Management of high-risk prostate cancer: Radiation therapy and hormonal therapy

Cancer Treatment Reviews xxx (2013) xxx–xxx

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Anti-Tumour Treatment

Management of high-risk prostate cancer: Radiation therapy and hormonal therapy Takuma Nomiya a,⇑, Hiroshi Tsuji a, Shingo Toyama a, Katsuya Maruyama a, Kenji Nemoto b, Hirohiko Tsujii a, Tadashi Kamada a a b

National Institute for Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan Yamagata University Hospital, Yamagata, Japan

a r t i c l e

i n f o

Article history: Received 24 February 2013 Received in revised form 4 April 2013 Accepted 8 April 2013 Available online xxxx Keywords: Prostatic neoplasms Radiotherapy Androgen antagonists Clinical trial Review

s u m m a r y The prognosis of high-risk prostate cancer is poor with a high mortality rate. The Radiation Therapy Oncology Group (RTOG) has performed dose-escalation studies of external beam radiation therapy (EBRT) and has developed high-precision radiation therapy (RT) methods such as intensity-modulated RT, carbon ion therapy, and proton beam therapy. High-dose rate brachytherapy (HDR-BT) is also studied as an option for high-risk prostate cancer treatment. Past clinical trials have suggested that the local control rate of high-risk prostate cancer improves with total EBRT dose, even for doses >70 Gy. Several randomized controlled trials, including RTOG 94-06, have shown significantly better prognoses with higher doses (>75 Gy) than with lower doses (<70 Gy). A proton beam therapy trial (PROG 95–09) also showed similar results. A phase II clinical trial (National Institute for Radiological Sciences, Japan; trial 9904) showed that carbon ion therapy resulted in very good biochemical recurrence-free survival rates among high-risk prostate cancer patients, demonstrating particle therapy to be a valid treatment option. RTOG 86-10 showed that short-term neo-adjuvant hormonal therapy (HT) was inadequate for high-risk prostate cancer but effective for intermediate-risk prostate cancer, whereas RTOG 92-02 and the European Organisation for Research and Treatment of Cancer (EORTC) 22863 showed significant improvements in the prognosis of high-risk groups receiving long-term (>2 years) HT combined with definitive RT. Further studies are warranted to elucidate optimal irradiation doses, HT treatment durations, and combination therapy schedules. Ó 2013 Elsevier Ltd. All rights reserved.

Introduction Several risk classifications for prostate cancer are used to define the prognosis of the disease in routine medical practice, and the classifications proposed by D’Amico et al.1 and the National Comprehensive Cancer Network (NCCN)2 are particularly well known. The risk classification by D’Amico et al. defines high-risk prostate cancer as disease accompanied by a prostate specific antigen (PSA) level of >20 ng/mL, a Gleason score of P8, and/or T-factor PT2c. The NCCN guideline defines high-risk prostate cancer as disease accompanied by a PSA level of >20 ng/mL, a Gleason score of P8, and/or T-factor PT3a or disease accompanied by two or more intermediate risk factors. Although there are some differences between the risk classifications, the boundaries of each risk are generally consistent. On the other hand, the consensus of definition of PSA failure after definitive radiation therapy (RT) has been changed several times. Fixed PSA cutoff values were used previously. While three ⇑ Corresponding author. Tel.: +81 43 206 3360; fax: +81 43 206 6506. E-mail addresses: [email protected], [email protected] (T. Nomiya).

consecutive increases in PSA have been defined as biochemical failure by the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus statement, a PSA increase of P2.0 ng/mL above the nadir PSA level has been defined as biochemical failure by the Radiation Therapy Oncology Group (RTOG)–ASTRO Phoenix consensus conference.3,4 Of late, the latter consensus tends to be used more often in clinical practice. Because the definition of PSA failure after RT differs according to treatment period, unconverted PSA recurrence rates and biochemical recurrence-free survival (bRFS) rates are presented in this paper. Search strategy and selection criteria A search of PubMed (Medline; http://www.ncbi.nlm.nih.gov/ pubmed) was used to identify related English language papers using the following search terms: (1) ‘‘high-risk’’ [title] AND ‘‘prostate cancer’’ [All Fields] AND (‘‘radiotherapy’’ [Subheading] OR ‘‘radiotherapy’’ [All Fields] OR ‘‘radiotherapy’’ [MeSH Terms]), and (2) ‘‘high-risk’’ [title] AND ‘‘prostate cancer’’ [All Fields] AND ((‘‘androgens’’ [MeSH Terms] OR ‘‘androgens’’ [All Fields] OR ‘‘androgen’’ [All Fields] OR ‘‘androgens’’ [Pharmacological Action])

0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctrv.2013.04.003

Please cite this article in press as: Nomiya T et al. Management of high-risk prostate cancer: Radiation therapy and hormonal therapy. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.04.003

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T. Nomiya et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx

AND deprivation [All Fields] AND (‘‘therapy’’ [Subheading] OR ‘‘therapy’’ [All Fields] OR ‘‘therapeutics’’ [MeSH Terms] OR ‘‘therapeutics’’ [All Fields]). Studies with a publication date between 1980 and 2012 were included. Studies regarding definitive surgery, RT for postoperative recurrence, and those that did not include clinical outcomes of RT and/or hormonal therapy (HT) were excluded. The websites of several major clinical trial groups (RTOG, European Organisation for Research and Treatment of Cancer (EORTC), SWOG (Southwest Oncology Group), etc.) were searched for clinical trials of radiation and HTs and publications that included clinical outcomes in high-risk prostate cancer cases were included.

