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Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)†
EURURO-8650; No. of Pages 10 E U R O P E A N U RO L O GY X X X ( 2 019 ) X X X – X X X
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Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y Akira Yokomizo a, Masashi Wakabayashi b, Takefumi Satoh c, Katsuyoshi Hashine d, Takahiro Inoue e, Kiyohide Fujimoto f, Shin Egawa g, Tomonori Habuchi h, Kiyotaka Kawashima i, Osamu Ishizuka j, Nobuo Shinohara k, Mikio Sugimoto l, Yasushi Yoshino m, Keiji Nihei n, Haruhiko Fukuda b, Ken-ichi Tobisu o, Yoshiyuki Kakehi l, Seiji Naito a,*, JCOG0401 Investigators a
Department of Urology, Harasanshin Hospital, Fukuoka, Japan;
b
Japan Clinical Oncology Group Data Centre/Operations Office, National Cancer Centre
Hospital, Tokyo, Japan; c Department of Urology, Kitasato University School of Medicine, Kanagawa, Japan;
d
Department of Urology, National Hospital
Organization Shikoku Cancer Centre, Ehime, Japan; e Department of Urology, Kyoto University Hospital, Kyoto, Japan; f Department of Urology, Nara Medical University, Nara, Japan;
g
Department of Urology, Jikei University Hospital, Tokyo, Japan;
h
Department of Urology, Akita University Graduate School of
Medicine, Akita, Japan; i Department of Urology, Tochigi Cancer Centre, Tochigi, Japan; j Department of Urology, Shinshu University School of Medicine, Nagano, Japan;
k
Department of Renal and Genitourinary Surgery, Hokkaido University Hospital, Hokkaido, Japan; l Department of Urology, Faculty of
Medicine, Kagawa University, Kagawa, Japan;
m
Department of Urology, Nagoya University School of Medicine, Nagoya, Japan;
n
Division of Radiation
Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital, Bunkyo City, Japan; o Tokyo Metropolitan Cancer and Infectious disease Centre, Komagome Hospital, Bunkyo City, Japan
Article info
Abstract
Article history: Accepted November 29, 2019
Background: No standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP). Objective: To determine whether radiotherapy hormone therapy is superior to hormone therapy alone in such patients. Design, setting, and participants: This study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to <0.1 ng/ml after RP, and then increased to 0.4–1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr. Outcome measurements and statistical analysis: The primary endpoint was time to treatment failure (TTF) of BCL. Results and limitations: TTF of BCL was significantly longer in the SRT SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40– 0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall
Keywords: Radical prostatectomy Prostate-specific antigen failure Salvage therapy
y
This study was presented in part at the Annual Congress of the European Society of Medical Oncology, Madrid, Spain, September, 8–12 2017. * Corresponding author. Department of Urology, Harasanshin Hospital, 1-8 Taihaku-machi, Hakataku, Fukuoka 812-0033, Japan. Tel.: +81-92-291-3434; fax: +81-92-291-3167. E-mail address: [email protected] (S. Naito).
https://doi.org/10.1016/j.eururo.2019.11.023 0302-2838/© 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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survival did not differ between the arms. The most frequent grade 3–4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions. Conclusions: Initial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT SHT is more beneficial than SHT alone. Patient summary: Patients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy. © 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
1.
Introduction
Despite improvements in both the detection of and the surgical techniques for early prostate cancer, up to 35% of men develop prostate-specific antigen (PSA) failure after radical prostatectomy (RP) [1]. Most post-RP recurrences are detected by an increase in PSA concentration alone; whether such increases arise from local recurrence or distant metastasis is unknown [2]. Salvage radiation therapy (SRT) is a standard option, but given that it is uncertain whether PSA failure comes from local, regional, distant, or combined sites of recurrence, many patients who will not benefit are also treated. Retrospective studies suggest that despite this, SRT improves outcomes [2,3], but there is no high-level evidence based on randomised trials [4]. In their study, van Stam et al [5] reported that patients who receive SRT have greater immediate declines in selected health-related quality of life (QOL) domains, and significantly more diarrhoea and bowel symptoms than patients who undergo RP alone. As the side effects of SRT are generally mild but definite, it is desirable to understand how SRT impacts outcomes. Notably, patients with local recurrence may benefit from SRT, whereas those with metastatic disease may benefit from systemic treatment, the most common being salvage hormone therapy (SHT) [6]. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TOAD) trial was a randomised, nonblinded, phase 3 trial to identify the optimal timing of starting androgen-deprivation therapy (ADT) in PSA-relapsed patients after definitive therapy [7]. They identified that immediate ADT improves overall survival (OS) compared with delayed therapy [7], suggesting that early intervention of hormone therapy was recommended in these patients. We conducted a randomised phase 3 trial to determine whether SRT SHT is superior to SHT in patients with PSA failure after RP.
tomography (CT), and a bone scan; (6) no history of chemotherapy, radiation therapy (RT), or endocrine therapy for any cancer; (7) age between 20 and 79 yr; (8) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (9) no blood transfusion within 28 d of entry; (10) sufficient organ function within 28 d of entry; and (11) written informed consent. The exclusion criteria were as follows: (1) synchronous or metachronous (within 5 yr) malignancy other than carcinoma in situ; (2) mental disease or mental symptoms that would affect the participant’s decision to participate; (3) continuous medication of steroids (excluding external use of steroids for skin); (4) ischaemic heart disease or arrhythmia that needs medical treatment; (5) poorly controlled hypertension; (6) poorly controlled diabetes mellitus; (7) history of cerebral infarction or myocardial infarction within 6 mo; and (8) liver cirrhosis. A summarised protocol of JCOG0401 was described previously [6]. The study was performed in accordance with the Ethical Guidelines for Clinical Research and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. This trial is registered with University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR), C000000026 and the protocol was approved by each institutional review board. 2.2.
After confirming the eligibility criteria by telephone or fax contact with the Japan Clinical Oncology Group (JCOG) Data Center, patients were randomly assigned (1:1) to receive SRT SHT versus SHT. Randomisation was achieved by the minimisation method with balancing factors of Gleason score on the RP specimen (7 vs >8), interval between operation and PSA failure (<2 vs 2 yr), and institution. All patients and clinicians were unblinded to study treatment. 2.3.
2.
Patients and methods
2.1.
Trial design and participants
The inclusion criteria are as follows: (1) a diagnosis of localised prostate cancer (clinical stage T1–2N0M0) that was treated by RP; (2) pathological stage: pT0/2/3 and pN0/ x; (3) serum level of PSA once it has reached <0.1 ng/ml after RP and then increased to 0.4 ng/ml; (4) a serum level of PSA between 0.4 and 1.0 ng/ml at study entry; (5) no clinical recurrence based on abdominal and pelvic computed
Randomisation
Intervention
The SHT group started protocol treatment with bicalutamide (BCL) at 80 mg/d, which is the approved dosage in Japan. This dosage was fixed in Japan according to a phase 1 study [8], and a dosage of 150 mg daily in Western countries was not allowed in Japan. After failure of BCL treatment, it was followed by a luteinising hormonereleasing hormone (LH-RH) analogue as described in the Supplementary material. The SRT SHT group started protocol treatment with external beam irradiation at a total dose of 64.8 Gy/36 Fr (50 d) delivered to the prostatic
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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bed. Details of the SRT are presented in the Supplementary material. For those who developed RT treatment failure, BCL was started in the same way as in the SHT group. No treatments were performed if the patients had no treatment failure after SRT. After treatment failure of BCL, an LH-RH analogue was administered as in the case of the SHT group. In this study, “PSA progression” was defined as described in the Supplementary material. 2.4.
