time of 6.5 months (SRS) vs 4.9 months (no SRS).⁷

There are sparse data and reporting related to QOL measurements after SRS for brain metastasis. Andrews and colleagues reported improved functional and independent abilities at 6 months after completion of SRS therapy.⁷ The criteria used in that study for performance assessments included the Karnofsky Performance Status (KPS) scale, the need for steroid use, and mental status. They found that KPS improvement was statistically significant, and patients were able to decrease the dosage of steroid medication at 6 months after therapy with SRS (Table 3). Despite these reports suggesting superior outcomes with SRS, more rigorous investigations that adequately control for other factors influencing QOL in patients with cancer are needed.

Two major limitations of SRS include large tumor size and multiple numbers of metastatic brain lesions. As the radiation dose to adjacent normal brain tissue quickly increases with larger tumor lesions (> 3-4 cm), the complication risks consequently rise proportionally, necessitating a decrease in the prescribed dose. Patients with poor performance status 
(< 70 KPS) and presence of active/progressive extracranial disease are also not ideal candidates for SRS.

Other unfavorable conditions for SRS include life expectancy of 
< 6 months, metastatic lesions in the posterior fossa, and severe acute CNS symptoms due to increased intracranial pressure, brain edema, or massive tumor effects. These factors do not necessarily contraindicate SRS but can increase the risks of such treatment. The authors recommend an experienced multispecialty approach to patients presenting with these findings.

Managing Brain Metastastis

To prevent symptoms related to brain edema (due to brain tumor itself and/or radiation-induced edema), steroid medication is generally administered to most patients, 1 to 3 days prior to initiation of radiation therapy. Corticosteroid use typically results in rapid improvement of existing CNS symptoms, such as headaches, and helps prevent the development of additional CNS symptoms due to radiation therapy-induced cerebral edema. A dexamethasone dose as low as 4 mg per day may be effective for prophylaxis if no symptoms or signs of increased intracranial pressure or altered consciousness exist. If the patient experiences symptomatic elevations in intracranial pressure, however, a 16-mg dose of dexamethasone per day orally, following a loading dose of 10-mg IV dexamethasone, should be considered. The latter scenario is not common.

Related: Pulmonary Vein Thrombosis Associated With Metastatic Carcinoma

The benefits of steroids, however, need to be carefully balanced against the possible adverse effects (AEs) associated with steroid use, including peripheral edema, gastrointestinal bleeding, risk of infections, hyperglycemia, insomnia, as well as mental status changes, such as anxiety, depression, and confusion. In long-term users, the additional AEs of oral candidiasis and osteoporosis should also be taken into account.

Craniotomy vs SRS

A retrospective study by Schöggl and colleagues compared single brain metastasis cases treated using either Gamma Knife or brain surgery followed by WBRT (30 Gy/10 fractions).³ Local control was significantly better after radiosurgery 
(95% vs 83%), and median survival was 12 months and 9 months after radiosurgery and brain surgery, respectively. There was no significant difference in OS.

Another comparative study of SR and SRS for solitary brain metastasis revealed no statistically significant difference in survival between the 
2 therapeutic modalities (SR or SRS); the 1-year survival rate was 62% (SR) and 56% (SRS).⁴ A significant prognostic factor for survival was a good performance status of the patients. There was, however, a significant difference in local tumor control: None of the patients in the SRS group experienced local recurrence in contrast to 19 (58%) patients in the SR group.

Whereas selection criteria and treatment choice depend to a large extent on tumor location, tumor size, and availability of SRS, most studies demonstrated that both surgery and SRS result in comparable OS rates for patients with a single brain metastasis.

Multiple Brain Metastases

Jawahar and colleagues studied the role of SRS for multiple brain metastases.⁸ In their retrospective review of 50 patients with ≥ 3 brain metastases, they found an overall response rate (RR) of 82% and a median survival of 12 months after SRS. As a result of similar studies and their own data, Hasegawa and colleagues recommended radiosurgery alone as initial therapy for patients with a limited number of brain metastases.⁹

SRS vs SRS Plus WBRT

Studies on the role of SRS plus WBRT are somewhat conflicting. A Radiation Therapy Oncology Group study revealed statistically significant improvement in median survival when SRS boost therapy was added to WBRT in patients with a single brain metastasis compared with SRS alone.⁵ According to another study, the addition of SRS to WBRT provided better intracranial and local control of metastatic tumors.¹⁰

A randomized controlled study by Aoyama and colleagues reported no survival improvement using SRS and WBRT in patients with 1 to 4 brain metastases compared with SRS alone.¹¹ In addition, a retrospective review found no difference in median survival outcomes between SRS alone and SRS plus WBRT (Table 4). In the absence of a clear survival benefit with the use of both modalities and in light of the added toxicity of WBRT, most clinicians have ceased offering both modalities upfront and instead reserve WBRT as a salvage option in cases of subsequent intracranial progression of disease.

SRS vs WBRT

In general, both SR (crainotomy) and SRS for the treatment of brain metastases seem to be effective therapeutic modalities. Comparisons of both treatments did not reveal significant differences and showed similar outcomes after treatment of smaller lesions. For example, Rades and colleagues reported that SRS alone is as effective as surgery and WBRT for limited metastatic lesions (< 2) in the brain.¹⁶ Either SRS or surgery can be used, depending on performance status and metastatic burden (size, location, number of lesions, etc).

