Management of High Risk Prostate Cancer
▪ 12A Combined Hormone Therapy and Radiation Therapy for High-Risk Prostate Cancer
Michel Bolla
Mack Roach III
INTRODUCTION
High-risk prostate cancer is conventionally considered to include men with locally advanced prostate cancer (T3-4 N0-X M0), those with high-grade disease defined as a Gleason scores of 8 to 10 (T1-2 N0-X M0) or those with a pretreatment serum PSA > 20 ng/mL (1). Introduced by Huggins (2), the primary treatment of locally advanced prostate cancer was once hormone therapy (HT) obtained by an androgen suppression (AS) with orchiectomy or estrogens. AS is based on the dependence of prostatic epithelial and adenocarcinoma cells on androgenic hormones, and more than 80% of the patients respond favorably to surgical or chemical castration with side effects (3), which resulted in a replacement by an agonist analog of the luteinizing hormone-releasing hormone (LHRH), during the 1980s with the same efficacy (4). During the 1970s and 1980s, patients with high-risk prostate cancer were treated by definitive conventional irradiation, but the poor results in terms of local control and survival (5,6) prompted the advent of phases III randomized trials combining radiotherapy (RT) and AS.
Nowadays the incidence of locally advanced prostate cancer has decreased as a result of screening (7) and long-term HT has become a “standard of care.” The incidence of early T-stage localized prostate cancer is increasing, and selected patients with intermediate or poor risk may benefit from shortterm HT. The local control remains of paramount importance, better obtained by three-dimensional conformal radiotherapy and/or intensified modulated radiotherapy (3D-CRT and/or IMRT), which has replaced conventional irradiation without increasing the risk of morbidity (8). We consider successively the rationale of the combined approach, the results of phase III trials devoted to locally advanced prostate cancer and high-risk localized prostate cancer (Table 12A.1), and the questions that remain unsolved so far, the combination with chemotherapy and finally morbidity and quality of life referring to HT.
RATIONALE FOR COMBINING ANDROGEN SUPPRESSION WITH RADIATION THERAPY
The objectives of combining AS with irradiation are numerous: (i) to decrease the volume of the prostate, thereby decreasing the volume of the treatment fields and improving the dose-volume histogram; (ii) to reduce the risk of local relapse within the irradiated volume by inhibiting repopulation during irradiation; (iii) to decrease the occurrence of distant metastases due to infraclinical deposits at the time of diagnosis; and (iv) to improve the effectiveness of radiation by an additive or supraadditive effect. To assess the effect of sequencing of AD by the means of castration and RT on prostate cancer growth, animal studies have been done on transplantable androgen-dependent tumor, treated by radiation alone, radiation preceded by orchiectomy, radiation followed by orchiectomy, and/or androgen restoration. Zietman et al. (9) have used a transplantable murine mammary androgendependent tumor (Shionogi tumor model) as allografts in the hind limbs of athymic nude mice and have shown that neoadjuvant AD (given 12 days before RT) provides the greatest effect according to TCD 50. Joon et al. (10) used Dunning R3327-G rat prostate tumors transplanted in the flanks of Copenhagen rats, and a supraadditive apoptotic response was obtained when castration was initiated 3 days prior to radiation. Kaminski et al. (11) have used R3327-G rat prostate tumors implanted in the flanks of Copenhagen rats and have calculated the tumor volume doubling time: The results suggest that neoadjuvant AD may result in prolonged suppression of tumor growth, even after testosterone replacement. All these results were obtained from animal models under experimental conditions that do not allow hormonal treatment during and after irradiation to be delivered in a more protracted way.
COMBINED HORMONE THERAPY AND RADIATION THERAPY: RESULTS OF THE PHASE III TRIALS
Very High Risk
The main trials showing a survival benefit were launched by the Radiation Therapy Oncology Group (RTOG) and the Radiotherapy Oncology Group of the European Organisation on Treatment and Research on Cancer (EORTC). These trials are mainly devoted to T3-4 N0-X M0 patients, but the cohorts include sometimes bulky T2 patients; all these trials deal with goserelin acetate (Zoladex), an agonist analog of LHRH. Two trials were done before with conventional modalities of castration. One, conducted at the MD Anderson Cancer Center on a small cohort of 78 T3 NX M0 patients treated by pelvic RT alone or combined with DES (5 mg), has shown a striking difference in 15-year disease-free survival in favor of the combined treatment, not translated in improvement of overall survival (12). The other, launched by the Medical Research Council (13), focused on 277 T2-4 NX M0 cases treated by castration (90), RT (88), or combined treatment (99): irradiation was left to the discretion of each treatment centre; it resulted that orchiectomy delayed the onset of distant metastases, and RT or orchiectomy proved equally effective in controlling local disease.