Data collection
All patient data were collected in a comprehensive database to an independent research centre (JCOG Data Center). All patients were followed up by their urologists at least every 3 mo with PSA measurement for >5 yr. CT and bone scan were performed every 1 yr if the patients had no treatment failure. The diagnostic radiographs before RP and at PSA failure, RT planning materials, and charts of the whole SRT course were collected for quality assurance (QA) of SRT. QA reviews were performed regularly at the Radiotherapy Support Centre in Tokyo, Japan, and feedback was sent to each institution by the study coordinator (N.K.). 2.5.
Primary and secondary study endpoints
The primary endpoint was time to treatment failure (TTF) of BCL, defined as the time from randomisation to treatment failure of BCL or censoring at the date of last follow-up. Secondary endpoints were TTF of protocol treatment, clinical relapse-free survival (RFS), OS, adverse events, and patient-reported QOL. Findings concerning QOL will be reported elsewhere. In this study, “PSA progression” was defined as follows: (1) PSA increase beyond 04 ng/ml if previous value had been <04 ng/ml; (2) any PSA increase if previous value had been >0.4 ng/ml; and (3) PSA concentration higher than that at the time of enrolment. SRT treatment failure was defined as follows: (1) PSA progression; (2) clinical progression or clinical recurrence; (3) grade 3 adverse event, including proctitis, rectal bleeding, urinary retention, and haematuria; (4) patient refusal to continue treatment; (5) death from any cause; and (6) poor compliance (less than two-thirds of planned dose). Treatment failure of BCL was defined as follows: (1) PSA progression; (2) clinical progression or clinical recurrence (or both); (3) fourth suspension of BCL treatment because of an adverse event; (4) patient refusal to continue treatment; (5) death from any cause; (6) poor compliance (less than two-thirds of planned dose) of oral BCL at two consecutive visits; and (7) BCL treatment not resumed within 12 wk of the date of suspension. The TTF of SRT was defined by PSA progression, clinical recurrence, and match in the criteria for discontinuation of SRT such as adverse events and patients’ refusal. These criteria are described in detail in the Supplementary material. The definition of failure of protocol treatment is also described in the Supplementary material.
2.6.
3
Statistical analyses
This trial was designed to evaluate the superiority of SRT SHT therapy over SHT alone in terms of TTF [9–11]. A rationale for the target number of patients was as described in the Supplementary material. In brief, a sample size of 200 patients was planned on the basis of Schoenfeld and Richter’s [12] methods, with one-sided alpha of 5%, power of 80%, TTF of BCL in the SHT group of 5.0 yr, TTF of BCL in the SRT SHT group of 8.3 yr, and 5-yr follow-up after 4 yr of accrual. However, because there were more ineligible patients than expected, the planned sample size was increased from 200 to 210 patients. However, the planned sample size did not maintain sufficient power for comparison of secondary endpoints, such as OS, between arms. Proportion of TTF will be estimated using the Kaplan-Meier method. A stratified log-rank test with adjustment factors used in randomisation except for institution is performed in TTF. Hazard ratios (HRs) and its 95% confidence intervals (CIs) are estimated through the Cox’s proportional hazard model. All analyses were performed on an intention-to-treat basis. 3.
Results
3.1.
Patient characteristics
Between May 17, 2004 and May 20, 2011, 210 patients (105 in each arm) were enrolled (Fig. 1) from 36 Japanese study centres (Supplementary material). The background of these ineligible patients is described in the Supplementary material. Baseline characteristics including distribution of Gleason score, median time from prostatectomy to PSA recurrence, time from recurrence to initiation of SRT, and PSA at randomisation were well balanced between groups (Table 1). The median PSA value before SRT was 0.478 (interquartile range: 0.433–0.587). Notably, a high proportion of positive surgical margins (PSMs) were observed in both arms: 60 (57.1%) of 105 patients in the SHT group and 61 (58.1%) of 105 patients in the SRT SHT group. 3.2.
Follow-up
At the time of final analysis, the median duration of followup for all patients alive was 5.5 yr (interquartile range, 2.9– 7.5 yr). There were two (1.9%) prostate cancer deaths and nine (8.6%) deaths from other causes in the SHT group, and three (2.9%) prostate cancer deaths and nine (8.6%) deaths from other causes in the SRT SHT group. 3.3.
Endpoints
3.3.1.
TTF of BCL
Treatment failure of BCL was recorded in 64 (61%) of 105 patients in the SHT group versus 47 (45%) of 105 patients in the SRT SHT group, with median TTF of 5.6 yr (95% CI 4.5– 6.6) in the SHT group versus 8.6 yr (95% CI 7.2–not estimable) in the SRT SHT group. Five-year freedom from treatment failure of BCL was 57.0% (95% CI 46.7–66.0) in the SHT group and 69.7%
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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Fig. 1 – CONSORT diagram of the trial. BCL = bicalutamide; LHRHA = luteinising hormone-releasing hormone analogue; RT = radiotherapy.
(95% CI 59.6–77.7) in the SRT SHT group (HR 0.555, 95% CI 0.376–0.818; one-sided p = 0.001; Fig. 2). In the SRT SHT group, 32 (31%) of 102 patients did not have SRT treatment failure and therefore did not receive hormone therapy.
3.3.2.
Relapse-free survival
As to RFS, seven (6.7%) clinical relapses and 10 (9.5%) deaths occurred in the SHT group, and six (5.7%) clinical relapses and nine (8.6%) deaths occurred in the SRT SHT group.
Table 1 – Baseline characteristics according to intention to treat.
Age ECOG PS Gleason score
Time from RP to PSA failure (mo) Time from RP to PSA failure (yr) Time from recurrence to initiation of ST (wk) PSA at randomisation cT1b cT1c cT2a cT2b pT2a pT2b pT3a pT3b Surgical margin negative Surgical margin positive Surgical margin unknown
0 1 7 8 8 9 <2 2
SHT group (n = 105)
SRT SHT group (n = 105)
70 (65–74) 102 (97.1) 3 (2.9) 71 (67.6) 34 (32.4) 89 (84.8) 16 (15.2) 30.2 (17.1–47.7) 38 (36.2) 67 (53.8) 5.6 (3.5–11.0) 0.470 (0.430–0.550) 1 (1.0) 44 (41.9) 30 (28.6) 30 (28.6) 12 (11.4) 45 (42.9) 34 (32.4) 14 (13.3) 43 (41.0) 60 (57.1) 2 (1.9)
71 (67–75) 105 (100.0) 0 (0.0) 71 (67.6) 34 (32.4) 89 (84.8) 16 (15.2) 30.7 (18.8–44.9) 40 (38.1) 65 (61.9) 8.0 (6.0–15.1) 0.480 (0.430–0.570) 0 (0.0) 58 (55.2) 30 (28.6) 17 (16.2) 11 (10.5) 42 (40.0) 44 (41.9) 8 (7.6) 43 (41.0) 61 (58.1) 1 (1.0)
ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; PS = performance status; PSA = prostate-specific antigen; RP = radical prostatectomy; SHT = salvage hormone therapy; SRT = salvage radiotherapy; ST = salvage therapy. Data are presented as n (%) or median (IQR) unless otherwise noted.
