Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

External-beam irradiation, interstitial implantation of radioisotopes, and radical prostatectomy are used.[1] The results of radical prostatectomy in stage III patients are greatly inferior compared to patients with stage II cancer. Interstitial implantation of radioisotopes is technically difficult in large tumors. External-beam irradiation using a linear accelerator is the most appropriate treatment for the majority of patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival.[2,3] Prognosis is greatly affected by whether regional lymph nodes are evaluated and proven not to be involved. The patient's symptoms related to cancer, age, and coexisting medical illnesses should be taken into account before deciding on a therapeutic plan. In a series of 372 patients treated with radiation therapy and followed for 20 years, 47% eventually died of prostate cancer, but 44% died of intercurrent illnesses without evidence of prostate cancer.[3]

Hormonal therapy should be considered in conjunction with radiation. Several studies have investigated its utility in patients with locally advanced disease. A prospective, randomized trial was performed by the Radiation Therapy Oncology Group (RTOG) (RTOG 85-31) in patients with T3, N0, or any T, N1, M0 disease who received prostatic and pelvic radiation therapy and then were randomized to receive immediate adjuvant goserelin or observation with administration of goserelin at time of relapse. In patients assigned to receive adjuvant goserelin, the drug was started during the last week of the radiation therapy course and was continued indefinitely or until signs of progression. The actuarial overall 5-year survival rate for the entire population of 945 analyzable patients was not statistically significantly different (75% on the adjuvant arm versus 71% on the observation arm, p=0.52). The authors report an improved actuarial 5-year local control rate (84% versus 71%, p<.0001), freedom from distant metastasis (83% versus 70%, p<.001), and disease-free survival (60% versus 44%, p<.0001).[4][Level of evidence: 1iiA]

A similar trial was performed by the European Organization for Research and Treatment of Cancer (EORTC). Patients with T1, T2 (WHO grade 3), N0-NX or T3, T4, N0 disease were randomized to receive either pelvic/prostate radiation, or identical radiation and adjuvant goserelin (with cyproterone acetate for 1 month) starting with radiation and continuing for 3 years. The 401 patients available for analysis were followed for a median of 45 months. The Kaplan- Meier estimates of overall survival at 5 years were 79% on the adjuvant arm and 52% on the radiation arm alone (p=0.001). Similarly, 5-year disease-free survival (85% versus 48%, p<0.001) and local control (97% versus 77%, p<0.001) favored the adjuvant arm.[5][Levels of evidence: 1iiA,1iiDi] Two smaller studies, with 78 and 91 patients each, have also shown similar results.[6,7]

The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (AHCPR). A majority of patients have more advanced disease, but patients with bulky T2b tumors were included in the study groups are-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease. Randomized clinical trial evidence comparing radiation therapy to radiation with prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year overall survival in favor of radiation therapy plus continued androgen suppression compared to radiation therapy alone (hazard ratio=0.631, 95% confidence interval=0.479-0.831).[8][Level of evidence: 1iiA]

Additionally, the RTOG did a study on patients with bulky local disease (T2b, T2c, T3, or T4), with or without nodal involvement below the common iliac chain: 456 men were evaluable and were randomized to receive either radiation alone or radiation with androgen ablation started 8 weeks prior to radiation and continued for 16 weeks. At 5 years, overall survival was identical, and local control (54% versus 29%) and disease-free survival (36% versus 15%) favored the combined arm.[9][Level of evidence: 1iiA] This trial only assessed short-term hormonal therapy, not long-term therapy as the studies analyzed by the AHCPR did.

Initial results from a randomized study of immediate hormonal treatment (orchiectomy or luteinizing hormone-releasing hormone (LHRH) analogue) versus deferred treatment (watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better overall survival and prostate cancer-specific survival with the immediate treatment. The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.[10][Level of evidence: 1iiA]

Treatment options:

1. External-beam radiation.[2,3,11-13] Hormonal therapy should be considered in addition to external-beam radiation.[4,5,9,8] Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[14] Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.[15]

2. Hormonal manipulations (orchiectomy or LHRH agonist).[10][Level of evidence: 1iiA]

3. Radical prostatectomy usually with pelvic lymphadenectomy (highly selected patients).[16] Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery.[13,17,18] However, because the duration of follow-up in available studies is still relatively short, the value of postoperative irradiation in reducing the incidence of local failure has yet to be determined. Clinical trials are in progress. Careful treatment planning is necessary to avoid morbidity. The role of preoperative ("neoadjuvant") hormonal therapy is not established at the present time.[19,20] Also, the morphologic changes induced by neoadjuvant androgen ablation may even complicate assessment of surgical margins and capsular involvement.[21]

4. Careful observation without further immediate treatment.[22]

Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.

1. Radiation therapy.[2,3,11,12] External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography based 3-D conformal treatment planning is under clinical evaluation.

2. Hormonal manipulations effectively used as initial therapy for prostate cancer:

a) orchiectomy

b) leuprolide or other LHRH agonists (Zoladex) in daily or depot preparations (these agents may be associated with tumor flare)

c) estrogen

3. Palliative surgery (transurethral resection).

4. Interstitial implantation combined with external-beam radiation therapy is being used in selected T3 patients, but little information is available.[23]

5. Clinical trials employing alternative forms of radiation therapy. A randomized trial from the RTOG reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy, compared to standard photon radiation therapy.[24] A subsequent randomized study from the same group compared fast neutron radiation therapy to standard photon radiation therapy. Local-regional control was improved with neutron treatment but no difference in overall survival was seen, although follow-up was shorter in this trial. Decreased complications were seen with the use of a multileaf collimator.[25] Proton-beam radiation therapy is also under investigation.[26]

6. Other clinical trials.[27] Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with prostate cancer.

7. Ultrasound-guided percutaneous cryosurgery is under clinical evaluation.

Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes followed by thawing.[28][Level of evidence: 3iiiDiii] It is less well established than standard prostatectomy and long-term outcomes are not known. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development.