There are some inconsistencies in the final results of various studies, such as survival, local tumor control, mortality rate, and pattern of failures. For large, symptomatic brain metastasis, initial surgical debulking remains the preferred approach as a way of achieving immediate decompression and relief of swelling/symptoms. Additionally, for patients who have > 10 brain lesions and/or a histology that corroborates diffuse subclinical involvement of the brain parenchyma (eg, small-cell lung cancer), WBRT is also typically preferred to upfront SRS. Alternatively, radiosurgery is the preferred method for fewer and smaller lesions as a way of minimizing the toxicity from whole brain irradiation. The optimal treatment of multiple small brain metastases remains controversial with some investigators recommending SRS for > 4 metastases only in the setting of controlled extracranial disease based on the more favorable expected survival of such patients.

Multidisciplinary Approach for Lung and Breast Cancers

Prognostic outcomes of patients with brain metastases can vary by primary cancer type. Therefore, clinicians should consider cancer-specific management and tailor their recommendation for specific types of radiation depending on the 
individual cancer diagnosis. Various investigators have attempted to develop disease-specific prognostic tools to aid clinicians in their decision making. For example, Sperduto and colleagues analyzed significant indexes and diagnosis-specific prognostic factors and published the 
diagnostic-specific graded prognostic assessment factors.¹⁷ They were able to identify several significant prognostic factors, specific to different primary cancer types.

Bimodality Therapies

For certain cancers such as lung and breast primary cancers, bimodality therapy using chemotherapy and radiation treatment should be considered based on promising responses reported in the literature.

Recent studies on the efficacy of chemotherapy for brain metastases from small-cell lung cancer (43%-82%) have also been reported.^18-20 Postmus and colleagues reported superior RR of 57% with combination chemotherapy and radiation vs a 22% RR for chemotherapy alone.²¹ They also found favorable long-term survival trends in patients treated with combined radiochemotherapy.

The efficacy of chemotherapy in non-small cell carcinoma of the lung has been reported in multiple phase 2 studies using various chemotherapeutic agents. The reported RR ranged from 35% to 50%.^22-24 Comparative studies of combined chemoradiotherapy demonstrated a 33% RR in contrast to a 27% RR for combined therapy or chemotherapy alone, respectively. However, no difference was noted in median survival rates.²⁵

Care must be taken when interpreting these studies due to heterogeneity of the patient population studied and a lack of data on potential synergistic toxicities between radiation to the CNS and systemic therapy. The authors generally avoid concurrent chemotherapy during CNS irradiation in patients who may have significant survival times > 1 year.

The prognosis of breast cancer patients with brain metastasis largely depends on the number and size of metastatic brain lesions, performance status, extracranial or systemic involvement, and systemic treatment following brain irradiation. The median survival of patients with brain metastasis and radiation therapy is generally about 18 months. The median survival for patients with breast cancer who develop brain metastasis was 3 years from diagnosis of the primary breast cancer.²⁶

Recent advances in systemic agents/options for patients with breast cancer can significantly affect the decision-making process in regard to the treatment of brain lesions in these patients. For example, a few retrospective studies have clearly demonstrated the beneficial effect of trastuzumab in patients with breast cancer with brain metastasis. The median OS in HER2-positive patients with brain metastasis was significantly extended to 41 months when treated with HER2-targeted trastuzumab vs only 
13 months for patients who received no treatment.^27,28 As a result of the expected prolonged survival, SRS for small and isolated brain lesions has recently become a much more attractive option as a way of mitigating the deleterious long-term effect of whole brain irradiation (memory decline, somnolence, etc).

Summary

Stereotactic radiosurgery is a newly developed radiation therapy technique of highly conformal and focused radiation. For the treatment of patients with favorable prognostic factors and limited brain metastases, especially single brain metastasis, crainiotomy and SRS seems similarly effective and appropriate choices of therapy. Some studies question the possible benefits of additional WBRT to local therapy, such as crainiotomy or radiosurgery.

Some authors recommend deferral of WBRT after local brain therapy and reserving it for salvage therapy in cases of recurrence or progression of brain disease because of possible long-term AEs of whole brain irradiation as well as deterioration of QOL in long-term survivors. Thus, the role of additional WBRT to other local therapy has not been fully settled; further randomized studies may be necessary. Due to the controversies and complexities surrounding the treatment choices for patients with brain disease, all treatment decisions should be individualized and should involve close multidisciplinary collaboration between neurosurgeons, medical oncologists, and radiation oncologists.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Since the 1980s, patients with a single intracranial metastatic lesion traditionally have been treated with surgery followed by whole brain radiation therapy (WBRT). However, there is growing concern about the debilitating cognitive effects associated with WBRT in long-term survivors.