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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– –
Fig. 2 – Kaplan-Meier estimates of percentage of 5-yr freedom from treatment failure of bicalutamide. BCL = bicalutamide; CI = confidence interval; NE = not estimable; SHT = salvage hormone therapy; SRT = salvage radiation therapy; TTF = time to treatment failure.
Table 2 – Adverse events during protocol treatmenta
Five-year RFS was 93.8% (95% CI 86.8–97.2) in the SHT group and 88.9% (95% CI 80.9–93.7) in the SRT SHT group (HR 0.904, 95% CI 0.45–1.81; p = 0.77; Fig. 3).
SRT SHT group (n = 103)
NCI-CTC version 2.0 SHT group (n = 104) Gr. 1–2 Gr. 3
Gr. 4 Gr. 1–2 Gr. 3
Gr. 4
9 (9) 90 (87) 47 (45) 25 (24) 26 (25) 24 (23) 95 (91) 9 (9) 7 (6) 7 (6) 38 (37) 11 (11) 86 (83)
0 0 0 0 0 0 0 0 0 0 – – –
0 0 0 0 0 0 0 0 0 0 – – –
3.3.3. Leukocytopenia Anaemia Thrombocytopenia Gamma-GTP Fatigue Hot flushes Gynaecomastia Haematuria Rectal bleeding Proctitis incontinence Erectile dysfunction Loss of libido
1 (<1) 0 0 3 1 (<1) 0 4 (4) 0 0 0 0 83 (80) –
6 (6) 76 (74) 34 (33) 26 (25) 27 (26) 10 (10) 36 (35) 22 (21) 34 (33) 55 (53) 60 (6) 9 (9) 73 (71)
1 (<1) 1 (<1) 1 (<1) 2 (2) 0 0 2 (2) 3 (3) 1 (<1) 0 5 (5) 76 (74) –
Gr. = grade; SHT = salvage hormone therapy; SRT = salvage radiotherapy; NCI-CTC = National Cancer Institute-Common Toxicity Criteria. Data are number of patients with at least one episode of that event (% of patients). a No grade 5 events were identified.
Overall survival
Five-year OS was 99.0% (95% CI 93.4–99.9) in the SHT group and 91.4% (95% CI 84.2–95.4%) in the SRT SHT group (HR 1.030, 95% CI 0.46–2.3; p = 0.94; Fig. 4). 3.3.4.
Safety
Any adverse events during protocol treatment are summarised in Table 2. Notably, a higher frequency of gynaecomastia of any grade occurred in the SHT group (99, 95%) than in the SRT SHT group (38, 37%). Rectal bleeding and proctitis of any grade occurred in seven (6%) patients in the SHT group, and in 35 (34%) and 55 (53%) patients, respectively, in the SRT SHT group. QA data for SRT were determined to be fully evaluable in 102 of 105 patients in the SRT SHT group (Supplementary material, ST1).
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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Fig. 3 – Kaplan-Meier estimates of relapse-free survival. CI = confidence interval; NE = not estimable; RFS = relapse-free survival; SHT = salvage hormone therapy; SRT = salvage radiation therapy.
4.
Discussion
In this JCOG0401 trial, 5-yr freedom from treatment failure of BCL was significantly higher in the SRT SHT than in the SHT group. In addition, 31% of patients who received SRT initially did not require SHT at all. No previous randomised trials have compared SRT SHT with SHT in patients with PSA failure after RP. RP is one of the curative treatments for localised prostate cancer. Most post-RP recurrences are detected only by an increase in PSA concentration [1]. Patients with post-RP local recurrence may benefit from RT, whereas those with metastatic disease may benefit from systemic treatment, the most common of which is ADT [1,6]. Therefore, identification of sites of recurrence is important in selecting the treatment strategy for patients with PSA failure after primary therapy. CT scanning and bone scintigraphy are most frequently used to detect metastatic sites; however, these two modalities usually cannot detect sites of recurrence in patients with PSA < 1.0 ng/ml [6]. Recently, new radiographic techniques such as choline positron emission tomography (PET)/CT and prostate-specific membrane antigen–based PET/CT have been developed; these
techniques may alter disease monitoring in patients with post-RP PSA failure [13]. However, these modalities have limitations in patients with PSA failure <1.0 ng/ml [13]. Even with recent advances in RP and imaging technologies, the results of the present study (JCOG0401) contribute significant clinical evidence regarding treatment of prostate cancer. SRT is usually administered for biochemical recurrence without a histological proof of local recurrence [13], even though no studies have directly compared SRT with SHT. Early SRT can achieve cure in patients with post-RP PSA failure. In European Association of Urology guidelines, PSA value of 0.2 ng/ml is defined as biochemical recurrence. However, in clinical practice, the defined value of biochemical recurrence does not necessarily match the starting point of salvage treatment. Amling et al [14] suggested that a PSA level of >0.4 ng/ml may be the most appropriate cut-off point to use, since a significant number of patients with lower PSA did not have a subsequent PSA progression. Based on this report, we set the PSA value of 0.4 ng/ml as a starting point of salvage treatment. Subsequently, Stephenson et al [15] analysed 3125 RP cases and found that PSA of at least 0.4 ng/ml followed by
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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7
Fig. 4 – Kaplan-Meier estimates of overall survival. CI = confidence interval; OS = overall survival; SHT = salvage hormone therapy; SRT = salvage radiation therapy.
another increase best explained metastatic progression. More than 60% of patients treated before their PSA has increased to >0.5 ng/ml achieve undetectable PSA concentrations [16–19], corresponding with an up to 80% chance of 5-yr progression-free survival [20]. Our study also clearly identified an advantage of initial SRT over initial SHT by BCL in patients with low post-RP PSA concentrations (0.4–1.0 ng/ml). Early SRT was effective in 31% of the SRT SHT group at a median follow-up of 5.5 yr, thus avoiding the need for SHT. Our results demonstrated that SRT may be feasible for patients with post-RP PSA failure even if we do not have a histological proof of local recurrence. Administration of early SRT made it possible for some patients with treatment failure in our study to avoid SHT. As shown in Table 2, given the higher rates of gynaecomastia (91%) and hot flushes (23%) in the SHT group, avoiding SHT by first administering SRT may be favourable to patients with post-RP PSA failure. There has been ongoing debate regarding the optimal schedule of SRT and dosage to the prostate bed in patients with post-RP PSA failure. At the time of starting this study, no standard dose fractionations of SRT had been identified by prospective studies. In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) published a consensus panel statement [21] that recommended a total dose of 64 Gy (or slightly more) divided into 1.8–2.0 Gy/fr on
the basis of analysing data from four major institutions in the USA. On the basis of this ASTRO statement, we decided on a dosage of 64.8 Gy (1.8 Gy/fr) as the protocol treatment [6]. Similar total dosages were administered in Radiation Therapy Oncology Group (RTOG) 9601 (64.8 Gy) [22] and Group d’Etude des Tumeurs Urogenitales-Association Francaise d’Urologie (GETUG-AFU) 16 (66 Gy) [23], which were designed to investigate SRT hormone therapy in patients with post-RP PSA failure. In RTOG 9601, adverse bowel events of all grades were reported in 238/374 patients (70%), and grade 3 or worse genitourinary events in three patients (0.8%) in the RT-alone group. In GETUG-AFU 16, late adverse genitourinary events of all grades were reported in 261/372 patients (70%), and grade 3 or worse genitourinary events in 29 patients (8%) in the RT-alone group [23]. In our study, rectal bleeding and proctitis of any grade occurred in 35 (34%) and 55 (53%) patients, respectively, in the SRT SHT group, but only one patient (<1%) had grade 3 rectal bleeding (Table 2). There was a lower frequency of adverse genitourinary events than in these studies [22,23], which may be attributable to the higher quality of radiation, as evidenced by the results of quality assessment of SRT in JCOG0401. In GETUG-AFU 16, the prostate bed was not clearly defined and no quality control was reported [24], and RTOG 9601 provided no description of the methods used for quality assessment of SRT [22].
