Japanese Journal of Clinical Oncology Advance Access originally published online on November 28, 2005
Japanese Journal of Clinical Oncology 2005 35(12):745-752; doi:10.1093/jjco/hyi193
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© 2005 Foundation for Promotion of Cancer Research
Phase II Feasibility Study of High-Dose Radiotherapy for Prostate Cancer Using Proton Boost Therapy: First Clinical Trial of Proton Beam Therapy for Prostate Cancer in Japan
Radiation Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
For reprints and all correspondence: Keiji Nihei, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: knihei{at}east.ncc.go.jp
Received June 20, 2005; accepted October 10, 2005
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Abstract |
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Objective: To assess the feasibility of high-dose radiotherapy for prostate cancer using proton boost therapy following photon radiotherapy.
Methods: The primary endpoint was acute grade 3 or greater genitourinary (GU) and gastrointestinal (GI) toxicities. The study included patients with clinical stage T1-3N0M0 prostate cancer. Radiotherapy consisted of 50 Gy/25 fx photon irradiation to the prostate and the bilateral seminal vesicles followed by proton boost of 26 GyE/13 fx to the prostate alone. Hormonal therapy was allowed before and during the radiation therapy.
Results: Between January 2001 and January 2003, 30 patients were enrolled in this study. Acute grade 1/2 GU and GI toxicities were observed in 20/4 and 17/0 patients, respectively. With the median follow-up period of 30 months (range 20–45), late grade 1/2 GU and GI toxicities occurred in 2/3 and 8/3 patients, respectively. No grade 3 or greater acute or late toxicities were observed. All patients were alive, but six patients relapsed biochemically after 7–24 months.
Conclusions: Proton boost therapy following photon radiotherapy for prostate cancer is feasible. To evaluate the efficacy and safety of proton beam therapy, a multi-institutional phase II trial is in progress in Japan.
Key Words: proton beam therapy • prostate cancer • clinical trial
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INTRODUCTION |
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The age-adjusted prostate cancer incidence rate per 100 000 Japanese men has doubled during the last two decades from 9.8 to 19.9, and the incidence increases exponentially as age rises above 50 years. This is caused by more Westernized dietary habits, the advancing aging of society and the more widespread use of screening tests for prostate-specific antigen (PSA). It is also expected that the situation will continue to approach that of Western countries in the near future. The issue of how to manage this disease has thus become an important topic in Japan as well as in Western countries.
Previous reports have shown that there is a dose–response relationship in irradiating prostate cancer, and a higher dose >70 Gy is potentially beneficial for prostate cancer (1,2). However, other reports have revealed that, with conventional radiotherapy techniques, rectal complications increase drastically at >70 Gy (3,4). Several techniques to deliver higher doses to the prostate have been developed and have become widespread, such as three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), charged particle therapy (heavy ion and proton) and brachytherapy. These techniques can allow good target dose coverage with a minimal dose to the surrounding normal tissue to improve tumor control with acceptable toxicity. To evaluate the efficacy and safety of high-dose irradiation for prostate cancer, dose escalation studies using 3D-CRT or IMRT were conducted by the Radiation Therapy Oncology Group (RTOG) and many institutions (5–11). Large series of brachytherapy or implantation of radioactive sources into the prostate are also reported, and there are ongoing RTOG trials using brachytherapy with or without external beam radiotherapy (12–16).
Charged particles have a physical depth-dose characteristic called the ‘Bragg peak’. A single proton beam has a low entrance dose, a maximal dose at a user-defined depth and no exit dose. The ‘Bragg peak’ can be spread out and shaped to conform to the depth and volume of an irregular target. Proton beam therapy (PBT) can thus create an inherently three-dimensional conformal dose distribution without extra dose to the surrounding normal tissue compared with conformal photon radiotherapy (17).
In National Cancer Center Hospital East (NCCHE), proton facilities were introduced and applied to clinical use in 1998, and we started to conduct a feasibility study of proton boost therapy following photon therapy for prostate cancer in 2001. The purpose of this study was to assess the feasibility of high-dose radiotherapy for prostate cancer employing proton boost therapy following photon radiotherapy. The institutional review board reviewed and approved the trial protocol.
