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Hormones and radiation therapy in locally advanced adenocarcinoma of the prostate
Hormones and Radiation Therapy in Locally Advanced Adenocarcinoma of the Prostate Colleen A. Lawton Hormonal dependency of prostate cancer was first described in 1895 by White who showed the initial observation between castration and the treatment of prostatic disease in men with bladder outlet obstruction secondary to benign prostatic hypertrophy. Subsequently, in 1940 Huggins and Hodges demonstrated the association between normal and hyperplastic epithelium of canine prostate glands and adequate levels of circulating androgens. This pioneering work led extensive investigation of the role of androgens in both prostatic growth for benign and malignant disease. The goal of this article is to review the role of hormonal manipulation in prostate cancer in general and more specifically to focus on the role of radiation therapy and hormonal manipulation in locally advanced adenocarcinoma of the prostate. The article is divided into
sections that outline the role of different types of hormonal manipulation that are currently available along with the early work combining hormonal manipulation and radiation therapy for prostate cancer. Subsequently, a thorough review of the phase III trials performed to evaluate the potential role of hormonal manipulation in addition to radiation therapy in locally advanced adenocarcinoma of the prostate. Included in that discussion is a section on the potential toxicities of hormonal manipulation. Finally, the current recommendations for the use of hormonal manipulation combined with radiation therapy in locally advanced adenocarcinoma of the prostate is described. © 2003 Elsevier Inc. All rights reserved.
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androgen starts with the conversion of 17hydroxyl progesterone to dehydroepiandrosterone (DHEA). DHEA can go on to form DHEA-sulfate or androstenedione and subsequently testosterone.6 This pathway can be completed in the human testes, but in addition the adrenal glands produce DHEA, DHEAS, and androstenedione. The prostate, along with other tissues, has the enzymes necessary to convert the DHEA, DHEAS, and androstenedione to testosterone and ultimately to dihydrotestosterone (DHT). It is the DHT molecule that is taken up by the prostate and binds to the cytosolic receptor. This receptor complex is then translocated into the nucleus of prostate cells and activates messenger RNA and protein synthesis and is important in sustaining prostatic epithelium (Fig 1). It is important to realize that given 2 sources of testosterone in humans and therefore, DHT (ie the testis and adrenals), 90% of circulating testosterone is of testicular origin, whereas 60% of prostatic testosterone is of testicular origin.6 This discrepancy points to the important contribution of the adrenals to androgen production. With the synthesis of androgens understood, there are 3 ways to decrease testosterone, and therefore, decrease DHT. The first method is suppression of the pituitary luteinizing hormone (LH) release. The LH-hormone agonist (LHRH agonists) interferes with the hypothalamic-pituitary-testicular axis that regulates the production of testosterone. Examples are goserelin acetate
ormone dependency of the prostate was first described in 1895 by White1 who showed the first association between castration and the treatment of prostatic disease in men with bladder outlet obstruction secondary to benign prostatic hypertrophy. Subsequently, Huggins2 in 1940 showed an association between the normal and hyperplastic epithelium of canine prostate glands and adequate levels of circulating androgens. Finally, in 1941, Huggins and Hodges3,4 showed the androgen dependence of prostatic adenocarcinoma through the castration and measuring of serum acid phosphatase levels on patients with metastatic disease. This pioneering work led to extensive investigation of the role of androgens in prostatic growth, both benign and malignant. It was Walsh5 who summarized the precise mechanism of action of androgens on prostatic growth. To understand the potential role of androgen manipulation for locally advanced prostate cancer, one must understand the basics of androgen synthesis. In humans, the synthesis of
From the Medical College of Wisconsin, Radiation Oncology, Milwaukee, WI. Address reprint requests to Colleen A. Lawton, MD, FACR, Medical College of Wisconsin, Department of Radiation Oncology, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1302-0007$30.00/0 doi:10.1053/srao.2003.50013
Seminars in Radiation Oncology, Vol 13, No 2 (April), 2003: pp 141-151
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Early Work Combining Radiation Therapy and Hormonal Manipulations
Figure 1. A schematic of androgen synthesis.
and leuprolide. Diethylstilbestrol (DES) also decreases LH release. LHRH agonists initially (ie, after 2-3 days) cause an increase in LH production and therefore testosterone production, but after 3 to 5 days, the LH release and testosterone production declines to castrate levels in approximately 3 to 4 weeks.6 The second method to decrease androgen production is through the use of compounds that block the effect of the androgen at the target organ. These compounds interfere with the cellular events that mediate androgen actions. In effect, they inhibit the binding of the DHT to the receptor complex. There are 2 groups of these antiandrogens: nonsteroidal and steroidal. Examples of nonsteroidal antiandrogens are flutamide, biclutamide, and nilutamide. Examples of the steroidal antiandrogens are megestrol acetate and cyproterone acetate. The final mechanism to alter androgen synthesis is inhibition of steroidal genesis. Both aminoglutethimide and ketoconazole work in this manner. Given a basic understanding of the mechanisms of potential androgen suppression, locally advanced prostate cancer and the role of antiandrogens combined with radiation to treat these patients are now discussed.
Theoretically, a decrease in androgens could aid the control of locally advanced prostate cancer in 1 of 2 ways: either through cytoreduction or through control of micrometastatic disease. It was Green et al7 in 1975 who reported one of the initial studies combining radiation therapy with estrogens. This study included 80 patients treated with radiation therapy for adenocarcinoma of the prostate, 35 of whom also received estrogens during the radiation and for 3 months after radiation therapy. The majority of the patients had locally advanced but nonmetastatic disease. Although the dose of estrogen was not specified, the authors report that those patients who had the most favorable tumor response were those who received estrogen.7 Green et al7 note that neither estrogens alone nor radiation therapy alone reliably controlled locally advanced prostate cancer but that the combination in their study proved to give the best tumor control. In 1978, van der Werf-Messing8 reported on 142 patients with T3-4NXM0 adenocarcinoma of the prostate of whom 26 received hormones alone, 32 received hormones and external radiation therapy, and 84 patients were treated with external radiation alone. Results of this work showed actuarial uncorrected survival rates after 3 to 5 years that were slightly better for patients treated with external radiation therapy alone, although there was no statistically significant difference between the arms. Cardiovascular events contributed to 40% of the intercurrent deaths in patients who received hormones (ie, estrogens), which is almost the same death rate as metastatic deaths in the radiation alone group.8 These data were some of the first to suggest that any benefit of hormonal manipulation in conjunction with radiation therapy may be offset by the cardiovascular toxicity of estrogens. At about the same time, Camuzzi et al9 reported in a rat model, the role of estrogen, and radiation therapy for prostatic adenocarcinoma. They found similar findings to van der WerfMessing in that the combination of radiation therapy and estrogen therapy did not show greater inhibition of tumor growth than radiation therapy alone.9 Green et al10 continued pursuing the concept of estrogens and radiation therapy in locally ad-
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vanced disease. In 1981, they reported on a group of 35 patients with pelvic or pelvic plus periaortic lymph node metastasis.10 This group of patients was treated with 3 mg/d of DES for 8 weeks before radiation therapy and maintained throughout radiation therapy. The DES was discontinued in 25 patients after 6 months. Eighteen unselected patients of the initial 35 who had radiation therapy and DES had comparison diagnostic studies performed to evaluate the response of the primary tumor and lymph node metastasis to the DES. Results of the study suggested a benefit to DES regarding cytoreduction and the benefit of this before radiation in allowing the radiation therapy to better control the cytoreduced disease.10 Continuing this work in 1984, Green et al11 reported on 36 patients with bulky prostate cancer. Twenty-five patients received estrogen for cytoreduction (3 mg DES) before radiation therapy. This group of patients was compared with 11 patients treated with radiation therapy alone. These data revealed a local control rate of 72% for the combined group (median follow-up, 4 years) compared with 55% local control for the RT-only group.11 Building on the concept of the potential benefit of hormonal manipulation for locally advanced disease, Kramolowsky12 published data from the University of Iowa in 1987. He reported on 68 patients with D1 (pelvic lymph node positive patients). Of this group (all of whom received some form of local therapy including radiation therapy), 22 had immediate orchiectomy, 27 delayed orchiectomy, 8 immediate exogenous hormone therapy, and 11 had no hormone therapy. The median interval of progression to bony metastasis was 43 months with the delayed hormone group versus 100 months for the immediately treated patients.12 A suggestion of a survival benefit was also reported with the median survival of 90 months in the delayed hormone group versus 150 months in the immediately treated group (P ⫽ .1110). In 1989, Pilepich et al13 reported on the Radiation Therapy Oncology Group’s (RTOG’s) first trial (83-07) looking at the potential benefit of hormonal cytoreduction in locally advanced prostate cancer. This was a phase II trial designed to compare the efficacy and toxicity of megestrol versus DES used as cytoreductive agents before and during radiation therapy. Eligible patients were those with histologically confirmed locally
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advanced adenocarcinoma of the prostate, clinical stage B2 and C without regional lymph node involvement or with lymph node involvement limited to the pelvis. Because of the emerging data linking DES to cardiovascular events, patients with medical conditions potentially predisposing to the thromboembolic sequelae of endocrine therapy were not eligible. Patients were stratified by clinical stage, histologic grade, and nodal status and were randomized to receive either megestrol 40 mg orally 3 times a day or DES 1 mg orally 3 times a day. Drugs were started 2 months before the beginning of radiation therapy and continued during radiation therapy and then stopped. Radiation therapy included treatment to the lymphatics to approximately 45 Gy and then a boost to the prostate for a total of 65 to 70 Gy. Two hundred and three patients were accrued; 197 were analyzable. With a median follow-up of 32 months, only 6.5% of all evaluable patients manifested evidence of local failure. There appeared to be no significant difference between the DES and megestrol regarding efficacy, (endpoint was tumor clearance), yet the DES appeared to be more effective in suppressing testosterone but with a price of an increase in toxicity. Toxicities of gynecomastia and fluid retention were seen in 55% and 21% of the DES patients, respectively, versus only 7% and 6% of the megestrol patients, respectively. The conclusion of this trial was that hormonal cytoreduction was feasible and potentially beneficial and should be tested in a phase III trial.13 During the same time frame as the RTOG was performing protocol 83-07, Porter et al14 were performing similar work in Canada.14 They reported on 2 pilot projects. The first in Alberta involved 15 patients treated with cyproterone acetate before definitive external radiation therapy. After 12 weeks of cyproterone acetate at a dose of 300 mg/d, approximately 80% of patients were thought by rectal examination to have local control and this was increased to over 90% after radiation therapy was complete. They reported on a similar group of 53 patients treated with radiation therapy alone during the same time period in which only 75% were locally controlled by rectal examination 12 months after radiation therapy. In addition, they found no discernible side effects of the cyproterone acetate during the 12 weeks of therapy. The other pilot study was done in Ontario on 18 patients. Cyproterone ac-
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etate was used to cytoreduce 18 patients. Four had a complete response to the cyproterone acetate before radiation therapy and 12 had partial responses. No complications were observed related to the cyproterone acetate. The authors pointed to the need for phase III work to finally answer the questions raised by multiple pilot trials suggesting a benefit of hormonal cytoreduction to radiation therapy.