External beam RT: photon beams Although prophylactic pelvic irradiation has been routinely performed for prostate cancer treatment in the past, prophylactic irradiation to the pelvic lymph nodes (LNs) is rarely performed at present on the basis of the results of several clinical trials. A summary of clinical trials on definitive RT for prostate cancer is shown in Table 1. In a randomized controlled trial (RCT) named RTOG 75-06, the outcomes of patients with LN metastasis-negative stage C (LN stage C) cancer who received whole pelvic (WP) irradiation were compared with those of patients with pelvic LN metastasis who received WP and prophylactic periaortic LN (PALN) irradiation.5 The results showed that 5-year disease-free survival (DFS) rate for the two groups (WP + PALN and WP alone) was 37% and 42%, respec-

tively, and there were no significant differences in overall survival (OS), DFS, and metastasis-free survival between the two arms. The study also showed that extended prophylactic irradiation did not decrease the recurrence rate. In RTOG 77-06, prostate cancer patients without LN metastasis (T1-2N0M0) were randomly assigned to a WP irradiation arm and a localized prostatic irradiation arm and outcomes were compared.6 The 5-year DFS rate for the two groups was 64% and 67%, respectively, which were not significant (N.S.), and there were no significant differences in OS and local control rate (LCR) between the two groups. Following these results, the standard irradiation field for LN prostate cancer began to shift toward a local irradiation field. Kuban et al.7 evaluated the treatment outcomes of 652 patients treated during the same period and reported that the 5-year bRFS rate was 47% for patients with stage C cancer, 49% for patients with a Gleason score of P8, and 44% for patients with a PSA level of >20 ng/mL. However, these outcomes were worse than those recently reported for high-risk prostate cancer patients, which may be explained by the lower prescribed irradiation dose (approximately 65 Gy/7 weeks) and the lack of consensus regarding combination HT. The MD Anderson Cancer Center (Houston, TX, USA) conducted a phase III RT dose-escalation study that involved a conventional dose group (70 Gy/35 fractions) and a high-dose group (78 Gy/ 39fr.). There was a significant difference in the 6-year bRFS rate between the two groups (64% vs. 70%, respectively, p = 0.03), whereas subgroup analyses showed a more significant difference in 6-year bRFS rates between the two arms (43% vs. 62%, p = 0.01) in patients

Table 1 Clinical trials of radiation therapy for high-risk prostate cancer. Trials (authors)

Category of trials

No. of total patients

Treatment arms (subgroup)

RTOG75-06

Phase III (RT field)

523

Phase III (RT field)

445

MDACC Pollack et al.

Phase III (RT dose)

305

MSKCC Zelefesky et al. RTOG94-06

Phase III (RT dose)

2047

Phase III (RT dose/fraction size)

1051

MSKCC Cahlon et al. MGH Shipley et al.

Prospective study

478

Phase III (RT dose)

202

LLUMC Slater et al.

Prospective study (Proton)

643

PROG95-09

Phase III (RT dose)

392

Phase II (Carbon ion) Phase II (Carbon ion)

201

Arms WP + PALN WP Arms WP Prostate bed Arms Low-dose High-dose Arms (High-risk) Low-dose High-dose Arms (High-risk) Low-dose Intermediate-dose High-dose Arms (High-risk) Ultra-high-dose Arms (GS 4or5) Low-dose High-dose Arms (GS 8-10) Photon + Proton Proton Arms (Inter-High risk) Low-dose High-dose Arms (High-risk) Single-arm Arms (High-risk) Single-arm

RTOG77-06

NIRS 9904(1) Tsuji et al. NIRS 9904(3) (ongoing)

986

Total dose/ fractions

Type of radiation

65 Gy/35fr. 65 Gy/35fr.

Photon Photon

65 Gy/35fr. 65 Gy/35fr.

Photon Photon

70 Gy/35fr. 78 Gy/39fr.

Photon Photon

670.2 Gy 75.6–86.4 Gy

Photon Photon

68.4 Gy/38fr. 73.8 Gy/41fr. 79.2 Gy/44fr.

Photon Photon Photon

86.4 Gy/48fr.

Photon

67.2 Gy/36fr. 75.6CGE/40fr.

Photon Photon + Proton

75GyE/40fr. 74GyE/37fr.

Photon + Proton Proton

70.2 Gy/39fr. 79.2 Gy/44fr.

Photon + Proton Photon + Proton

66GyE/20fr.

Carbon ion

57.6GyE/16fr.

