Patient Selection for Prostate Brachytherapy: More Myth Than Fact

ABSTRACT: ABSTRACT: Prostate brachytherapy efficacy and morbidity are primarily dependenton implant quality and patient management. While most allegedcontraindications to brachytherapy have been propagated based onphysician bias rather than clinical data, a number of evidence-basedfactors contributing to radiation-related morbidity have accumulated.Refinements in patient selection may result in further improvements inbiochemical and quality-of-life outcomes. Herein, we have summarizedevidence-based vs unsubstantiated patient selection factors that affectoutcome.

Following permanent prostate brachytherapy with or without supplemental external-beam radiation therapy, encouraging longterm biochemical outcomes-including a morbidity profile that compares favorably with competing local modalities- have been reported for patients with low-, intermediate-, and high-risk features.[1,2] The efficacy and morbidity of prostate brachytherapy are dependent on implant quality. Substantial differences have been reported in the incidence and clinical course of brachytherapyrelated morbidities, with many of the conflicts likely related to patient selection, technical differences in treatment planning, intraoperative technique, or variation in patient management philosophies.[3-6]

With the assimilation of brachytherapy into the conventional urooncology armamentarium, a rapidly expanding body of literature regarding patient selection and treatment approach has been reported.[1,2,7-15] Although not all patients are acceptable candidates for brachytherapy, a reliable set of pretreatment criteria for predicting implant-related morbidity has not been formulated. While most alleged contraindications to brachytherapy have been propagated with little supporting data, an increasing number of evidence-based factors contributing to radiation-related morbidity have accumulated (Table 1). Accordingly, we have summarized evidence-based vs unsubstantiated patient selection factors that affect outcome in this setting.

Prostate Size

Despite the fact that no clear relationship exists between prostate size and increased urinary morbidity,[6,16-18] large prostate size remains a relative contraindication to brachytherapy due to technical concerns and the perception that patients with large prostates are at higher risk for acute and prolonged urinary morbidity.[13,14] Patients with a prostate volume > 50 cm³ are often counseled not to proceed with brachytherapy or are first given neoadjuvant hormonal therapy for cytoreduction.

Contrary to popular opinion, patients with large prostate glands can be implanted with acceptable morbidity.[6,16-18] In a recent study using the patient-administered Expanded Prostate Cancer Index Composite (EPIC), a validated instrument designed to evaluate patient function after prostate cancer treatment, longterm urinary function did not correlate with prostate size.[17] On the other extreme, favorable dosimetry with minimal urinary morbidity has been reported for patients with prostate glands < 20 cm³, leading investigators to conclude that in experienced hands,postimplant dosimetric quality is independent of prostate size.[6,17,19]

Transition Zone

In contrast to overall prostate size, transition zone volume has consistently correlated with brachytherapy-related urinary morbidity (Figure 1).[20-22] Thomas and colleagues reported that transition zone volume was the most important predictor of acute urinary retention following magnetic resonance-guided prostate brachytherapy.[20] In addition, the transition zone index (TZI = transition zone volume/ prostate gland volume) was reported to correlate with time to normalization of International Prostate Symptom Score (IPSS), maximum increase in IPSS, and the need for postimplant surgical intervention.[21] In patients receiving neoadjuvant hormonal therapy for cytoreduction, IPSS normalization, prolonged catheter dependency, and the need for a postbrachytherapy transurethral resection (TURP) were best predicted by the percent decrease in transition zone volume.[22] Indeed, the transition zone and its variants may have greater predictive power for prolonged urinary dysfunction and the need for subsequent intervention than any other single parameter.

International Prostate Symptom Score

Currently, no reliable preimplant criteria can be used to predict who will develop prolonged urinary retention. The role of the IPSS in predicting urinary morbidity (including urinary retention) has been studied extensively, with conflicting conclusions.[6,9,13,14,17,23-27] Although almost all brachytherapy patients develop urinary irritative/obstructive symptomatology, with 2% to 34% developing acute urinary retention,[5,6,20,23-25] only approximately 2% to 5% require a urinary catheter for more than 1 week.[6,28] Preimplant IPSS does correlate with the duration of postimplant obstructive symptomatology[6,23,26] but does not predict for long-term urinary quality of life (QOL).[17]

