Long-term outcomes after treatment with brachytherapy and supplemental conformal radiation for prostate cancer patients having intermediate and high-risk features

Authors


Abstract

BACKGROUND.

This study summarizes long-term outcomes from treatment of prostate cancer with increased risk of extracapsular cancer extension (ECE) using brachytherapy-based treatment.

METHODS.

A total of 282 consecutive patients were treated from 1992–1996 by 1 author (M.D.). Two hundred forty-three patients had at least 1 higher risk feature for ECE including Gleason Score 7–10 (172), prostate-specific antigen (PSA) above 10 (166), and clinical stages T2c (109) and T3 (107). Using National Comprehensive Cancer Network (NCCN) guidelines, 119 patients had intermediate-risk disease and 124 had high-risk disease. Patients received pelvic 3-dimensional conformal external beam radiation followed by a palladium (Pd)-103 boost. Generous brachytherapy margins were utilized. Biochemical failure was defined using ASTRO Consensus Definition, nadir +2 and PSA >0.2 ng/mL at last follow-up. The nonfailing patient follow-up period was 1–14 years (median, 9.5 years). Biochemical data and original biopsy slides were independently re-reviewed at the University of Washington (by K.W. and L.T., respectively).

RESULTS.

Overall actuarial freedom from biochemical progression at 14 years was 81%, including 87% and 72% having intermediate and high-risk disease, respectively. Absolute risk of failure decreased progressively, falling to 1% beyond 6 years after treatment. All failing patients had prostate biopsies without evidence of local recurrence. The strongest predictor of failure was Gleason score (P = .03) followed by PSA (P = .041). Treatment morbidity was limited to temporary RTOG grade 1–2 urinary and gastrointestinal symptoms.

CONCLUSIONS.

High tumor control rates are possible with beam radiation followed by Pd-103 brachytherapy. Despite perceptions that brachytherapy is inappropriate for patients at higher risk for ECE, this series strengthens the rationale that brachytherapy-based treatment may be a desirable modality for such patients. Cancer 2007. © 2007 American Cancer Society.

Prostate brachytherapy was reintroduced in the late 1980s after the development of transrectal ultrasound and sophisticated treatment planning capabilities.1 Whereas it met with much skepticism initially, favorable longer-term outcomes are fueling its widespread adoption.2 Brachytherapy has enjoyed widespread acceptance for treatment of low-risk patients, ie, those with a prostate-specific antigen (PSA) <10 ng/mL and Gleason score 6, and low volume cancer in the biopsy core specimens.3, 4 However, there is continued controversy regarding its use for patients at higher risk of extracapsular cancer extension (ECE). It has been well established that patients with higher PSA and Gleason scores are at higher risk of ECE, with the likelihood of ECE being approximately 50% in patients with a PSA over 10 ng/mL or a Gleason score of 7 or higher.5 It has been assumed that external beam radiation (EBRT) alone should be the basis of treatment for such patients, the logic being that EBRT would provide better coverage of ECE.6 Some early reports appeared to support the concept of brachytherapy being ill-advised for these patients.7, 8

Whereas it may seem superficially logical to avoid brachytherapy for patients at higher risk of ECE, studies regarding the radial extent of ECE have cast doubt on such a policy. Most important, ECE is typically limited to 3–5 mm, and can be treated with peripherally loaded implants that provide adequate dose to the periprostatic tissues. Although some early reports showed poor results using brachytherapy in patients having higher risk features, there is a growing number of reports showing favorable results with brachytherapy-based treatment for patients at high likelihood of ECE.9–12

One criticism of most brachytherapy outcome reports has been the lack of long-term follow-up, with the possibility of prematurely concluding that cancer had been eradicated in high-risk patients. Reports to date have generally been limited to a median follow-up of 5 years. Accordingly, we updated our ongoing analysis of higher risk patients treated with brachytherapy-based therapy.

MATERIALS AND METHODS

Two hundred eighty-two consecutive patients were treated between 1992 through 1996 by 1 author (M.D.). Of the 282 patients, 243 had at least 1 higher risk feature for ECE including Gleason score of 7 or higher (172 patients), PSA above 10 ng/mL (166 patients) with 109 clinical stage T2c and 107 clinical stage T3 patients (remaining patients included 14 T2b, 10 T2a, and 3 T1c). Ninety-three patients had both a PSA above 10 and Gleason score of 7 or greater; 185 patients had all 3 high-risk factors (Gleason score, PSA, and clinical stage).

