Treatment Options After Failure of Radiation Therapy A Review Daniel B. Rukstalis, MD

MANAGEMENT OF RADIATION FAILURE IN PROSTATE CANCER Treatment Options After Failure of Radiation Therapy A Review Daniel B. Rukstalis, MD Division of Urology, MCP Hahnemann University, Philadelphia, PA Radioresistant or recurrent prostate cancer represents a serious health risk for approximately 20% 30% of patients treated with primary radiation therapy for clinically localized prostate cancer. The majority of patients exhibit large volume and poorly differentiated disease at the time of diagnosis, which limits the ability of salvage therapy to eradicate the cancer. Early detection with serum PSA monitoring and prostate needle biopsy following primary radiation therapy may identify residual adenocarcinoma at an earlier stage and increase the likelihood of successful salvage therapy. Radical prostatectomy, prostate cryoablation, and brachytherapy comprise the options for salvage treatment available for radiorecurrent prostate cancer. The goal of disease eradication must be balanced against the potential for serious treatment-related side effects. As a result, many patients receive noncurative therapy with androgen ablation despite the real risk of disease progression and mortality. [Rev Urol. 2002;4(suppl 2):S12 S17] 2002 MedReviews, LLC Key words: Radiorecurrent prostate cancer Early detection Salvage therapy Toxicity Despite the absence of a clearly articulated national policy for screening for prostate cancer, the widespread adoption of early detection approaches in men has resulted in the diagnosis of approximately 200,000 new cases each year. Additionally, the application of serum prostate-specific antigen (PSA) and digital rectal examination (DRE) has increased the likelihood that these cancers will be clinically nonpalpable, small in volume, and pathologically confined to the prostate. Therefore the majority of these individuals will appear initially to have localized disease and, following a complex decision process, will undergo an attempt at curative therapy. It can be argued that these patients then diverge into two distinct populations. The larger population will be cured of the prostate cancer by their chosen primary treatment and, with the possible exception of S12 VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY

Treatment Options After Radiation Failure therapy for treatment-related side effects, require only routine surveillance. The second group will experience persistence or recurrence of their disease and face the need for additional therapy and possible disease-related mortality. The stratification of an individual patient into one or the other of these two groups is difficult for any local therapy but particularly challenging for patients treated with radiation therapy. Recent technological advances have increased the attractiveness of both external beam radiation therapy and brachytherapy as primary therapy for localized prostate cancer to such an extent that approximately 50,000 patients are treated with these modalities each year. 1 Although these treatments are designed to ablate all glandular elements of the prostate, the obliterative process can take many months and may ultimately be incomplete. Therefore the definitive assignment of patients to one of the two groups following treatment is often difficult, even when based on DRE, serum PSA levels, and prostate needle biopsy. The remainder of this review will examine the arguments for careful screening of patients treated with radiation therapy for localized prostate cancer, recommendations for follow-up testing, and salvage therapy options once persistent disease has been identified. Detection of Persistent Prostate Cancer Following Radiation Therapy The variable and often protracted natural history of untreated prostate cancer has complicated the development of a cogent policy for screening for early-stage cancer. In fact, patients with well-differentiated or moderately well-differentiated prostate cancer exhibit an 87% 10-year disease-specific survival rate when managed with noncurative therapy alone. 