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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Recent data from RTOG 9601 [22] suggest that the addition of 2 yr of BCL to SRT improves both cancer-specific survival and OS. According to GETUG-AFU 16, 6 mo treatment with a gonadotropin-releasing hormone (GnRH) analogue significantly improves 5-yr progression-free survival [23]. These two trials contained more patients at high risk after RP than in the present study; they clearly identified that the addition of hormone therapy to SRT was beneficial in these high-risk patients. Although the type of hormone therapy differed between these two studies, SRT with hormone therapy could become a standard approach in high-risk post-RP patients [22,23]. There are several prospective ongoing randomised controlled trials related to JCOG0401. Radiotherapy-Adjunct Versus Early Salvage (RAVES) is a phase 3 trial to investigate the timing of RT for prostate cancer with high-risk features [25]. Radiation and Androgen Deprivation in Combination with Local Surgery (RADICALS) is a large randomised trial addressing both the timing of treatment after RP (adjuvant vs early salvage) and the duration of SHT (none vs short term vs long term) used in addition to prostate bed RT [26]. GETUG-AFU 17 is a randomised phase 3 trial that is studying the timing of giving triptorelin and RT after RP for intermediate-risk stage 3 or stage 4 prostate cancer (NCT00667069). The results of these studies have not yet been revealed, but these will have implications for the present study and will identify the optimal salvage/ adjuvant treatment after PSA failure after RP. This study has several limitations. First, as in any randomised controlled trial, patients were selected based on specific criteria and the results may not be generalisable to other patient cohorts. Second, this study had very few patients and very short follow-up to allow definitive conclusions concerning OS and RFS. There were no significant differences in OS and RFS in this study. We estimate that this could be due to a short follow-up time. In addition, new androgen receptor targeting agents such as enzalutamide and abiraterone in castration-resistant prostate cancer might affect the OS after the salvage treatment of RP. Third, the primary endpoint of this study was TTF of BCL but not OS. As the 10-yr OS rate is expected to be >80% in this study and many events from other than primary cancer are expected in these elderly patients, we considered that OS was not the optimal primary endpoint. TTF of the LH-RH analogue may be an appropriate primary endpoint for castration-resistant prostate cancer, but PSA failure had to occur up to three times in the SRT SHT therapy group, thereby prejudicing evaluation. As TTF of BCL can be evaluated earlier than TTF of an LH-RH analogue, we considered it a good surrogate endpoint and therefore selected it as a primary endpoint. Fourth, the primary endpoint was designed to be analysed by one-sided p value. We consider that the choice of performing a one-sided or a two-sided test for primary analysis is determined based on a clinical hypothesis. When the SRT SHT group is inferior to the SHT group in terms of the primary endpoint of TTF, SHT still remains an optional regimen regardless of being statistically significant or not. Since the primary decision would be made using the results of statistical test whether
SRT SHT is superior to SHT, the one-sided test was used in TTF. One-sided alpha of 5% for analysis of primary endpoints may not necessarily be acceptable since one-sided alpha of 2.5% should be used in accordance with the ICH E9 guideline [27]. We know that this is a limitation of this study. However, considering the number of patients who are eligible for this study, we prioritise feasibility. Fifth, the high PSM rate in this trial was observed, and it should be one of the limitations when applying these results to a more general population. 5.
Conclusions
Initial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT SHT is more beneficial than SHT alone. Author contributions: Seiji Naito had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Yokomizo, Naito, Fukuda. Acquisition of data: Yokomizo, Satoh, Hashine, Inoue, Fujimoto, Egawa, Habuchi, Kawashima, Ishizuka, Shinohara, Sugimoto, Yoshino, Tobisu, Kakehi, Naito. Analysis and interpretation of data: Yokomizo, Naito, Fukuda. Drafting of the manuscript: Yokomizo, Naito, Fukuda. Critical revision of the manuscript for important intellectual content: Tobisu, Kakehi. Statistical analysis: Wakabayashi. Obtaining funding: Yokomizo, Naito. Administrative, technical, or material support: Wakabayashi, Fukuda. Supervision: Tobisu, Kakehi. Other: radiation quality control: Nihei. Financial disclosures: Seiji Naito certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Akira Yokomizo has received personal fees from Astellas Pharma Inc., AstraZeneca, Bayer, Janssen Pharmaceutical K.K., Sanofi, and Takeda Pharmaceutical Company Ltd. Masashi Wakabayashi has received personal fees from Chugai Pharmaceutical Co., Ltd. and Johnson & Johnson K.K. Medical Company. Takefumi Satoh has received personal fees from Bayer AG, Janssen Pharmaceutical K.K., Nihon Medi-Physics Co. Ltd., AstraZeneca, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, and Daiichi Sankyo Company Limited. Katsuyoshi Hashine has received personal fees from Kyowa Hakko Kirin Co. Ltd., Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Sanofi, Bristol-Myers Squibb, MSD K.K., Pfizer, Bayer, and Astellas Pharma Inc. Takahiro Inoue has received personal fees from Astellas Pharma Inc., Janssen Pharmaceutical K.K., Astra Zeneca, Takeda Pharmaceutical Company Ltd., Bayer, Sanofi, MSD K.K., Bristol-Myers Squibb, Ono Pharmaceutical Co. Ltd., and Pfizer Inc. Kiyohide Fujimoto has received personal fees from Chugai Pharmaceutical Co. Ltd., NIppon Kayaku Co. Ltd., Ferring Pharmaceuticals, Pfizer Inc., Bayer, ASKA Pharmaceutical Co. Ltd., Daiichi Sankyo Company Ltd., Novartis International AG, SBI Pharma, KYORIN Pharmaceutical Co. Ltd., MSD K. K., Tsumura & Co., Taiho Pharmaceutical Co. Ltd., FUJIFILM Corporation, Ono Pharmaceutical Co. Ltd., Sanofi, Asahi Kasei, Janssen Pharmaceutical K.K., and Kissei Pharmaceutical Co. Ltd. Shin Egawa has received personal fees from Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd.,
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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Funding/Support and role of the sponsor: This work was supported by Health Sciences Research Grants for Clinical Research for Evidence Based Medicine and Grants-in-Aid for Cancer Research (016) from the Ministry of Health, Labour and Welfare, Japan.