Patients were classified into prognostic risk groups as defined by the National Comprehensive Cancer Network guidelines (intermediate risk: T2B to T2C or Gleason 7, or PSA 10–20; high risk: T3A or Gleason 8–10, or PSA above 20). In all, 119 patients had intermediate-risk disease and 124 had high-risk disease. All patients who met 1 or more higher risk criteria were strongly encouraged to have Pd-103 plus supplemental 3-dimensional conformal external beam radiation (3D-CRT) vs full-course 3D-CRT or Pd-103 alone. Patient ages ranged from 43 to 88 years (median, 66 years).

The original biopsy slides for 164 of the 243 patients were retrieved and re-reviewed by a single pathologist (L.T.) to independently verify the patients' tumor grade, with 20% identified to be undergraded and 8% being overgraded. All biochemical data were also independently re-reviewed at the University of Washington (K.W.). A median of 25 PSAs were recorded per patient (mean, 24.5, range, 10–40), with 21 and 29 representing the 10th and 90th percentiles, respectively. Only 1 patient had a staging pelvic lymphadenectomy. Postimplant biopsies were only performed for patients having a rising PSA. Enzymatic prostatic acid phosphatase (PAP) was analyzed independent of risk stratification grouping, as this author (M.D.) has identified the importance of this marker previously.13 PAP was determined by the method of Roy et al.14 with values up to 2.5 U considered normal. Sixty-seven patients had abnormally elevated PAPs.

Patients received a median 41 Gy 3D-CRT to the pelvic field covering the prostate, seminal vesicles, and lymph nodes up to the common iliacs (dose range, 39–54 Gy), followed 2 to 4 weeks later by a Pd-103 boost, using transrectal ultrasound and fluoroscopic guidance. Only free seeds were utilized and all patients underwent postimplant computerized tomography (CT) imaging for dosimetric analysis and source counting on postoperative Day 1. Extraprostatic seed placement was routinely performed. The prescribed minimum Pd-103 dose to the prostate was 80–90 Gy (pre-NIST-99). A median of 104.3 mCi Pd-103 was implanted with a range of 48–144 mCi. The median source strength was 1.4 mCi (range, 1.0–1.6 mCi/source). Generous brachytherapy margins were utilized; the clinical target volume extended 0.5–1.0 cm anterolaterally to the TRUS prostate margin (no posterior margin was added beyond the TRUS delineated posterior border). Patients having 3 higher risk features (PSA, Gleason, clinical stage) were encouraged to receive hormonal agents and 103 patients received neoadjuvant or adjunctive hormones, median duration 4 months (maximum, 6 months). Patients were generally followed at 3, 6, and 12 months, and every 6–12 months thereafter, at which time data were obtained from personal visits along with in-house self-reporting forms including the International Prostate Symptom Score (IPSS)and Rectal Functioning Assessment Score (RAFS). Patients experiencing proctitis beyond 6 months underwent colonoscopy to rule out fistulas or ulceration.

Freedom from biochemical failure was defined using the ASTRO Consensus Definition (3 consecutive PSA rises), nadir +2 ng/mL, and having a serum PSA >0.2 ng/mL at last follow-up.15 Using the ASTRO Consensus Definition and nadir +2 ng/mL facilitates easy comparison with current and prior radiation studies. Using PSA >0.2 ng/mL for disease failure allows for reasonable comparison with radical prostatectomy series. Patients were censored at last follow-up if their serum PSA was still decreasing (3 patients). Patients whose serum PSA nadired at a value >0.2 ng/mL or who exceeded nadir +2 or 3 consecutive PSA rises were scored as failures at the time at which their PSA progressed. The follow-up period for nonfailing patients ranged from 1–14 years (median, 9.5 years) and 13 patients were at risk at 14 years. Freedom-from-failure curves were calculated by the method of Kaplan-Meier. Differences between groups were determined by log-rank or Student t-test.

RESULTS

Forty-one patients developed biochemical failure. The overall actuarial freedom from biochemical progression at 14 years is 81%, with 182 patients followed beyond 5 years and 61 patients followed beyond 10 years (Fig. 1). The overall freedom-from-failure for the 119 patients with intermediate-risk disease was 87%, whereas the overall freedom-from-failure for the 124 patients having high-risk features was 72% at 14 years. (Fig. 2). The absolute risk of failure decreased progressively with time, falling to 1% by 6 years after treatment (Fig. 3). Of the 41 patients with biochemical failure, 27 (66%) failed within the first 3 years after treatment. Follow-up prostate biopsies were performed on all failing patients. There were no pathologically documented local failures nor was there clinical evidence of local failure.

Figure 1.