Limbrick and colleagues studied the outcomes of surgery followed by stereotactic radiosurgery (SRS) instead of WBRT and found that the less invasive surgical resection (SR) followed by SRS was an equally effective therapeutic option for the treatment of patients with limited metastatic disease to the brain.¹ Median overall survival (OS) was 20 months and was 
22 and 13 months for Classes 1 and 2 recursive partitioning analysis (RPA) patients, respectively. Recursive partitioning analysis refers to 3 prognostic classes based on a database of 
3 trial studies and 1,200 patients (Table 1).² According to RPA, the best survival was observed in Class 1 patients, and the worst survival was seen in Class 3 patients. Limbrick and colleagues found that survival outcome was equivalent to or greater than that reported by other studies using surgery plus WBRT or SRS plus WBRT.¹ The WBRT was not used and was reserved as salvage therapy in cases of initial failure such as disease progression of brain metastasis.

Radiation Therapies

Stereotactic radiosurgery is not a surgical procedure but a newly developed radiotherapy technique. It is a highly precise, intensive form of radiation therapy, focused on the tumor, with the goal of protecting the surrounding normal brain tissue as much as possible. Radiosurgery was initially introduced with the Gamma Knife by Lars Leksell several decades ago in order to deliver an intense radiation dose to a small, well-defined, single focal point using extreme precision. Stereotactic radiosurgery delivers efficient and focused radiation treatment to the tumor lesion.

There are 2 practical and commercially available radiation delivery systems for SRS: linear accelerator (LINAC)-based radiosurgery and Gamma Knife systems. Use of the Gamma Knife is limited largely to treatment of central nervous system (CNS) malignancies and certain head and neck cancers. Linear 
accelerator-based SRS is applicable to neoplasms in any organ system of the body (Table 2).

Proton therapy is yet another evolving and completely different mode of radiation therapy. There are currently 14 proton therapy centers in operation in the U.S., and 11 more centers are now under construction. Proton therapy uses charged heavy-particle therapy using proton beams, whereas conventional LINAC-based radiotherapy is X-ray radiotherapy, which uses high energy photon beams. Because of their relatively large mass, protons have little scatter of radiation to surrounding normal structures and can remain sharply focused on the tumor lesion. Accordingly, proton therapy delivers negligible radiation doses beyond tumor lesions, and much of the surrounding normal tissues can be saved from excessive and unnecessary radiation doses.

Related: Bone Metastasis: A Concise Overview

A single proton beam produces a narrow Bragg peak dose distribution at depth, and multiple consecutive stepwise series of different energies of proton beams are needed to administer complete coverage of the target tumor volume. The accumulation of these beam energies produces a uniform radiation dose distribution covering the entire tumor volume (Figure 1). In spite of the theoretical beneficial effects of proton beam therapy, more clinical experience is needed for it to be validated. Even then, the significantly higher costs of proton therapy represent another barrier to its wider implementation. Proton beam radiosurgery is still, in large part, an evolving technology, not widely and uniformly available.

Role of Radiosurgery

Photon (X-ray)-based radiosurgery can be an alternative to craniotomy. Patients can return to their activities immediately after treatment. The ideal candidate for radiosurgery should have a small tumor (1-3 cm is best) with a well-defined margin. Retrospective studies reported no significant difference in therapy outcomes between the 2 therapies.^3,4 Additional benefits of radiosurgery include low morbidity and mortality. Furthermore, radiosurgery can be applied to tumors near critical structures, such as the thalamus, basal ganglia, and brainstem, that are otherwise surgically inaccessible.

Most brain metastases are well defined and spherical, so they are ideally treated using SRS (Figure 1). Additionally, the brain is encased in the bony skull, which prevents significant intrafraction motion and provides a reproducible fidulial for accurate setup. Radiosurgery can tailor the radiation dose in order to precisely concentrate radiation distribution to the tumor lesion with a rapid dose falloff beyond the margin of the tumor bed, so surrounding normal brain tissues are spared from high-dose radiation. In sharp contrast, WBRT indiscriminately irradiates the entire brain without sparing the adjacent normal brain tissue (Figure 2). However, because of its limited dose distribution, radiosurgery offers no protection elsewhere in the brain from future metastasis, which is a benefit of whole brain radiation.

Future Use of SBRT

Based on successful experience with intracranial lesions, stereotactic techniques have been expanded to additional anatomical body sites other than the brain. Stereotactic body radiation therapy (SBRT), also called stereotactic body ablative radiotherapy, is progressively gaining acceptance and is being applied to various extracranial tumors, especially lung cancers and hepatic malignancies. Dosimetric studies and early phase clinical trials have clearly established the feasibility, safety, and efficacy of SBRT for certain tumor sites, such as lung, liver, kidney, spine, and paraspinal tumors. Additionally, SBRT may reduce treatment time and therapy costs and thus provide increased convenience to patients.

Effectiveness of SRS

Stafinski and colleagues conducted a meta-analysis of randomized trials to study the effectiveness of SRS in improving the survival as well as the quality of life (QOL) and functional status following SRS of patients with brain metastasis.⁵ This study found that SRS plus WBRT increased OS for patients with single brain metastasis compared with WBRT alone. Although no significant difference in OS was found in patients with multiple brain metastases, the addition of SRS to WBRT improved the local control and functional independence of this group of patients.