Phase III Trials Three phase III trials were performed in the midand late 1980s to expand on the early work of the RTOG, Canadian pilot studies, and similar work performed in Western Europe. Two of these trials were performed in the United States by the RTOG (85-31 and 86-10),15,16 and the other was done in Europe by the European Organization for Research and Treatment of Cancer (EORTC).17 RTOG protocol 85-31 was a phase III prospective randomized trial designed to address the question of the potential role of adjuvant hormonal manipulation in radiation therapy for patients with unfavorable prostate cancer.15 Unfavorable prostate cancer patients were defined as those with regional lymph node involvement or gross extension of the palpable tumor beyond the prostate (clinical T3). T1 and T2 patients were eligible if there was either radiographic or histologic evidence of spread to the regional lymph nodes (pelvic and/or periaortic). Patients who had undergone prostatectomy were eligible if there was histologic evidence of pT3 disease (ie, through the prostatic capsule) with positive margins and/or seminal vesicle involvement. No patients could have distant metastatic disease. Nine hundred and seventy seven patients were accrued to this study from February 1987 through April 1992. These patients were randomized to receive either radiation therapy and adjuvant goserelin (arm I) starting during the last week of radiation therapy and continued indefinitely or until signs of progression or receive radiation therapy alone followed by observation with the use of goserelin if the patient showed signs of relapse (arm II). Treatment with radiation therapy was as follows: for patients with evidence of tumor spread to the pelvic lymphatics (obturator, external, or internal iliac lymph nodes) the initial treatment included a standard whole pelvis field to the level of the L-5 S-1 interspace. For patients with evidence
Table 1. Patient Characteristics for RTOG Protocol 85-31
Characteristic Gleason score 2-5 6-7 8-10 Centrally reviewed Gleason score Not done 2-5 6-7 8-10 Nodes Negative Positive* Acid phosphatase Not elevated Elevated Prostatectomy No Yes
Adjuvant Zoladex (n ⫽ 477)
Zoladex at Relapse (n ⫽ 468)
No.
%
No.
%
69 256 152
14 54 32
74 248 146
16 53 31
41 63 234 139
14 54 32
42 61 228 137
14 54 32
337 140
71 29
345 123
74 26
308 169
65 35
309 159
66 34
406 71
85 15
400 68
86 14
*Pathologic assessment was performed in 66% of node-positive cases. Reprinted with permission.15
of spread to the common iliac nodes, the upper border of the radiation field was raised to the L2-3 interspace. For patients with evidence of spread to the periaortic area, the upper border was extended to the T-11 vertebra. Postoperatively, patients with pN0 disease were not treated to the whole pelvis. The initial fields received a total of 44 to 46 Gy followed by a boost to the prostate of 20 to 25 Gy, bringing the total dose to the prostate to 65 to 70 Gy. Postoperatively, patients received a total dose of 60 to 65 Gy.15 For arm I patients, goserelin 3.6 mg was given as a subacute injection to the anterior abdominal wall on a monthly basis. Of the 977 patients accrued, 488 were on arm I (the adjuvant goserelin arm) and 489 on arm II. An initial analysis of this study occurred in June of 1996.15 Patient characteristics are shown in Table 1. Thirty-two patients were classified as ineligible and excluded from the analysis. Results of this initial report with a median follow-up of 4.5 years showed a statistically significant improvement in local progression, no evidence of disease (NED) survival, freedom from distant metastasis, and NED survival as defined by prostate-specific antigen (PSA)
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Table 2. Efficacy Endpoints: Summary of Efficacy Endpoints for All Patients
Local failure Distant metastases NED survival NED survival w/PSA ⬍1.5 ng/mL NED survival w/PSA ⬍4 ng/mL Absolute survival Cause-specific failure
I II I II I II I II I II I II I II
Total
No. of Failures
477 468 477 468 477 468 438 429 438 429 477 468 477 468
92 155 103 154 244 306 252 370 234 337 182 207 65 80
5 Year (%) 15% 31% 15% 29% 62% 44% 54% 21% 59% 28% 75% 71% 9% 13%
8 Year (%) 23% 37% 27% 37% 36% 25% 32% 8% 35% 13% 49% 47% 16% 21%
P Value ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 .36 .23
Reprinted with permission.18
less than 4 ng/mL or NED survival as defined by PSA ⬍1.5 ng/mL.15 Yet overall survival was not statistically improved. Subset analysis by Gleason score showed an overall survival benefit for patients with centrally reviewed Gleason scores 8 to 10. An update of this trial was reported in 2001 with a median follow-up of 5.6 years for all patients and 6 years for living patients.18 This update confirms the initial benefit reported on the adjuvant goserelin plus radiation therapy arm for endpoints of local failure, distant metastasis, NED survival, and PSA-defined NED survival (Table 2).18 Yet overall survival and cause specific failure were not statistically improved (P ⫽ .36 and .23, respectively; Table 2). Subset analysis did confirm the benefit in terms of all endpoints including overall survival and cause specific failure for Gleason score 8 to 10 patients who had not undergone prostatectomy.18 Further support for the use of adjuvant hormonal manipulation came from the EORTC.17 Bolla et al17 published on a group of 415 patients with locally advanced prostate cancer who were randomly assigned to radiation therapy alone versus radiation therapy plus adjuvant goserelin. Patients who were eligible for this trial included those less than 80 years of age with biopsy proven adenocarcinoma of the prostate whose disease was T1 or T2, N0-NX with World Health Organization histologic grade 3 or any T3 or T4 tumor without positive regional lymph nodes. Lymph node evaluation was done by computed tomography, bipedal lymphography, or lymph node dissection.