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Appendix A. Supplementary data
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Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. eururo.2019.11.023.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority
Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y Akira Yokomizo a, Masashi Wakabayashi b, Takefumi Satoh c, Katsuyoshi Hashine d, Takahiro Inoue e, Kiyohide Fujimoto f, Shin Egawa g, Tomonori Habuchi h, Kiyotaka Kawashima i, Osamu Ishizuka j, Nobuo Shinohara k, Mikio Sugimoto l, Yasushi Yoshino m, Keiji Nihei n, Haruhiko Fukuda b, Ken-ichi Tobisu o, Yoshiyuki Kakehi l, Seiji Naito a,*, JCOG0401 Investigators a
Department of Urology, Harasanshin Hospital, Fukuoka, Japan;
b
Japan Clinical Oncology Group Data Centre/Operations Office, National Cancer Centre
Hospital, Tokyo, Japan; c Department of Urology, Kitasato University School of Medicine, Kanagawa, Japan;
d
Department of Urology, National Hospital
Organization Shikoku Cancer Centre, Ehime, Japan; e Department of Urology, Kyoto University Hospital, Kyoto, Japan; f Department of Urology, Nara Medical University, Nara, Japan;
g
Department of Urology, Jikei University Hospital, Tokyo, Japan;
h
Department of Urology, Akita University Graduate School of
Medicine, Akita, Japan; i Department of Urology, Tochigi Cancer Centre, Tochigi, Japan; j Department of Urology, Shinshu University School of Medicine, Nagano, Japan;
k
Department of Renal and Genitourinary Surgery, Hokkaido University Hospital, Hokkaido, Japan; l Department of Urology, Faculty of
Medicine, Kagawa University, Kagawa, Japan;
m
Department of Urology, Nagoya University School of Medicine, Nagoya, Japan;
n
Division of Radiation
Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital, Bunkyo City, Japan; o Tokyo Metropolitan Cancer and Infectious disease Centre, Komagome Hospital, Bunkyo City, Japan
Article info
Abstract
Article history: Accepted November 29, 2019
Background: No standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP). Objective: To determine whether radiotherapy hormone therapy is superior to hormone therapy alone in such patients. Design, setting, and participants: This study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to <0.1 ng/ml after RP, and then increased to 0.4–1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr. Outcome measurements and statistical analysis: The primary endpoint was time to treatment failure (TTF) of BCL. Results and limitations: TTF of BCL was significantly longer in the SRT SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40– 0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall
Keywords: Radical prostatectomy Prostate-specific antigen failure Salvage therapy
y
This study was presented in part at the Annual Congress of the European Society of Medical Oncology, Madrid, Spain, September, 8–12 2017. * Corresponding author. Department of Urology, Harasanshin Hospital, 1-8 Taihaku-machi, Hakataku, Fukuoka 812-0033, Japan. Tel.: +81-92-291-3434; fax: +81-92-291-3167. E-mail address: [email protected] (S. Naito).
https://doi.org/10.1016/j.eururo.2019.11.023 0302-2838/© 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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survival did not differ between the arms. The most frequent grade 3–4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions. Conclusions: Initial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT SHT is more beneficial than SHT alone. Patient summary: Patients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy. © 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
1.
Introduction
Despite improvements in both the detection of and the surgical techniques for early prostate cancer, up to 35% of men develop prostate-specific antigen (PSA) failure after radical prostatectomy (RP) [1]. Most post-RP recurrences are detected by an increase in PSA concentration alone; whether such increases arise from local recurrence or distant metastasis is unknown [2]. Salvage radiation therapy (SRT) is a standard option, but given that it is uncertain whether PSA failure comes from local, regional, distant, or combined sites of recurrence, many patients who will not benefit are also treated. Retrospective studies suggest that despite this, SRT improves outcomes [2,3], but there is no high-level evidence based on randomised trials [4]. In their study, van Stam et al [5] reported that patients who receive SRT have greater immediate declines in selected health-related quality of life (QOL) domains, and significantly more diarrhoea and bowel symptoms than patients who undergo RP alone. As the side effects of SRT are generally mild but definite, it is desirable to understand how SRT impacts outcomes. Notably, patients with local recurrence may benefit from SRT, whereas those with metastatic disease may benefit from systemic treatment, the most common being salvage hormone therapy (SHT) [6]. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TOAD) trial was a randomised, nonblinded, phase 3 trial to identify the optimal timing of starting androgen-deprivation therapy (ADT) in PSA-relapsed patients after definitive therapy [7]. They identified that immediate ADT improves overall survival (OS) compared with delayed therapy [7], suggesting that early intervention of hormone therapy was recommended in these patients. We conducted a randomised phase 3 trial to determine whether SRT SHT is superior to SHT in patients with PSA failure after RP.
tomography (CT), and a bone scan; (6) no history of chemotherapy, radiation therapy (RT), or endocrine therapy for any cancer; (7) age between 20 and 79 yr; (8) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (9) no blood transfusion within 28 d of entry; (10) sufficient organ function within 28 d of entry; and (11) written informed consent. The exclusion criteria were as follows: (1) synchronous or metachronous (within 5 yr) malignancy other than carcinoma in situ; (2) mental disease or mental symptoms that would affect the participant’s decision to participate; (3) continuous medication of steroids (excluding external use of steroids for skin); (4) ischaemic heart disease or arrhythmia that needs medical treatment; (5) poorly controlled hypertension; (6) poorly controlled diabetes mellitus; (7) history of cerebral infarction or myocardial infarction within 6 mo; and (8) liver cirrhosis. A summarised protocol of JCOG0401 was described previously [6]. The study was performed in accordance with the Ethical Guidelines for Clinical Research and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. This trial is registered with University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR), C000000026 and the protocol was approved by each institutional review board. 2.2.
After confirming the eligibility criteria by telephone or fax contact with the Japan Clinical Oncology Group (JCOG) Data Center, patients were randomly assigned (1:1) to receive SRT SHT versus SHT. Randomisation was achieved by the minimisation method with balancing factors of Gleason score on the RP specimen (7 vs >8), interval between operation and PSA failure (<2 vs 2 yr), and institution. All patients and clinicians were unblinded to study treatment. 2.3.
2.
Patients and methods
2.1.
Trial design and participants
The inclusion criteria are as follows: (1) a diagnosis of localised prostate cancer (clinical stage T1–2N0M0) that was treated by RP; (2) pathological stage: pT0/2/3 and pN0/ x; (3) serum level of PSA once it has reached <0.1 ng/ml after RP and then increased to 0.4 ng/ml; (4) a serum level of PSA between 0.4 and 1.0 ng/ml at study entry; (5) no clinical recurrence based on abdominal and pelvic computed
Randomisation
Intervention
The SHT group started protocol treatment with bicalutamide (BCL) at 80 mg/d, which is the approved dosage in Japan. This dosage was fixed in Japan according to a phase 1 study [8], and a dosage of 150 mg daily in Western countries was not allowed in Japan. After failure of BCL treatment, it was followed by a luteinising hormonereleasing hormone (LH-RH) analogue as described in the Supplementary material. The SRT SHT group started protocol treatment with external beam irradiation at a total dose of 64.8 Gy/36 Fr (50 d) delivered to the prostatic
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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bed. Details of the SRT are presented in the Supplementary material. For those who developed RT treatment failure, BCL was started in the same way as in the SHT group. No treatments were performed if the patients had no treatment failure after SRT. After treatment failure of BCL, an LH-RH analogue was administered as in the case of the SHT group. In this study, “PSA progression” was defined as described in the Supplementary material. 2.4.