Related: Palliative Radiotherapy for the Management of Metastatic Cancer

Kondziolka and colleagues reported a local failure rate at 1 year of merely 8% following SRS boost therapy after WBRT compared with 100% without SRS.⁶ There was also a remarkable difference in median time to local failure—36 months vs 6 months, respectively. A randomized study designed to assess the possible benefit of SRS for the treatment of brain metastasis found a survival gain for patients with a single brain metastasis with a median survival time of 6.5 months (SRS) vs 4.9 months (no SRS).⁷

There are sparse data and reporting related to QOL measurements after SRS for brain metastasis. Andrews and colleagues reported improved functional and independent abilities at 6 months after completion of SRS therapy.⁷ The criteria used in that study for performance assessments included the Karnofsky Performance Status (KPS) scale, the need for steroid use, and mental status. They found that KPS improvement was statistically significant, and patients were able to decrease the dosage of steroid medication at 6 months after therapy with SRS (Table 3). Despite these reports suggesting superior outcomes with SRS, more rigorous investigations that adequately control for other factors influencing QOL in patients with cancer are needed.

Two major limitations of SRS include large tumor size and multiple numbers of metastatic brain lesions. As the radiation dose to adjacent normal brain tissue quickly increases with larger tumor lesions (> 3-4 cm), the complication risks consequently rise proportionally, necessitating a decrease in the prescribed dose. Patients with poor performance status 
(< 70 KPS) and presence of active/progressive extracranial disease are also not ideal candidates for SRS.

Other unfavorable conditions for SRS include life expectancy of 
< 6 months, metastatic lesions in the posterior fossa, and severe acute CNS symptoms due to increased intracranial pressure, brain edema, or massive tumor effects. These factors do not necessarily contraindicate SRS but can increase the risks of such treatment. The authors recommend an experienced multispecialty approach to patients presenting with these findings.

Managing Brain Metastastis

To prevent symptoms related to brain edema (due to brain tumor itself and/or radiation-induced edema), steroid medication is generally administered to most patients, 1 to 3 days prior to initiation of radiation therapy. Corticosteroid use typically results in rapid improvement of existing CNS symptoms, such as headaches, and helps prevent the development of additional CNS symptoms due to radiation therapy-induced cerebral edema. A dexamethasone dose as low as 4 mg per day may be effective for prophylaxis if no symptoms or signs of increased intracranial pressure or altered consciousness exist. If the patient experiences symptomatic elevations in intracranial pressure, however, a 16-mg dose of dexamethasone per day orally, following a loading dose of 10-mg IV dexamethasone, should be considered. The latter scenario is not common.

Related: Pulmonary Vein Thrombosis Associated With Metastatic Carcinoma

The benefits of steroids, however, need to be carefully balanced against the possible adverse effects (AEs) associated with steroid use, including peripheral edema, gastrointestinal bleeding, risk of infections, hyperglycemia, insomnia, as well as mental status changes, such as anxiety, depression, and confusion. In long-term users, the additional AEs of oral candidiasis and osteoporosis should also be taken into account.

Craniotomy vs SRS

A retrospective study by Schöggl and colleagues compared single brain metastasis cases treated using either Gamma Knife or brain surgery followed by WBRT (30 Gy/10 fractions).³ Local control was significantly better after radiosurgery 
(95% vs 83%), and median survival was 12 months and 9 months after radiosurgery and brain surgery, respectively. There was no significant difference in OS.

Another comparative study of SR and SRS for solitary brain metastasis revealed no statistically significant difference in survival between the 
2 therapeutic modalities (SR or SRS); the 1-year survival rate was 62% (SR) and 56% (SRS).⁴ A significant prognostic factor for survival was a good performance status of the patients. There was, however, a significant difference in local tumor control: None of the patients in the SRS group experienced local recurrence in contrast to 19 (58%) patients in the SR group.

Whereas selection criteria and treatment choice depend to a large extent on tumor location, tumor size, and availability of SRS, most studies demonstrated that both surgery and SRS result in comparable OS rates for patients with a single brain metastasis.

Multiple Brain Metastases

Jawahar and colleagues studied the role of SRS for multiple brain metastases.⁸ In their retrospective review of 50 patients with ≥ 3 brain metastases, they found an overall response rate (RR) of 82% and a median survival of 12 months after SRS. As a result of similar studies and their own data, Hasegawa and colleagues recommended radiosurgery alone as initial therapy for patients with a limited number of brain metastases.⁹

SRS vs SRS Plus WBRT

Studies on the role of SRS plus WBRT are somewhat conflicting. A Radiation Therapy Oncology Group study revealed statistically significant improvement in median survival when SRS boost therapy was added to WBRT in patients with a single brain metastasis compared with SRS alone.⁵ According to another study, the addition of SRS to WBRT provided better intracranial and local control of metastatic tumors.¹⁰

A randomized controlled study by Aoyama and colleagues reported no survival improvement using SRS and WBRT in patients with 1 to 4 brain metastases compared with SRS alone.¹¹ In addition, a retrospective review found no difference in median survival outcomes between SRS alone and SRS plus WBRT (Table 4). In the absence of a clear survival benefit with the use of both modalities and in light of the added toxicity of WBRT, most clinicians have ceased offering both modalities upfront and instead reserve WBRT as a salvage option in cases of subsequent intracranial progression of disease.