Carbon ion

Treatment outcomes

References

5y-DFS 37% 42% 5y-DFS 64% 67% 6y-FFF 24% 10% 5y-bRFS 45% 65% 5y-bRFS 42% 62% 68% 5y-bRFS 72% 5y-LCR 64% 94% 5y-bRFS 50%

5

5y-bRFS 63.4% 79.5% 5y-bRFS 80.5% 5y-bRFS 88.5%

25

6

8

9

10

11

23

24

31

a

RTOG: Radiation Therapy Oncology Group, PROG: Proton Radiation Oncology Group, MDACC: M.D. Anderson Cancer Center, MSKCC: Memorial Sloan-Kettering Cancer Center, MGH: Massachusetts General Hospital, LLUMC: Loma Linda University Medical Center, NIRS: National Institute for Radiological Sciences, WP: Whole Pelvic irradiation, PALN: ParaAortic Lymph Node irradiation, fr.: fractions, DFS: Disease-Free Survival, FFF: Freedom-From Failure, bRFS: biochemical Recurrence-Free Survival, GS: Gleason Score, CGE: Cobalt Gray Equivalent, GyE: Gray Equivalent. a Unpublished.

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T. Nomiya et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx

with a PSA level of >10 ng/mL.8 However, there was no significant difference in bRFS rate between the two arms in patients with a PSA level of 610 ng/mL. Zelefsky et al.9 conducted a dose-escalation study at Memorial Sloan-Kettering Cancer Center (New York, NY, USA), where patients were treated with 66–86.4 Gy of photon beam therapy. There was a significant difference in the 5-year bRFS rate between patients administered P75.6 Gy and those administered 670.2 Gy (85% vs. 65%, respectively, p < 0.0001) in the intermediate-risk group, although there was no significant difference in the PSA recurrence rate in the low-risk group. Analysis of the high-risk group also showed a significantly higher 5-year bRFS rate for patients who received higher doses than for those who received lower doses (65% vs. 45%, respectively, p < 0.0001). Recently, the long-term outcome of a phase I/II clinical study (RTOG 94-06) that included 1051 T12N0 prostate cancer patients and compared the outcomes among 5 treatment arms (68.4 Gy/38fr., 73.8 Gy/41fr., 79.2 Gy/44fr., 74 Gy/37fr. and 78 Gy/39fr. over 7.5–9 weeks) was reported.10 Analysis of the high-risk group revealed 5-year bRFS rates, as defined by the Phoenix criteria, of 42%, 62%, 68%, 54%, and 67%, respectively, indicating a clear improvement in accordance with the total irradiation dose. On the other hand, no correlation between bRFS rate and total irradiation dose was found in the low-risk group, although the bRFS rate was correlated with treatment duration. These results suggest that bRFS rates for prostate cancer patients treated with RT improve in a dose-dependent manner, even with doses >70 Gy. This is particularly observed for high-risk patients. A recent study reported the outcome of 478 prostate cancer patients treated with ‘‘ultra-high dose RT’’ with a dose of 86 Gy/48fr. using IMRT.11 In the subgroup-analysis limited to high-risk patients (n = 186), the 5-year bRFSs were 72% (ASTRO definition) and 70% (PSA nadir +2.0). Another study reported the outcome of IGRT (image-guided RT) with 78 Gy/39fr. for prostate cancer patients (including 57 high-risk patients).12 The 5-year bRFS of the patients with highrisk prostate cancer was 70.8%. These outcomes of IMRT/IGRT were slightly better than those of the past studies on EBRT alone.

Brachytherapy Brachytherapy (BT) is an alternative technique of external beam RT (EBRT) for prostate cancer treatment and is classified into two methods: low-dose rate brachytherapy (LDR-BT), which uses 125iodine or 103-palladium permanent seed implants, and high-dose rate brachytherapy (HDR-BT), which uses 192-iridium among other isotopes. Because the probability of lymph node metastasis increases in high-risk prostate cancer patients, localized therapy (e.g., LDR-BT alone) is considered to be insufficient and treatment combinations of EBRT and HDR-BT or HT are generally recommended.13,14 Galalae et al.15 analyzed the treatment outcomes of 611 patients treated with HDR-BT (80–123 Gy) combined with EBRT (45–50 Gy in conventional fractionation) in three hospitals (Seattle Prostate Institute, Seattle, WA, USA; University of Kiel, Kiel, Germany; and William Beaumont Hospital, Royal Oak, MI, USA).15 The proportion of low-risk (group I), intermediate-risk (group II), and high-risk (group III) patients was 7.5% (46/611), 31% (188/611), and 59% (359/611), respectively, and the 5-year bRFS rate for these groups was 96%, 88%, and 69%, respectively. Demanes et al.16 analyzed 209 patients treated with EBRT (36 Gy/20fr.) combined with HDR-BT (22–24 Gy/4fr.) and reported 5-year bRFS rates of 90%, 87%, and 69% in the low-risk (70/209; 33.5%), intermediate-risk (92/209; 44%), and high-risk (47/209; 22.5%) groups, respectively. Other groups have reported similar outcomes that were comparable to those of radical surgical treatments or standard EBRT alone for high-risk prostate cancer.17 An RCT was conducted at Mount Vernon Cancer Centre (Middlesex, UK) to compare EBRT (55 Gy/20fr.) alone