TABLE 12A.1 SUMMARY OF MAJOR PROSPECTIVE TRIALS USING HORMONAL THERAPY AND RADIOTHERAPY | ||||||||||||||||||||||||||||||||||||||||||||
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Concomitant and Long-Term LHRH Adjuvant Hormonal Treatment
The EORTC study 22863 recruited 415 patients with cT1-2 NO histological grade 3 OMS, cT3-4 N0 M0 to compare RT with concomitant and adjuvant hormone therapy (AHT) to RT alone, with HT in case of relapse; 82% of patients were T3, 10% T4, and 89% N0. The hormone treatment was oral cyproterone acetate, 50 mg 3 times daily for 1 month, beginning 1 week before the start of RT and subcutaneous injection of Zoladex 3.6 mg every 4 weeks for 3 years starting on the first day of RT. The pelvic target volume received 50 Gy and the prostatic target volume 20 Gy. With a median follow-up of 66 months, there was a significant difference in survival, 78% in favor of the combination versus 62% for RT alone (p = 0.001) (14).The updated results with a median follow-up of 9.1 years confirm that the addition of hormonotherapy increased the clinical disease-free survival from 22.7% to 47.7% at 10 years (p < 0.0001), distant progression-free survival (PFS) from 30.2% to 51.0% at 10 years (p < 0.0001), and overall survival from 39.8% to 58.1% at 10 years (p = 0.0004). The 10-year prostate cancer mortality was 31.0% with RT alone and 11.2% with long-term androgen suppression (LTAS) combined with RT (p < 0.001) (15).
Long-Term LHRH Adjuvant Hormonal Treatment
The RTOG Trial 85-31 was designed to evaluate the effectiveness of indefinite Zoladex alone after RT; 977 patients with stages T3-4 M0 with or without lymph node involvement, or pT3 after radical prostatectomy in the event of capsule invasion, positive margins, or seminal vesicle involvement were included. Monthly administration of Zoladex was started during the last week of radiation therapy and was continued indefinitely or until relapse (arm 1) or started at relapse (arm 2); no antiandrogen was given at the very start of Zoladex, to inhibit the initial rise of LH and then of testosterone. Fifteen percent of patients had undergone radical prostatectomy in group 1 and 14% in group 2, and 29% and 26% had lymph node involvement in group 1 and 2, respectively. The pelvic target volume received 45 Gy and the prostate target volume 65 to 70 Gy. Patients with a pT3 tumor received 60 to 65 Gy to the postoperative target volume. The combined approach has been associated with all 8-year efficacy endpoints except overall survival (49% vs. 47%; p = 0.36); subset analysis by Gleason score revealed a significant overall survival (p = 0.036) in favor of the AHT arm for centrally reviewed Gleason 8 to 10 patients who had not previously undergone prostatectomy (16). With a median follow-up time of 7.6 years, statistical significances were reached in favor of the AHT arm for 10-year overall survival (49% vs. 39%; p < 0.002), 10-year incidence of distant metastases (24% vs. 39%; p < 0.001), and disease-specific mortality (16% vs. 22%; p = 0.005) (17).
In this trial, 173 patients had biopsy-proven pN1 lymph nodes, and 98 of these received RT plus AHT; with a median follow-up of 6.5 years, multivariate analysis revealed that the combined approach had a statistical impact on all endpoints: overall survival (p = 0.03), disease-specific failure (p = 0.014), metastatic failure (p < 0.0005), and biochemical control (p < 0.0001) (18). These data are in keeping with those of Granfors et al. (19) who compared the combination of orchiectomy and RT (45) to RT alone and androgen ablation at clinical disease progression (46) for T1-4 pN0-3 M0; the study was prematurely closed due to an insufficient accrual. After a median follow-up of 9.3 years, there was a
significant difference in overall survival (p = 0.02) and PFS (p = 0.005) in favor of the combined arm; this difference was mainly caused by lymph node positive tumors. In conclusion, patients with pathologically or clinically involved pelvic lymph nodes should be considered for RT plus immediate long-term HT.
significant difference in overall survival (p = 0.02) and PFS (p = 0.005) in favor of the combined arm; this difference was mainly caused by lymph node positive tumors. In conclusion, patients with pathologically or clinically involved pelvic lymph nodes should be considered for RT plus immediate long-term HT.