The radiation therapy fields were defined as whole pelvis with a 4-field technique (L5 to S-1 upper border, ischial tuberosities lower border, and 1 cm beyond the maximum width of the bony pelvis laterally) to a total dose of 50 Gy followed by a reduction to treat the prostate plus seminal vesicles for an additional 20 Gy. For those patients who received the adjuvant hormonal manipulation, it consisted of goserelin 3.6 mg subcutaneously every 4 weeks starting with the first day of radiation therapy and continuing for 3 years along with 150 mg of a steroidal antiandrogen (cyproterone acetate) given orally for 1 month starting 1 week before the goserelin to inhibit the rise of testosterone because of the goserelin. Of the 415 patients accrued between May 1987 and September 1995, 208 were randomly assigned to the radiation therapy alone group and 207 to the radiation therapy plus hormonal manipulation group. The initial analysis of this trial was reported in July 1997.17 With a median follow-up of 45 months, (14 patients were considered ineligible) of the 401 eligible patients (198 radiation therapy only and 203 radiation therapy plus hormones) the overall survival at 5 years for the radiation therapy plus adjuvant hormonal manipulation group was 79% versus 62% for the radiation therapy alone group. Of the 58 deaths in the radiation therapy only group, 26 were because of prostate cancer (50%), whereas of the 35 deaths in the radiation therapy plus adjuvant hormone group only 6 were because of prostate cancer (17%). PSA-determined disease-free survival at 5 years was likewise statistically improved
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Table 3. Efficacy Endpoints RTOG 86-10: Summary for All Patients (n ⫽ 456)
Local failure Distant metastases NED survival bNED survival w/PSA ⬍4 ng/mL bNED survival w/PSA ⬍1.5 ng/mL Survival Cause-specific failure
I II I II I II I II I II I II I II
Total
No. of Failures
5 Year (%)
8 Year (%)
P Value
226 230 226 230 226 230 201 203 201 203 226 230 226 230
72 98 82 104 160 183 158 180 170 194 112 136 52 74
22 35 29 39 49 34 39 20 28 10 72 68 15 20
30 42 34 45 33 21 24 10 16 3 53 44 23 31
.016 .04 .004 ⬍.0001 ⬍.0001 .10 .05
Reprinted with permission.16
with the addition of the hormonal manipulation 85% versus 48%. Local control was 97% for the combined group versus 77% for the radiation therapy alone group. An update of this trial was presented at the annual American Society of Therapeutic Radiation Oncology (ASTRO) meeting in 1999 with subsequent publication.20,32 With a median follow-up of 66 months, there continued to be statistically significant improvement in survival 78% versus 62% (P ⫽ .0002) and clinical disease-free survival 74% versus 40% (P ⫽ .0001) and 5-year specific survival 79% versus 94%.20,32 Economically this benefit of adding yearly hormonal manipulation to XRT can be equated to a mean increase in survival time of about 1 year and has been shown to reduce health care costs.33 With the adjuvant hormonal manipulation well addressed by the 2 previously mentioned trials, the RTOG opened protocol 86-10 to look at the neoadjuvant or potential cytoreduction question.16 In this phase III trial, patients with locally advanced prostate cancer, bulky clinical T2 through T4 (palpable tumor dimensions of 25 mL or more with or without pelvic lymph node involvement, but no distant metastasis), were randomized to receive goserelin 3.6 mg subacute every 4 weeks and flutamide 250 mg 3 times a day for 2 months before and 2 months during the radiation therapy (arm I) or radiation therapy alone (arm II). Patients with positive lymph nodes were eligible if the lymph nodes remained below the common iliac level. Four hundred and seventy-one patients were accrued to this study of
which 456 were evaluable, 226 on arm I and 230 on arm II. The radiation therapy for this trial consisted of whole-pelvis irradiation to the top of L5-S1 for patients who had no evidence of tumor spread to the pelvic lymphatics or to the L2-3 interspace for patients with known pelvic lymph node involvement. Dose to the whole pelvis was 44 to 46 Gy with up to 50 Gy acceptable followed by a 15 to 20 Gy boost to the prostate. Of the 456 patients determined to be eligible at a median follow-up of 4.5 years, the radiation therapy plus neoadjuvant hormonal manipulation arm showed a statistically significant improvement in local progression of 46% versus 71% (P ⬍ .001) and progression-free survival 36% versus 15% (P ⬍ .001).19 There was a trend toward improvement in distant metastasis-free survival (P ⫽ .09) but no improvement in overall survival.19 An update of this trial was published in 2001 with a median follow-up of 6.7 years and 8.6 years for surviving patients.16 For all patients entered a statistical benefit to the neoadjuvant hormones plus radiation therapy arm was seen in the following endpoints: local failure, incidence of distant metastasis, NED survival, biochemical NED survival with PSA less than 4 ng/mL as well as biochemical NED survival with PSA less than 1.5 ng/mL, and cause-specific failure (Table 3). Of particular interest was that the patients who seemed to benefit the most from this cytoreduction were patients with Gleason scores 2 to 6. In patients with centrally reviewed Gleason scores 2 to 6 (n ⫽ 129), there was an improvement in all
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Table 4. Efficacy Endpoints RTOG 86-10: Summary of Endpoints for Centrally Reviewed Gleason 2-6 (n ⫽ 129)
Local failure Distant metastases NED survival bNED survival w/PSA ⬍4 ng/mL bNED survival w/PSA ⬍1.5 ng/mL Survival Cause-specific failure
I II I II I II I II I II I II I II
Total
No. of Failures
5 Year (%)
8 Year
P Value
71 58 71 58 71 58 64 52 64 52 71 58 71 58
17 29 11 21 39 44 39 44 47 47 24 34 1 13
14 35 12 28 67 48 61 24 45 13 84 79 0 9
21 46 13 34 50 32 47 — 30 — 70 52 2 17
.005 .006 .004 ⬍.0001 ⬍.0001 .015 .0002
Reprinted with permission.16
endpoints including overall survival for the neoadjuvant hormone plus radiation therapy group (Table 4). Yet the survival improvement was not seen in either the centrally reviewed Gleason score 7 (n ⫽ 126) or in the Gleason score 8 to 10 (n ⫽ 124). In both of these higher-grade groups, the only endpoints statistically improved with neoadjuvant hormonal manipulation was biochemical NED survival. This suggested that this short-course hormonal manipulation and radiation was not the correct use of hormonal manipulation for the higher-grade tumors. A subset analysis of RTOG 85-31 and 86-10 also reported in 2001 provided further support of the concept of long-term adjuvant hormonal manipulation over short-term hormonal manipulation for locally advanced nonmetastatic prostate cancer patients.21 In this analysis, the patients from RTOG protocols 85-31 and 86-10 were combined to look at radiation therapy alone versus short course hormonal manipulation and radiation therapy versus long-term hormonal manipulation and radiation therapy. The long-term hormonal manipulation did not affect overall survival for the entire group of patients, but for the GS 7 group as well as the 8 to 10 subset the long-term hormonal manipulation did improve both cause specific survival as well as overall survival.21 RTOG protocol 92-02 was the phase III trial designed to answer the question now pending between short-course hormonal manipulation versus long-term hormonal manipulation and ra-
diation therapy for locally advanced disease patients.22 This trial randomized patients with clinical T2c-T4 prostate cancer and PSA less than 150 ng/mL to either goserelin and flutamide 250 mg 3 times a day 2 months before and 2 months during radiation therapy followed by no further therapy or the same treatment plus 24 months of goserelin. Fifteen hundred fifty-four patients were accrued to this study, of which 34 were found to be ineligible. Radiation therapy was 44 to 50 Gy to the pelvic lymph nodes and 65 to 70 Gy total to the prostate. With a median follow-up of 4.8 years, the group with long-term androgen deprivation showed a statistically significant improvement in disease-free survival 54% versus 37% (P ⫽ .0001), clinical local progression 6.2% versus 13% (P ⫽ .001), freedom from distant metastasis 11% versus 17% (P ⫽ .001), and biochemical NED control 21% versus 46% (P ⫽ .0001).22 There was a trend for a cause-specific survival difference favoring the long-term androgen deprivation arm 92% versus 87% (P ⫽ .07). Overall survival was not different. In a subset analysis of the Gleason score 8 to 10 tumors, there was an improvement in both overall survival 80% versus 69% (P ⫽ .02) and disease-specific survival 90% versus 78% (P ⫽ .007) favoring the long-term hormone arm. Another prospective randomized trial addressing the issue of radiation therapy plus or minus hormonal manipulation was published by Laverdiere et al.23 Between 1991 and 1994, they accrued 120 patients to a 3-arm trial of radiation
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alone versus radiation therapy plus three months of neoadjuvant hormonal manipulation in the form of a LHRH agonist versus radiation therapy plus the neoadjuvant LHRH agonist and an additional 6 months of adjuvant LHRH agonist.23 Eligible patients included those with adenocarcinoma of the prostate with measurable disease by digital rectal examination and no evidence of distant metastasis. At 12 and 24 months there was a statistically significant decrease in the positive biopsy rates in favor of the radiation plus hormone arms. In addition, there was an increase in biochemical control at 12 months with the hormonal radiation arms but not at 24 months.23 The most recent reported prospective randomized trial to address the timing of hormonal manipulation was RTOG protocol 94-13. Eligible patients were those with adenocarcinoma of the prostate whose estimated risk of pelvic lymph node involvement was ⬎15% based on the equation % ⫹ LN ⫽ (2/3) PSA ⫹ ([GS ⫺ 6] ⫻ 10) 34,35 or patients with T2c-T4 GS ⱖ 6 even if by the equation their risk of lymph node involvement did not meet 15%. Patients randomized had a mean PSA of 22.8 ng/mL, 67% had T2c to T4 clinically staged disease, and 72% had a Gleason score of 7 to 10. Randomization was to neoadjuvant hormone manipulation consisting of an LHRH agonist plus an antiandrogen for 2 months before and during radiation therapy or the same hormonal manipulation for 4 months after radiation therapy.24 Patients were also randomized between whole-pelvis radiation therapy plus a boost to the prostate versus radiation therapy to the prostate only. With a median follow-up of 59.3 months, patients treated with neoadjuvant hormonal manipulation and radiation had a 4-year progression-free survival of 53% versus 48% for the adjuvant hormone arm (P ⫽ .33). Patients treated with whole-pelvis radiation therapy plus a boost had a 4-year progression-free survival rate of 56% versus 46% for the prostateonly radiation therapy (P ⫽ .014). In the wholepelvis radiation therapy plus neoadjuvant hormonal manipulation arm, the progression-free survival rate was 61% at 4 years versus 45%, 49%, and 47% for the prostate-only plus neoadjuvant hormonal manipulation, whole-pelvis plus adjuvant hormonal manipulation arm, and prostateonly with adjuvant hormonal manipulation arm, respectively (P ⫽ .005).24 Overall survival was not
statistically different for any of the arms (P ⫽ .15); it was 88% versus 83%, 81%, and 82%, respectively for the whole-pelvis plus neoadjuvant hormonal manipulation versus prostate-only plus neoadjuvant hormonal manipulation, whole-pelvis adjuvant hormonal manipulation, and prostateonly adjuvant hormonal manipulation arms.24 Summary of Current Data Based on the trials completed to date, there appears to be several subsets of prostate cancer patients who benefit from hormonal manipulation plus radiation therapy over radiation therapy alone. Patients with clinical T3 tumors without evidence of distant metastasis and Gleason score ⱕ6 benefit from a short-course neoadjuvant total androgen suppression including a LHRH agonist and an antiandrogen (flutamide) for 4 months (2 months before radiation therapy and during radiation therapy). Patients with any T stage and no evidence of distant metastatic prostate cancer with Gleason scores 8 to 10 benefit from longterm LHRH treatment (ie, ⱖ2 years). Patients with T3, Gleason score 7 tumors also appear to benefit from long-term hormonal manipulation based on a meta-analysis of the RTOG protocols.25 These benefits do come with some potential toxicity, which will be discussed next.
