Int. J. Cancer (Radiat. Oncol. Invest): 96, 91–93 (2001) © 2001 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Adjuvant Radiotherapy following Radical Prostatectomy Is More Effective and Less Toxic Than Salvage Radiotherapy for a Rising Prostate Specific Antigen Mitchell S. Anscher, M.D. Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina SUMMARY Despite the trend toward earlier diagnosis of adenocarcinoma of the prostate, approximately 25% of men undergoing radical prostatectomy will have pathologic evidence of cancer extending outside of the prostate. These patients are at high risk for subsequent recurrence. Such relapses are almost always manifested initially as a rise in the Prostate Specific Antigen (PSA). Currently utilized PSA assays, however, will not detect a recurrence smaller than 107 to 108 cells, nor does PSA identify the site of recurrence. In contrast, the pathologic findings at the time of surgery can be used to reliably distinguish patients at risk for local recurrence from those more likely to fail distantly. Furthermore, adjuvant pelvic radiotherapy after prostatectomy, given to patients with an undetectable PSA who are at high risk for local recurrence, results in a higher disease free survival and fewer side effects than if radiotherapy is delayed until the PSA begins to rise. Thus, patients at high risk for local failure following radical prostatectomy, but at low risk for distant metastases (i.e., those with positive surgical margins and an undetectable PSA) should be offered immediate adjuvant radiotherapy. © 2001 Wiley-Liss, Inc.
Key words: prostate cancer; adjuvant radiotherapy; salvage radiotherapy
THE MAGNITUDE OF THE PROBLEM Adenocarcinoma of the prostate is the most commonly diagnosed malignancy and the second leading cause of cancer deaths in men in the United States. In 2000, an estimated 180,400 new cases will be diagnosed and 31,900 deaths will occur from this disease [1]. Widespread implementation of screening with Prostate Specific Antigen (PSA) has resulted in earlier diagnosis and an increase in the number of patients treated with radical prostatectomy. Despite this trend toward earlier clinical diagnosis, about 25% of men undergoing radical prostatectomy (approximately 15,000 men in 2000) will have pathologic evidence of cancer extending outside of the prostate (pathologic stage III) [2].
Optimal therapy for these men remains a major public health issue. It is the author’s opinion that men with pathologic stage III adenocarcinoma of the prostate should be offered postoperative radiotherapy before their PSA becomes detectable. PATHOLOGY ACCURATELY PREDICTS RECURRENCE Prior to the advent of PSA, recommendations for adjuvant radiotherapy following radical prostatectomy were made on the basis of the pathologic findings at the time of prostatectomy. Previous research had shown that patients with positive surgical margins, extracapsular extension, and/or highgrade histology (Gleason scores of 8–10) were at increased risk for local recurrence, whereas patients
Correspondence to: Mitchell S. Anscher, M.D., Box 3085 DUMC, Durham, NC 27710. Phone: (919) 660-2113; Fax: (919) 684-3953; E-mail:
[email protected] Received 10 January 2001; Accepted 7 February 2001 Published online 15 March 2001.
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Anscher: Adjuvant RT for pStage III Prostate Cancer
Table 1.
Comparison of Adjuvant vs. Salvage Radiotherapy following Radical Prostatectomy Adjuvant RTa
Salvage RTa
Author
#pts (A/S)
F/U (mos)
S
DFSb
LC
S
DFSb
LC
McCarthy Morris Nudell Vicini Valicenti
27/37 40/48 36/35 38/19 52/27
33 31 35 48 36/46
— — — 83% —
67% 81% 80% 67% 93%
— — — — —
— — — 100% —
54% 48% 55% 24% 44%
— — — — —
#A/S ⳱ adjuvant/salvage; DFS ⳱ disease-free survival; F/U ⳱ follow-up; mos ⳱ months; LC ⳱ local control; pts ⳱ number of patients; RT ⳱ radiotherapy; S ⳱ survival. a All data are 3-year actuarial values except for that of Vicini, which are 5-year actuarial figures. b In each case except McCarthy [16], DFS was significantly better for adjuvant vs. salvage RT.
with seminal vesicle invasion were at greater risk for distant failure [3]. The available data, all of it retrospective, indicated a significant improvement in local control from adjuvant radiotherapy in patients at high risk for local recurrence, especially those with positive margins [4,5]. These studies also showed improvement in survival and diseasefree survival, but because of small numbers, these differences were not statistically significant. STANDARD ASSAYS FOR PSA ARE TOO INSENSITIVE The introduction of PSA into the clinic has forced us to redefine a successful outcome after radical prostatectomy. There is no doubt that PSA is the most sensitive indicator of the presence of residual prostate cancer after attempted surgical removal of the gland [6]. Patients with detectable PSA following radical prostatectomy almost certainly have residual cancer present [6]. Conversely, the absence of detectable PSA postoperatively does not guarantee that an individual patient is free of prostate cancer. The problem lies in the limitations in our ability to detect very small amounts of cancer [7], as illustrated below. Suppose a patient whose PSA is 8 ng/ml is found to have a prostate cancer that is approximately 1 cc in size. It can be estimated that this 1 cc prostate cancer, which contains 108–109 cells [8], will contribute about 3.5 ng/ml to the serum PSA [9]. This patient undergoes a radical prostatectomy that removes all of the benign prostate and 99.9% of the cancer cells, but the margins of resection are positive microscopically. The surgical procedure would reduce his PSA to 0.0035 ng/ml, well below the limits of detectability of the commonly used clinical assays. This patient would still have 105–106 cancer cells present, yet the patient and his physicians might be lulled into a false sense of security by his undetectable PSA.