Neoadjuvant and Concomitant Short-Term Combined Androgen Suppression
The RTOG trial 86-10 was designed to test the potential value of a combined androgen suppression (CAS) with Zoladex and flutamide, prior to (2 months) and during radiation therapy (2 months) with respect to RT alone, or at relapse; 471 patients with bulky (5 × 5 cm) tumors (T2-4) with or without regional lymph node involvement were included; 7% had a positive nodal status in the combined treatment arm versus 9% in the RT alone arm. Thirty percent of patients had a T2 tumor, 70% T3-4, and 91% of tumors were node-negative. Hormonal treatment consisted of oral flutamide (250 mg 3×day) and a subcutaneous injection of Zoladex 3.6 mg every 4 weeks (20). The pelvis received 45 Gy and the prostate target volume 65 to 70 Gy. At 8 years, AS has been associated with all efficacy endpoints except overall survival, but subset analysis demonstrated that a significant enhancement in overall survival was seen in patients with Gleason score 2 to 6: 70% versus 52%; p = 0.015. These results were maintained at 10 years with a significant difference in disease specific mortality (23% vs. 36%; p = 0.01), distant metastases (35% vs. 47%; p = 0.006), disease-free survival (11% vs. 3%; p < 0.0001), but no difference in 10-year overall survival (43% vs. 34%; p = 0.12) (21).
The Trans-Tasman Radiation Oncology Group 96.01 trial has included 818 men randomly assigned to RT alone (66 Gy/33 fractions) (22), 3 months’ androgen deprivation with goserelin and flutamide starting 2 months before RT or 6 months’ AS with the same regimen starting 5 months before RT; median follow-up was 5.9 years. Compared with patients assigned RT alone those assigned 3 months’ AS had significantly improved local failure (p = 0.001), biochemical failure-free survival (p = 0.002), and disease-free survival (p = 0.0001). Six months’ AS improved local failure (p < 0.0001), biochemical failure-free survival (p < 0.0001), distant failure (p = 0.04), and prostate cancer-specific survival (p = 0.04) (Fig. 12A.1)
 FIGURE 12A.1. Treatment schema for the Trans-Tasman Radiation Oncology Group and TTROG 96.01 randomized prospective Trial of radiation therapy and adjuvant hormonal therapy. (PSA, prostate specific antigen). |
These two trials suggest that the significant impact of HT on disease-specific survival is certainly due to the concomitant component of HT during RT. In the trial reported by Crook’s et al. (23), 378 patients were randomized between 3 months and 8 months of neoadjuvant CAS with flutamide and goserelin before RT (66 Gy): With a median follow-up of 44 months, there was no impact on biochemical control or survival. Nevertheless, starting AS 2 or 3 months before RT may be useful to decrease the tumor volume of high-risk prostate cancer and improve DVH, while treating the patient immediately instead of delaying the onset of irradiation.
Short-Term Neoadjuvant Versus Short-Term Adjuvant Combined Androgen Suppression with Whole Pelvis or Prostate Only Radiotherapy
RTOG 94-13 study is a four-arm trial devoted to 1,323 patients T1c-4 N0 M0 PSA < 100 ng with an estimated risk of lymph node involvement more than 15%. The first randomization is done between neoadjuvant concurrent hormone therapy (NCHT)—2 months before and 2 months during RT—and 4-month AHT after RT; the second randomization took place between whole pelvis radiotherapy (WPRT) followed by a boost to the prostate or prostate only radiotherapy (PORT). WPRT plus NCHT improved the 4-year PFS (61%) compared with PORT + NCHT (45%), PORT + AHT (49%), and WPRT +AHT (47%) (p = 0.008), and there was no advantage to WPRT over PORT without neoadjuvant AS (24). With longer follow-up, PFS and biochemical failure (Phoenix definition) continue to favor the WPRT arm (p = 0.034 and 0.0098, respectively), but we await the major secondary endpoints, cause-specific and overall survival, since not enough events had occurred (25).