Potential Toxicity of Hormonal Manipulation Hormonal manipulation, whether done as a short course over a few months or as a long-term maneuver over years, does have associated toxicities. These toxicities relate to the type of hormonal manipulation that is used. A brief overview of the toxicities is presented later. Using the LHRH agonists, which have been used in all the trials discussed in this article, results in impotence and hot flashes of varying degrees for the vast majority of patients. Yet other toxicities from these LHRH agonists are surfacing. Osteoporosis is a concern for patients who use these LHRH agonists. There is extensive data emerging to show that not only does osteoporosis occur in patients as measured by changes in bone mineral density,2729,36 but that the changes in bone mineral density are translating into clinically documented bone fractures.28 Given this information, serious consideration of
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evaluation for and treatment of osteoporosis should be done in patients treated with LHRH agonists, especially those in whom long-term LHRH treatment is planned. Use of preventative measures such as exercise, vitamin D, and calcium supplements need to be considered as well. Another concern for patients using LHRH agonists is anemia. A decrease in hematopoiesis does occur with advancing age, but there are data to show that the use of LHRH agonists can augment these problems and should be monitored.27 Other toxicities include loss of libido, weight gain, muscle wasting, and changes in texture of hair and skin.30 The antiandrogens used in the trials mentioned such as flutamide, cyproterone acetate, and bicalutamide have toxicities as well. Flutamide can cause diarrhea and occasionally breast and nipple tenderness, liver toxicity, and changes in hematopoiesis.30 Although bicalutamide appears to have fewer gastrointestinal toxicities, it still carries a risk of breast tenderness and gynecomastia.30 Yet none of the antiandrogens used alone carry the same risk of loss of libido and impotence that the LHRH agonists have.30 Finally, in RTOG protocol 92-02, there was a statistically significant increase in gastrointestinal toxicities (grade 3 and 4) in the long-term androgen deprivation arm.22 Subsequent analysis by the RTOG of patients on multiple trials comparing radiation therapy alone versus radiation therapy and androgen deprivation did not confirm this finding.31 Thus far, there does not appear to be any statistically significant augmentation in radiation therapy toxicities by the use of hormonal manipulation.
Conclusions Given the extensive scientific work that has been done regarding the potential benefit of hormonal manipulation and radiation therapy for patients with adenocarcinoma of the prostate, it is clear that there are benefits to the combination. Both a potential for cytoreduction as well as the potential control of micrometastatic disease has been documented. Patients with nonmetastatic, clinical T3 tumors, and Gleason scores ⱕ6 represent a group who benefit from hormonal cytoreduction.16 Although patients with any T stage and nondistant metastatic disease, Gleason scores 8 to 10 tumors benefit from long-term hormonal
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manipulation, most likely representing the control of micro-metastatic disease.15,20,22 Yet the following questions still remain: 1. To achieve the cytoreductive benefit seen in the clinical T3, Gleason score 6 tumors, does one need the LHRH agonist and the antiandrogen or would the LHRH agonist be enough? For cost and toxicity reasons, this is important. 2. To achieve the benefits seen in the high-grade patients, how long do they need to be on the LHRH agonist? Would 1 year be enough versus 2 or 3 as has been shown? What about the potential role for chemotherapy for these patients in addition to radiation therapy? RTOG protocol 99-02 is addressing this question. 3. What about Gleason score 7 tumors; if they are a 3 ⫹ 4 versus a 4 ⫹ 3, should they get different hormonal manipulation (ie, 3 ⫹ 4 short course v 4 ⫹ 3 long course)? Recent data suggests that these 2 types of Gleason score 7 tumors act differently.26 4. What does radiation therapy add to hormonal manipulation for locally advanced prostate cancer patients? This is currently being addressed in a prospective way through the National Cancer Institute of Canada Intergroup Study. We await these results. 5. Are there advantages to a longer course of neoadjuvant hormonal manipulation for patients with intermediate risk disease? Currently, RTOG protocol 99-10 is addressing this question. 6. Given the benefits seen with hormonal manipulation and radiation therapy for locally advanced disease and the benefits in dose escalation, what would be the overall benefit to dose escalation and hormonal manipulation? 7. How can we decrease the toxicity of the hormonal manipulations? For example, should we evaluate all patients for osteoporosis and suggest interventions early? All of these questions and many others still remain. We have made great strides in this area of prostate cancer treatment, yet there remains much in the way of fertile ground from which to grow some excellent scientifically based answers. We look to many of the ongoing protocols and some yet to come to answer these questions.