SRS vs WBRT

In general, both SR (crainotomy) and SRS for the treatment of brain metastases seem to be effective therapeutic modalities. Comparisons of both treatments did not reveal significant differences and showed similar outcomes after treatment of smaller lesions. For example, Rades and colleagues reported that SRS alone is as effective as surgery and WBRT for limited metastatic lesions (< 2) in the brain.¹⁶ Either SRS or surgery can be used, depending on performance status and metastatic burden (size, location, number of lesions, etc).

There are some inconsistencies in the final results of various studies, such as survival, local tumor control, mortality rate, and pattern of failures. For large, symptomatic brain metastasis, initial surgical debulking remains the preferred approach as a way of achieving immediate decompression and relief of swelling/symptoms. Additionally, for patients who have > 10 brain lesions and/or a histology that corroborates diffuse subclinical involvement of the brain parenchyma (eg, small-cell lung cancer), WBRT is also typically preferred to upfront SRS. Alternatively, radiosurgery is the preferred method for fewer and smaller lesions as a way of minimizing the toxicity from whole brain irradiation. The optimal treatment of multiple small brain metastases remains controversial with some investigators recommending SRS for > 4 metastases only in the setting of controlled extracranial disease based on the more favorable expected survival of such patients.

Multidisciplinary Approach for Lung and Breast Cancers

Prognostic outcomes of patients with brain metastases can vary by primary cancer type. Therefore, clinicians should consider cancer-specific management and tailor their recommendation for specific types of radiation depending on the 
individual cancer diagnosis. Various investigators have attempted to develop disease-specific prognostic tools to aid clinicians in their decision making. For example, Sperduto and colleagues analyzed significant indexes and diagnosis-specific prognostic factors and published the 
diagnostic-specific graded prognostic assessment factors.¹⁷ They were able to identify several significant prognostic factors, specific to different primary cancer types.

Bimodality Therapies

For certain cancers such as lung and breast primary cancers, bimodality therapy using chemotherapy and radiation treatment should be considered based on promising responses reported in the literature.

Recent studies on the efficacy of chemotherapy for brain metastases from small-cell lung cancer (43%-82%) have also been reported.^18-20 Postmus and colleagues reported superior RR of 57% with combination chemotherapy and radiation vs a 22% RR for chemotherapy alone.²¹ They also found favorable long-term survival trends in patients treated with combined radiochemotherapy.

The efficacy of chemotherapy in non-small cell carcinoma of the lung has been reported in multiple phase 2 studies using various chemotherapeutic agents. The reported RR ranged from 35% to 50%.^22-24 Comparative studies of combined chemoradiotherapy demonstrated a 33% RR in contrast to a 27% RR for combined therapy or chemotherapy alone, respectively. However, no difference was noted in median survival rates.²⁵

Care must be taken when interpreting these studies due to heterogeneity of the patient population studied and a lack of data on potential synergistic toxicities between radiation to the CNS and systemic therapy. The authors generally avoid concurrent chemotherapy during CNS irradiation in patients who may have significant survival times > 1 year.

The prognosis of breast cancer patients with brain metastasis largely depends on the number and size of metastatic brain lesions, performance status, extracranial or systemic involvement, and systemic treatment following brain irradiation. The median survival of patients with brain metastasis and radiation therapy is generally about 18 months. The median survival for patients with breast cancer who develop brain metastasis was 3 years from diagnosis of the primary breast cancer.²⁶

Recent advances in systemic agents/options for patients with breast cancer can significantly affect the decision-making process in regard to the treatment of brain lesions in these patients. For example, a few retrospective studies have clearly demonstrated the beneficial effect of trastuzumab in patients with breast cancer with brain metastasis. The median OS in HER2-positive patients with brain metastasis was significantly extended to 41 months when treated with HER2-targeted trastuzumab vs only 
13 months for patients who received no treatment.^27,28 As a result of the expected prolonged survival, SRS for small and isolated brain lesions has recently become a much more attractive option as a way of mitigating the deleterious long-term effect of whole brain irradiation (memory decline, somnolence, etc).

Summary

Stereotactic radiosurgery is a newly developed radiation therapy technique of highly conformal and focused radiation. For the treatment of patients with favorable prognostic factors and limited brain metastases, especially single brain metastasis, crainiotomy and SRS seems similarly effective and appropriate choices of therapy. Some studies question the possible benefits of additional WBRT to local therapy, such as crainiotomy or radiosurgery.

Some authors recommend deferral of WBRT after local brain therapy and reserving it for salvage therapy in cases of recurrence or progression of brain disease because of possible long-term AEs of whole brain irradiation as well as deterioration of QOL in long-term survivors. Thus, the role of additional WBRT to other local therapy has not been fully settled; further randomized studies may be necessary. Due to the controversies and complexities surrounding the treatment choices for patients with brain disease, all treatment decisions should be individualized and should involve close multidisciplinary collaboration between neurosurgeons, medical oncologists, and radiation oncologists.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Since the 1980s, patients with a single intracranial metastatic lesion traditionally have been treated with surgery followed by whole brain radiation therapy (WBRT). However, there is growing concern about the debilitating cognitive effects associated with WBRT in long-term survivors.