2 It is therefore difficult to determine the value of early detection efforts and treatment for these patients. This expectation of prolonged survival for a man with untreated prostate cancer Recurrent prostate adenocarcinoma following radiation therapy poses a serious health risk to men. Table 1 PSA-Progression-Free Survival After Radiation Author N 5-year 10-year Zelefsky et al 24 1100 85% (low risk) 58% (moderate) 38% (high risk) Ragde et al 7 219 66% Shipley et al 9 1765 65.8% Zietman et al 10 314 63% may bias physicians toward a less intensive diagnostic approach to all forms of clinically localized prostate cancer. However, persistent prostate cancer following radiation therapy represents a more aggressive disease state that results in cancer-related death in at least 27% of patients within 5 years of exhibiting a rising PSA. 3 Furthermore, recurrent neoplasms demonstrate a 24% increase in Gleason 8 10 cancers and a 31% increase in aneuploid tumors when compared to pretreatment characteristics. 4 Finally, these cancers are often large in volume and are associated with extracapsular extension and positive margins in 40% 60% and lymph node metastases in 14% 34% cases. 5 Clearly, recurrent prostate adenocarcinoma following radiation therapy poses a serious health risk to men. Conceptually, the limited population of men at risk is readily identifiable, and hence an active early detection approach could be expected to reduce the stage of presentation and reduce mortality. Both benign and malignant prostatic glandular epithelia are injured by radiation therapy, which ultimately results in clearance of damaged cells through the process of programmed cell death. This process may take many months following the completion of therapy, and so diagnostic tests, including serum PSA and prostate needle biopsy, must be interpreted with caution. In particular, serum PSA levels decline slowly over 6 18 months after radiation, with a nadir value often reached as late as 33 months. 6 PSA levels can actually rise following brachytherapy and may fluctuate during surveillance due to benign prostatic disease. 7,8 The American Society for Therapeutic Radiology and Oncology consensus panel attempted to deal with these confounding findings by defining biochemical failure after radiation therapy as three successive increases in PSA after reaching a PSA nadir. 9 Although this definition is now the VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY S13

Treatment Options After Radiation Failure continued standard in the radiation therapy literature, it may underestimate the ultimate biochemical failure rates and delay the diagnosis of a persistent cancer. A potentially more clinically useful parameter would be a PSA nadir below 0.5 ng/ml. Approximately 90% of patients who achieve this PSA nadir within 2 years remain free of recurrent disease. 10 Additionally, any rise in PSA levels following the nadir is associated with a high risk of recurrent disease. It is important to note that the rate of disease progression following salvage radical prostatectomy is lowest when the disease is treated at a serum PSA below 10 ng/ml. In one salvage prostatectomy series, cancer-specific 5-year survival rate was 100% for patients with PSA below 4.0 ng/ml. 11 Therefore earlier identification of radioresistant prostate cancer may Author N Follow-Up % Residual Cancer Crook et al 6 118 4 y 38.0% Crook et al 13 226 33 mo 30.5% Siders et al 4 125 71.2% Stone et al 14 268 24 mo 11.0% result in more efficacious salvage therapy. Information regarding PSAprogression-free survival following radiation therapy is provided in Table 1. Once a meaningful elevation in the serum PSA level has been identified, a transrectal ultrasound and prostate needle biopsy are warranted. Again, the biopsy findings must be interpreted with an understanding of the histologic effects of radiation on prostate tissue. Severe radiation effects with both nuclear and cytoplasmic alterations are seen in many prostatic biopsies and may confound the diagnosis of residual cancer. 12 It is possible that this explains the finding that 67% of patients with adenocarcinoma on a biopsy at 12 months following radiation will convert to negative histology by 16 29 months. 13 Given the delayed clearance of neoplastic cells after a course of external beam radiation or brachytherapy, it appears wise to perform any initial prostate biopsy at 12 18 months posttreatment. This could be coincident with a PSA nadir above 0.5 ng/ml or any rise in the serum PSA level. The incidence of positive biopsy results after primary radiation Both benign and malignant prostatic glandular epithelia are injured by radiation therapy. Table 2 Results of Prostate Biopsy After Radiation therapy varies widely in the literature but appears to be higher for external beam radiation than for brachytherapy. 