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References 1. White JW: The present position of the surgery of the hypertrophied prostate. Ann Surg 18:152-188, 1893 2. Huggins C, Clark PJ: Quantitative studies of prostatic secretion, II. The effect of castration and of estrogen injection on the normal and on the hyperplastic prostate glands of dogs. J Exp Med 72:747, 1940 3. Huggins C, Hodges C: The effects of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Studies on prostate cancer. Cancer Res 1:293-297, 1941 4. Huggins C, Stevens RE, Hodges C: The effect of castration on advanced carcinoma of the prostate gland. Studies on prostate cancer. Arch Surg 43:209-223, 1941 5. Walsh PC. Physiologic basis for hormonal therapy in carcinoma of the prostate. Urol Clin North Am 2:125-140, 1975 6. Hanks GE, Myers CE, Scardino PT: Cancer of the prostate, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology. Philadelphia PA, Lippincott JB, 1993, pp 1073-1113 7. Green N, Melbye R, Lipsett J, et al: Measures to improve therapeutic response and prevent complication. Urology 3:287-290, 1975 8. van der Werf-Messing B: Prostatic cancer treated at the Rottcrdam Radiotherapy Institute. Strahlentherapie 154: 537-541, 1978 9. Camuzzi F, Block N, Stover B, et al: Investigation of different combinations of estrogen therapy and radiation therapy on prostatic adenocarcinoma. Urology 15:443447, 1980 10. Green N, Bodner H, Broth E, et al: Response of lymph node metastasis to sequential estrogen and radiation therapy in prostate carcinoma. Urology 18:137-142, 1981 11. Green N, Chang C, Goldberg H, et al: Improved control of bulky prostate carcinoma with sequential estrogen and radiation therapy. Int J Radiat Oncol Biol Phys 10:971976, 1984 12. Kramolowsky E: The value of testosterone deprivation in stage D1 carcinoma of the prostate. J Urol 139:1242-1244, 1988 13. Pilepich MV, Krall JM, John J, et al: Hormonal cytoreduction in locally advanced carcinoma of the prostate treated with definitive radiotherapy: Preliminary results of RTOG 83-07. Int J Radiat Oncol Bio Phys 16:813-817, 1989 14. Porter AT, Venner PM: The role of cytoreduction prior to definitive radiotherapy in locally advanced prostate cancer—The Canadian Perspective. EORTC Genitourinary Group Monogram 8 Treatment of Prostatic Cancer— Facts and Controversies. Wiley-Liss Inc, 1990, pp 231-237 15. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorableprognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 15:1013-1021, 1997 16. Pilepich MV, Winter K, John MJ, et al: Phase III RTOG trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001
17. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295300, 1997 18. Lawton CA, Winter K, Murray K, et al: Updated results of the phase III RTOG trial 85-31. Evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49:937-946, 2001 19. Pilepich MF, Krall JM, 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 45:616-623, 1995 20. Bolla M, Collette L, Gonzalez D, et al: Long term results of immediate adjuvant hormonal therapy with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: A phase III EORTC study. Proceedings of the 41st Annual ASTRO Meeting. Int J Radiat Oncol Biol Phys 45:147, 1999 21. Horwitz EM, Winter K, Hanks GE, et al: Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs short term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 49:947-956, 2001 22. Hanks GE, Lu D, Machtay M, et al: RTOG Protocol 92-02: A phase III trial of the use of long term total androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 48:112, 2000 23. Laverdiere J, Gomez JL, Cusan L, et al: Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys 37:247-252, 1997 24. Roach III M, Lu C, Lawton C, et al: A phase III trial comparing whole pelvic (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): Preliminary analysis of RTOG 94-13. Proceedings of the 43rd annual ASTRO meeting. Int J Radiat Oncol Biol Phys 51:3, 2001 25. Roach III M, Lu J, Pilepich M, et al: Predicting long-term survival and the need for hormonal therapy: A metaanalysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 47:617-627, 2000 26. Makarov D, Sanderson H, Partin A, et al: Gleason score 7 prostate cancer on needle biopsy: Is the prognostic difference in Gleason scores 4 ⫹ 3 and 3 ⫹ 4 independent of the number of involved cores? J Urol 167:2440-2442, 2002 27. Stege R: Potential side-effects of endocrine treatment of long duration in prostate cancer. Prostate Suppl 10:38-42, 2000 28. Townsend MF, Sanders WH, Northway RO, et al: Associated with luteining hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 79:545-550, 1997 29. Berruti A, Dogliotti L, Terrone C, et al: Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients
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with prostate cancer without apparent bone metastases given given androgen deprivation therapy. J Urol 167: 2361-2367, 2002 30. McLead DG, Vogelzang NJ: Initial management of metastatic prostate cancer, in Vogelzang NJ, Scardino PT, Shipley WU, et al (eds): Comprehensive Textbook of Genitourinary Oncology. Philadelphia PA, Lippincott, 2000, pp 824-854 31. Cox J, Lu J, Pilepich M, et al. Does hormone therapy influence the risk of late effects in normal tissues irradiated for carcinoma of the prostate? Data from prospective trials of the RTOG. Presented at Am Radium Society (ARS), Monte Carlo, CA, April 4-8, 1998 32. Bolla M, Collette L, Blank L, et al: Long term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomized trial. Lancet 360:103-108, 2002
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33. Neymark N, Adriaenssen I, Gorelia T, et al: Estimating survival gain for economic evaluations with survival time as principal endpoints: A cost-effectiveness analysis of adding early hormonal therapy to radiotherapy in patients with locally advanced prostate cancer. Health Econ 11:233-248, 2002 34. Roach MRE: The use of prostate specific antigen, clinical stage, and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 150:1923-1924, 1993 35. Roach M, Marquez C, You H, et al. Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 28:33-37, 1993 36. Ross RW, Small EJ: Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 167:1952-1956, 2002
sections that outline the role of different types of hormonal manipulation that are currently available along with the early work combining hormonal manipulation and radiation therapy for prostate cancer. Subsequently, a thorough review of the phase III trials performed to evaluate the potential role of hormonal manipulation in addition to radiation therapy in locally advanced adenocarcinoma of the prostate. Included in that discussion is a section on the potential toxicities of hormonal manipulation. Finally, the current recommendations for the use of hormonal manipulation combined with radiation therapy in locally advanced adenocarcinoma of the prostate is described. © 2003 Elsevier Inc. All rights reserved.
H
androgen starts with the conversion of 17hydroxyl progesterone to dehydroepiandrosterone (DHEA). DHEA can go on to form DHEA-sulfate or androstenedione and subsequently testosterone.6 This pathway can be completed in the human testes, but in addition the adrenal glands produce DHEA, DHEAS, and androstenedione. The prostate, along with other tissues, has the enzymes necessary to convert the DHEA, DHEAS, and androstenedione to testosterone and ultimately to dihydrotestosterone (DHT). It is the DHT molecule that is taken up by the prostate and binds to the cytosolic receptor. This receptor complex is then translocated into the nucleus of prostate cells and activates messenger RNA and protein synthesis and is important in sustaining prostatic epithelium (Fig 1). It is important to realize that given 2 sources of testosterone in humans and therefore, DHT (ie the testis and adrenals), 90% of circulating testosterone is of testicular origin, whereas 60% of prostatic testosterone is of testicular origin.6 This discrepancy points to the important contribution of the adrenals to androgen production. With the synthesis of androgens understood, there are 3 ways to decrease testosterone, and therefore, decrease DHT. The first method is suppression of the pituitary luteinizing hormone (LH) release. The LH-hormone agonist (LHRH agonists) interferes with the hypothalamic-pituitary-testicular axis that regulates the production of testosterone. Examples are goserelin acetate
ormone dependency of the prostate was first described in 1895 by White1 who showed the first association between castration and the treatment of prostatic disease in men with bladder outlet obstruction secondary to benign prostatic hypertrophy. Subsequently, Huggins2 in 1940 showed an association between the normal and hyperplastic epithelium of canine prostate glands and adequate levels of circulating androgens. Finally, in 1941, Huggins and Hodges3,4 showed the androgen dependence of prostatic adenocarcinoma through the castration and measuring of serum acid phosphatase levels on patients with metastatic disease. This pioneering work led to extensive investigation of the role of androgens in prostatic growth, both benign and malignant. It was Walsh5 who summarized the precise mechanism of action of androgens on prostatic growth. To understand the potential role of androgen manipulation for locally advanced prostate cancer, one must understand the basics of androgen synthesis. In humans, the synthesis of
From the Medical College of Wisconsin, Radiation Oncology, Milwaukee, WI. Address reprint requests to Colleen A. Lawton, MD, FACR, Medical College of Wisconsin, Department of Radiation Oncology, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1302-0007$30.00/0 doi:10.1053/srao.2003.50013
Seminars in Radiation Oncology, Vol 13, No 2 (April), 2003: pp 141-151
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Early Work Combining Radiation Therapy and Hormonal Manipulations
Figure 1. A schematic of androgen synthesis.
and leuprolide. Diethylstilbestrol (DES) also decreases LH release. LHRH agonists initially (ie, after 2-3 days) cause an increase in LH production and therefore testosterone production, but after 3 to 5 days, the LH release and testosterone production declines to castrate levels in approximately 3 to 4 weeks.6 The second method to decrease androgen production is through the use of compounds that block the effect of the androgen at the target organ. These compounds interfere with the cellular events that mediate androgen actions. In effect, they inhibit the binding of the DHT to the receptor complex. There are 2 groups of these antiandrogens: nonsteroidal and steroidal. Examples of nonsteroidal antiandrogens are flutamide, biclutamide, and nilutamide. Examples of the steroidal antiandrogens are megestrol acetate and cyproterone acetate. The final mechanism to alter androgen synthesis is inhibition of steroidal genesis. Both aminoglutethimide and ketoconazole work in this manner. Given a basic understanding of the mechanisms of potential androgen suppression, locally advanced prostate cancer and the role of antiandrogens combined with radiation to treat these patients are now discussed.