In contrast to three recently published patient selection guidelines,[9,13,14] prospective studies have demonstrated little correlation between preimplant IPSS, urodynamic studies, postvoid residual urine volume, maximum flow rate, or preimplant cystourethroscopy and acute or long-term urinary function.[24,27] However, the prophylactic and prolonged use of alpha-blockers results in a return of IPSS to baseline significantly faster than is seen in patients not receiving alpha-blockers or receiving them after substantial exacerbation of urinary symptoms.[6,28] A prospective randomized trial comparing palladium (Pd)-103 with iodine (I)-125 for patients with low-risk prostate cancer (prostate-specific antigen [PSA] ≤ 10 ng/mL, Gleason score ≤ 6, and clinical stage T1c-T2a) has shown significantly faster resolution of IPSS in the Pd-103 arm.[29]

Pubic Arch Interference

Pubic arch interference-the obstruction of anterior needle placement insertion by a narrow pubic arch-has long been considered a relative contraindication to brachytherapy. Although recommendations have included transrectal ultrasound to evaluate the pubic arch in all patients, neoadjuvant hormonal therapy for cytoreduction, and/or a nonbrachytherapy approach for patients with large prostate glands,[9,14] prostate volume is a poor predictor of pubic arch interference.[30] By using the extended lithotomy position or veering needles around the arch, almost all patients can be successfully implanted with favorable postimplant dosimetry regardless of the degree of pubic arch interference.[30,31] In fact, data regarding the incidence of significant pubic arch interference is limited, and its clinical significance in experienced hands is highl questionable.

Transurethral Resection of the Prostate

In the early-to-mid 1990s, urinary incontinence developed in approximately 50% of patients with a history of a transurethral resection of the prostate gland (TURP) prior to implantation. In more contemporary series, however, the risk of incontinence in patients with preimplant TURP has been reported to be 6% or less, because of the adoption of peripheral source loading and limitation of the radiation dose to the TURP defect to approximately 110% of the prescription dose.[32,33] Using the EPIC instrument, patients with a preimplant TURP have been found to have urinary QOL approaching that of non- TURP brachytherapy patients.[34] A TURP is of greater concern in the postimplant than in the preimplant setting.

After brachytherapy, approximately 2% of patients develop prolonged urinary retention, but the vast majority are eventually able to urinate without surgical intervention.[34] If a postimplant TURP or transurethral incision of the prostate (TUIP) is necessary, it should be delayed for as long as possible. Significant urinary morbidity has been demonstrated in approximately 50% of patients undergoing a postimplant TURP, and patients with a pre- or postimplant TURP have an especially high risk of urinary incontinence.[34]

To minimize postbrachytherapy TURP-related incontinence, Stone and Stock have recommended preservation of the bladder neck at the 5 and 7 o'clock positions, with minimal cautery to maintain sufficient prostatic urethral blood supply.[35] Although it has been suggested that a safe minimum time to perform a TURP/TUIP is 2 months for Pd-103 and 6 months for I-125,[35] we discourage surgical intervention for at least the first 12 months following brachytherapy. Because most patients with brachytherapy-related urinary obstruction will eventually spontaneously void, a TURP/TUIP should be approached with extreme caution and only after substantial time has transpired.[24,35]

Median Lobe Hyperplasia

Median lobe hyperplasia (the protrusion of hypertrophied prostate tissue into the bladder) has been reported to be a relative contraindication to brachytherapy because of concerns for an increased risk of postimplant urinary morbidity and/or technical difficulties encountered while implanting intravesical tissue.[14]

In a small contemporary series, Wallner and colleagues reported complete dosimetric coverage of the median lobe in all patients.[36] However, 25% of patients developed prolonged postimplant urinary retention, and additional patients developed prolonged IPSS elevation. Although median lobe hypertrophy should not be considered an absolute contraindication to brachytherapy, patients with this condition should be approached with caution. It is conceivable that preimplant resection of the intravesical component could reduce the incidence of brachytherapy-related morbidity.

Prostatitis

Prostatitis has been regarded as a relative contraindication to brachytherapy despite the lack of supporting documentation. In a recent series, however, investigators found no relationship between the presence or severity of prostatitis and the incidence of urinary retention or prolonged IPSS elevation following implantation.[37]

Age

Patient age may be a stronger predictor of prostate cancer curability than are differences in preimplant PSA.[38] Older patients have been reported to be at increased risk for extracapsular extension, higher Gleason scores, and a greater propensity for distant metastases.[38,39] Although clinicians have been reluctant to recommend brachytherapy for younger patients, outstanding biochemical outcomes (with a median PSA < 0.1 ng/mL) have been reported for hormone-naive men ≤ 62 years of age undergoing brachytherapy.[40,41] On the other extreme, older patients may tolerate brachytherapy as well as younger men.[6,17,42] Patient age alone should not influence treatment decisions.