There were three reasons why we adopted the photon/proton combined treatment. First, we followed the experiences of Loma Linda University Medical Center (LLUMC) and Massachusetts General Hospital (MGH) who also used combination therapy at the beginning (18,19). Second, it was our first experience of using the proton beam for prostate cancer and the safety was not confirmed. Third, the proton machine was unfortunately unstable at the beginning and a longer schedule of proton treatment was considered to be impractical.
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PATIENTS AND METHODS |
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ENDPOINTS
The primary endpoint was acute grade 3 or greater genitourinary (GU) and gastrointestinal (GI) toxicities. The secondary endpoints were to evaluate the other toxicities, the PSA-failure free survival and the overall survival.
Late toxicities are often regarded as an important issue after high-dose radiotherapy. Although the relationship between acute and late toxicities is not clear, we decided to use acute toxicities as the primary endpoint of the current study, so that safety of the treatment could be ensured as soon as possible. Late toxicity was also monitored afterwards and if severe late toxicity was observed, the study would be suspended for evaluation of the safety by the study committee.
Acute toxicities were evaluated by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) ver2.0 within 90 days from the beginning of radiotherapy. Thereafter, late toxicities were evaluated by the RTOG/EORTC (European Organisation for Research and Treatment of Cancer) late radiation morbidity scoring schema. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition based on three consecutive PSA rises, and the date of the failure was backdated to the midpoint between the nadir and the first rise (20). The Kaplan–Meier method was used to evaluate the PSA-failure free survival and the overall survival. The base date for reckoning a period of time was the day on which the radiotherapy started.
PATIENT ELIGIBILITY CRITERIA
The eligibility criteria of this study were (i) pathologically proven adenocarcinoma; (ii) clinical stage T1-3N0M0 (1997UICC); (iii) performance status 0–2; (iv) no serious complications; (v) appropriate organ functions; (vi) no previous history of pelvic radiotherapy; (vii) no previous surgery; and (viii) written informed consent. Hormonal therapy was allowed before and during the radiation therapy, but was stopped after the radiation therapy.
PRETREATMENT EVALUATION
To estimate the local disease extension and distant metastasis, all patients received physical examinations, bone scans, and pelvic CT and/or MRI. All biopsy slides were reviewed by institutional pathologists to confirm Gleason scores (GS) as a pathological grade. Pretreatment serum PSA values were obtained before both radiotherapy and hormonal therapy.
Initial PSA value and GS were not included in the eligibility criteria, because the primary endpoint was to assess the feasibility.
RADIATION THERAPY
Radiotherapy consisted of 50 Gy/25 fx photon irradiation to the prostate and the bilateral seminal vesicles followed by proton boost therapy of 26 GyE/13 fx to the prostate alone. The unit of ‘GyE’ means the photon equivalent dose calculated from the physical dose and the relative biological effectiveness (RBE). The RBE in our institution was defined as 1.1 from previous biological experiments (21).
In the photon treatment, the clinical target volume (CTV) was defined as the prostate and the bilateral seminal vesicles, and the planning target volume (PTV) was defined as the CTV plus 10 mm margins for interfraction prostate motion and set-up error in all directions and 5 mm was added to the PTV for penumbra margin. The photon beam was delivered by 240° arc dynamic conformal technique (Fig. 1a). The patient position was aligned with laser markers in the usual manner, and verification of patient positioning was performed at the beginning of the treatment and whenever necessary thereafter.
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In the proton boost therapy, the CTV was defined as the prostate alone and the treated volume was defined as the CTV plus 5 mm margin for PTV margin in all directions, and 5 mm was added to the PTV for penumbra margin. Daily verification of patient positioning was performed by the image subtraction method using digital radiography (22). The daily actual images were compared orthogonally with the reference images and the subtracted images were adjusted so that the pelvic bone structure disappeared (Fig. 2). Since daily verification of patient positioning was performed, the PTV margin in the proton boost therapy took only the interfraction prostate motion into account. The proton beam was delivered by lateral opposed portals (Fig. 1b).
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Although the eligibility criteria included patients from low-risk to high-risk, the same target volume definition was applied to all cases to assess the feasibility of the treatment. The dose–volume histograms (DVHs) of the rectum and the urinary bladder were all checked while planning each of the photon and the proton treatments, but no DVH constraints were used in the current study.