Theoretically, a decrease in androgens could aid the control of locally advanced prostate cancer in 1 of 2 ways: either through cytoreduction or through control of micrometastatic disease. It was Green et al7 in 1975 who reported one of the initial studies combining radiation therapy with estrogens. This study included 80 patients treated with radiation therapy for adenocarcinoma of the prostate, 35 of whom also received estrogens during the radiation and for 3 months after radiation therapy. The majority of the patients had locally advanced but nonmetastatic disease. Although the dose of estrogen was not specified, the authors report that those patients who had the most favorable tumor response were those who received estrogen.7 Green et al7 note that neither estrogens alone nor radiation therapy alone reliably controlled locally advanced prostate cancer but that the combination in their study proved to give the best tumor control. In 1978, van der Werf-Messing8 reported on 142 patients with T3-4NXM0 adenocarcinoma of the prostate of whom 26 received hormones alone, 32 received hormones and external radiation therapy, and 84 patients were treated with external radiation alone. Results of this work showed actuarial uncorrected survival rates after 3 to 5 years that were slightly better for patients treated with external radiation therapy alone, although there was no statistically significant difference between the arms. Cardiovascular events contributed to 40% of the intercurrent deaths in patients who received hormones (ie, estrogens), which is almost the same death rate as metastatic deaths in the radiation alone group.8 These data were some of the first to suggest that any benefit of hormonal manipulation in conjunction with radiation therapy may be offset by the cardiovascular toxicity of estrogens. At about the same time, Camuzzi et al9 reported in a rat model, the role of estrogen, and radiation therapy for prostatic adenocarcinoma. They found similar findings to van der WerfMessing in that the combination of radiation therapy and estrogen therapy did not show greater inhibition of tumor growth than radiation therapy alone.9 Green et al10 continued pursuing the concept of estrogens and radiation therapy in locally ad-
Adenocarcinoma of the Prostate
vanced disease. In 1981, they reported on a group of 35 patients with pelvic or pelvic plus periaortic lymph node metastasis.10 This group of patients was treated with 3 mg/d of DES for 8 weeks before radiation therapy and maintained throughout radiation therapy. The DES was discontinued in 25 patients after 6 months. Eighteen unselected patients of the initial 35 who had radiation therapy and DES had comparison diagnostic studies performed to evaluate the response of the primary tumor and lymph node metastasis to the DES. Results of the study suggested a benefit to DES regarding cytoreduction and the benefit of this before radiation in allowing the radiation therapy to better control the cytoreduced disease.10 Continuing this work in 1984, Green et al11 reported on 36 patients with bulky prostate cancer. Twenty-five patients received estrogen for cytoreduction (3 mg DES) before radiation therapy. This group of patients was compared with 11 patients treated with radiation therapy alone. These data revealed a local control rate of 72% for the combined group (median follow-up, 4 years) compared with 55% local control for the RT-only group.11 Building on the concept of the potential benefit of hormonal manipulation for locally advanced disease, Kramolowsky12 published data from the University of Iowa in 1987. He reported on 68 patients with D1 (pelvic lymph node positive patients). Of this group (all of whom received some form of local therapy including radiation therapy), 22 had immediate orchiectomy, 27 delayed orchiectomy, 8 immediate exogenous hormone therapy, and 11 had no hormone therapy. The median interval of progression to bony metastasis was 43 months with the delayed hormone group versus 100 months for the immediately treated patients.12 A suggestion of a survival benefit was also reported with the median survival of 90 months in the delayed hormone group versus 150 months in the immediately treated group (P ⫽ .1110). In 1989, Pilepich et al13 reported on the Radiation Therapy Oncology Group’s (RTOG’s) first trial (83-07) looking at the potential benefit of hormonal cytoreduction in locally advanced prostate cancer. This was a phase II trial designed to compare the efficacy and toxicity of megestrol versus DES used as cytoreductive agents before and during radiation therapy. Eligible patients were those with histologically confirmed locally
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advanced adenocarcinoma of the prostate, clinical stage B2 and C without regional lymph node involvement or with lymph node involvement limited to the pelvis. Because of the emerging data linking DES to cardiovascular events, patients with medical conditions potentially predisposing to the thromboembolic sequelae of endocrine therapy were not eligible. Patients were stratified by clinical stage, histologic grade, and nodal status and were randomized to receive either megestrol 40 mg orally 3 times a day or DES 1 mg orally 3 times a day. Drugs were started 2 months before the beginning of radiation therapy and continued during radiation therapy and then stopped. Radiation therapy included treatment to the lymphatics to approximately 45 Gy and then a boost to the prostate for a total of 65 to 70 Gy. Two hundred and three patients were accrued; 197 were analyzable. With a median follow-up of 32 months, only 6.5% of all evaluable patients manifested evidence of local failure. There appeared to be no significant difference between the DES and megestrol regarding efficacy, (endpoint was tumor clearance), yet the DES appeared to be more effective in suppressing testosterone but with a price of an increase in toxicity. Toxicities of gynecomastia and fluid retention were seen in 55% and 21% of the DES patients, respectively, versus only 7% and 6% of the megestrol patients, respectively. The conclusion of this trial was that hormonal cytoreduction was feasible and potentially beneficial and should be tested in a phase III trial.13 During the same time frame as the RTOG was performing protocol 83-07, Porter et al14 were performing similar work in Canada.14 They reported on 2 pilot projects. The first in Alberta involved 15 patients treated with cyproterone acetate before definitive external radiation therapy. After 12 weeks of cyproterone acetate at a dose of 300 mg/d, approximately 80% of patients were thought by rectal examination to have local control and this was increased to over 90% after radiation therapy was complete. They reported on a similar group of 53 patients treated with radiation therapy alone during the same time period in which only 75% were locally controlled by rectal examination 12 months after radiation therapy. In addition, they found no discernible side effects of the cyproterone acetate during the 12 weeks of therapy. The other pilot study was done in Ontario on 18 patients. Cyproterone ac-
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etate was used to cytoreduce 18 patients. Four had a complete response to the cyproterone acetate before radiation therapy and 12 had partial responses. No complications were observed related to the cyproterone acetate. The authors pointed to the need for phase III work to finally answer the questions raised by multiple pilot trials suggesting a benefit of hormonal cytoreduction to radiation therapy.
Phase III Trials Three phase III trials were performed in the midand late 1980s to expand on the early work of the RTOG, Canadian pilot studies, and similar work performed in Western Europe. Two of these trials were performed in the United States by the RTOG (85-31 and 86-10),15,16 and the other was done in Europe by the European Organization for Research and Treatment of Cancer (EORTC).17 RTOG protocol 85-31 was a phase III prospective randomized trial designed to address the question of the potential role of adjuvant hormonal manipulation in radiation therapy for patients with unfavorable prostate cancer.15 Unfavorable prostate cancer patients were defined as those with regional lymph node involvement or gross extension of the palpable tumor beyond the prostate (clinical T3). T1 and T2 patients were eligible if there was either radiographic or histologic evidence of spread to the regional lymph nodes (pelvic and/or periaortic). Patients who had undergone prostatectomy were eligible if there was histologic evidence of pT3 disease (ie, through the prostatic capsule) with positive margins and/or seminal vesicle involvement. No patients could have distant metastatic disease. Nine hundred and seventy seven patients were accrued to this study from February 1987 through April 1992. These patients were randomized to receive either radiation therapy and adjuvant goserelin (arm I) starting during the last week of radiation therapy and continued indefinitely or until signs of progression or receive radiation therapy alone followed by observation with the use of goserelin if the patient showed signs of relapse (arm II). Treatment with radiation therapy was as follows: for patients with evidence of tumor spread to the pelvic lymphatics (obturator, external, or internal iliac lymph nodes) the initial treatment included a standard whole pelvis field to the level of the L-5 S-1 interspace. For patients with evidence
Table 1. Patient Characteristics for RTOG Protocol 85-31
Characteristic Gleason score 2-5 6-7 8-10 Centrally reviewed Gleason score Not done 2-5 6-7 8-10 Nodes Negative Positive* Acid phosphatase Not elevated Elevated Prostatectomy No Yes
Adjuvant Zoladex (n ⫽ 477)
Zoladex at Relapse (n ⫽ 468)
No.
%
No.
%
69 256 152
14 54 32
74 248 146
16 53 31
41 63 234 139
14 54 32
42 61 228 137
14 54 32
337 140
71 29
345 123
74 26
308 169
65 35
309 159
66 34
406 71
85 15
400 68
86 14
*Pathologic assessment was performed in 66% of node-positive cases. Reprinted with permission.15
of spread to the common iliac nodes, the upper border of the radiation field was raised to the L2-3 interspace. For patients with evidence of spread to the periaortic area, the upper border was extended to the T-11 vertebra. Postoperatively, patients with pN0 disease were not treated to the whole pelvis. The initial fields received a total of 44 to 46 Gy followed by a boost to the prostate of 20 to 25 Gy, bringing the total dose to the prostate to 65 to 70 Gy. Postoperatively, patients received a total dose of 60 to 65 Gy.15 For arm I patients, goserelin 3.6 mg was given as a subacute injection to the anterior abdominal wall on a monthly basis. Of the 977 patients accrued, 488 were on arm I (the adjuvant goserelin arm) and 489 on arm II. An initial analysis of this study occurred in June of 1996.15 Patient characteristics are shown in Table 1. Thirty-two patients were classified as ineligible and excluded from the analysis. Results of this initial report with a median follow-up of 4.5 years showed a statistically significant improvement in local progression, no evidence of disease (NED) survival, freedom from distant metastasis, and NED survival as defined by prostate-specific antigen (PSA)
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Table 2. Efficacy Endpoints: Summary of Efficacy Endpoints for All Patients
Local failure Distant metastases NED survival NED survival w/PSA ⬍1.5 ng/mL NED survival w/PSA ⬍4 ng/mL Absolute survival Cause-specific failure
I II I II I II I II I II I II I II
Total
No. of Failures
477 468 477 468 477 468 438 429 438 429 477 468 477 468
92 155 103 154 244 306 252 370 234 337 182 207 65 80
5 Year (%) 15% 31% 15% 29% 62% 44% 54% 21% 59% 28% 75% 71% 9% 13%
8 Year (%) 23% 37% 27% 37% 36% 25% 32% 8% 35% 13% 49% 47% 16% 21%
P Value ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 .36 .23
Reprinted with permission.18
less than 4 ng/mL or NED survival as defined by PSA ⬍1.5 ng/mL.15 Yet overall survival was not statistically improved. Subset analysis by Gleason score showed an overall survival benefit for patients with centrally reviewed Gleason scores 8 to 10. An update of this trial was reported in 2001 with a median follow-up of 5.6 years for all patients and 6 years for living patients.18 This update confirms the initial benefit reported on the adjuvant goserelin plus radiation therapy arm for endpoints of local failure, distant metastasis, NED survival, and PSA-defined NED survival (Table 2).18 Yet overall survival and cause specific failure were not statistically improved (P ⫽ .36 and .23, respectively; Table 2). Subset analysis did confirm the benefit in terms of all endpoints including overall survival and cause specific failure for Gleason score 8 to 10 patients who had not undergone prostatectomy.18 Further support for the use of adjuvant hormonal manipulation came from the EORTC.17 Bolla et al17 published on a group of 415 patients with locally advanced prostate cancer who were randomly assigned to radiation therapy alone versus radiation therapy plus adjuvant goserelin. Patients who were eligible for this trial included those less than 80 years of age with biopsy proven adenocarcinoma of the prostate whose disease was T1 or T2, N0-NX with World Health Organization histologic grade 3 or any T3 or T4 tumor without positive regional lymph nodes. Lymph node evaluation was done by computed tomography, bipedal lymphography, or lymph node dissection.