Obesity

Obesity presents substantial procedural difficulties for radical prostatectomy and external-beam radiation therapy, but only relatively minor problems for brachytherapy, and as such, is not a contraindication.[43] Favorable dosimetric, biochemical, and QOL outcomes have been demonstrated for patients with grade II (body mass index [BMI] = 30-34.9 kg/m²) and III (BMI ≥ 35.0 kg/m²) obesity who undergo brachytherapy.[43]

Tobacco

A correlation between cigarette smoking and aggressive prostate cancer and/or prostate cancer-related deaths has been reported. Consistent with these findings, tobacco consumption correlated with a trend for poorer biochemical progression-free survival following permanent prostate brachytherapy.[44] In addition, tobacco may exacerbate brachytherapyinduced morbidity.

In one recent study, although the absolute differences were small, tobacco was the strongest predictor for adverse late urinary QOL including adverse changes in the EPIC-determined urinary-specific subscales of function, incontinence, irritation/obstruction, bother, and IPSS.[17] Evaluation of late rectal function using the Rectal Function Assessment Score (R-FAS) demonstrated that tobacco was a statistically significant predictor for diminished late rectal function.[42] Accordingly, tobacco consumption may be a weak contraindication to brachytherapy, but its role in treatment selection for radical prostatectomy or external-beam radiation therapy has not been clarified.

Diabetes Mellitus

Although diabetes mellitus may not adversely affect late urinary or rectal function following brachytherapy,[17,42] it is a significant risk factor for brachytherapy-related erectile dysfunction, with a 100% incidence as measured by the International Index of Erectile Function (IIEF).[3]

Inflammatory Bowel Disease

Some have considered inflammatory bowel disease, ulcerative colitis, and regional enteritis (Crohn's disease) to be relative contraindications to radiation therapy. However, Grann and Wallner reported no increased risk of gastrointestinal morbidity in such patients undergoing I-125 brachytherapy.[45]

Adverse Pathologic Features

High Gleason score, perineural invasion, and extensive tumor in the biopsy specimen have correlated with a higher likelihood of extraprostatic cancer extension, lending to the perception that patients with high-risk features may not be adequately treated with brachytherapy.[8,9,12] In striking contrast to this hypothesis, multiple brachytherapy series have demonstrated favorable biochemical outcomes for hormone-naive patients at high risk of extraprostatic extension.[46-53]

Although some patients with adverse pathologic features have subclinical distant metastatic disease at diagnosis, a high 5-year cause-specific survival has been reported in hormone-naive patients using either dose-escalated high-dose-rate brachytherapy or external-beam radiation therapy.[53,54] These findings are in sharp contrast to the assumption that most patients with adverse pathologic features have subclinical distant metastases at diagnosis. Instead, an aggressive locoregional approach that includes generous periprostatic brachytherapy treatment margins and/or the addition of supplemental external-beam therapy can result in a high likelihood of cancer eradication (Figure 2).[55] Consistent with this finding, an evaluation of Radiation Therapy Oncology Group trials revealed an improved 5-year overall survival for patients with higher Gleason scores who received higher external-beam doses.[54]

Because pathologic evaluation of radical prostatectomy specimens has demonstrated that almost all cases of extraprostatic extension are limited to within 5 mm of the prostatic capsule, high-quality brachytherapy with or without supplemental external-beam radiotherapy should sterilize extraprostatic extension.[56] The relative resiliency of brachytherapy to adverse pathologic features, including percentpositive biopsies, is likely a result of intraprostatic dose escalation with therapeutic radiation dose delivery to the periprosatic region.[47,48]

Prostatic Acid Phosphatase

Pretreatment enzymatic prostatic acid phosphatase (PAP) is predictive of biochemical outcome and/or disease- specific survival following potentially curative local treatment modalities.[52,57-59] and may obviate the need for radiographic staging in almost all newly diagnosed untreated prostate cancer patients.[60] In contemporary radical prostatectomy series, enzymatic PAP did not predict organ-confined disease or lymph node status, but was an independent predictor of biochemical recurrence.[57,58]

Similarly, PAP was the single strongest predictor of freedom from biochemical progression for intermediate- and high-risk brachytherapy patients.[52] Following Pd-103 brachytherapy, approximately 40% of patients remained free of biochemical progression 10 years after brachytherapy despite markedly elevated pretreatment PAP determinations (> 5 ng/mL).[52] Although a substantial minority of brachytherapy patients with an elevated pretreatment enzymatic PAP determination remain curable, these patients should benefit from effective adjuvant systemic therapy, possibly including hormonal manipulation.