Long-Term Androgen Suppression Alone is Inferior to Long-Term Androgen Suppression Plus Radiation Therapy
The abovementioned studies have shown the efficacy of hormonal treatment combined with RT, but the impact of LTAS
alone was not assessed so far (Fig. 12A.2). The SPCG-7/SFUO-3 trial has included 875 patients with T1b-2, G2-3, or T3 of any WHO histological grade (1,2,3) (78% of T3) with baseline PSA < 70 ng/mL; patients were randomly allocated to endocrine treatment alone (3 months of total androgen blockade followed by continuous treatment using flutamide [439 patients]) or to the same endocrine treatment combined with RT (436 patients). After a median follow-up of 7.6 years, the cumulative incidence at 10 years for prostate cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus RT group for a relative risk of 0.44 (0.30-0.66); the cumulative incidence for overall mortality was 39.4% and 29.6% with a relative risk of 0.68 (0.52-0.89) (26). In conclusion, in patients with locally advanced or high-risk localized prostate cancer, the combination of RT to HT halved the 10-year prostate cancer-specific mortality and decreased overall mortality with fully acceptable risk of side effects, compared to HT alone.
alone was not assessed so far (Fig. 12A.2). The SPCG-7/SFUO-3 trial has included 875 patients with T1b-2, G2-3, or T3 of any WHO histological grade (1,2,3) (78% of T3) with baseline PSA < 70 ng/mL; patients were randomly allocated to endocrine treatment alone (3 months of total androgen blockade followed by continuous treatment using flutamide [439 patients]) or to the same endocrine treatment combined with RT (436 patients). After a median follow-up of 7.6 years, the cumulative incidence at 10 years for prostate cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus RT group for a relative risk of 0.44 (0.30-0.66); the cumulative incidence for overall mortality was 39.4% and 29.6% with a relative risk of 0.68 (0.52-0.89) (26). In conclusion, in patients with locally advanced or high-risk localized prostate cancer, the combination of RT to HT halved the 10-year prostate cancer-specific mortality and decreased overall mortality with fully acceptable risk of side effects, compared to HT alone.
 FIGURE 12A.2. Treatment schema for the Scandinavian Prostate Cancer Group Study and the Swedish Association for Urological Oncology and SPCG-7/SFUO-3 randomized prospective trial of radiation therapy and adjuvant hormonal therapy. (PSA, prostate specific antigen). |
Short-Term Androgen Suppression is Inferior to Long-Term Androgen Suppression
The aim of RTOG protocol 92-02 devoted to 1,554 patients classified as T2c-4N0 was to investigate the value of an LTAS after a short-term androgen suppression (STAS). All patients received 2 months of CAS with Zoladex and flutamide before RT, followed during RT; a radiation dose of 65 to 70 Gy was given to the prostate. Patients were randomly assigned to receive no additional therapy or 24 months of Zoladex. Compared with the STAS, the LTAS arm showed significant improvement in all efficacy endpoints except 5-year overall survival; in a subset of patients Gleason scores 8 to 10, the LTAS arm had significantly better overall survival: 81% versus 70.7%, (p = 0.04) (27). The 10-year results confirmed significant benefits in all 10-year efficacy endpoint terms except overall survival (p = 0.35); in a subset analysis, the overall survival benefit was limited to patients with Gleason score 8 to 10 (p = 0.006) (28).
EORTC (22863) and RTOG (85,86) trials have demonstrated that LTAS (>2 years) is recommended for high-risk prostate cancer (level I evidence), but they do not precisely determine the optimal duration of hormonal treatment combined with external-beam irradiation. That is why the EORTC equivalence trial 22961 (Fig. 12A.3) randomly assigned patients who had received 3D-CRT plus 6 months of AS to two groups: one to receive no further treatment (STAS) and the other to receive 2.5 years of further treatment with an LHRH agonist (triptorelin) (LTAS). An outcome of noninferiority of STAS as compared to LTAS required a HR of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429; 970 patients were randomized: 483 STAS and 487 LTADS. At a median followup of 6.4 years, the 5-year overall survival shows 84.8% for the LTAS arm and 81% for the STAS arm with an estimated HR of 1.42 (p = 0.008). The 5-year clinical PFS was 80.5% for the LTAS arm and 68.7% for STAS arm (p < 0.0001). The 5-year biochemical PFS was 77.7% on the LTAS arm versus 56.8% for the STAS arm p < 0.0001. In conclusion, the combination of RT plus 6 months of AS provides inferior survival as compared with RT plus 3 years of AS (29).