Data collection
All patient data were collected in a comprehensive database to an independent research centre (JCOG Data Center). All patients were followed up by their urologists at least every 3 mo with PSA measurement for >5 yr. CT and bone scan were performed every 1 yr if the patients had no treatment failure. The diagnostic radiographs before RP and at PSA failure, RT planning materials, and charts of the whole SRT course were collected for quality assurance (QA) of SRT. QA reviews were performed regularly at the Radiotherapy Support Centre in Tokyo, Japan, and feedback was sent to each institution by the study coordinator (N.K.). 2.5.
Primary and secondary study endpoints
The primary endpoint was time to treatment failure (TTF) of BCL, defined as the time from randomisation to treatment failure of BCL or censoring at the date of last follow-up. Secondary endpoints were TTF of protocol treatment, clinical relapse-free survival (RFS), OS, adverse events, and patient-reported QOL. Findings concerning QOL will be reported elsewhere. In this study, “PSA progression” was defined as follows: (1) PSA increase beyond 04 ng/ml if previous value had been <04 ng/ml; (2) any PSA increase if previous value had been >0.4 ng/ml; and (3) PSA concentration higher than that at the time of enrolment. SRT treatment failure was defined as follows: (1) PSA progression; (2) clinical progression or clinical recurrence; (3) grade 3 adverse event, including proctitis, rectal bleeding, urinary retention, and haematuria; (4) patient refusal to continue treatment; (5) death from any cause; and (6) poor compliance (less than two-thirds of planned dose). Treatment failure of BCL was defined as follows: (1) PSA progression; (2) clinical progression or clinical recurrence (or both); (3) fourth suspension of BCL treatment because of an adverse event; (4) patient refusal to continue treatment; (5) death from any cause; (6) poor compliance (less than two-thirds of planned dose) of oral BCL at two consecutive visits; and (7) BCL treatment not resumed within 12 wk of the date of suspension. The TTF of SRT was defined by PSA progression, clinical recurrence, and match in the criteria for discontinuation of SRT such as adverse events and patients’ refusal. These criteria are described in detail in the Supplementary material. The definition of failure of protocol treatment is also described in the Supplementary material.
2.6.
3
Statistical analyses
This trial was designed to evaluate the superiority of SRT SHT therapy over SHT alone in terms of TTF [9–11]. A rationale for the target number of patients was as described in the Supplementary material. In brief, a sample size of 200 patients was planned on the basis of Schoenfeld and Richter’s [12] methods, with one-sided alpha of 5%, power of 80%, TTF of BCL in the SHT group of 5.0 yr, TTF of BCL in the SRT SHT group of 8.3 yr, and 5-yr follow-up after 4 yr of accrual. However, because there were more ineligible patients than expected, the planned sample size was increased from 200 to 210 patients. However, the planned sample size did not maintain sufficient power for comparison of secondary endpoints, such as OS, between arms. Proportion of TTF will be estimated using the Kaplan-Meier method. A stratified log-rank test with adjustment factors used in randomisation except for institution is performed in TTF. Hazard ratios (HRs) and its 95% confidence intervals (CIs) are estimated through the Cox’s proportional hazard model. All analyses were performed on an intention-to-treat basis. 3.
Results
3.1.
Patient characteristics
Between May 17, 2004 and May 20, 2011, 210 patients (105 in each arm) were enrolled (Fig. 1) from 36 Japanese study centres (Supplementary material). The background of these ineligible patients is described in the Supplementary material. Baseline characteristics including distribution of Gleason score, median time from prostatectomy to PSA recurrence, time from recurrence to initiation of SRT, and PSA at randomisation were well balanced between groups (Table 1). The median PSA value before SRT was 0.478 (interquartile range: 0.433–0.587). Notably, a high proportion of positive surgical margins (PSMs) were observed in both arms: 60 (57.1%) of 105 patients in the SHT group and 61 (58.1%) of 105 patients in the SRT SHT group. 3.2.
Follow-up
At the time of final analysis, the median duration of followup for all patients alive was 5.5 yr (interquartile range, 2.9– 7.5 yr). There were two (1.9%) prostate cancer deaths and nine (8.6%) deaths from other causes in the SHT group, and three (2.9%) prostate cancer deaths and nine (8.6%) deaths from other causes in the SRT SHT group. 3.3.
Endpoints
3.3.1.
TTF of BCL
Treatment failure of BCL was recorded in 64 (61%) of 105 patients in the SHT group versus 47 (45%) of 105 patients in the SRT SHT group, with median TTF of 5.6 yr (95% CI 4.5– 6.6) in the SHT group versus 8.6 yr (95% CI 7.2–not estimable) in the SRT SHT group. Five-year freedom from treatment failure of BCL was 57.0% (95% CI 46.7–66.0) in the SHT group and 69.7%
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Fig. 1 – CONSORT diagram of the trial. BCL = bicalutamide; LHRHA = luteinising hormone-releasing hormone analogue; RT = radiotherapy.
(95% CI 59.6–77.7) in the SRT SHT group (HR 0.555, 95% CI 0.376–0.818; one-sided p = 0.001; Fig. 2). In the SRT SHT group, 32 (31%) of 102 patients did not have SRT treatment failure and therefore did not receive hormone therapy.
3.3.2.
Relapse-free survival
As to RFS, seven (6.7%) clinical relapses and 10 (9.5%) deaths occurred in the SHT group, and six (5.7%) clinical relapses and nine (8.6%) deaths occurred in the SRT SHT group.
Table 1 – Baseline characteristics according to intention to treat.
Age ECOG PS Gleason score
Time from RP to PSA failure (mo) Time from RP to PSA failure (yr) Time from recurrence to initiation of ST (wk) PSA at randomisation cT1b cT1c cT2a cT2b pT2a pT2b pT3a pT3b Surgical margin negative Surgical margin positive Surgical margin unknown
0 1 7 8 8 9 <2 2
SHT group (n = 105)
SRT SHT group (n = 105)
70 (65–74) 102 (97.1) 3 (2.9) 71 (67.6) 34 (32.4) 89 (84.8) 16 (15.2) 30.2 (17.1–47.7) 38 (36.2) 67 (53.8) 5.6 (3.5–11.0) 0.470 (0.430–0.550) 1 (1.0) 44 (41.9) 30 (28.6) 30 (28.6) 12 (11.4) 45 (42.9) 34 (32.4) 14 (13.3) 43 (41.0) 60 (57.1) 2 (1.9)
71 (67–75) 105 (100.0) 0 (0.0) 71 (67.6) 34 (32.4) 89 (84.8) 16 (15.2) 30.7 (18.8–44.9) 40 (38.1) 65 (61.9) 8.0 (6.0–15.1) 0.480 (0.430–0.570) 0 (0.0) 58 (55.2) 30 (28.6) 17 (16.2) 11 (10.5) 42 (40.0) 44 (41.9) 8 (7.6) 43 (41.0) 61 (58.1) 1 (1.0)
ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; PS = performance status; PSA = prostate-specific antigen; RP = radical prostatectomy; SHT = salvage hormone therapy; SRT = salvage radiotherapy; ST = salvage therapy. Data are presented as n (%) or median (IQR) unless otherwise noted.
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– –
Fig. 2 – Kaplan-Meier estimates of percentage of 5-yr freedom from treatment failure of bicalutamide. BCL = bicalutamide; CI = confidence interval; NE = not estimable; SHT = salvage hormone therapy; SRT = salvage radiation therapy; TTF = time to treatment failure.