Isotope

To date, no definitive data support the potential curative superiority of one isotope over another for any clinical stage, Gleason score, or pretreatment PSA.[11,29,61] However, a prospective randomized trial has suggested that Pd-103 may be more efficacious in terms of biochemical outcome for patients with suboptimal day 0 dosimetry.[61] In addition, the same prospective randomized trial reported faster resolution of IPSS and bowel dysfunction in the Pd-103 arm.[29]

Supplemental Therapies

An important part of brachytherapy patient selection concerns the use of supplemental therapies. Both external-beam radiation therapy and adjuvant hormonal manipulation have been widely advocated as supplements to brachytherapy in patients with adverse pathologic and/or biochemical features. Arguments supporting their use have been largely based on theory or on suboptimal results with monotherapeutic brachytherapy in isolated series.

External-Beam Radiation Therapy
The rationale for supplemental external- beam radiotherapy combined with brachytherapy is to enhance the coverage of periprostatic tissue, escalate the dose to the intraprostatic tumor, and/or supplement inadequate radiation dose coverage. The American Brachytherapy Society has recommended monotherapy for patients with clinical stage T1-2a disease, PSA ≤ 10 ng/mL, and Gleason score ≤ 6, with the addition of supplemental external- beam therapy for all other patients.[7] However, the utility of supplemental external-beam therapy has been questioned by investigators reporting favorable biochemical outcomes with monotherapeutic brachytherapy in patients with higher PSA and/or Gleason scores.[49,62] It is likely that high-quality implantation with generous periprostatic margins may obviate the need for combined-modality therapy in low-, intermediate-, and selected high-risk patients.[49,55]

In addition to growing doubts regarding the use of supplemental external-beam therapy with high-quality brachytherapy, supplemental radiotherapy exacerbates brachytherapyrelated morbidity. Supplemental radiotherapy combined with a brachytherapy boost has resulted in an increased trend for late hematuria,[63] a deleterious effect on late urinary function,[17] compromised late rectal function,[42] and a greater risk of erectile dysfunction.[3] An ongoing prospective randomized trial being conducted at the University of Washington, the Veterans Administration Puget Sound Health Care System, and the Schiffler Cancer Center is comparing different doses of supplemental radiotherapy for patients with higher-risk features, and will hopefully further define the role of supplemental radiotherapy.[64]

Hormonal Therapy
Despite recent reports detailing favorable biochemical outcomes for hormone-nave brachytherapy patients with higher-risk features,[49-52,62] intermediate- and high-risk prostate brachytherapy patients often receive hormonal manipulation as an extrapolation from the literature on conventional radiotherapy doses (65-70 Gy). The favorable interaction between conventional doses of radiotherapy and hormonal therapy likely results from the inability of conventional radiotherapy doses to sterilize large bulky prostate cancers and, as such, may not be applicable to brachytherapy.

In a large retrospective matchedpair analysis, no benefit for hormonal manipulation with brachytherapy was discerned for any risk group, Gleason score, pretreatment PSA, or clinical stage.[65] In addition, Lee and colleagues reported that hormonal manipulation did not alter biochemical outcome for high-risk patients with "high-dose" postimplant day 30 dosimetry.[62] Although it is possible that subgroups of high-risk brachytherapy patients may benefit from hormonal therapy, that patient population has not been definitively identified.

In addition to a lack of evidence that hormonal therapy increases the efficacy of high-quality brachytherapy, hormonal therapy has been implicated in brachytherapy-related morbidity. Although conflicting results have been reported regarding a potential relationship between acute urinary retention and neoadjuvant (≤ 6 month duration) hormonal therapy,[6,22,23,28] the largest of these studies reported that hormonal manipulation did not affect prolonged catheter dependency (73 days), IPSS normalization, or the need for postbrachytherapy surgical intervention.[22] In contrast, hormonal manipulation of > 6 months' duration resulted in deleterious changes in the EPIC subscores of function and irritation/ obstruction, with a trend for poorer bother and postimplant IPSS scores.[17] Although hormonal therapy has been reported to increase rectal bleeding after definitive doses of external-beam radiation therapy, a recent study using the patient-administered R-FAS instrument failed to discern such a relationship.[66] In terms of erectile function, conflicting results have been reported regarding the potential deleterious effect of neoadjuvant hormonal therapy.[3]

Conclusions

Most brachytherapy studies have demonstrated favorable and durable biochemical outcomes with acceptable morbidity. While there is no shortage of opinions regarding symptoms or circumstances that render the use of brachytherapy inadvisable, most are baseless: Reports to date have failed to establish any firm contraindication. Even in situations where patients present with alleged contraindications, brachytherapy may still be the best choice compared to the alternatives. Continued efforts to refine patient selection, brachytherapy quality, and postimplant management should further decrease brachytherapy- related morbidity.

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