Japanese Journal of Clinical Oncology Advance Access originally published online on May 30, 2006
Japanese Journal of Clinical Oncology 2006 36(5):290-294; doi:10.1093/jjco/hyl030
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© 2006 Foundation for Promotion of Cancer Research
Monotherapy with Carbon Ion Radiation for Localized Prostate Cancer
1 Department of Urology, Graduate School of Medicine, Chiba University, 2 Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba 3 Department of Surgical Pathology, Kanagawa Cancer Center, Yokohama, Japan
For reprints and all correspondence: Jun Shimazaki, Department of Urology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba-shi 260-8670, Japan. E-mail: shimajun{at}opal.famille.ne.jp
Received December 24, 2005; accepted February 13, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Radiation treatment for localized prostate cancer has become a prominent choice of monotherapy, and carbon ion beam is a powerful means for this purpose.
Methods: In total, 37 patients with localized prostate cancer were treated by monotherapy with carbon ion radiation and the outcome, more than 4 years later, was followed.
Results: PSA relapse-free survival was overall 85%, 5 years after radiation, and 96% in low-risk patients. Local control was mostly achieved, and no cancer-specific death was obtained. Except in cases of relapse, 1.0 ng/ml or less of PSA was shown in 78%, 3 years after radiation. Half of biopsy specimens out of 12 cases revealed non-viable or no cancer cells after a rather short time from treatment.
Conclusion: Monotherapy with carbon ion radiation may be an excellent treatment for localized prostate cancer with low risk.
Key Words: prostate cancer • localized stage • radiotherapy • carbon ion radiation
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INTRODUCTION |
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Recently the incidence of prostate cancer has been increasing in Japan, and more than half of the patients are organ-confined or in locally advanced stages. For these patients, radiation therapy is one of the curative strategy, and many radiological techniques are being used. Carbon ion radiation may be a powerful means of radiotherapy for prostate cancer, because it shows a Bragg peak in the human body and gives a high dose of radiation energy to the prostate without adverse effects to the surrounding tissues.
The Heavy Ion Medical Accelerator in Chiba (HIMAC) was built at the National Institute of Radiological Sciences, and treatment was initiated with carbon ion radiation for many kinds of solid tumors (1,2). Treatment for prostate cancer by HIMAC started in 1995 and 
400 patients have been treated to date. The patients were divided into either low-risk group [T1b,c and T2ab, Gleason score 
6, and PSA (prostate-specific antigen) 20 ng/ml] or high-risk group (T2c,T3, Gleason score 
7, and/or PSA >20), supplemented without or with hormone therapy, respectively. Results of first (96 cases) and second (273 cases) series were reported (3,4). Of these patients, 37 received monotherapy with carbon ion radiation between April 1998 and December 2001. Based on these studies, a possibility has arisen to establish the carbon ion radiation as a new independent treatment. Studying the effect for >4 years, we present this report which describes the outcomes of these 37 patients.
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PATIENTS AND METHODS |
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The clinical records of 37 patients who received monotherapy were examined by mid-2005. Carbon ion radiation was performed according to the method previously described as the routine technique (4). Briefly, 60 GyE (first Phase I/II clinical trial)–66GyE (second Phase I/II clinical trial) in 20 fractions were irradiated to the entire prostate and most parts of the seminal vesicle with one anterior–posterior port and a pair of lateral ports. After radiation, these patients were observed without any additional therapy for prostate cancer until clinical relapse was evident. Staging was performed according to TNM 2002 (5). Pre-treatment biopsy was performed with 6–8 cores via rectal or perineal approaches. After radiation, sample tissues were taken for biopsy from suitable portions in some patients, and radiation effects were graded as follows: positive residual tumor without any treatment effect (Oa) or with degeneration but none of them are non-viable (Ob), less than one-half (1) or more than one-half (2) of residual tumor are non-viable, only non-viable tumor cells are observed (3a) and no tumor cells and/or tissues are detected (3b) according to the Japanese General Rule for Clinical and Pathological Studies on Prostate Cancer (6). PSA value was expressed as ng/ml of total PSA. During follow-up, PSA was measured every 2–3 months, and images (CT or MRI of the pelvic area) were taken every year. PSA relapse was determined by ASTRO criteria (7). Definition of PSA relapse was not a prerequisite with other objective findings. After PSA relapse, findings of the prostate and pelvic lymph nodes were examined with digital rectal examination and images for detection of clinically local relapse. PSA doubling time at relapse was calculated by loge 2 divided by the slope which was obtained from the least square method on three or more points. The histological grade and radiation effect were examined by one central pathologist (M.H.). Analysis of morbidity was performed according to Radiation Therapy Oncology Group / European Organization for Research and Treatment of Cancer Scoring System. Survival curve was constructed using the Kaplan–Meier method.