To control rectum and bladder filling, all patients were instructed to urinate and drink half a liter of water 30 min before each treatment and were encouraged to have a regular bowel movement to empty their rectums. Both legs were fixed by a vacuum cushion in the supine position for patient immobilization. Using our way of patient positioning and rectal/bladder filling, we previously analysed the interfraction prostate motion and set-up error quantitatively (23) and confirmed that the PTV margin in the current study described above was necessary and sufficient.
FOLLOW-UP STUDY
All patients were seen by radiation oncologists once or twice a week during the radiation therapy to assess subjective symptoms including urinary frequency, urgency, retention, painful urination, rectal discomfort, diarrhea, anal pain, rectal bleeding and so on. After the completion of radiation therapy, subjective symptoms and biochemical data were followed up every 3 months during the first 2 years and every 6 months thereafter. Radiographic examinations and biopsy were not performed unless clinical disease progression was suspected.
SAMPLE SIZE
We determined <15% grade 3 GU/GI toxicities as acceptance of feasibility. Initially, 15 evaluable patients were to be accrued to assess the feasibility of this study. If no acute grade 3 or greater GU/GI toxicities were observed, the feasibility of this study would be approved and further 15 evaluable patients would be accrued to assess the efficacy. This would provide at least 90% confidence (0/15) that the true toxicity rate was <15%. However, if one grade 3 or greater GU/GI toxicity was observed, then an additional evaluable 10 patients would be accrued. If no further grade 3 or greater GU/GI toxicities were observed, the feasibility of this study would be approved and five evaluable patients would be accrued to assess the efficacy. This would provide at least 90% confidence (1/25) that the true toxicity rate was <15%. If two or more grade 3 or greater toxicities were observed in the first 15 patients, then accrual would be suspended and the events will be reviewed by the Assessment Committee of the study. This study design has a detection power of 73% when the true acute grade 3 or greater GU/GI toxicities are <10%. In total, 30 patients were to be accrued.
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RESULTS |
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When the first 15 patients were followed up for 90 days from the beginning of the radiotherapy, no acute grade 3 or greater GU/GI toxicities occurred. Therefore, the feasibility of this study was approved and further 15 patients were accrued.
In total, 30 patients were enrolled in this study between January 2001 and January 2003. The patient and tumor characteristics (Table 1) were as follows: median age, 73 (range 54–87); T1c/T2a/T2b/T3a, 4/8/11/7; median initial PSA value, 19.2 (range 4.7–66.9); Gleason score 4–5/6/7/8–10, 4/15/8/3; and previous hormonal therapy Yes/No, 21/9. The median duration of hormonal therapy was 7 months, ranging from 1 to 23 months. Three prognostic risk groups were defined as follows: low-risk group, iPSA 
10, GS 6 and T1-2; high-risk group, iPSA >20, GS 
8 or T3; and intermediate-risk group, all others except for the above. There were 5/11/14 patients in the low/intermediate/high-risk groups, respectively.
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Acute grades 1 and 2 GU toxicities were observed in 20 and 4 patients, respectively. The four grade 2 cases were all urinary frequency and urgency. There were 17 grade 1 GI toxicities. No patient experienced grade 3 or greater acute toxicity (Table 2).
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With a median follow-up period of 30 months (range 20–45), late grades 1 and 2 GU and GI toxicities occurred in 2 and 3, and 8 and 3 patients, respectively. The three grade 2 GU toxicities were two urinary frequency and one gross hematuria, and the three grade 2 GI toxicities were all rectal bleeding (Table 3). No patient experienced grade 3 or greater late toxicity. In 10 patients who experienced grade 1 or 2 rectal bleeding, the events occurred at 8–17 months with a median of 14 months after the radiation therapy.
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Between those who received hormonal therapy and those who did not, there was no difference in the acute toxicities, but the latter group experienced more late toxicities (5/9, 55%) than the former (9/21, 43%). One patient who had previously received transurethral resection of the prostate did not suffer any late toxicity at 20 months after the radiotherapy.
All patients were alive, but six patients relapsed biochemically after 7–24 months. The PSA-failure free survivals for all patients are shown in Fig. 3. The PSA-failure free survivals at 1 year and 2 years were 93% (95% confidence interval (CI) = 84–100%) and 77% (95% CI = 63–94%), respectively, by ASTRO definition.