Additional support can be found in a retrospective analysis assessing combined HT with external irradiation (median follow-up > 45 months), which showed that long-term AD (median duration 25.6 months) improves 5-year overall survival (87.5%) with respect to short-term AD (75%) (p = 0.009) in patients with a PSA level > 20 ng/mL, irrespective of Gleason score and T stage (30).
Intermediate- and High-Risk Localized Prostate Cancer
A prospective trial concerning 206 localized prostate cancer was performed by D’Amico to determine whether a survival benefit was obtained when adding 6 months of AS to 70 Gy 3D-CRT for patients of T1b to T2b NX M0 with a baseline PSA ≥ 10 ng/mL and ≤40 ng or a Gleason score of at least 7 (range 5-10); low-risk patients were ineligible unless they had radiologic evidence of extracapsular extension or seminal vesicle invasion. After a median follow-up of 4.5 years, patients who received 3D-CRT plus AS had a higher survival (p = 0.04) and a lower cancer specific mortality (p = 0.02) (31). With a median follow-up of 7.6 years, overall survival was higher for men who were randomized RT and AS compared with RT: 74% versus 61% (p = 0.01), but the survival benefit varies according to comorbidity illness profile; among the 49 patients with moderate or severe comorbidity, the 8-year overall survival was 25% for those randomized to RT and AS as compared to 54% for those with RT (p = 0.08) (32).
In RTOG trial 94-08 (33), which has accrued 1,979 patients with T1b-T2b localized prostate cancer, a stratification was
done with PSA (lower than 20 ng/mL), histological grade, and nodal status. Patients were randomized between neodjuvant CAB, 2 months before conventional irradiation and 2 months during irradiation (66.6 Gy) versus irradiation alone. The 10-year overall survival was 62% for the combined approach versus 57% (p = 0.03). In conclusion, the addition of neoadjuvant and concomitant CAB—4 to 6 months—with irradiation (66.6-70 Gy) improved overall survival in men with intermediate-or poor-risk localized prostate cancer without moderate or severe comorbidity.
done with PSA (lower than 20 ng/mL), histological grade, and nodal status. Patients were randomized between neodjuvant CAB, 2 months before conventional irradiation and 2 months during irradiation (66.6 Gy) versus irradiation alone. The 10-year overall survival was 62% for the combined approach versus 57% (p = 0.03). In conclusion, the addition of neoadjuvant and concomitant CAB—4 to 6 months—with irradiation (66.6-70 Gy) improved overall survival in men with intermediate-or poor-risk localized prostate cancer without moderate or severe comorbidity.
 FIGURE 12A.3. Treatment schema for the European Organization for Research and Treatment of Cancer (EORTC) and EORTC 22961 randomized prospective trial of radiation therapy and adjuvant hormonal therapy. (PSA, prostate specific antigen). |
UNSOLVED QUESTIONS
Is Combined Androgen Suppression During 4 or 6 Months of Value as Compared with 6-Month LHRH Analog Alone?
The rationale of using an antiandrogen in association with an LHRH agonist is (a) to block the androgens of adrenal origin, which are left free to continue to stimulate prostate cancer (34); (b) to block the androgen receptors to prevent the socalled “flare” that can result due to the surge in testosterone resulting from the use of LHRH agonist; and (c) to contribute independent antitumor activity. We do not know the optimal duration of combined androgen blockade in high-risk patients, and the range in the abovementioned trials was 4 to 6 months. To resolve this question, it is likely to require a very large study, and since a meta-analysis of 27 randomized trials devoted to advanced prostate cancer has shown that the addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3%, with a range of uncertainty between 0% and 5% the range, it is unlikely that the effect would be very large (35). On the other hand, although the effect might be quite small in patients with metastatic disease, it might be larger in men with high risk but localized prostate analogous to the benefits of adjuvant 5-Fu chemotherapy for regional as compared to metastatic disease (36,37,38). Considering this hypothetical gain with the possibility of using dose escalation, the choice of a combined androgen blockade or an LHRH agonist has to be left to the discretion of physicians. However, since no trials using short-term HT have been completed with LHRH alone, the authors recommend at a minimum that an antiandrogen be given for 1 month to inhibit the clinical effects of testosterone due to the transient rise of LH, which may have a potential harmful effect when LHRH analogs are prescribed alone (39).