Table 2 – Adverse events during protocol treatmenta
Five-year RFS was 93.8% (95% CI 86.8–97.2) in the SHT group and 88.9% (95% CI 80.9–93.7) in the SRT SHT group (HR 0.904, 95% CI 0.45–1.81; p = 0.77; Fig. 3).
SRT SHT group (n = 103)
NCI-CTC version 2.0 SHT group (n = 104) Gr. 1–2 Gr. 3
Gr. 4 Gr. 1–2 Gr. 3
Gr. 4
9 (9) 90 (87) 47 (45) 25 (24) 26 (25) 24 (23) 95 (91) 9 (9) 7 (6) 7 (6) 38 (37) 11 (11) 86 (83)
0 0 0 0 0 0 0 0 0 0 – – –
0 0 0 0 0 0 0 0 0 0 – – –
3.3.3. Leukocytopenia Anaemia Thrombocytopenia Gamma-GTP Fatigue Hot flushes Gynaecomastia Haematuria Rectal bleeding Proctitis incontinence Erectile dysfunction Loss of libido
1 (<1) 0 0 3 1 (<1) 0 4 (4) 0 0 0 0 83 (80) –
6 (6) 76 (74) 34 (33) 26 (25) 27 (26) 10 (10) 36 (35) 22 (21) 34 (33) 55 (53) 60 (6) 9 (9) 73 (71)
1 (<1) 1 (<1) 1 (<1) 2 (2) 0 0 2 (2) 3 (3) 1 (<1) 0 5 (5) 76 (74) –
Gr. = grade; SHT = salvage hormone therapy; SRT = salvage radiotherapy; NCI-CTC = National Cancer Institute-Common Toxicity Criteria. Data are number of patients with at least one episode of that event (% of patients). a No grade 5 events were identified.
Overall survival
Five-year OS was 99.0% (95% CI 93.4–99.9) in the SHT group and 91.4% (95% CI 84.2–95.4%) in the SRT SHT group (HR 1.030, 95% CI 0.46–2.3; p = 0.94; Fig. 4). 3.3.4.
Safety
Any adverse events during protocol treatment are summarised in Table 2. Notably, a higher frequency of gynaecomastia of any grade occurred in the SHT group (99, 95%) than in the SRT SHT group (38, 37%). Rectal bleeding and proctitis of any grade occurred in seven (6%) patients in the SHT group, and in 35 (34%) and 55 (53%) patients, respectively, in the SRT SHT group. QA data for SRT were determined to be fully evaluable in 102 of 105 patients in the SRT SHT group (Supplementary material, ST1).
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Fig. 3 – Kaplan-Meier estimates of relapse-free survival. CI = confidence interval; NE = not estimable; RFS = relapse-free survival; SHT = salvage hormone therapy; SRT = salvage radiation therapy.
4.
Discussion
In this JCOG0401 trial, 5-yr freedom from treatment failure of BCL was significantly higher in the SRT SHT than in the SHT group. In addition, 31% of patients who received SRT initially did not require SHT at all. No previous randomised trials have compared SRT SHT with SHT in patients with PSA failure after RP. RP is one of the curative treatments for localised prostate cancer. Most post-RP recurrences are detected only by an increase in PSA concentration [1]. Patients with post-RP local recurrence may benefit from RT, whereas those with metastatic disease may benefit from systemic treatment, the most common of which is ADT [1,6]. Therefore, identification of sites of recurrence is important in selecting the treatment strategy for patients with PSA failure after primary therapy. CT scanning and bone scintigraphy are most frequently used to detect metastatic sites; however, these two modalities usually cannot detect sites of recurrence in patients with PSA < 1.0 ng/ml [6]. Recently, new radiographic techniques such as choline positron emission tomography (PET)/CT and prostate-specific membrane antigen–based PET/CT have been developed; these
techniques may alter disease monitoring in patients with post-RP PSA failure [13]. However, these modalities have limitations in patients with PSA failure <1.0 ng/ml [13]. Even with recent advances in RP and imaging technologies, the results of the present study (JCOG0401) contribute significant clinical evidence regarding treatment of prostate cancer. SRT is usually administered for biochemical recurrence without a histological proof of local recurrence [13], even though no studies have directly compared SRT with SHT. Early SRT can achieve cure in patients with post-RP PSA failure. In European Association of Urology guidelines, PSA value of 0.2 ng/ml is defined as biochemical recurrence. However, in clinical practice, the defined value of biochemical recurrence does not necessarily match the starting point of salvage treatment. Amling et al [14] suggested that a PSA level of >0.4 ng/ml may be the most appropriate cut-off point to use, since a significant number of patients with lower PSA did not have a subsequent PSA progression. Based on this report, we set the PSA value of 0.4 ng/ml as a starting point of salvage treatment. Subsequently, Stephenson et al [15] analysed 3125 RP cases and found that PSA of at least 0.4 ng/ml followed by
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Fig. 4 – Kaplan-Meier estimates of overall survival. CI = confidence interval; OS = overall survival; SHT = salvage hormone therapy; SRT = salvage radiation therapy.
another increase best explained metastatic progression. More than 60% of patients treated before their PSA has increased to >0.5 ng/ml achieve undetectable PSA concentrations [16–19], corresponding with an up to 80% chance of 5-yr progression-free survival [20]. Our study also clearly identified an advantage of initial SRT over initial SHT by BCL in patients with low post-RP PSA concentrations (0.4–1.0 ng/ml). Early SRT was effective in 31% of the SRT SHT group at a median follow-up of 5.5 yr, thus avoiding the need for SHT. Our results demonstrated that SRT may be feasible for patients with post-RP PSA failure even if we do not have a histological proof of local recurrence. Administration of early SRT made it possible for some patients with treatment failure in our study to avoid SHT. As shown in Table 2, given the higher rates of gynaecomastia (91%) and hot flushes (23%) in the SHT group, avoiding SHT by first administering SRT may be favourable to patients with post-RP PSA failure. There has been ongoing debate regarding the optimal schedule of SRT and dosage to the prostate bed in patients with post-RP PSA failure. At the time of starting this study, no standard dose fractionations of SRT had been identified by prospective studies. In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) published a consensus panel statement [21] that recommended a total dose of 64 Gy (or slightly more) divided into 1.8–2.0 Gy/fr on
the basis of analysing data from four major institutions in the USA. On the basis of this ASTRO statement, we decided on a dosage of 64.8 Gy (1.8 Gy/fr) as the protocol treatment [6]. Similar total dosages were administered in Radiation Therapy Oncology Group (RTOG) 9601 (64.8 Gy) [22] and Group d’Etude des Tumeurs Urogenitales-Association Francaise d’Urologie (GETUG-AFU) 16 (66 Gy) [23], which were designed to investigate SRT hormone therapy in patients with post-RP PSA failure. In RTOG 9601, adverse bowel events of all grades were reported in 238/374 patients (70%), and grade 3 or worse genitourinary events in three patients (0.8%) in the RT-alone group. In GETUG-AFU 16, late adverse genitourinary events of all grades were reported in 261/372 patients (70%), and grade 3 or worse genitourinary events in 29 patients (8%) in the RT-alone group [23]. In our study, rectal bleeding and proctitis of any grade occurred in 35 (34%) and 55 (53%) patients, respectively, in the SRT SHT group, but only one patient (<1%) had grade 3 rectal bleeding (Table 2). There was a lower frequency of adverse genitourinary events than in these studies [22,23], which may be attributable to the higher quality of radiation, as evidenced by the results of quality assessment of SRT in JCOG0401. In GETUG-AFU 16, the prostate bed was not clearly defined and no quality control was reported [24], and RTOG 9601 provided no description of the methods used for quality assessment of SRT [22].