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DISCUSSIONS |
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HIGH-DOSE RADIOTHERAPY FOR PROSTATE CANCER
The dose–response relationship in irradiating prostate cancer was demonstrated by Patterns of Care Study and other institutional studies in the 1980s (1,2). A higher local control rate was obtained as the radiation dose to the prostate increased to >70 Gy. Regarding toxicity it was also reported that serious complications drastically increased when using doses >70 Gy, if the conventional radiation technique was used (3,4). As computed radiography and radiotherapy devices developed, more precise radiotherapy techniques were put into clinical use, such as 3D-CRT, IMRT, particle therapy and brachytherapy. These techniques can allow good target dose coverage with a minimal dose to the surrounding normal tissue when performing high-dose radiotherapy for prostate cancer.
Many institutions have tried to conduct high-dose external beam radiotherapy with >70 Gy for prostate cancer using 3D-CRT or IMRT (5–8). They reported satisfactory clinical outcomes of high-dose radiotherapy for prostate cancer, including both efficacies and morbidities, but these single institutional data cannot confirm the usefulness of high-dose radiotherapy as a standard treatment for prostate cancer. To evaluate the safety and to determine the recommendable dose of high-dose radiotherapy, RTOG started to conduct a dose escalation study (RTOG 9406) using 3D-CRT (9–11). The patient accrual has finished and the safety of high-dose 3D-CRT will be confirmed. There are several large series treating patients with localized prostate cancer by using permanent implant brachytherapy with or without external beam radiotherapy for >10 years (14–16). To confirm these retrospective data, RTOG also started to conduct prospective studies of permanent implant brachytherapy with or without external beam radiotherapy.
Until now, there have been two phase III studies with final results, comparing high-dose with standard-dose radiotherapy for prostate cancer. One was conducted by MGH using proton boost therapy (24), and the other was conducted by MD Anderson Cancer Center using 3D-CRT (25). In the MGH trial, patients with T3-T4NX/N0-2 prostate cancer received 67.2 Gy by photon radiotherapy or 75.6 Gy by photon/proton combined therapy. There was no significant difference between the two groups in any survival outcome. In the MD Anderson trial, 305 patients with T1–T3 prostate cancer were randomized to receive a standard-dose of 70 Gy or a high-dose of 78 Gy. The freedom from failure rate at 6 years in the high-dose group (74%) was significantly better than that in the standard-dose group (64%). To assess the efficacy of high-dose radiotherapy in a multi-institutional setting, RTOG is now conducting a phase III study comparing a high-dose of 82.28 Gy with a standard-dose of 72.93 Gy for prostate cancer.
Thus although there are many promising outcomes and wide experiences of high-dose radiotherapy for prostate cancer, the topic remains under investigation and the optimal dose for each risk group has not been established.
PBT FOR PROSTATE CANCER
PBT for prostate cancer started at MGH in the 1970s (18). In the phase III trial previously described, there was no significant difference in survival outcomes between high-dose and standard-dose groups (24). At LLUMC, >1200 patients with prostate cancer were treated by PBT. They used photon radiotherapy to the pelvis at 45 Gy followed by proton boost to the prostate at 30 Gy for high-risk patients, and PBT alone with a total dose of 74 Gy for low-risk patients. The overall 5 year and 8 year actuarial biochemical disease-free survival rates were 75 and 73%, respectively (26,27). MGH and LLUMC cooperatively completed the phase III trial using proton boost therapy following photon radiotherapy, which randomized patients with early prostate cancer to receive a dose of 70.2 or 79.2 Gy. They are now conducting another dose escalation phase I/II study using >80 Gy of PBT alone.
In Japan, PBT was first used at Tsukuba University in 1985. They experienced PBT with 14 prostate cancer patients, but the evaluation was performed retrospectively and this cannot be considered as an establishment of policy for PBT for prostate cancer in Japan. In NCCHE, PBT was applied to clinical use in 1998, and the present study for prostate cancer started in 2001. Owing to the small number of patients and short duration of follow-up, the effectiveness of PBT for prostate cancer should not be assessed from the current study. However, because no patient experienced any grade 3 or greater toxicities, the feasibility of the proton boost therapy following photon radiotherapy was confirmed.