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vs. EBRT (35.75 Gy/17fr.) with HDR-BT (17 Gy/2fr.).18 Although the author concluded that the bRFS rate for the EBRT + HDR-BT group was significantly better than that for the EBRT-alone group (p = 0.03), a comparison between dose-escalated EBRT and EBRT + BT should be performed more carefully because the prescription dose and schedule of the trial were not standard. According to the American Brachytherapy Society (ABS) guidelines, LDR-BT treatment alone is contraindicated for high-risk prostate cancer.19 Nonetheless, Prada et al.20 evaluated 734 prostate cancer patients treated with LDR-BT (145 Gy with 125I) alone and reported a 5-year bRFS rate of 92%, 84%, and 65% for the low-risk (487/734; 66%), intermediate-risk (219/734; 30%), and high-risk (28/734; 4%) groups, respectively. Included in this study was a small number of high-risk prostate cancer patients treated with LDR-BT alone. The ABS guidelines accept LDR-BT combined with EBRT for high-risk prostate cancer patients and further suggest standard booster doses of 100–110 and 90–100 Gy with 125I and 103 Pd, respectively.21 Fang et al.22 analyzed 174 prostate cancer patients with high Gleason scores (P8) and intermediate-low PSA levels (615 ng/mL) and reported 5- and 10-year bRFS rates of 90% for both. Although LDR-BT with EBRT is tolerable and effective in prostate cancer patients with high Gleason scores and low PSA levels, there are several unresolved limitations for use in high-risk prostate cancer patients. Additionally, it remains unclear whether LDR/HDR-BT combined with EBRT is more invasive than EBRT alone and whether robot-assisted radical prostatectomy is less invasive than conventional radical retropubic prostatectomy.

Proton beam therapy There are few published reports regarding treatment outcomes following proton beam therapy as a single treatment modality, whereas there have been many reports on treatment outcomes following combinations of proton and photon beam therapies. A proton beam has an advantage in dose distribution with its characteristics of Bragg Peak like a carbon ion beam (see below ‘‘Heavy ion therapy’’). An RCT of 202 patients that compared two treatment arms [67.2 Gy via photon beam therapy vs. 75.6 Cobalt Gray Equivalent (CGE) via photon and proton beam therapy] was performed at Massachusetts General Hospital (MGH; Boston, MA, USA). A subgroup analysis limited to high-risk patients with Gleason scores of 4 or 5 found a 5-year LCR of 64% and 94%, respectively, and an 8-year LCR of 19% and 84%, respectively (p = 0.0014).23 However, completion rate of the combination therapy groups was lower than that of single therapy group, indicating room for improvement in treatment methods. Slater et al.24 reported the treatment outcomes of 1255 patients with stage Ia–III prostate cancer treated with proton beam therapy and/or photon beam therapy at Loma Linda University Medical Center (LLUMC; Loma Linda, CA, USA). The total dose was increased up to 74–75 CGE in their study. Analysis of the high-risk group showed a 5-year bRFS rate of 50% for patients with a Gleason score of P8 and 48% for patients with a PSA level of >20 ng/mL (ASTRO definition). Additional analysis revealed that the 5-year RFS rate for patients with a PSA nadir of 60.5, 0.5–1.0, and >1.0 ng/mL was 88%, 72%, and 31%, respectively, suggesting that the PSA nadir value was correlated with treatment outcome. An RCT (PROG/ACR 95-09) that compared two radiation doses of 70.2 GyE (CGE) and 79.2 GyE administered through photon beam therapy followed by proton beam therapy was conducted by MGH/LLUMC during the 1990s.25 The 5-year bRFS rate for the high-dose group was significantly better than that for the low-dose group (61.4% vs. 80.4%, respectively, p < 0.001). The 5-year bRFS rate for the high-dose group was also significantly better in an analysis limited to intermediate- and high-risk patients (63.4% vs. 79.5%,