What is the Value of Dose Escalation?
Several trials have shown a significant benefit of dose escalation exceeding 68 to 70 Gy for patients with prostate cancer classified as T1b-T3. Based on these trials, it is clear that 70 Gy is no more sufficient in high-risk localized prostate cancer. The MD Anderson Cancer Center phase III trial (40), which accrued 301 patients with stage T1b-T3, showed an improvement in freedom from biochemical failure or clinical failure in favor of the 78-Gy arm. Biochemical control was 78% for the 78-Gy arm, as compared with 59% for the 70-Gy arm (p = 0.004) with an even greater benefit seen in patients with initial PSA > 10 ng/mL: 78% versus 39%, p = 0.0014.
For high-risk localized prostate cancer, since we do not have data of high-dose RT alone (78/80 Gy) compared to 70 Gy plus AS, the standard treatment has to remain the latter. Dearnaley et al. reported the findings of the MRC Trial RT01 assessing whether higher than standard-dose “conventional dose” EBRT could improve outcomes when administered with
CAS. The hazard ratio (HR) for freedom from PSA failure was 0.67 (95% CI 0.53-0.85; p = 0.0007) for the dose escalated group and the 5-year control rate was 71% for the high dose compared to 60% for conventional dose group. Of note, there was also a trend for improved freedom from salvage AS, HR of 0.78 (0.57-1.07; p = 0.12); and metastases-free survival was 0.74 (0.47-1.18; p = 0.21) (41). We are eager to wait the results of EORTC trial 22991, which has accrued 820 patients, comparing 3D-CRT +/− IMRT alone with three levels of dose (70, 74, 78 Gy) versus the same regimen plus 6 months AS. In intermediate-risk localized prostate cancer, there is likely a room for dose escalation alone, provided the dose is ≥78Gy. The results of RTOG trial 94-08 in good and intermediaterisk localized prostate cancer have shown an improvement of 10-year overall survival (33) with 66.6 Gy plus 4 months of CAB, but we do not have data concerning a trial with a dose escalation RT alone arm.
CAS. The hazard ratio (HR) for freedom from PSA failure was 0.67 (95% CI 0.53-0.85; p = 0.0007) for the dose escalated group and the 5-year control rate was 71% for the high dose compared to 60% for conventional dose group. Of note, there was also a trend for improved freedom from salvage AS, HR of 0.78 (0.57-1.07; p = 0.12); and metastases-free survival was 0.74 (0.47-1.18; p = 0.21) (41). We are eager to wait the results of EORTC trial 22991, which has accrued 820 patients, comparing 3D-CRT +/− IMRT alone with three levels of dose (70, 74, 78 Gy) versus the same regimen plus 6 months AS. In intermediate-risk localized prostate cancer, there is likely a room for dose escalation alone, provided the dose is ≥78Gy. The results of RTOG trial 94-08 in good and intermediaterisk localized prostate cancer have shown an improvement of 10-year overall survival (33) with 66.6 Gy plus 4 months of CAB, but we do not have data concerning a trial with a dose escalation RT alone arm.
For patients with locally advanced prostate cancer, dose escalation will certainly have an impact on survival outcomes, as suggested by the Zapatero trial (42). They reported on a cohort of 416 patients: 181 low-risk treated by 3D-CRT alone, 75 intermediate-risk allocated to receive neoadjuvant 4 to 6 months before and during 3D-CRT, and 160 high-risk receiving neoadjuvant and adjuvant 3D-CRT 2 years after RT. With a stratification for treatment group, the 5-year biochemical disease-free survival for high-risk patients with AS was 63% for dose less than 72 Gy and 84% for dose ≥72 Gy (p = 0.003).
In a MSKC retrospective analysis (8), 296 cT3 patients were treated with dose escalation, and prior to RT, 189 (43%) were treated with STAS. They noted that CRT +/− IMRT was associated with excellent tumor control and survival outcomes with a 10-year local control rates of 88% and a 10-year cause specific survival of 83%, respectively, 88% for T3a and 79% for T3b. The incidence of late grade 3 urinary and rectal toxicities was remarkable at only 4% and 1%. In conclusion, in the management of locally advanced prostate cancer, (despite the absence of level I evidence for a significant impact on overall survival), based on the promising results associated with the use of innovative techniques allowing dose escalation, it appears that bulky tumors should be treated to 76 to 78 Gy.