MOST PATIENTS LIVE LONG ENOUGH TO RELAPSE Despite the mounting evidence that the majority of patients with pathologic stage III prostate cancer are destined to have a recurrence, many physicians argue that it is reasonable to defer treatment in this patient population until the PSA begins to rise, at which point pelvic radiotherapy may be offered. It is argued that prostate cancer is a disease of elderly men (mean age at diagnosis ⳱ 69 years), and since it may be several years before relapse occurs, these men are likely to die of an unrelated medical event. One should consider, however, that properly selected patients for radical prostatectomy will have a life expectancy of at least 10 years, well beyond the median time to failure without adjuvant therapy for pathologic stage III prostate cancer [5,10,11]. ADJUVANT TREATMENT LEADS TO IMPROVED DISEASE-FREE SURVIVAL Using PSA, we can now reassess the value of preventing recurrence with adjuvant radiotherapy in patients at risk for local failure following radical prostatectomy. Although no prospective data exist, several retrospective reports have recently been published that have directly compared the results of adjuvant radiotherapy to salvage radiotherapy (i.e., therapy that is delayed until the PSA begins to rise) [12–16] (Table 1). Patients with overt local failure, who have a worse outcome following radiotherapy than do patients with an isolated biochemical relapse, are not included in this analysis [17]. Even if one excludes these patients with the least favorable prognosis from the salvage radiotherapy group, all but one study [16] report a significant improvement in disease-free survival with adjuvant vs. salvage radiotherapy. Thus, the available retrospective data support the use of adjuvant radiotherapy following radical prostatectomy for patients at high risk for local recurrence, rather than delaying treatment until the PSA begins to rise.
Anscher: Adjuvant RT for pStage III Prostate Cancer
ADJUVANT THERAPY IS LESS TOXIC THAN SALVAGE RADIOTHERAPY Not only is adjuvant radiotherapy effective in preventing recurrences of prostate cancer, but also by using modern techniques, it can be safely administered with few serious side effects [18,19]. Severe (grade 3 to 4) gastrointestinal complications are extremely rare [17,20]. Urinary strictures may occur in 5% to 10% of patients [17,20]. A recent randomized trial found that adjuvant pelvic radiotherapy had no significant impact on urinary continence compared with prostatectomy alone [19]. In contrast, salvage radiotherapy may lead to poorer urinary control in 5% to 10% of patients [17], probably due to the higher doses required for salvage radiotherapy. CONCLUSIONS Since we have established that adjuvant radiotherapy is both more effective and safer than salvage treatment, to whom should it be offered? Unfortunately, there are no published randomized studies on which to base a decision. Hopefully, the recently completed randomized Intergroup trial of adjuvant radiation vs. observation for pathologic stage III prostate cancer will shed light on this subject. Until these data are published, patients at high risk for local failure but low risk for distant metastases (i.e., those with positive surgical margins and an undetectable PSA) should be offered immediate adjuvant radiotherapy. REFERENCES 1. Greenlee R, Murray T, Bolden S, Wingo P. Cancer statistics 2000. CA Cancer J Clin 2000;50:7–33. 2. Mettlin C, Murphy G, Lee F, Littrup P, Chesley A, Babaian R, Badalament R, Kane R, Mostofi F. Characteristics of prostate cancer detected in the American Cancer Society-National Prostate Cancer Detection Project. J Urol 1994;152:1737–1740. 3. Anscher M, Prosnitz L. Multivariate analysis of factors predicting local relapse after radical prostatectomy— possible indications for postoperative radiotherapy. Int J Radiat Oncol Biol Phys 1991;21:941–947. 4. Anscher M, Robertson C, Prosnitz L. Adjuvant radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate: 10 year update. Int J Radiat Oncol Biol Phys 1995;33:37–43. 5. Schild S, Wong W, Grado G, Halyard M, Novicki D, Swanson S, Larson T, Ferrigni R. The results of radical retropubic prostatectomy and adjuvant therapy for pathologic Stage C prostate cancer. Int J Radiat Oncol Biol Phys 1995;34:535–541. 6. Ablin R. A retrospective and prospective overview of prostate-specific antigen. J Cancer Res Clin Oncol 1997;123:583–594.
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