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respectively, p = 0.03). The rate for low- and high-dose groups with a PSA nadir of <0.5 ng/mL was 45% and 60%, respectively (p = 0.003), and the time to achieve a PSA nadir was 28 and 40 months, respectively. Taken together, these results illustrate that high-dose RT can decrease the PSA level to a greater extent than low-dose RT and can maintain the low level for longer periods. The relative biological effectiveness (RBE) of proton beam therapy (approximately 1.1) is similar to that of photon beam therapy, suggesting that treatment dose for both therapies can be calculated in almost the same way.26 However, an optimal radiation dose through proton or photon beam therapy for high-risk prostate cancer remains unknown. In this regard, the outcomes of an ongoing phase II dose-escalation trial of 82 GyE/41fr. administered through proton beam therapy alone are eagerly awaited (03-12; American College of Radiology, Reston, VA, USA).27 Heavy ion (carbon ion) therapy A carbon ion (12C) beam is used in almost all heavy ion therapy institutions; therefore, the terms heavy ion therapy and carbon ion therapy carry almost the same meaning at present. A characteristic common to carbon ion and proton beams is that both stop at a certain depth in a material and produce an energy surge called a Bragg peak,28 whereas a major difference is RBE, which is the ratio of cancer cells killed by a particular beam at the same physical dose as that used during photon or gamma ray irradiation. The RBE of the carbon ion beam is estimated at 2–3, whereas that of the proton beam is approximately 1.1.29 Therefore, there is virtually no difference between the total prescription doses of photon and proton beams; however, the prescription dose of the carbon ion beam in GyE (CGE) should not be simply compared with that of photon or proton beams. Furthermore, from the viewpoint of differences in RBE between carbon ion and photon/proton beams, it is easier to shorten the treatment duration of carbon ion therapy than shorten the duration of photon/proton therapies. In the mid-1990s, a phase I/II clinical study of carbon ion therapy starting from a dose of 54 GyE/20fr. for prostate cancer was initiated using the Heavy Ion Medical Accelerator (HIMAC) at the National Institute for Radiological Sciences (NIRS) in Chiba.30 Patients with T1–T3N0M0 prostate cancer were treated with carbon ion therapy with a localized irradiation field (prostate + seminal vesicle), and the dose was escalated up to 72 GyE/20fr. On the basis of the results of this clinical trial, a fractionation schedule of 66 GyE/20fr. was adopted in a subsequent phase II clinical study of 201 patients with prostate cancer, which showed an overall 5-year bRFS rate of 83.2% and a bRFS rate of 80.5% for 164 high-risk patients (T3 and/or a Gleason score of P8 and/or a PSA level of >20 ng/mL).31 In the subgroup-analyses, the 5-year bRFS rate was 73% for T3 patients and 70% for patients with a Gleason score of P8 or a PSA level of >20 ng/mL. Phase II of this carbon ion therapy clinical trial (9904) is being continued with some modifications in treatment schedule (66 GyE/20fr./5 weeks–57.6 GyE/16fr./4 weeks).32,33 Approximately 1000 patients have been treated in this phase II trial (9904), and a subgroup analysis limited to high-risk patients (n = 515) has shown a 5-year bRFS rate of 88.5%. Reportedly, physical advantages (e.g., Bragg Peak), biological advantages (e.g., greater RBE), and extensive experience in treating patients using the HIMAC (overall >5000 patients) contributed to an overall improvement in treatment outcomes. Adverse effects of RT External beam RT Almost all transient acute adverse effects caused by RT are not severe. However, some side effects do not manifest for 2–3 years

after treatment; therefore, these patients present more important study subjects than those with curable acute effects. For example, gastrointestinal (GI) or genitourinary (GU) hemorrhage are relatively significant late effects of RT. Duncan et al.34 reported that late effects occurred in approximately 1000 patients treated with 60 Gy/30fr. of photon beam irradiation from 1970 to 1985, and the rate of G2 (grade 2 by RTOG criteria) rectal toxicity, G2 urethral toxicity, and PG3 GU/GI toxicity was 5.1%, 7.7%, and 2.3%, respectively. A subsequent analysis of 526 patients treated with 65 Gy of photon beam therapy in RTOG 75-06 and 77-06 showed that the rate of PG3 GI toxicity and PG3 GU toxicity was 2.9% and 5.9%, respectively.35 Pollack et al.8 conducted an RCT to compare two radiation doses of 70 Gy/35fr. and 78 Gy/39fr. and reported that the rate of G2 rectal toxicity was 12% and 26%, respectively, and that the rate of late side effects was significantly higher in the high-dose group than in the low-dose group (p = 0.001). They concluded that the radiation dose to the rectum was significantly correlated with the probability of late-onset toxicity; therefore, they recommended a lower rectal dose. On the other hand, the rate of PG2 GU toxicity was 10% in both the high- and low-dose groups. Vargas et al.36 evaluated rectal toxicity in a dose-escalation study of an 80-Gy dose delivered through photon beam threedimensional conformal RT (3D-CRT) and reported that the rate of PG2 and PG3 rectal toxicity was 20% and 4%, respectively. Although the toxicity rate increased with an increase in prescription dose, computer-based 3D-CRT planning and image-guided RT (IGRT) achieved low toxicity rates, even with an 80-Gy dose of photon beam irradiation. Zelefesky et al.37 conducted a clinical trial involving two groups, one that received 3D-CRT and one that received intensity-modulated RT (IMRT). Both groups received the same prescription dose of 81 Gy. The G2 rectal toxicity rate was significantly lower in the IMRT group than in the 3D-CRT group (2% vs. 14%, respectively, p = 0.005), which may be explained by the improved rectal dose administered in IMRT compared with 3D-CRT. Brachytherapy An advantage of BT is a short treatment duration, but it also carries the disadvantage of being invasive. A urethral stricture is a relatively frequent late adverse effect of BT, and past studies have reported that late G2, G3, and G4 GU toxicity rates were 7.7%, 6.7%, and 1%, respectively.16,38 Among patients with late GU toxicity, the proportion of those with a history of transurethral resection of the prostate (TURP) in the G3 and G4 groups was 36% (5/14) and 100% (2/2), respectively. Therefore, an indication of BT for the treatment of prostate cancer patients with a history of TURP should be carefully considered. Although the incidence of urinary incontinence after general EBRT and BT is low, the abovementioned study reported a rate of 3.8%, and all patients with this complication had a history of TURP.16 On the other hand, G1–2 and G3 late GI toxicity rates are reported to be 2% and 0%, respectively, indicating that severe late GI toxicity is not often exhibited in patients with BT. Furthermore, the sexual potency rate after BT has been reported to be 67%. Particle beam therapy (carbon/proton) A dose-escalation RCT (PROG 95-09) of 392 patients found no significant difference in late G2 GU toxicities between two groups treated with 70.2 GyE and 79.2 GyE, respectively, with combined proton and photon beams (18% vs. 20%, respectively, N.S.); however, the rate of G2 rectal toxicity was significantly higher in the 79.2 GyE group than in the 70.2 GyE group (17% vs. 8%, respectively, p = 0.005).25 However, the rate of G3 GU/GI toxicity and that