Combined freedom from biochemical progression (ASTRO Consensus Definition, prostate-specific antigen [PSA] >0.2 ng/mL, nadir +2) for all 243 patients treated with Pd-103 plus median 41 Gy beam radiation. (No significant variance was identified when plotting graphs using all 3 definitions.)

Figure 2.

Likelihood of subsequent biochemical progression vs years after treatment for patients having National Comprehensive Cancer Network (NCCN) intermediate risk vs NCCN high risk.

Figure 3.

Likelihood of subsequent biochemical failure vs years after treatment. The numerators are the numbers of patients who fail subsequently and denominators are the number of patients still at risk at each timepoint.

Treatment morbidity was limited to temporary 3–6-month Radiation Therapy Oncology Group (RTOG) grade 1–2 urinary and rectal symptoms. One patient who had both a TUIP and TURP posttreatment developed low-volume stress incontinence. No patient developed rectal fistula or ulceration.

Of the 3 risk features (PSA, Gleason, clinical stage) only pretreatment PSA and Gleason score were each associated with a higher failure rate. There was no statistical significance between clinical stage (P = .4). In Cox proportional hazard multivariate analysis, considering each factor as a continuous variable and comparing pretreatment parameters by Student t-test in patients with or without failure, the strongest predictor of failure was Gleason score (P = .03) (Fig. 4) and PSA (P = .041) (Fig. 5). Neoadjuvant and adjunctive hormonal therapy did not affect the failure rates (P ≤ .3, Fig. 6). Consistent with this author's (M.D.) previous experience, PAP was identified as a strong predictor of biochemical failure (Fig. 7).

Figure 4.

Freedom from biochemical progression (ASTRO Consensus Definition, prostate-specific antigen [PSA] >0.2 ng/mL, nadir +2) stratified per Gleason score.

Figure 5.

Freedom from biochemical progression (ASTRO Consensus Definition, prostate-specific antigen [PSA] >0.2 ng/mL, nadir +2) stratified per PSA elevation.

Figure 6.

Freedom from biochemical progression (ASTRO Consensus Definition, prostate-specific antigen [PSA] >0.2 ng/mL, nadir +2) with or without adjuvant hormonal therapy.

Figure 7.

Freedom from biochemical progression (ASTRO Consensus Definition, prostate-specific antigen [PSA] >0.2 ng/mL, nadir +2) stratified per prostatic acid phosphatase (PAP).

DISCUSSION

The reintroduction of brachytherapy in the late 1980s was met with tremendous skepticism and misconceptions regarding which patients, if any, are best served with this modality. Skepticism has given way to widespread acceptance of brachytherapy alone for patients with low PSA and Gleason score.2 However, there is still a widespread perception that brachytherapy is not appropriate for patients at higher risk of ECE. A recent European consensus statement, for instance, recommended that brachytherapy be limited to patients with low PSA and Gleason scores.3 On the contrary, this and other series suggest that brachytherapy-based treatment may, in fact, be a desirable treatment modality for such patients when performed in combination with EBRT. Brachytherapy, if designed to deliver generous cancericidal margins around the prostate, given along with supplemental EBRT, appears capable of eradicating both larger intraprostatic tumor masses along with ECE.18–21 Although a median of 4 months of hormones conferred no survival advantage (P = .9), those patients who did receive hormones had the most adverse features. Additionally, 2 recent studies (Trans-Tasman randomized control trial and Harvard study) both demonstrated a survival advantage when utilizing a longer duration of androgen suppression (median 6 months) plus radiation therapy.16, 17

Because there is a large degree of overlap in PSA, Gleason score, and clinical stage between patients with or without biochemical failure, even patients with markedly elevated parameters appear to have a reasonable chance for cure. Accordingly, our policy is to treat patients for cure, even with markedly elevated parameters, as long as a bone scan and pelvic CT are negative for metastatic disease.

Initial studies showing favorable tumor control rates with brachytherapy-based regimens were met with considerable skepticism due to short follow-up times. However, the growing number of studies with long-term follow-up almost uniformly show results that compare favorably with those with surgery or beam radiation alone. It is encouraging that the failure rate decreased to near zero with follow-up beyond 6 years, with no pathologic local failures documented. Whereas longer follow-up will always be sought, evidence from this patient group at higher risk of ECE and others suggest that the relatively high tumor control rates with brachytherapy-based therapy are quite durable.9, 10, 20 This growing body of favorable reports strengthens the rationale that brachytherapy-based treatment may be a desirable treatment modality for such patients.

Acknowledgements

The authors thank Araceli Mares for assistance with data management.

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