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RESULTS |
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Patients' characteristics are shown in Table 1. Seven cases showed
7 of Gleason score alone, and one was >20 of PSA alone, but the other factors fitted the criteria of low risk. Two cases exceeded low-risk category of Gleason score and PSA, but they were enrolled because of low stage. Therefore, there were 27 low-risk patients. Of 37 patients, PSA relapse was found in 6. PSA relapse-free survival is shown in Fig. 1, and the rate at 5 years was 85%. In low-risk patients, PSA relapse-free survival at 5 years was 96%. No clinically local relapse occurred, thus the local control rate was 100% throughout the observation period (>4 years). Three patients died (hepatocellular carcinoma, malignant lymphoma and unknown cause but with a negative biopsy after radiation). These three cases did not show PSA relapse with signs of clinical relapse of prostate cancer. Therefore, cause-specific survival was regarded as 100% at 5 years after radiation.
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After radiation, PSA was gradually decreased except in relapse cases (Fig.2). There was no PSA bounce following radiation. After treatment, patients with <0.5 ml of PSA were 11, 46, 42% at 1, 2 and 3 years, respectively, and those with <1 ng/ml of PSA were 37, 73, 78% at 1, 2 and 3 years, respectively, without values at PSA relapse and thereafter. Moreover, except in one patient (3%), PSA of others was <1.5 ng/ml at 3 years.
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The clinical courses of PSA relapse patients are shown in Table 2. Case nos 1–3 and 5 revealed long durations between the start of treatment and PSA relapse [ave. 46 months (28.1–61.0)], and their PSA doubling time at relapse was rather long [ave. 16 months (10.4–20.2)]. After relapse, these patients showed a very slow increase in PSA. No adjuvant treatment was delivered to cases 1, 2 and 5 until now, but case 3 received hormone therapy because of the biopsy finding, which showed definitely viable residual cancer tissues after radiation (Table 3). Conversely, case nos 4 and 6 showed a short doubling time and distant metastasis appeared 7 and 16 months after PSA relapse, respectively, regardless of no signs of clinically local relapse. They were treated with hormone therapy and control of the cancer was achieved currently.
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Post-radiation biopsy was performed in 12 patients (Table 3). Six biopsy specimens of 12 cases revealed therapeutic effects of grade 3a or 3b (no viable tumor or no residual tumor). Of the other six cases, one case (Tables 2 and 3, no.3) with pre-treatment Gleason score 6 showed PSA relapse 28 months after radiation. The other five cases revealed only a small volume of degenerative residual tumor cells and/or tissues with only a scarce amount of viable cells, but three cases subsequently showed PSA relapse (Tables 2 and 3, nos 1, 2 and 4). In some cases, Gleason score of the remaining cancer cells after radiation showed upgrading. Apparently the time of biopsy after radiation or the radiation doses did not affect any significant histological effects, partly attributable to the rather short period between radiation and examination.