DOSE DISTRIBUTION AND TOXICITIES
We analysed the rectal DVHs using the current study cohort. The rectal DVHs in the photon/proton combined therapy (the current study) were compared with those produced by planning in PBT alone. Figure 4 shows the apparent advantage of the rectal DVHs using PBT alone compared with those using photon/proton combined treatment (28). In that study, the rectal DVH using PBT alone was much superior to the DVH constraints of 3D-CRT and just comparable to those of IMRT introduced by other institutions and clinical trials.
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Comparison of late GI toxicities between other series of external radiation therapy is shown in Table 4. The frequency of late grades 2 and 3 GI toxicities in RTOG 9406 (11) was less than that of other reports, but this was probably owing to the lower total doses with a smaller fraction size of 1.8 Gy rather than 2.0 Gy. LLUMC reported 21% late grade 2 GI toxicities in patients who received photon/proton combined therapy or PBT alone (27). Because they considered isolated rectal bleeding (grade 1) and transfusion (grade 3) as grade 2, the true frequency of late grade 2 GI toxicities was supposed to be <21%. Table 4 shows that the frequency of grades 1 and 2 late rectal toxicities in the current study was comparable to that of other reports using high-dose external beam radiotherapy.
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As the RTOG 9406 study reported, severe late toxicities (grade 3) significantly decreased using 3D-CRT compared with those observed in historical studies using conventional radiotherapy. However, moderate late toxicities (grade 1/2) were unexpectedly increased by high-dose radiotherapy using 3D-CRT (11). Grades 1 and 2 toxicities are not severe but have a significant impact on a patients' quality of life, so it becomes a matter of great importance how we can reduce both severe and moderate late toxicities. As shown in Table 4, Memorial Sloan Kettering Cancer Center reported reduced actuarial incidences of moderate toxicities (grade 2) by using IMRT, even with a higher dose level (6). As described above, because PBT alone can produce rectal DVH just as well as IMRT, it is expected that not only grade 3 but grade 1/2 toxicities can be reduced by using PBT alone, at least to the same extent as when using IMRT. And the discussion thus far about rectal toxicities can also be applied to GU and other toxicities.
COMPARISON WITH IMRT
By using IMRT, multiple portals of photon beams three-dimensionally expose a large volume of the surrounding normal tissues to low radiation doses. In contrast, PBT alone can generate sufficient dose coverage to the prostate by lateral opposed portals with no radiation exposure to the ventral and dorsal portion of the body (Fig. 1b). Discussed from such a viewpoint as difference in physical characteristics between photon and proton beams, it is suggested that PBT alone can further reduce the toxicity compared with IMRT. Because of using just lateral opposed portals, the conformity of the prescribed dose to the target volume by PBT is poorer than that by IMRT, but intensity-modulated proton therapy which is now developing for clinical application will improve the conformity of the current PBT and realize more ideal dose painting in the target volume in the future (29).
Regarding the risk of second malignancy as long-term sequelae, Brenner et al. (30) reported interesting data from the Surveillance, Epidemiology and End Results (SEER) Program cancer registry (1973–93). Radiotherapy for prostate cancer was associated with a small but statistically significant increase in the risk of second solid tumors, particularly for long-term survivors, relative to treatment with surgery. By sparing the large volume of the surrounding normal tissues from exposure of low radiation doses, it is expected that using PBT to treat prostate cancer can decrease the risk of radiation-related second malignancy. Diagnosis at younger ages and earlier stages is resulting in longer survival times for patients with prostate cancer, and radiation-related second malignancy risk becomes a more significant issue in the future.
FUTURE DIRECTIONS
Although MGH and LLUMC have large experiences using PBT, the data of retrospective analysis and combination with photon therapy were included. A multi-institutional prospective clinical trial can further confirm the efficacy and safety of proton therapy. As discussed above, because the dose distribution generated by PBT alone is superior to that by photon/proton combined treatment (the current study), the feasibility of the current study should warrant the safety of PBT alone for prostate cancer with the same total dose. There are now five institutions with proton facilities in Japan, and we are conducting a multi-institutional phase II trial in which we treat low- and intermediate-risk prostate cancer by PBT alone with a total dose of 74 GyE. The primary endpoint is the incidence of grade 2 rectal bleeding at 2 years. This study will certainly confirm the clinical advantage of PBT for prostate cancer.
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Acknowledgments |
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This paper was presented at the 40th semi-annual meeting of Particle Therapy Cooperative Group (PTCOG) in Paris, 2004.
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References |
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