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Routine long-term androgen suppression following standard radiotherapy improves disease-free survival in men with unfavourable-prognosis prostate cancer compared with relapse-initiated therapy
TREATMENT/ INTERVENTION
Routine long-term androgen suppression following standard radiotherapy improves disease-free survival in men with unfavourable-prognosis prostate cancer compared with relapse-initiated therapy Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV. Updated results of the phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavourable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 49(4): 937^946.
BACKGROUND Prostatic adenocarcinoma is highly hormone-dependent. Previous work has found that adjuvant androgen suppression improves survival in the short term in men with unfavourable-prognosis prostate cancer. OBJECTIVE To investigate whether the e¡ects of adjuvant androgen suppression last long term for people with unfavourable-prognosis prostate cancer. DESIGN Randomized controlled trial. SETTING United States, number of centres not listed;1987^October 1998. PARTICIPANTS Nine hundred and seventy-seven people with adenocarcinoma of the prostate with regional lymphatic involvement or gross extension of primary tumour (clinical stage T3 or T1 and T2 with regional lymph node involvement). Age, gender and other demographics not speci¢ed. Those with bulky primary lesions (tumour dimension 25 cm3) were not eligible. INTERVENTIONS Radiation and adjuvant goserelin; or radiation therapy alone (followed by goserelin at the time of relapse). Adjuvant goserelin (3.6 mg administered subcutaneously in anterior abdominal wall monthly) began during the last week of radiation and continued until signs of progression. Follow-up ranged from 0.23 to 11 years (median 5.6 years).
Commentary Many prospective randomised studies have found that adding adjuvant hormonal therapy to radical radiotherapy of locally
46
Evidence-based Oncology (2002) 3, 46 ^ 47 doi:10.1054/ebon.2001.0182, available online at http://www.idealibrary.com.on
MAIN OUTCOME MEASURES Disease-free survival; local and regional failure. MAIN RESULTS At 8- year follow-up, the adjuvant goserelin group had a lower rate of local failure (23 vs 37%) and distant metastasis (27 vs 37%) than those receiving radiation therapy alone (both po0.0001). 36% of the goserelin group survived without disease at 8 years compared to 25% of the radiation alone group ( po0.0001).There were no signi¢cant di¡erences in absolute survival or death due to prostate cancer or treatment (see Table 1). No data on treatment harms is provided. CONCLUSION Adjuvant androgen suppression improves long-term disease-free survival in people with unfavourable-prognosis prostate cancer. The best treatment duration is uncertain. METHOD NOTES Power
No power calculation is present
Blinding Adequate randomization/ balanced groups Intention-to-treat analysis
No Well balanced, fully randomized groups Yes
Sources offunding: None listed. Correspondence to: Dr CA Lawton, Medical College of W|sconsin, Department of radiation Oncology, 8701 Watertown Plank Road, Milwaukee WI 53226 (E-mail: Colleen@[email protected]).
advanced prostate cancer results improved local control, freedom of distant metastases or duration of PSA response when compared to definitive radiation therapy in men with locally advanced prostate cancer.1^5 Together these suggest that men with & 2002 Elsevier Science Ltd. All rights reserved
0.23
Literature cited
Note: 95% con¢dence limits are in parentheses.