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of G4 GU/GI toxicity was 62% and 0% in both groups. These results suggest the advantages of dose distribution of proton beam against photon beam radiation. Late rectal toxicity among 175 patients who received 66 GyE/ 20fr. through carbon ion therapy was analyzed in a phase II study (9904 at NIRS) that followed an initial phase I/II study performed by the NIRS in Japan.39 This study reported that the rate of G1, G2, and G3 rectal toxicity was 13%, 2%, and 0%, respectively. This phase II study is ongoing with minor modifications. Meanwhile, 9904-(3), which is a >500-patient phase II study of a carbon ion therapy dose of 57.6 GyE/16fr., reported late G2 rectal toxicity, G2 GU toxicity, and G3 GU/GI toxicity rates of <1%,<3%, and 0%, respectively, indicating that carbon ion therapy can achieve a good local control rate and decrease toxicity. Collectively, these clinical trials showed that a high dose of photon beam radiation equivalent to 80 Gy was sufficient to control high-risk prostate cancer; however, this dose is toxic to normal tissues. Therefore, high-precision RT such as IMRT, IGRT, carbon ion therapy, and proton beam therapy are essential for the treatment of high-risk prostate cancer. Hormonal therapy for high-risk prostate cancer Androgen-deprivation therapy (ADT) or maximal androgen blockade is a recent treatment for intermediate- or high-risk prostate cancer patients. Luteinizing hormone-releasing hormone (a gonadotropin-releasing hormone) analogs (e.g. goserelin and leuprorelin) are available as injectable solutions while anti-androgen drugs (e.g. bicalutamide and flutamide) are available as oral tablets. Clinical trials on HT combined with RT for prostate cancer are listed in Table 2. A randomized phase II HT/RT combination study (RTOG 83-07) compared a Megestrol and diethylstilbestrol group and reported 7year local recurrence rates of 16% and 20%, respectively, but there was no significant difference between the groups.40 A phase III trial (RTOG 85-31) was conducted to compare two groups of patients who did or did not receive adjuvant HT (AHT; gocerelin) after RT and found that the 5-year bRFS rate (PSA 64.0 ng/mL) was significantly better in the group of patients that received AHT than in the group of patients who did not (57% vs. 28%, p < 0.0001).41 Furthermore, local control rate, distant metastasis-free survival rate, and cause-specific survival rate were significantly better in the group that received AHT than in the group that did not, and in a subgroup analysis limited to high-risk patients with a Gleason score of P8 (n = 276; 32%), the 5-year OS was sig-