The radiation therapy fields were defined as whole pelvis with a 4-field technique (L5 to S-1 upper border, ischial tuberosities lower border, and 1 cm beyond the maximum width of the bony pelvis laterally) to a total dose of 50 Gy followed by a reduction to treat the prostate plus seminal vesicles for an additional 20 Gy. For those patients who received the adjuvant hormonal manipulation, it consisted of goserelin 3.6 mg subcutaneously every 4 weeks starting with the first day of radiation therapy and continuing for 3 years along with 150 mg of a steroidal antiandrogen (cyproterone acetate) given orally for 1 month starting 1 week before the goserelin to inhibit the rise of testosterone because of the goserelin. Of the 415 patients accrued between May 1987 and September 1995, 208 were randomly assigned to the radiation therapy alone group and 207 to the radiation therapy plus hormonal manipulation group. The initial analysis of this trial was reported in July 1997.17 With a median follow-up of 45 months, (14 patients were considered ineligible) of the 401 eligible patients (198 radiation therapy only and 203 radiation therapy plus hormones) the overall survival at 5 years for the radiation therapy plus adjuvant hormonal manipulation group was 79% versus 62% for the radiation therapy alone group. Of the 58 deaths in the radiation therapy only group, 26 were because of prostate cancer (50%), whereas of the 35 deaths in the radiation therapy plus adjuvant hormone group only 6 were because of prostate cancer (17%). PSA-determined disease-free survival at 5 years was likewise statistically improved
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Table 3. Efficacy Endpoints RTOG 86-10: Summary for All Patients (n ⫽ 456)
Local failure Distant metastases NED survival bNED survival w/PSA ⬍4 ng/mL bNED survival w/PSA ⬍1.5 ng/mL Survival Cause-specific failure
I II I II I II I II I II I II I II
Total
No. of Failures
5 Year (%)
8 Year (%)
P Value
226 230 226 230 226 230 201 203 201 203 226 230 226 230
72 98 82 104 160 183 158 180 170 194 112 136 52 74
22 35 29 39 49 34 39 20 28 10 72 68 15 20
30 42 34 45 33 21 24 10 16 3 53 44 23 31
.016 .04 .004 ⬍.0001 ⬍.0001 .10 .05
Reprinted with permission.16
with the addition of the hormonal manipulation 85% versus 48%. Local control was 97% for the combined group versus 77% for the radiation therapy alone group. An update of this trial was presented at the annual American Society of Therapeutic Radiation Oncology (ASTRO) meeting in 1999 with subsequent publication.20,32 With a median follow-up of 66 months, there continued to be statistically significant improvement in survival 78% versus 62% (P ⫽ .0002) and clinical disease-free survival 74% versus 40% (P ⫽ .0001) and 5-year specific survival 79% versus 94%.20,32 Economically this benefit of adding yearly hormonal manipulation to XRT can be equated to a mean increase in survival time of about 1 year and has been shown to reduce health care costs.33 With the adjuvant hormonal manipulation well addressed by the 2 previously mentioned trials, the RTOG opened protocol 86-10 to look at the neoadjuvant or potential cytoreduction question.16 In this phase III trial, patients with locally advanced prostate cancer, bulky clinical T2 through T4 (palpable tumor dimensions of 25 mL or more with or without pelvic lymph node involvement, but no distant metastasis), were randomized to receive goserelin 3.6 mg subacute every 4 weeks and flutamide 250 mg 3 times a day for 2 months before and 2 months during the radiation therapy (arm I) or radiation therapy alone (arm II). Patients with positive lymph nodes were eligible if the lymph nodes remained below the common iliac level. Four hundred and seventy-one patients were accrued to this study of
which 456 were evaluable, 226 on arm I and 230 on arm II. The radiation therapy for this trial consisted of whole-pelvis irradiation to the top of L5-S1 for patients who had no evidence of tumor spread to the pelvic lymphatics or to the L2-3 interspace for patients with known pelvic lymph node involvement. Dose to the whole pelvis was 44 to 46 Gy with up to 50 Gy acceptable followed by a 15 to 20 Gy boost to the prostate. Of the 456 patients determined to be eligible at a median follow-up of 4.5 years, the radiation therapy plus neoadjuvant hormonal manipulation arm showed a statistically significant improvement in local progression of 46% versus 71% (P ⬍ .001) and progression-free survival 36% versus 15% (P ⬍ .001).19 There was a trend toward improvement in distant metastasis-free survival (P ⫽ .09) but no improvement in overall survival.19 An update of this trial was published in 2001 with a median follow-up of 6.7 years and 8.6 years for surviving patients.16 For all patients entered a statistical benefit to the neoadjuvant hormones plus radiation therapy arm was seen in the following endpoints: local failure, incidence of distant metastasis, NED survival, biochemical NED survival with PSA less than 4 ng/mL as well as biochemical NED survival with PSA less than 1.5 ng/mL, and cause-specific failure (Table 3). Of particular interest was that the patients who seemed to benefit the most from this cytoreduction were patients with Gleason scores 2 to 6. In patients with centrally reviewed Gleason scores 2 to 6 (n ⫽ 129), there was an improvement in all
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Table 4. Efficacy Endpoints RTOG 86-10: Summary of Endpoints for Centrally Reviewed Gleason 2-6 (n ⫽ 129)
Local failure Distant metastases NED survival bNED survival w/PSA ⬍4 ng/mL bNED survival w/PSA ⬍1.5 ng/mL Survival Cause-specific failure
I II I II I II I II I II I II I II
Total
No. of Failures
5 Year (%)
8 Year
P Value
71 58 71 58 71 58 64 52 64 52 71 58 71 58
17 29 11 21 39 44 39 44 47 47 24 34 1 13
14 35 12 28 67 48 61 24 45 13 84 79 0 9
21 46 13 34 50 32 47 — 30 — 70 52 2 17
.005 .006 .004 ⬍.0001 ⬍.0001 .015 .0002
Reprinted with permission.16
endpoints including overall survival for the neoadjuvant hormone plus radiation therapy group (Table 4). Yet the survival improvement was not seen in either the centrally reviewed Gleason score 7 (n ⫽ 126) or in the Gleason score 8 to 10 (n ⫽ 124). In both of these higher-grade groups, the only endpoints statistically improved with neoadjuvant hormonal manipulation was biochemical NED survival. This suggested that this short-course hormonal manipulation and radiation was not the correct use of hormonal manipulation for the higher-grade tumors. A subset analysis of RTOG 85-31 and 86-10 also reported in 2001 provided further support of the concept of long-term adjuvant hormonal manipulation over short-term hormonal manipulation for locally advanced nonmetastatic prostate cancer patients.21 In this analysis, the patients from RTOG protocols 85-31 and 86-10 were combined to look at radiation therapy alone versus short course hormonal manipulation and radiation therapy versus long-term hormonal manipulation and radiation therapy. The long-term hormonal manipulation did not affect overall survival for the entire group of patients, but for the GS 7 group as well as the 8 to 10 subset the long-term hormonal manipulation did improve both cause specific survival as well as overall survival.21 RTOG protocol 92-02 was the phase III trial designed to answer the question now pending between short-course hormonal manipulation versus long-term hormonal manipulation and ra-
diation therapy for locally advanced disease patients.22 This trial randomized patients with clinical T2c-T4 prostate cancer and PSA less than 150 ng/mL to either goserelin and flutamide 250 mg 3 times a day 2 months before and 2 months during radiation therapy followed by no further therapy or the same treatment plus 24 months of goserelin. Fifteen hundred fifty-four patients were accrued to this study, of which 34 were found to be ineligible. Radiation therapy was 44 to 50 Gy to the pelvic lymph nodes and 65 to 70 Gy total to the prostate. With a median follow-up of 4.8 years, the group with long-term androgen deprivation showed a statistically significant improvement in disease-free survival 54% versus 37% (P ⫽ .0001), clinical local progression 6.2% versus 13% (P ⫽ .001), freedom from distant metastasis 11% versus 17% (P ⫽ .001), and biochemical NED control 21% versus 46% (P ⫽ .0001).22 There was a trend for a cause-specific survival difference favoring the long-term androgen deprivation arm 92% versus 87% (P ⫽ .07). Overall survival was not different. In a subset analysis of the Gleason score 8 to 10 tumors, there was an improvement in both overall survival 80% versus 69% (P ⫽ .02) and disease-specific survival 90% versus 78% (P ⫽ .007) favoring the long-term hormone arm. Another prospective randomized trial addressing the issue of radiation therapy plus or minus hormonal manipulation was published by Laverdiere et al.23 Between 1991 and 1994, they accrued 120 patients to a 3-arm trial of radiation