Do We Need Pelvic Lymph Node Irradiation for High-Risk Patients?
The RTOG 9413 trial (24,25) has shown a positive impact of neoadjuvant AS with WPRT on PFS. Although the results of RTOG 9413 were not confirmed by the GETUG-01 trial, there are important differences between the studies that may explain the different conclusions (43). First the French study was smaller with a target sample size of 444 T1b-T3 N0 pNX M0 patients (compared to more than 1,200 on RTOG 9413). In the GETUG trial, STAS was allowed but not required for patients in the high-risk group, and 56.8% of the patients had a lymph node risk lower than 15% according to the Roach formula (thus the number of patients at risk for positive nodes was much smaller) (44). They noted no difference in 5-year PFS between the pelvic (46 Gy) and prostate RT (66-70 Gy) arm, with a 42-month median follow-up, but none of the patients received WPRT using the RTOG cutoff at L5-S1 interspace. Investigators from the RTOG have should this to be a critical determinant of outcome (44). The definition of the limit of the pelvic fields is of paramount importance and Shih et al. (45) have shown that by using lymphotropic nanoparticlesenhanced magnetic resonance imaging, 80% of the metastatic nodes were located only in the pelvis with a superior border of 2 cm above the common iliac bifurcation; moreover, lateral rectal shielding to reduce the rectal dose contribution resulted in an underdosage of the presacral lymph nodes (46). We need a consensus about the definition of the pelvic lymph nodes PTV, allowing to choose an optimal IMRT technique to be able to cover the correct lymph node volume and to prescribe an appropriate dose (47).
CHEMOTHERAPY
Taxanes are radiosensitizer agents, which block the cell cycle during the G2/M-phase, inhibiting the antiapoptotic effect of bcl-2 and inducing apoptosis (48,49). Moreover, docetaxel has been shown to produce a cytotoxic effect during the S-phase, known to be radioresistant (50). In androgen-dependent and -independent human prostate cancer xenografts, docetaxel showed a significant antitumoral effect in hormone-sensitive tumors compared with mitoxantrone and estramustine (51). In patients with castration-resistant prostate cancer, the results of randomized trials showed a significant improvement in biological response and survival in favor of docetaxelcontaining regimens compared with the reference treatment (52,53). These results have prompted testing the drug in locally advanced prostate cancer within the frame of phase II trials assessing the feasibility of concomitant or concomitant and adjuvant docetaxel (54,55), with RT and phase III randomized trials assessing the role of adjuvant docetaxel with AS and RT (56).
HEALTH-RELATED QUALITY OF LIFE RELATED TO ANDROGEN SUPPRESSION
AS is known to adversely affect quality of life, leading to hot flushes, fatigue, impact on cognitive function, sexual side effects, anemia, weight gain, insulin resistance, bone loss (57,58) increased diagnoses of cardiac disease (59), and metabolic side effects (60). These side effects assessed by a self-administered questionnaire (60) are in relation with the prevalent comorbidities of the patients and the duration of the treatment. As regards the cardiovascular mortality, the retrospective analysis made on the data of the EORTC and RTOG trials by taking into account all deaths linked to cardiovascular disease have shown that long-term AS did not increase the cumulative incidence estimates of cardiovascular mortality as compared with short-term or no androgen deprivation (15,29,61,62). Using data of the 92-02 RTOG trial, Smith et al. (63) have found that weight, but not prevalent diabetes, is associated with prostate cancer mortality in men undergoing combined treatment, but prevalent diabetes was associated with greater all-cause and non-prostate cancer mortality. Many studies have demonstrated that chronic AS was associated with an increased risk of fractures: Shahinian et al. (58) studying records from the Surveillance, Epidemiology, and end results database and Medicare mentioned that of men surviving at least 5 years, 19.4% of those who received AS had a fracture versus 12.6% of those not receiving this treatment (p < 0.001). After RT and 6 months of androgen blockade, fatigue, hot flushes, and sexual problems increased significantly and both statistically (p < 0.001) and clinically (29); for patients continuing AS after 6 months for 2.5 years more, there were statistically significant differences between the groups in term of insomnia (p = 0.006), hot flushes (p < 0.001), and sexual interest and activity (p < 0.001), but overall quality of life did not differ significantly between the two groups (p = 0.37) (29).
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