Limbrick and colleagues studied the outcomes of surgery followed by stereotactic radiosurgery (SRS) instead of WBRT and found that the less invasive surgical resection (SR) followed by SRS was an equally effective therapeutic option for the treatment of patients with limited metastatic disease to the brain.¹ Median overall survival (OS) was 20 months and was 
22 and 13 months for Classes 1 and 2 recursive partitioning analysis (RPA) patients, respectively. Recursive partitioning analysis refers to 3 prognostic classes based on a database of 
3 trial studies and 1,200 patients (Table 1).² According to RPA, the best survival was observed in Class 1 patients, and the worst survival was seen in Class 3 patients. Limbrick and colleagues found that survival outcome was equivalent to or greater than that reported by other studies using surgery plus WBRT or SRS plus WBRT.¹ The WBRT was not used and was reserved as salvage therapy in cases of initial failure such as disease progression of brain metastasis.

Radiation Therapies

Stereotactic radiosurgery is not a surgical procedure but a newly developed radiotherapy technique. It is a highly precise, intensive form of radiation therapy, focused on the tumor, with the goal of protecting the surrounding normal brain tissue as much as possible. Radiosurgery was initially introduced with the Gamma Knife by Lars Leksell several decades ago in order to deliver an intense radiation dose to a small, well-defined, single focal point using extreme precision. Stereotactic radiosurgery delivers efficient and focused radiation treatment to the tumor lesion.

There are 2 practical and commercially available radiation delivery systems for SRS: linear accelerator (LINAC)-based radiosurgery and Gamma Knife systems. Use of the Gamma Knife is limited largely to treatment of central nervous system (CNS) malignancies and certain head and neck cancers. Linear 
accelerator-based SRS is applicable to neoplasms in any organ system of the body (Table 2).

Proton therapy is yet another evolving and completely different mode of radiation therapy. There are currently 14 proton therapy centers in operation in the U.S., and 11 more centers are now under construction. Proton therapy uses charged heavy-particle therapy using proton beams, whereas conventional LINAC-based radiotherapy is X-ray radiotherapy, which uses high energy photon beams. Because of their relatively large mass, protons have little scatter of radiation to surrounding normal structures and can remain sharply focused on the tumor lesion. Accordingly, proton therapy delivers negligible radiation doses beyond tumor lesions, and much of the surrounding normal tissues can be saved from excessive and unnecessary radiation doses.

Related: Bone Metastasis: A Concise Overview

A single proton beam produces a narrow Bragg peak dose distribution at depth, and multiple consecutive stepwise series of different energies of proton beams are needed to administer complete coverage of the target tumor volume. The accumulation of these beam energies produces a uniform radiation dose distribution covering the entire tumor volume (Figure 1). In spite of the theoretical beneficial effects of proton beam therapy, more clinical experience is needed for it to be validated. Even then, the significantly higher costs of proton therapy represent another barrier to its wider implementation. Proton beam radiosurgery is still, in large part, an evolving technology, not widely and uniformly available.

Role of Radiosurgery

Photon (X-ray)-based radiosurgery can be an alternative to craniotomy. Patients can return to their activities immediately after treatment. The ideal candidate for radiosurgery should have a small tumor (1-3 cm is best) with a well-defined margin. Retrospective studies reported no significant difference in therapy outcomes between the 2 therapies.^3,4 Additional benefits of radiosurgery include low morbidity and mortality. Furthermore, radiosurgery can be applied to tumors near critical structures, such as the thalamus, basal ganglia, and brainstem, that are otherwise surgically inaccessible.

Most brain metastases are well defined and spherical, so they are ideally treated using SRS (Figure 1). Additionally, the brain is encased in the bony skull, which prevents significant intrafraction motion and provides a reproducible fidulial for accurate setup. Radiosurgery can tailor the radiation dose in order to precisely concentrate radiation distribution to the tumor lesion with a rapid dose falloff beyond the margin of the tumor bed, so surrounding normal brain tissues are spared from high-dose radiation. In sharp contrast, WBRT indiscriminately irradiates the entire brain without sparing the adjacent normal brain tissue (Figure 2). However, because of its limited dose distribution, radiosurgery offers no protection elsewhere in the brain from future metastasis, which is a benefit of whole brain radiation.

Future Use of SBRT

Based on successful experience with intracranial lesions, stereotactic techniques have been expanded to additional anatomical body sites other than the brain. Stereotactic body radiation therapy (SBRT), also called stereotactic body ablative radiotherapy, is progressively gaining acceptance and is being applied to various extracranial tumors, especially lung cancers and hepatic malignancies. Dosimetric studies and early phase clinical trials have clearly established the feasibility, safety, and efficacy of SBRT for certain tumor sites, such as lung, liver, kidney, spine, and paraspinal tumors. Additionally, SBRT may reduce treatment time and therapy costs and thus provide increased convenience to patients.

Effectiveness of SRS

Stafinski and colleagues conducted a meta-analysis of randomized trials to study the effectiveness of SRS in improving the survival as well as the quality of life (QOL) and functional status following SRS of patients with brain metastasis.⁵ This study found that SRS plus WBRT increased OS for patients with single brain metastasis compared with WBRT alone. Although no significant difference in OS was found in patients with multiple brain metastases, the addition of SRS to WBRT improved the local control and functional independence of this group of patients.