14 A selective summary of prostate biopsy results after radiation is presented in Table 2. Salvage Therapy Options Salvage Radical Prostatectomy Salvage radical prostatectomy is the most commonly performed curative treatment for clinically localized prostate cancer after radiation therapy. This procedure is capable of eradicating the local lesion and providing long-term disease-specific survival. Several clinical series have reported actuarial cancer-specific survival rates of 64% 88% at 5 years with PSA-progression-free survival rate of 83%. 5,15 Despite the potential for successful extirpation of the cancer, the surgical procedure is complicated by the tissue effects of radiation and is associated with significant side effects. Radiation results in vascular occlusion with resulting tissue hypoxia, while alterations in basement membrane proteins lead to increased fibrosis. Hence anatomical planes between pelvic organs are often obliterated, with a poorly vascularized bladder and urethra available for surgical reconstruction. As a result, surgical extirpation is associated with a variety of treatment-related toxicities, such as universal erectile dysfunction, which can diminish enthusiasm for this treatment modality. Several of the more common treatment-related side effects of salvage radical prostatectomy are listed in Table 3. Additionally, the lack of clarity as to the exact definition of a recurrent prostate cancer and the most appropriate early-detection surveillance protocol following radiation can delay the diagnosis and treatment of prostate cancer. This is demonstrated by the fact that only 30% 62% of prostate specimens demonstrate organ-confined disease, whereas 51% exhibit cancer volumes above 5 cc. 11 It is significant that the majority of recurrent cancers in these series were detected by digital rectal examination or serum PSA levels above 10 ng/ml. Alternatively, one recent series S14 VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY

Treatment Options After Radiation Failure Table 3 Salvage Therapy Related Adverse Events Author N Rectal Injury Incontinence Stricture/Slough Salvage Prostatectomy Rogers et al 15 44 15% 58% 25% Lerner et al 5 132 6% 40% Vaidya et al 16 6 0% 16% 0% Salvage Cryoablation Liquid nitrogen Bales et al 17 23 0% 95% 13.6% Argon gas Chin et al 19 125 3% 20% 0% de la Taille et al 18 43 0% 9% 0% Salvage Brachytherapy Beyer 21 17 0% 24% Grado et al 20 49 4% 6% described the results in patients with radioresistent cancer identified upon biochemical failure. A total of 5 of 6 prostate specimens exhibited negative surgical margins. 16 Because a rise in serum PSA after radiation therapy can predate clinical failure by several years, and approximately 11% 60% of patients will manifest histologically apparent prostate cancer on prostate biopsy at 12 24 months after radiation therapy, it appears possible to identify candidates for salvage therapy at an earlier time point. It is reasonable to hypothesize that the benefit of salvage radical prostatectomy would be increased when offered to patients with putatively earlier-stage recurrent disease. Salvage Prostate Cryoablation The expectation of pelvic vascular injury and radiation-induced fibrosis has stimulated interest in salvage treatments that may ablate the prostate in situ. Percutaneous prostatic cryoablation represents such an approach. An early experience reported by Bales and coworkers in 1995 in 23 patients treated with cryoablation demonstrated an 86% negative biopsy rate at 3 months following the procedure but a 100% rate of adverse events. 17 Subsequently, several other groups have detailed their clinical experience with salvage cryoablation, demonstrating reasonable rates of disease control with improved toxicity. The incidence of negative postprocedure prostate biopsy ranges from 63% to 97%, and 60% to 96% achieve an undetectable PSA nadir. 18,19 Most recently, the application of an argon gas based cryoablation unit coupled with temperature monitoring of the freezing process has reduced the rate of urinary incontinence and rectal injury to 9% and 0%, respectively. 