16 Cause-speci¢c failure
21
0.36 49 Absolute survival
47
o0.0001 36 Disease-free survival
25
o0.0001 27 Distant metastases
37
Professor Pirkko Kellokumpu-Lehtinen DrTapioTulijoki Tampere University Hospital, Department of OncologyTampere, Finland
Not signi¢cant
0.6 (0.4 to 0.8) 0.7 (0.5 to 0.9) 1.5 (1.3 to 1.7) 1.1 (0.9 to 1.2) 0.7 (0.5 to 1) 14% bene¢t (8.2% to 19.8% bene¢t) 10% bene¢t (4.1% to 15.9% bene¢t) 11% bene¢t (5.2% to 16.8% bene¢t) 2% bene¢t (4.4% harm to 8.4% bene¢t) 5% bene¢t (0% to 9.9% bene¢t) 23 Local failure
37
o0.0001
7 to bene¢t (5 to 12 bene¢t) 10 to bene¢t (6 to 24 bene¢t) 9 to bene¢t (6 to 19 bene¢t) Not signi¢cant
Relative risk: goserelin vs radiation alone Absolute risk change with goserelin Number needed to treat with goserelin to e¡ect one person p-value Radiation only % ( n = 468) Adjuvant hormone % ( n = 477) Estimated 8-year outcomes
EvidenceTable 1 Survival outcomes for unfavourable prognosis prostate cancer treated with radiation and adjuvant goserelin or radiation therapy alone
& 2002 Elsevier Science Ltd. Allrights reserved
high-grade locally advanced prostate cancer should be o¡ered adjuvant hormonal treatment for a minimum of 2 years after radiotherapy. The present study evaluated adjuvant goserelin combined with radical external radiation vs radiation plus therapeutic androgen suppression following relapse. The trial, therefore, compares early vs delayed androgen suppression therapy in locally advanced prostate cancer patients.The study was carefully planned and the patient groups were well balanced. Local control, freedom of metastatic disease and duration of biochemical response were significantly improved by early androgen suppression. However, no overall survival benefit was found. Both prostatectomy and radical radiotherapy without adjuvant hormone treatment result in excellent survival in well-differentiated T1 tumours.6 In other sugroups with localised disease, delayed hormonal therapy may be as effective as early adjuvant treatment, yet spare patients the adverse effects of androgen suppression.7^ 8
1. Pilepich MV, Sause WT, Shipley WU et al. Androgen deprivation with radiation therapy compare with radiation therapy alone for locally advanced prostate cancer: a randomized comparative trial of the radiation therapy oncology group. Urology 1995; 45: 616. 2. Pilepich MV, Winter K, Mahdu JJ et al. Phase III radiation therapy oncology group (RTOG) trial 86 -10 and androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of prostate. Int J Radiat Oncol Biol Phys 2001; 50: 1243. 3. Horwitz EM, Winter K, Hanks GE et al. Subset analysis of RTOG 85-31 and 86 -10 indicates an advance for long term versus short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 2001; 49: 947. 4. Bolla M, Gonzales D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337: 295. 5. GranforsT, Modig H, Damber JE,Tomic R.Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998; 159(6): 2030. 6. Roach M, Lu J, Pilepich MV et al. Predicting long term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 200; 47: 617. 7. Anderson J. Quality of life aspects of treatment options for localized and locally advanced prostate cancer. Eur Urol 2001; 40: 24 ^30. 8. Lubeck DP, Grossfeld GD, Carroll PR. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 2001; 58: 94.
Level and Quality of Evidence (seeTable A, p. 50) 1c
Evidence-based Oncology (2002) 3, 46 ^ 47
47
Routine long-term androgen suppression following standard radiotherapy improves disease-free survival in men with unfavourable-prognosis prostate cancer compared with relapse-initiated therapy Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV. Updated results of the phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavourable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 49(4): 937^946.
BACKGROUND Prostatic adenocarcinoma is highly hormone-dependent. Previous work has found that adjuvant androgen suppression improves survival in the short term in men with unfavourable-prognosis prostate cancer. OBJECTIVE To investigate whether the e¡ects of adjuvant androgen suppression last long term for people with unfavourable-prognosis prostate cancer. DESIGN Randomized controlled trial. SETTING United States, number of centres not listed;1987^October 1998. PARTICIPANTS Nine hundred and seventy-seven people with adenocarcinoma of the prostate with regional lymphatic involvement or gross extension of primary tumour (clinical stage T3 or T1 and T2 with regional lymph node involvement). Age, gender and other demographics not speci¢ed. Those with bulky primary lesions (tumour dimension 25 cm3) were not eligible. INTERVENTIONS Radiation and adjuvant goserelin; or radiation therapy alone (followed by goserelin at the time of relapse). Adjuvant goserelin (3.6 mg administered subcutaneously in anterior abdominal wall monthly) began during the last week of radiation and continued until signs of progression. Follow-up ranged from 0.23 to 11 years (median 5.6 years).
Commentary Many prospective randomised studies have found that adding adjuvant hormonal therapy to radical radiotherapy of locally
46
Evidence-based Oncology (2002) 3, 46 ^ 47 doi:10.1054/ebon.2001.0182, available online at http://www.idealibrary.com.on
MAIN OUTCOME MEASURES Disease-free survival; local and regional failure. MAIN RESULTS At 8- year follow-up, the adjuvant goserelin group had a lower rate of local failure (23 vs 37%) and distant metastasis (27 vs 37%) than those receiving radiation therapy alone (both po0.0001). 36% of the goserelin group survived without disease at 8 years compared to 25% of the radiation alone group ( po0.0001).There were no signi¢cant di¡erences in absolute survival or death due to prostate cancer or treatment (see Table 1). No data on treatment harms is provided. CONCLUSION Adjuvant androgen suppression improves long-term disease-free survival in people with unfavourable-prognosis prostate cancer. The best treatment duration is uncertain. METHOD NOTES Power
No power calculation is present
Blinding Adequate randomization/ balanced groups Intention-to-treat analysis
No Well balanced, fully randomized groups Yes
Sources offunding: None listed. Correspondence to: Dr CA Lawton, Medical College of W|sconsin, Department of radiation Oncology, 8701 Watertown Plank Road, Milwaukee WI 53226 (E-mail: Colleen@[email protected]).