nificantly better for the patients who received AHT than for those who did not (66% vs. 55%, p = 0.03). A subsequent phase III trial (RTOG 86-10) was conducted to investigate the efficacy of short-term HT (SHT) combined with definitive RT.42 A total of 456 patients with T2–4 (bulky tumor) N0–1 prostate cancer were randomly assigned to groups that did or did not receive SHT for 4 months, and the results showed that the 8-year bRFS rate (PSA, 61.5 ng/mL) was significantly better for the group that received SHT than for the group that did not (24% vs. 10%, p < 0.0001). LCR, cause-specific survival (CSS) rate and metastasis-free survival rates were also significantly better for the group that received SHT. On the other hand, when analysis was limited to high-risk patients (T2–4 bulky tumor and a Gleason score of 8–10, n = 124; 27%), there was no significant difference in the 8-year OS rate between the group that received SHT and the group that did not (38% vs. 31%, N.S.); however, this difference became significant (70% vs. 52%, p = 0.015) when analysis was limited to relatively low-risk (T2–4 bulky tumor and a Gleason score of 2– 6, n = 129; 28%) patients. These results suggest that short-term HT combined with RT was effective for the treatment of intermediaterisk prostate cancer but insufficient for the treatment of high-risk prostate cancer. A phase III study conducted by the EORTC (22863) included a total of 415 high-risk prostate cancer patients (T1–2/World Health Organization (WHO) grade 3 or T3–4Nx/Any WHO grade) and compared patients who received RT (70 Gy) alone (RT-alone group) with patients who received RT followed by 3 years of HT (RT + HT).43 The 5-year OS rate was 62% and 78% (p < 0.0001), the 5-year RFS rate was 40% and 74% (p < 0.0001), and the 5-year CSS rate was 79% and 94% (p < 0.0001) for the RT-alone and RT + HT groups, respectively. The outcome of the RT + HT group was significantly better than that of the RT-alone group. A total of 1554 high-risk prostate cancer patients were enrolled in a phase III study (RTOG 92-02) comparing STADT + RT group (short-term neoadjuvant ADT of 4 months and RT) and LTADT + RT group (long-term adjuvant ADT for 24 months in addition to neoadjuvant ADT and RT).44 The 5-year DFS rates for the STADT and LTADT groups were 28% and 46% (p < 0.0001), respectively, and the 5-year CSS rates were 91% and 95% (p = 0.003), respectively. Therefore, the outcome of the LTADT group was significantly better than that of the STADT group. Furthermore, when subgroup analysis was limited to patients with a Gleason score of 8–10, the 5-year OS rate was significantly better for the LTADT group than for the STADT group (81% vs. 71%, p = 0.044).

Table 2 Clinical trials on hormonal therapy combined with definitive radiotherapy for intermediate- to high-risk prostate cancer. Trials

Category of trials

Treatment arms

RTOG83-07 (1995)

Randomized phase II

RTOG85-31 (1997)

Phase III

RTOG86-10 (2001)

Phase III

EORTC22863 (2002)

Phase III

RTOG92-02 (2003)

Phase III

NIRS 9904 (1) (2005)

Phase II

Arms Megestrol DES Arms ADT (+) ADT ( ) Arms ADT (+) ADT ( ) Arms ADT (+) ADT ( ) Arms Short-term ADT Long-term ADT Arms (High-risk) Long-term ADT

Duration

Timing

4 months 4 months

Neoadjuvant Neoadjuvant

Indefinitely –

Adjuvant –

4 months –

Neoadjuvant –

3 years –

Adjuvant –

4 months P24 months

NeoAdjuvant NeoAdjv. and Adjv.

P18 months

NeoAdjv. and Adjv.

Treatment outcomes

References

7y-LCR 16% 21% 5y-bRFS* 57% 28% 8y-bRFS 24% 10% 5y-DFS 74% 40% 5y-bRFS 28% 46% 5y-bRFS 80.5%

40

41

42

43

44

31

RTOG: Radiation Therapy Oncology Group, DES: diethylstilbestrol, ADT: Androgen Deprivation Therapy, RT: Radiation therapy, LCR: Local Control Rate, DFS: Disease-Free Survival, bRFS: biochemical Recurrence-Free Survival. * PSA (Prostate Specific Antigen) P4.0 ng/ml.

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Collectively, these clinical HT trials on HT for prostate cancer indicated an obvious improvement in the treatment outcomes of intermediate- and high-risk prostate cancer patients. However, short-term neoadjuvant ADT combined with RT seems to be insufficient for the treatment of high-risk prostate cancer but effective for the treatment of intermediate-risk prostate cancer. Although long-term ADT (P2 years) is recommended for high-risk prostate cancer, the optimal duration of ADT combined with definitive RT remains unclear. Adverse effects of HT The adverse effects of HT on the cardiovascular system are well documented. For example, a long-term analysis (EORTC 22863) limited to patients with pre-existing cardiovascular disease reported a 10-year cardiovascular-related mortality of 17% and 15% (N.S.) in the RT-alone and RT + HT groups, respectively.45 In a separate analysis within the same report, which was limited to patients without pre-existing cardiovascular disease, the 10-year cardiovascular-related mortality rate was 9% and 4% (N.S.) in the RT-alone and RT + HT groups, respectively. Efstathiou et al. reported a long-term analysis of cardiac toxicity in patients enrolled in RTOG 85-31 and RTOG 92-02.46,47 In the RTOG 85-31 study group (n = 945), cardiovascular-related mortality was 11.4% and 8.4% (N.S.) in the RT-alone and RT + HT groups, respectively, and in the RTOG 92-02 study group, cardiovascular-related mortality was 4.8% and 5.9% (N.S.) in the short-term and long-term HT groups, respectively. Taken together, these results suggest that HT significantly improves treatment outcomes in intermediateand high-risk prostate cancer patients without causing a significant increase in cardiovascular mortality. Although the risk of cardiovascular mortality following HT may be statistically insignificant, careful observation is required in patients with idiosyncrasy to these drugs. Lawton et al.48 analyzed 2922 patients enrolled in three RCTs (RTOG 85-31, 86-10, and 92-02). This analysis comprised three groups comprising 700–1200 patients each: RT-alone, RT with short-term HT, and RT with long-term HT groups. They found late G3 rectal toxicity rates of 4%, 1%, and 3%, respectively, and late PG3 GU toxicity rates of 9%, 5%, and 6%, respectively. With respect to the RT-alone group, the hazard ratio of late PG3 toxicity was 0.54 (p = 0.013) in the RT + SHT group and 0.77 (N.S.) in the RT + LHT group. Unexpectedly, the risk of late GU/GI toxicity was (significantly or not significantly) lower in the RT + HT group than in the RT-alone group. Therefore, the results of this study seem to be highly reliable because the enrolled patients were randomly assigned, a uniform irradiation dose was used, and both groups contained a large number of patients. Although the specific mechanisms remain unknown, there is a possibility of a protective effect of HT on some tissues. Conclusions A total irradiation dose of P78 Gy/8–9 weeks (or an equivalent dose) is significantly superior to a total irradiation dose of 70 Gy/7– 8 weeks for high-risk prostate cancer. However, an optimal dose of RT has not been defined. High-precision RT (e.g., IMRT, 3D-CRT with IGRT, carbon ion therapy, proton beam therapy, etc.) should be used to deliver doses of >75 Gy to avoid severe GU/GI toxicities. LDR-BT alone is not recommended for the treatment of highrisk prostate cancer. HDR-BT with EBRT can be one of several treatment options for high-risk prostate cancer. However, significant advantages as compared to high-dose EBRT alone have not been shown.