17 One common adverse event, sloughing of necrotic urethral tissue with secondary urinary obstruction, has also been reduced in incidence from 10% 15% to as low as 0% with alterations in technique and application of a urethral warming catheter. Therefore it appears that salvage cryoablation of the prostate is a viable and potentially attractive treatment for radioresistant prostate cancer. Salvage Brachytherapy Clinical experience with radiation therapy for localized prostate cancer has suggested that cancer eradication is improved at higher doses of radiation. Therefore proponents of external beam radiation therapy as primary treatment are now advocating doses greater than 80 Gy. Historically, patients have received from 60 to 70 Gy, which may be an inadequate dose. This has led to the application B of transperineal permanent brachytherapy for patients with recurrent clinically localized prostate cancer. In one series, 49 patients underwent permanent implantation for an additional dose of 120 126 Gy with a median follow-up of 23 months. A total of 28 patients exhibited clinical progression of disease, with an actuarial biochemical disease-free survival rate of 48%. 20 Treatment-related side effects included urinary incontinence in 6% 24%, persistent penile discomfort, and rectal bleeding. 21 These preliminary reports suggest that salvage brachytherapy may successfully control the local disease within the prostate in some patients, despite the fact that the cancer failed to respond to the initial external beam treatments. The ultimate toxicity of this approach remains to be established with patient-focused questionnaires. Salvage Androgen Ablation Therapy Hormonal manipulation is likely to be the therapy most commonly administered to patients with recurrent prostate cancer and yet it has been the least well studied to date. A total of 54% of urologists and radiation oncologists in one study recommended androgen ablation or observation with delayed androgen ablation for patients with recurrent VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY S15

Treatment Options After Radiation Failure continued prostate cancer. 22 Certainly, androgen ablation is not a curative intervention, and therefore the optimal timing of its application is uncertain. The cancer-specific survival after androgen ablation administered upon identification of local-only recurrence in one series of 72 patients was 70 (external beam) and 84 (brachytherapy) months. 23 Although this relatively short survival may be a reflection of the advanced stage of disease of these patients or the intrinsic response rate of prostate cancer to hormonal therapy, the more morbid attempts at salvage therapy, such as radical prostatectomy, cryoablation, and brachytherapy, should demonstrate improved survival beyond that of androgen ablation in order to be reasonably administered to patients with recurrent prostate cancer. Conclusion Radiorecurrent or resistant prostate cancer is an aggressive form of localized prostate cancer that poses significant health risks to the men with this disease. An active program of surveillance and early detection with serum PSA and prostate biopsy is warranted for patients treated with radiation as primary therapy. The best outcomes from salvage treatments have been accomplished in patients identified upon biochemical failure at a PSA level below 4.0 ng/ml. A routine prostate biopsy at 12 24 months after radiation therapy or in patients with a PSA nadir above 0.5 ng/ml is likely to identify residual cancer as early as possible. Although the exact natural history of this residual disease is unclear, it remains highly likely that these patients will experience a clinically relevant progression of their disease if left untreated. Salvage radical prostatectomy represents the current best curative therapy, while cryoablation and brachytherapy are attractive alternatives. It is important that these salvage local therapies minimize treatmentrelated side effects while demonstrating a disease-specific survival rate greater than androgen ablation. References 1. Mettlin CJ, Murphy GP, Rosenthal DS, et al. The National Cancer Data Base report on prostate carcinoma after the peak in incidence rates in the U.S. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83:1679 1684. 2. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med. 1994;330:242 248. 3. Sandler HM, Dunn RL, McLaughlin PW, et al. Overall survival after prostate-specific-antigendetected recurrence following conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2000;48:629 633. 4. Siders DB, Lee F. Histologic changes of irradiated prostatic carcinoma diagnosed by transrectal ultrasound. Hum Pathol. 1992;23:344 351. 5. Lerner SE, Blute ML, Zincke H. Critical evaluation of salvage surgery for radio-recurrent/resistant prostate cancer. J Urol. 1995;154:1103 1109. 