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alone versus radiation therapy plus three months of neoadjuvant hormonal manipulation in the form of a LHRH agonist versus radiation therapy plus the neoadjuvant LHRH agonist and an additional 6 months of adjuvant LHRH agonist.23 Eligible patients included those with adenocarcinoma of the prostate with measurable disease by digital rectal examination and no evidence of distant metastasis. At 12 and 24 months there was a statistically significant decrease in the positive biopsy rates in favor of the radiation plus hormone arms. In addition, there was an increase in biochemical control at 12 months with the hormonal radiation arms but not at 24 months.23 The most recent reported prospective randomized trial to address the timing of hormonal manipulation was RTOG protocol 94-13. Eligible patients were those with adenocarcinoma of the prostate whose estimated risk of pelvic lymph node involvement was ⬎15% based on the equation % ⫹ LN ⫽ (2/3) PSA ⫹ ([GS ⫺ 6] ⫻ 10) 34,35 or patients with T2c-T4 GS ⱖ 6 even if by the equation their risk of lymph node involvement did not meet 15%. Patients randomized had a mean PSA of 22.8 ng/mL, 67% had T2c to T4 clinically staged disease, and 72% had a Gleason score of 7 to 10. Randomization was to neoadjuvant hormone manipulation consisting of an LHRH agonist plus an antiandrogen for 2 months before and during radiation therapy or the same hormonal manipulation for 4 months after radiation therapy.24 Patients were also randomized between whole-pelvis radiation therapy plus a boost to the prostate versus radiation therapy to the prostate only. With a median follow-up of 59.3 months, patients treated with neoadjuvant hormonal manipulation and radiation had a 4-year progression-free survival of 53% versus 48% for the adjuvant hormone arm (P ⫽ .33). Patients treated with whole-pelvis radiation therapy plus a boost had a 4-year progression-free survival rate of 56% versus 46% for the prostateonly radiation therapy (P ⫽ .014). In the wholepelvis radiation therapy plus neoadjuvant hormonal manipulation arm, the progression-free survival rate was 61% at 4 years versus 45%, 49%, and 47% for the prostate-only plus neoadjuvant hormonal manipulation, whole-pelvis plus adjuvant hormonal manipulation arm, and prostateonly with adjuvant hormonal manipulation arm, respectively (P ⫽ .005).24 Overall survival was not
statistically different for any of the arms (P ⫽ .15); it was 88% versus 83%, 81%, and 82%, respectively for the whole-pelvis plus neoadjuvant hormonal manipulation versus prostate-only plus neoadjuvant hormonal manipulation, whole-pelvis adjuvant hormonal manipulation, and prostateonly adjuvant hormonal manipulation arms.24 Summary of Current Data Based on the trials completed to date, there appears to be several subsets of prostate cancer patients who benefit from hormonal manipulation plus radiation therapy over radiation therapy alone. Patients with clinical T3 tumors without evidence of distant metastasis and Gleason score ⱕ6 benefit from a short-course neoadjuvant total androgen suppression including a LHRH agonist and an antiandrogen (flutamide) for 4 months (2 months before radiation therapy and during radiation therapy). Patients with any T stage and no evidence of distant metastatic prostate cancer with Gleason scores 8 to 10 benefit from longterm LHRH treatment (ie, ⱖ2 years). Patients with T3, Gleason score 7 tumors also appear to benefit from long-term hormonal manipulation based on a meta-analysis of the RTOG protocols.25 These benefits do come with some potential toxicity, which will be discussed next.
Potential Toxicity of Hormonal Manipulation Hormonal manipulation, whether done as a short course over a few months or as a long-term maneuver over years, does have associated toxicities. These toxicities relate to the type of hormonal manipulation that is used. A brief overview of the toxicities is presented later. Using the LHRH agonists, which have been used in all the trials discussed in this article, results in impotence and hot flashes of varying degrees for the vast majority of patients. Yet other toxicities from these LHRH agonists are surfacing. Osteoporosis is a concern for patients who use these LHRH agonists. There is extensive data emerging to show that not only does osteoporosis occur in patients as measured by changes in bone mineral density,2729,36 but that the changes in bone mineral density are translating into clinically documented bone fractures.28 Given this information, serious consideration of
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evaluation for and treatment of osteoporosis should be done in patients treated with LHRH agonists, especially those in whom long-term LHRH treatment is planned. Use of preventative measures such as exercise, vitamin D, and calcium supplements need to be considered as well. Another concern for patients using LHRH agonists is anemia. A decrease in hematopoiesis does occur with advancing age, but there are data to show that the use of LHRH agonists can augment these problems and should be monitored.27 Other toxicities include loss of libido, weight gain, muscle wasting, and changes in texture of hair and skin.30 The antiandrogens used in the trials mentioned such as flutamide, cyproterone acetate, and bicalutamide have toxicities as well. Flutamide can cause diarrhea and occasionally breast and nipple tenderness, liver toxicity, and changes in hematopoiesis.30 Although bicalutamide appears to have fewer gastrointestinal toxicities, it still carries a risk of breast tenderness and gynecomastia.30 Yet none of the antiandrogens used alone carry the same risk of loss of libido and impotence that the LHRH agonists have.30 Finally, in RTOG protocol 92-02, there was a statistically significant increase in gastrointestinal toxicities (grade 3 and 4) in the long-term androgen deprivation arm.22 Subsequent analysis by the RTOG of patients on multiple trials comparing radiation therapy alone versus radiation therapy and androgen deprivation did not confirm this finding.31 Thus far, there does not appear to be any statistically significant augmentation in radiation therapy toxicities by the use of hormonal manipulation.
Conclusions Given the extensive scientific work that has been done regarding the potential benefit of hormonal manipulation and radiation therapy for patients with adenocarcinoma of the prostate, it is clear that there are benefits to the combination. Both a potential for cytoreduction as well as the potential control of micrometastatic disease has been documented. Patients with nonmetastatic, clinical T3 tumors, and Gleason scores ⱕ6 represent a group who benefit from hormonal cytoreduction.16 Although patients with any T stage and nondistant metastatic disease, Gleason scores 8 to 10 tumors benefit from long-term hormonal
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manipulation, most likely representing the control of micro-metastatic disease.15,20,22 Yet the following questions still remain: 1. To achieve the cytoreductive benefit seen in the clinical T3, Gleason score 6 tumors, does one need the LHRH agonist and the antiandrogen or would the LHRH agonist be enough? For cost and toxicity reasons, this is important. 2. To achieve the benefits seen in the high-grade patients, how long do they need to be on the LHRH agonist? Would 1 year be enough versus 2 or 3 as has been shown? What about the potential role for chemotherapy for these patients in addition to radiation therapy? RTOG protocol 99-02 is addressing this question. 3. What about Gleason score 7 tumors; if they are a 3 ⫹ 4 versus a 4 ⫹ 3, should they get different hormonal manipulation (ie, 3 ⫹ 4 short course v 4 ⫹ 3 long course)? Recent data suggests that these 2 types of Gleason score 7 tumors act differently.26 4. What does radiation therapy add to hormonal manipulation for locally advanced prostate cancer patients? This is currently being addressed in a prospective way through the National Cancer Institute of Canada Intergroup Study. We await these results. 5. Are there advantages to a longer course of neoadjuvant hormonal manipulation for patients with intermediate risk disease? Currently, RTOG protocol 99-10 is addressing this question. 6. Given the benefits seen with hormonal manipulation and radiation therapy for locally advanced disease and the benefits in dose escalation, what would be the overall benefit to dose escalation and hormonal manipulation? 7. How can we decrease the toxicity of the hormonal manipulations? For example, should we evaluate all patients for osteoporosis and suggest interventions early? All of these questions and many others still remain. We have made great strides in this area of prostate cancer treatment, yet there remains much in the way of fertile ground from which to grow some excellent scientifically based answers. We look to many of the ongoing protocols and some yet to come to answer these questions.
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