Related: Palliative Radiotherapy for the Management of Metastatic Cancer

Kondziolka and colleagues reported a local failure rate at 1 year of merely 8% following SRS boost therapy after WBRT compared with 100% without SRS.⁶ There was also a remarkable difference in median time to local failure—36 months vs 6 months, respectively. A randomized study designed to assess the possible benefit of SRS for the treatment of brain metastasis found a survival gain for patients with a single brain metastasis with a median survival time of 6.5 months (SRS) vs 4.9 months (no SRS).⁷

There are sparse data and reporting related to QOL measurements after SRS for brain metastasis. Andrews and colleagues reported improved functional and independent abilities at 6 months after completion of SRS therapy.⁷ The criteria used in that study for performance assessments included the Karnofsky Performance Status (KPS) scale, the need for steroid use, and mental status. They found that KPS improvement was statistically significant, and patients were able to decrease the dosage of steroid medication at 6 months after therapy with SRS (Table 3). Despite these reports suggesting superior outcomes with SRS, more rigorous investigations that adequately control for other factors influencing QOL in patients with cancer are needed.

Two major limitations of SRS include large tumor size and multiple numbers of metastatic brain lesions. As the radiation dose to adjacent normal brain tissue quickly increases with larger tumor lesions (> 3-4 cm), the complication risks consequently rise proportionally, necessitating a decrease in the prescribed dose. Patients with poor performance status 
(< 70 KPS) and presence of active/progressive extracranial disease are also not ideal candidates for SRS.

Other unfavorable conditions for SRS include life expectancy of 
< 6 months, metastatic lesions in the posterior fossa, and severe acute CNS symptoms due to increased intracranial pressure, brain edema, or massive tumor effects. These factors do not necessarily contraindicate SRS but can increase the risks of such treatment. The authors recommend an experienced multispecialty approach to patients presenting with these findings.

Managing Brain Metastastis

To prevent symptoms related to brain edema (due to brain tumor itself and/or radiation-induced edema), steroid medication is generally administered to most patients, 1 to 3 days prior to initiation of radiation therapy. Corticosteroid use typically results in rapid improvement of existing CNS symptoms, such as headaches, and helps prevent the development of additional CNS symptoms due to radiation therapy-induced cerebral edema. A dexamethasone dose as low as 4 mg per day may be effective for prophylaxis if no symptoms or signs of increased intracranial pressure or altered consciousness exist. If the patient experiences symptomatic elevations in intracranial pressure, however, a 16-mg dose of dexamethasone per day orally, following a loading dose of 10-mg IV dexamethasone, should be considered. The latter scenario is not common.

Related: Pulmonary Vein Thrombosis Associated With Metastatic Carcinoma

The benefits of steroids, however, need to be carefully balanced against the possible adverse effects (AEs) associated with steroid use, including peripheral edema, gastrointestinal bleeding, risk of infections, hyperglycemia, insomnia, as well as mental status changes, such as anxiety, depression, and confusion. In long-term users, the additional AEs of oral candidiasis and osteoporosis should also be taken into account.

Craniotomy vs SRS

A retrospective study by Schöggl and colleagues compared single brain metastasis cases treated using either Gamma Knife or brain surgery followed by WBRT (30 Gy/10 fractions).³ Local control was significantly better after radiosurgery 
(95% vs 83%), and median survival was 12 months and 9 months after radiosurgery and brain surgery, respectively. There was no significant difference in OS.

Another comparative study of SR and SRS for solitary brain metastasis revealed no statistically significant difference in survival between the 
2 therapeutic modalities (SR or SRS); the 1-year survival rate was 62% (SR) and 56% (SRS).⁴ A significant prognostic factor for survival was a good performance status of the patients. There was, however, a significant difference in local tumor control: None of the patients in the SRS group experienced local recurrence in contrast to 19 (58%) patients in the SR group.

Whereas selection criteria and treatment choice depend to a large extent on tumor location, tumor size, and availability of SRS, most studies demonstrated that both surgery and SRS result in comparable OS rates for patients with a single brain metastasis.

Multiple Brain Metastases

Jawahar and colleagues studied the role of SRS for multiple brain metastases.⁸ In their retrospective review of 50 patients with ≥ 3 brain metastases, they found an overall response rate (RR) of 82% and a median survival of 12 months after SRS. As a result of similar studies and their own data, Hasegawa and colleagues recommended radiosurgery alone as initial therapy for patients with a limited number of brain metastases.⁹

SRS vs SRS Plus WBRT

Studies on the role of SRS plus WBRT are somewhat conflicting. A Radiation Therapy Oncology Group study revealed statistically significant improvement in median survival when SRS boost therapy was added to WBRT in patients with a single brain metastasis compared with SRS alone.⁵ According to another study, the addition of SRS to WBRT provided better intracranial and local control of metastatic tumors.¹⁰

A randomized controlled study by Aoyama and colleagues reported no survival improvement using SRS and WBRT in patients with 1 to 4 brain metastases compared with SRS alone.¹¹ In addition, a retrospective review found no difference in median survival outcomes between SRS alone and SRS plus WBRT (Table 4). In the absence of a clear survival benefit with the use of both modalities and in light of the added toxicity of WBRT, most clinicians have ceased offering both modalities upfront and instead reserve WBRT as a salvage option in cases of subsequent intracranial progression of disease.