6. Crook JM, Choan E, Perry GA, et al. Serum prostate-specific antigen profile following radiotherapy for prostate cancer: implications for patterns of failure and definition of cure. Urology. 1998;51:566 572. 7. Ragde H, Korb LJ, Elgamal AA, et al. Modern prostate brachytherapy. Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up. Cancer. 2000;89:135 141. 8. Jani AB, Chen MH, Vaida F, et al. PSA-based outcome analysis after radiation therapy for prostate cancer: a new definition of biochemical failure after intervention. Urology. 1999;54:700 705. 9. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA. 1999;281:1598 1604. 10. Zietman AL, Tibbs MK, Dallow KC, et al. Use of PSA nadir to predict subsequent biochemical outcome following external beam radiation therapy for T1-2 adenocarcinoma of the prostate. Radiother Oncol. 1996;40:159 162. 11. Cheng L, Sebo TJ, Slezak J, et al. Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy. Cancer. 1998;83:2164 2171. 12. Cheng L, Cheville JC, Bostwick DG. Diagnosis of prostate cancer in needle biopsies after radiation therapy. Am J Surg Pathol. 1999;23:1173 1183. Main Points Persistent prostate cancer following radiation therapy results in cancer-related death in at least 27% of patients within 5 years of exhibiting a rising serum prostate-specific antigen (PSA) level. Approximately 90% of patients who achieve a PSA nadir below 0.5 ng/ml within 2 years remain free of recurrent disease. Disease progression following salvage radical prostatectomy is lowest when the disease is treated at a serum PSA below 10 ng/ml. Severe radiation effects with both nuclear and cytoplasmic alterations are seen in many prostatic biopsies and may confound the diagnosis of residual cancer; 67% of patients with adenocarcinoma on a biopsy at 12 months following radiation will convert to negative histology by 16 29 months. Incidence of positive biopsy results after primary radiation therapy appears to be higher for external beam radiation than for brachytherapy. Salvage radical prostatectomy is capable of eradicating the local lesion and providing long-term disease-specific survival, but it is complicated by the tissue effects of radiation and is associated with significant side effects, such as universal erectile dysfunction. An argon gas based cryoablation unit coupled with temperature monitoring of the freezing process has reduced the rate of urinary incontinence and rectal injury to 9% and 0%, respectively, in percutaneous prostatic cryoablation. Salvage brachytherapy may successfully control local disease within the prostate in some patients. S16 VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY

Treatment Options After Radiation Failure 13. Crook JM, Perry GA, Robertson S, Esche BA. Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients. Urology. 1995;45:624 631; discussion 631 632. 14. Stone NN, Stock RG, Unger P, Kao J. Biopsy results after real-time ultrasound-guided transperineal implants for stage T1-T2 prostate cancer. J Endourol. 2000;14:375 380. 15. Rogers E, Ohori M, Kassabian VS, et al. Salvage radical prostatectomy: outcome measured by serum prostate specific antigen levels. J Urol. 1995;153:104 110. 16. Vaidya A, Soloway MS. Salvage radical prostatectomy for radiorecurrent prostate cancer: morbidity revisited. J Urol. 2000;164:1998 2001. 17. Bales GT, Williams MJ, Sinner M, et al. Shortterm outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology. 1995;46:676 680. 18. de la Taille A, Hayek O, Benson MC, et al. Salvage cryotherapy for recurrent prostate cancer after radiation therapy: the Columbia experience. Urology. 2000;55:79 84. 19. Chin JL, Pautler SE, Mouraviev V, et al. Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol. 2001;165(6 pt 1):1937 1941; discussion 1941 1942. 20. Grado GL, Collins JM, Kriegshauser JS, et al. Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology. 1999;53:2 10. 21. Beyer DC. Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology. 1999;54:880 883. 22. Sylvester J, Grimm P, Blasco J, et al. The role of androgen ablation in patients with biochemical or local failure after definitive radiation therapy: a survey of practice patterns of urologists and radiation oncologists in the United States. Urology. 2001;58(2 suppl 1):65 70. 23. Schellhammer PF, Kuban DA, el-mahdi AM. Treatment of clinical local failure after radiation therapy for prostate carcinoma. J Urol. 1993;150:1851 1855. 24. Zelefsky MJ, Fuks Z, Hunt M, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol. 2001;166:876 881. VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY S17