advanced prostate cancer results improved local control, freedom of distant metastases or duration of PSA response when compared to definitive radiation therapy in men with locally advanced prostate cancer.1^5 Together these suggest that men with & 2002 Elsevier Science Ltd. All rights reserved
0.23
Literature cited
Note: 95% con¢dence limits are in parentheses.
16 Cause-speci¢c failure
21
0.36 49 Absolute survival
47
o0.0001 36 Disease-free survival
25
o0.0001 27 Distant metastases
37
Professor Pirkko Kellokumpu-Lehtinen DrTapioTulijoki Tampere University Hospital, Department of OncologyTampere, Finland
Not signi¢cant
0.6 (0.4 to 0.8) 0.7 (0.5 to 0.9) 1.5 (1.3 to 1.7) 1.1 (0.9 to 1.2) 0.7 (0.5 to 1) 14% bene¢t (8.2% to 19.8% bene¢t) 10% bene¢t (4.1% to 15.9% bene¢t) 11% bene¢t (5.2% to 16.8% bene¢t) 2% bene¢t (4.4% harm to 8.4% bene¢t) 5% bene¢t (0% to 9.9% bene¢t) 23 Local failure
37
o0.0001
7 to bene¢t (5 to 12 bene¢t) 10 to bene¢t (6 to 24 bene¢t) 9 to bene¢t (6 to 19 bene¢t) Not signi¢cant
Relative risk: goserelin vs radiation alone Absolute risk change with goserelin Number needed to treat with goserelin to e¡ect one person p-value Radiation only % ( n = 468) Adjuvant hormone % ( n = 477) Estimated 8-year outcomes
EvidenceTable 1 Survival outcomes for unfavourable prognosis prostate cancer treated with radiation and adjuvant goserelin or radiation therapy alone
& 2002 Elsevier Science Ltd. Allrights reserved
high-grade locally advanced prostate cancer should be o¡ered adjuvant hormonal treatment for a minimum of 2 years after radiotherapy. The present study evaluated adjuvant goserelin combined with radical external radiation vs radiation plus therapeutic androgen suppression following relapse. The trial, therefore, compares early vs delayed androgen suppression therapy in locally advanced prostate cancer patients.The study was carefully planned and the patient groups were well balanced. Local control, freedom of metastatic disease and duration of biochemical response were significantly improved by early androgen suppression. However, no overall survival benefit was found. Both prostatectomy and radical radiotherapy without adjuvant hormone treatment result in excellent survival in well-differentiated T1 tumours.6 In other sugroups with localised disease, delayed hormonal therapy may be as effective as early adjuvant treatment, yet spare patients the adverse effects of androgen suppression.7^ 8
1. Pilepich MV, Sause WT, Shipley WU et al. Androgen deprivation with radiation therapy compare with radiation therapy alone for locally advanced prostate cancer: a randomized comparative trial of the radiation therapy oncology group. Urology 1995; 45: 616. 2. Pilepich MV, Winter K, Mahdu JJ et al. Phase III radiation therapy oncology group (RTOG) trial 86 -10 and androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of prostate. Int J Radiat Oncol Biol Phys 2001; 50: 1243. 3. Horwitz EM, Winter K, Hanks GE et al. Subset analysis of RTOG 85-31 and 86 -10 indicates an advance for long term versus short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 2001; 49: 947. 4. Bolla M, Gonzales D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337: 295. 5. GranforsT, Modig H, Damber JE,Tomic R.Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998; 159(6): 2030. 6. Roach M, Lu J, Pilepich MV et al. Predicting long term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 200; 47: 617. 7. Anderson J. Quality of life aspects of treatment options for localized and locally advanced prostate cancer. Eur Urol 2001; 40: 24 ^30. 8. Lubeck DP, Grossfeld GD, Carroll PR. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 2001; 58: 94.
Level and Quality of Evidence (seeTable A, p. 50) 1c
Evidence-based Oncology (2002) 3, 46 ^ 47
47