SRS vs WBRT

In general, both SR (crainotomy) and SRS for the treatment of brain metastases seem to be effective therapeutic modalities. Comparisons of both treatments did not reveal significant differences and showed similar outcomes after treatment of smaller lesions. For example, Rades and colleagues reported that SRS alone is as effective as surgery and WBRT for limited metastatic lesions (< 2) in the brain.¹⁶ Either SRS or surgery can be used, depending on performance status and metastatic burden (size, location, number of lesions, etc).

There are some inconsistencies in the final results of various studies, such as survival, local tumor control, mortality rate, and pattern of failures. For large, symptomatic brain metastasis, initial surgical debulking remains the preferred approach as a way of achieving immediate decompression and relief of swelling/symptoms. Additionally, for patients who have > 10 brain lesions and/or a histology that corroborates diffuse subclinical involvement of the brain parenchyma (eg, small-cell lung cancer), WBRT is also typically preferred to upfront SRS. Alternatively, radiosurgery is the preferred method for fewer and smaller lesions as a way of minimizing the toxicity from whole brain irradiation. The optimal treatment of multiple small brain metastases remains controversial with some investigators recommending SRS for > 4 metastases only in the setting of controlled extracranial disease based on the more favorable expected survival of such patients.

Multidisciplinary Approach for Lung and Breast Cancers

Prognostic outcomes of patients with brain metastases can vary by primary cancer type. Therefore, clinicians should consider cancer-specific management and tailor their recommendation for specific types of radiation depending on the 
individual cancer diagnosis. Various investigators have attempted to develop disease-specific prognostic tools to aid clinicians in their decision making. For example, Sperduto and colleagues analyzed significant indexes and diagnosis-specific prognostic factors and published the 
diagnostic-specific graded prognostic assessment factors.¹⁷ They were able to identify several significant prognostic factors, specific to different primary cancer types.

Bimodality Therapies

For certain cancers such as lung and breast primary cancers, bimodality therapy using chemotherapy and radiation treatment should be considered based on promising responses reported in the literature.

Recent studies on the efficacy of chemotherapy for brain metastases from small-cell lung cancer (43%-82%) have also been reported.^18-20 Postmus and colleagues reported superior RR of 57% with combination chemotherapy and radiation vs a 22% RR for chemotherapy alone.²¹ They also found favorable long-term survival trends in patients treated with combined radiochemotherapy.

The efficacy of chemotherapy in non-small cell carcinoma of the lung has been reported in multiple phase 2 studies using various chemotherapeutic agents. The reported RR ranged from 35% to 50%.^22-24 Comparative studies of combined chemoradiotherapy demonstrated a 33% RR in contrast to a 27% RR for combined therapy or chemotherapy alone, respectively. However, no difference was noted in median survival rates.²⁵

Care must be taken when interpreting these studies due to heterogeneity of the patient population studied and a lack of data on potential synergistic toxicities between radiation to the CNS and systemic therapy. The authors generally avoid concurrent chemotherapy during CNS irradiation in patients who may have significant survival times > 1 year.

The prognosis of breast cancer patients with brain metastasis largely depends on the number and size of metastatic brain lesions, performance status, extracranial or systemic involvement, and systemic treatment following brain irradiation. The median survival of patients with brain metastasis and radiation therapy is generally about 18 months. The median survival for patients with breast cancer who develop brain metastasis was 3 years from diagnosis of the primary breast cancer.²⁶

Recent advances in systemic agents/options for patients with breast cancer can significantly affect the decision-making process in regard to the treatment of brain lesions in these patients. For example, a few retrospective studies have clearly demonstrated the beneficial effect of trastuzumab in patients with breast cancer with brain metastasis. The median OS in HER2-positive patients with brain metastasis was significantly extended to 41 months when treated with HER2-targeted trastuzumab vs only 
13 months for patients who received no treatment.^27,28 As a result of the expected prolonged survival, SRS for small and isolated brain lesions has recently become a much more attractive option as a way of mitigating the deleterious long-term effect of whole brain irradiation (memory decline, somnolence, etc).

Summary

Stereotactic radiosurgery is a newly developed radiation therapy technique of highly conformal and focused radiation. For the treatment of patients with favorable prognostic factors and limited brain metastases, especially single brain metastasis, crainiotomy and SRS seems similarly effective and appropriate choices of therapy. Some studies question the possible benefits of additional WBRT to local therapy, such as crainiotomy or radiosurgery.

Some authors recommend deferral of WBRT after local brain therapy and reserving it for salvage therapy in cases of recurrence or progression of brain disease because of possible long-term AEs of whole brain irradiation as well as deterioration of QOL in long-term survivors. Thus, the role of additional WBRT to other local therapy has not been fully settled; further randomized studies may be necessary. Due to the controversies and complexities surrounding the treatment choices for patients with brain disease, all treatment decisions should be individualized and should involve close multidisciplinary collaboration between neurosurgeons, medical oncologists, and radiation oncologists.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.