A combination of P2 years of ADT with RT significantly decreases the biochemical failure of high-risk prostate cancer therapy, while 4 months of neoadjuvant ADT combined with RT is considered to be insufficient for high-risk prostate cancer. Advances in RT technology, HT, and molecular-targeted therapy will further improve treatment outcomes in patients with high-risk prostate cancer. Conflict of interest The authors have no conflict of interest. References 1. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280(11):969–74. 2. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer. version 4.2011. National comprehensive cancer network guidelines. http://www.nccn.org/. 3. Consensus Statement. Guidelines for PSA following radiation therapy. American society for therapeutic radiology and oncology consensus panel. Int J Radiat Oncol Biol Phys 1997;37(5):1035–41. 4. Roach 3rd M, Hanks G, Thames Jr H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65(4):965–74. 5. Pilepich MV, Krall JM, Johnson RJ, et al. Extended field (periaortic) irradiation in carcinoma of the prostate – analysis of RTOG 75-06. Int J Radiat Oncol Biol Phys 1986;12(3):345–51. 6. Asbell SO, Krall JM, Pilepich MV, et al. Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06. Int J Radiat Oncol Biol Phys 1988;15(6):1307–16. 7. Kuban DA, El-Mahdi AM, Schellhammer PF. Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1995;32(2):307–16. 8. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53(5):1097–105. 9. Zelefsky MJ, Yamada Y, Fuks Z, et al. Long-term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes. Int J Radiat Oncol Biol Phys 2008;71(4):1028–33. 10. Michalski J, Bhandari M, Gupta N, et al. Clinical outcome of patients treated with 3D conformal radiation therapy (3D-CRT) for prostate cancer on RTOG 9406. Int J Radiat Oncol Biol Phys 2012;83(3):e363–70. 11. Cahlon O, Zelefsky MJ, Shippy A, et al. Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int J Radiat Oncol Biol Phys 2008;71(2):330–7. 12. Engels B, Soete G, Verellen D, Storme G. Conformal arc radiotherapy for prostate cancer: increased biochemical failure in patients with distended rectum on the planning computed tomogram despite image guidance by implanted markers. Int J Radiat Oncol Biol Phys 2009;74(2):388–91. 13. Partin AW, Yoo J, Carter HB, et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150(1):110–4. 14. Masson S, Persad R, Bahl A. HDR brachytherapy in the management of high-risk prostate cancer. Adv Urol 2012;2012:980841. http://dx.doi.org/10.1155/2012/ 980841. Epub 2012 Feb 22. 15. Galalae RM, Martinez A, Mate T, et al. Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer. Int J Radiat Oncol Biol Phys 2004;58(4):1048–55. 16. Demanes DJ, Rodriguez RR, Schour L, Brandt D, Altieri G. High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy’s 10-year results. Int J Radiat Oncol Biol Phys 2005;61(5):1306–16. 17. Aström L, Pedersen D, Mercke C, Holmäng S, Johansson KA. Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer. Radiother Oncol 2005;74(2):157–61. 18. Hoskin PJ, Motohashi K, Bownes P, Bryant L, Ostler P. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol 2007;84(2):114–20. 19. Nag S, Beyer D, Friedland J, Grimm P, Nath R. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44(4):789–99. 20. Prada PJ, Juan G, González-Suárez H, et al. Prostate-specific antigen relapse-free survival and side-effects in 734 patients with up to 10 years of follow-up with localized prostate cancer treated by permanent iodine implants. BJU Int 2010;106(1):32–6.

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