1. Paulson DF: Management of prostate malignancy. In: deKernion JB, Paulson DF, Eds.: Genitourinary Cancer Management. Philadelphia: Lea and Febiger, 1987, pp 107-160, 1987.
2. Babaian RJ, Zagars GK, Ayala AG: Radiation therapy of stage C prostate cancer: significance of Gleason grade to survival. Seminars in Urology 8(4): 225-231, 1990.
3. del Regato JA, Trailins AH, Pittman DD: Twenty years follow-up of patients with inoperable cancer of the prostate (stage C) treated by radiotherapy: report of a national cooperative study. International Journal of Radiation Oncology, Biology, Physics 26(2): 197-201, 1993.
4. Pilepich MV, Caplan R, Byhardt RW, et al.: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. Journal of Clinical Oncology 15(3): 1013-1021, 1997.
5. Bolla M, Gonzalez D, Warde P, et al.: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. New England Journal of Medicine 337(5): 295-300, 1997.
6. Zagars GK, Johnson DE, von Eschenbach AC, et al.: Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. International Journal of Radiation Oncology, Biology, Physics 14(6): 1085-1091, 1988.
7. Granfors T, Modig H, Damber JE, et al.: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. Journal of Urology 159(6): 2030-2034, 1998.
8. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, Evidence Report/Technology Assessment: Number 4, January 1999. Agency for Health Care Policy and Research, Rockville, MD. Available at: http://www.ahcpr.gov/clinic/prossumm.htm. Accessed 6/14/99.
9. Pilepich MV, Krall JM, Al-Sarraf M, et al.: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45(4): 616-623, 1995.
10. Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. British Journal of Urology 79(2): 235-246, 1997.
11. Pilepich MV, Johnson RJ, Perez CA, et al.: Prognostic significance of nodal involvement in locally advanced (stage C) carcinoma of prostate: RTOG experience. Urology 30(6): 535-540, 1987.
12. Perez CA, Garcia D, Simpson JR, et al.: Factors influencing outcome of definitive radiotherapy for localized carcinoma of the prostate. Radiotherapy and Oncology 16(1): 1-21, 1989.
13. Freeman JA, Lieskovsky G, Cook DW, et al.: Radical retropubic prostatectomy and postoperative adjuvant radiation for pathological stage C (PCN0) prostate cancer from 1976 to 1989: intermediate findings. Journal of Urology 149(5): 1029-1034, 1993.
14. Seymore CH, El-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.
15. Dearnaley DP, Khoo VS, Norman AR, et al.: Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 353(9149): 267-272, 1999.
16. Walsh PC, Jewett HJ: Radical surgery for prostatic cancer. Cancer 45(7 Suppl):1906-1911, 1980.
17. Lange PH, Reddy PK, Medini E, et al.: Radiation therapy as adjuvant treatment after radical prostatectomy. Journal of the National Cancer Institute Monographs 7: 141-149, 1988.
18. Ray GR, Bagshaw MA, Freiha F: External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. Journal of Urology 132(5): 926-930, 1984.
19. Witjes WP, Schulman CC, Debruyne FM: Preliminary results of a prospective randomized study comparing radical prostatectomy versus radical prostatectomy associated with neoadjuvant hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. Urology 49(Suppl 3A): 65-69, 1997.
20. Fair WR, Cookson MS, Stroumbakis N, et al.: The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostatic cancer: Memorial Sloan-Kettering Cancer Center results. Urology 49(Suppl 3A): 46-55, 1997.
21. Bazinet M, Zheng W, Begin LR, et al.: Morphologic changes induced by neoadjuvant androgen ablation may result in underdetection of positive surgical margins and capsular involvement by prostatic adenocarcinoma. Urology 49(5): 721-725, 1997.
22. Adolfsson J: Deferred treatment of low grade stage T3 prostate cancer without distant metastases. Journal of Urology 149(2): 326-329, 1993.
23. Blasko JC, Grimm PD, Ragde H: Brachytherapy and organ preservation in the management of carcinoma of the prostate. Seminars in Radiation Oncology 3(4): 240-249, 1993.
24. Laramore GE, Krall JM, Thomas FJ, et al.: Fast neutron radiotherapy for locally advanced prostate cancer: final report of a Radiation Therapy Oncology Group randomized clinical trial. American Journal of Clinical Oncology 16(2): 164-167, 1993.
25. Russell KJ, Caplan RJ, Laramore GE, et al.: Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. International Journal of Radiation Oncology, Biology, Physics 28(1): 47-54, 1993.
26. Shipley WU, Verhey LJ, Munzenrider JE, et al.: Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. International Journal of Radiation Oncology, Biology, Physics 32(1): 3-12, 1995.
27. Thompson IM, Southwest Oncology Group: Phase III Randomized Evaluation of Adjuvant Radiotherapy vs No Adjuvant Therapy Following Radical Prostatectomy and Pelvic Lymphadenectomy in Surgical Stage C Adenocarcinoma of the Prostate (Summary Last Modified 05/98), SWOG-8794, clinical trial, closed, 01/01/1997.
28. Shinohara K, Connolly JA, Presti JC, et al.: Cryosurgical treatment of localized prostate cancer (stages T1 to T4): preliminary results. Journal of Urology 156(1): 115-121, 1996.

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