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Recent data from RTOG 9601 [22] suggest that the addition of 2 yr of BCL to SRT improves both cancer-specific survival and OS. According to GETUG-AFU 16, 6 mo treatment with a gonadotropin-releasing hormone (GnRH) analogue significantly improves 5-yr progression-free survival [23]. These two trials contained more patients at high risk after RP than in the present study; they clearly identified that the addition of hormone therapy to SRT was beneficial in these high-risk patients. Although the type of hormone therapy differed between these two studies, SRT with hormone therapy could become a standard approach in high-risk post-RP patients [22,23]. There are several prospective ongoing randomised controlled trials related to JCOG0401. Radiotherapy-Adjunct Versus Early Salvage (RAVES) is a phase 3 trial to investigate the timing of RT for prostate cancer with high-risk features [25]. Radiation and Androgen Deprivation in Combination with Local Surgery (RADICALS) is a large randomised trial addressing both the timing of treatment after RP (adjuvant vs early salvage) and the duration of SHT (none vs short term vs long term) used in addition to prostate bed RT [26]. GETUG-AFU 17 is a randomised phase 3 trial that is studying the timing of giving triptorelin and RT after RP for intermediate-risk stage 3 or stage 4 prostate cancer (NCT00667069). The results of these studies have not yet been revealed, but these will have implications for the present study and will identify the optimal salvage/ adjuvant treatment after PSA failure after RP. This study has several limitations. First, as in any randomised controlled trial, patients were selected based on specific criteria and the results may not be generalisable to other patient cohorts. Second, this study had very few patients and very short follow-up to allow definitive conclusions concerning OS and RFS. There were no significant differences in OS and RFS in this study. We estimate that this could be due to a short follow-up time. In addition, new androgen receptor targeting agents such as enzalutamide and abiraterone in castration-resistant prostate cancer might affect the OS after the salvage treatment of RP. Third, the primary endpoint of this study was TTF of BCL but not OS. As the 10-yr OS rate is expected to be >80% in this study and many events from other than primary cancer are expected in these elderly patients, we considered that OS was not the optimal primary endpoint. TTF of the LH-RH analogue may be an appropriate primary endpoint for castration-resistant prostate cancer, but PSA failure had to occur up to three times in the SRT SHT therapy group, thereby prejudicing evaluation. As TTF of BCL can be evaluated earlier than TTF of an LH-RH analogue, we considered it a good surrogate endpoint and therefore selected it as a primary endpoint. Fourth, the primary endpoint was designed to be analysed by one-sided p value. We consider that the choice of performing a one-sided or a two-sided test for primary analysis is determined based on a clinical hypothesis. When the SRT SHT group is inferior to the SHT group in terms of the primary endpoint of TTF, SHT still remains an optional regimen regardless of being statistically significant or not. Since the primary decision would be made using the results of statistical test whether
SRT SHT is superior to SHT, the one-sided test was used in TTF. One-sided alpha of 5% for analysis of primary endpoints may not necessarily be acceptable since one-sided alpha of 2.5% should be used in accordance with the ICH E9 guideline [27]. We know that this is a limitation of this study. However, considering the number of patients who are eligible for this study, we prioritise feasibility. Fifth, the high PSM rate in this trial was observed, and it should be one of the limitations when applying these results to a more general population. 5.
Conclusions
Initial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT SHT is more beneficial than SHT alone. Author contributions: Seiji Naito had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Yokomizo, Naito, Fukuda. Acquisition of data: Yokomizo, Satoh, Hashine, Inoue, Fujimoto, Egawa, Habuchi, Kawashima, Ishizuka, Shinohara, Sugimoto, Yoshino, Tobisu, Kakehi, Naito. Analysis and interpretation of data: Yokomizo, Naito, Fukuda. Drafting of the manuscript: Yokomizo, Naito, Fukuda. Critical revision of the manuscript for important intellectual content: Tobisu, Kakehi. Statistical analysis: Wakabayashi. Obtaining funding: Yokomizo, Naito. Administrative, technical, or material support: Wakabayashi, Fukuda. Supervision: Tobisu, Kakehi. Other: radiation quality control: Nihei. Financial disclosures: Seiji Naito certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Akira Yokomizo has received personal fees from Astellas Pharma Inc., AstraZeneca, Bayer, Janssen Pharmaceutical K.K., Sanofi, and Takeda Pharmaceutical Company Ltd. Masashi Wakabayashi has received personal fees from Chugai Pharmaceutical Co., Ltd. and Johnson & Johnson K.K. Medical Company. Takefumi Satoh has received personal fees from Bayer AG, Janssen Pharmaceutical K.K., Nihon Medi-Physics Co. Ltd., AstraZeneca, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, and Daiichi Sankyo Company Limited. Katsuyoshi Hashine has received personal fees from Kyowa Hakko Kirin Co. Ltd., Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Sanofi, Bristol-Myers Squibb, MSD K.K., Pfizer, Bayer, and Astellas Pharma Inc. Takahiro Inoue has received personal fees from Astellas Pharma Inc., Janssen Pharmaceutical K.K., Astra Zeneca, Takeda Pharmaceutical Company Ltd., Bayer, Sanofi, MSD K.K., Bristol-Myers Squibb, Ono Pharmaceutical Co. Ltd., and Pfizer Inc. Kiyohide Fujimoto has received personal fees from Chugai Pharmaceutical Co. Ltd., NIppon Kayaku Co. Ltd., Ferring Pharmaceuticals, Pfizer Inc., Bayer, ASKA Pharmaceutical Co. Ltd., Daiichi Sankyo Company Ltd., Novartis International AG, SBI Pharma, KYORIN Pharmaceutical Co. Ltd., MSD K. K., Tsumura & Co., Taiho Pharmaceutical Co. Ltd., FUJIFILM Corporation, Ono Pharmaceutical Co. Ltd., Sanofi, Asahi Kasei, Janssen Pharmaceutical K.K., and Kissei Pharmaceutical Co. Ltd. Shin Egawa has received personal fees from Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd.,
Please cite this article in press as: Yokomizo A, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)y. Eur Urol (2019), https:// doi.org/10.1016/j.eururo.2019.11.023
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Funding/Support and role of the sponsor: This work was supported by Health Sciences Research Grants for Clinical Research for Evidence Based Medicine and Grants-in-Aid for Cancer Research (016) from the Ministry of Health, Labour and Welfare, Japan.
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support and article preparation (Ryunosuke Machida and Junki
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and survival outcomes with early salvage radiotherapy in men with
Dr. Trish Reynolds, MBBS, FRACP, from Edanz Group (www.edanzediting.
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com/ac) for editing a draft of this manuscript.
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Appendix A. Supplementary data
[18] Ohri N, Dicker AP, Trabulsi EJ, Showalter TN. Can early implementation of salvage radiotherapy for prostate cancer improve the
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