Slight morbidity on the urinary system was frequently noticed, but no adverse effects of Grade 3 or worse were experienced during or after radiation (Table 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Photon therapy for the treatment of localized prostate cancer was initiated during the 1960s, and has widely been performed worldwide since then. A multi-institutional pooled analysis of external beam radiation therapy delivered to 1765 patients with T1b, T1c and T2 at six US medical centers between 1985 and 1995 reported 65.8% of PSA relapse-free survival at 5 years (8). Patients with T1–T2 were treated with 68.4 Gy of conventional external beam radiation, and PSA relapse-free survival at 5 years was 62% (9). Similar survival at 5 years was reported in Japan (10). To improve survival with external beam radiotherapy, an increased dose was administered to patients with T1–T2, and the 5 years PSA relapse-free survival with
72 Gy was 81% in comparison with 51% with <72 Gy (11). Radiation with 78 Gy was beneficial for patients with >10 ng/ml of pre-treatment PSA but no significant dose–response was obtained from low-risk patients (12). This suggests that cancer control for low-risk patients is achieved with an adequate dose in proper fractions; therefore, 66 GyE/20 fractions of carbon ion radiation has been established in our system (4). This hypofractionated radiation gave an excellent effect and the results showed overall 85% of PSA relapse-free survival at 5 years, and 96% in low-risk patients. Of six PSA relapse cases (Table 2), four cases were not indicated in low-risk category (PSA 20 and/or Gleason score 6); therefore, 40% of high-risk patients subsequently experienced PSA relapse. In spite of two cases showing histologically incomplete radiation effect (Table 3, no.3 and 10), all revealed no clinically local signs of relapse. Therefore, carbon ion radiation may be a highly effective treatment for localized prostate cancer. In this sense, both radiation therapy and radical prostatectomy reveal similar PSA relapse-free rates for low-risk patients such as those with stage T1–T2ab, Gleason score 6 and PSA 10 ng/ml (13,14). For high-risk patients, additional managements might be necessary before and/or after radiation therapy. It has been reported that nadir PSA after radiation influences subsequent outcome. Patients with T1–T2 and 1–2 ng/ml of PSA 5 years after radiation revealed 10–20% incidence of subsequent PSA relapse after 10 years, in contrast with >60% of subsequent PSA relapse in patients with >2 ng/ml of PSA (15). Patients with 1 ng/ml or less of PSA 5 years after radiation may reveal 71–78% of disease-free survival subsequently (16). As PSA level gradually decreases after radiation, the exact value of nadir PSA is difficult to determine because of fluctuation over a short period. However, low PSA level after radiation may indicate low PSA relapse rate in the present cases.
PSA doubling time at relapse after radiation therapy was reported to be a reliable marker for discriminating between slow and fast progressions, and a cut-off value of 3 months was proposed (17). Criteria for PSA relapse were defined by ASTRO (7,18) in which three consecutive increases in PSA constitutes definition. Two relapse cases in the present report showed short PSA doubling time at relapse, and they turned out to have bone metastatic disease. In the other four relapse cases, their PSA showed a very slow increase and their courses seem to be mild progression. If other criteria of PSA relapse, for example nadir + 2 ng/ml which indicates 0.68 of sensitivity for relapse, were applied (19,20), none of these cases might be defined as PSA relapse. Although PSA relapse indicates a turning point of progression, other factors are needed to predict outcome. Calculation of doubling time is one way to more reliably predict the subsequent course after PSA relapse.
Radiation delivered to prostate induces various histological changes in both non-malignant and malignant cells, and shows diverse effects even within a single biopsy specimen (21). There is no universal evaluation system for histological effects in post-radiation biopsy specimens. A grading system of radiation-induced histological effects has been proposed, based on separately graded nuclear and cytoplasmic changes each classified on a three-point scale (no effect to heavily damaged), and the least reactive point was used to determine biopsy failure (22). In contrast, the Japanese rule for histological effect of treatment in prostate cancer classifies according to the proportional amount of non-viable tumor cells and/or tissues, which show nuclear pyknosis, karyorrhexis and karyolysis within all of residual tumor cells and/or tissues (6). Applying this grading system to the 12 cases of post-radiation biopsy specimens, significant degenerative effects of carbon ion radiation were observed in most cases. Patients with incomplete radiation effect experienced subsequent PSA relapse, but it is not clear whether a small volume of the residual tumor cells and/or tissues participated in the relapse. This suggests that histological findings are indeed one of the prognostic factors. Although we cannot exclude the possibility that biopsy specimens were taken from an inadequate area, the course of PSA after radiation supports an outcome without relapse in most of the present cases until now (23). An upgrading in Gleason score has been reported in residual tumor tissues, as was noticed in the present cases. It is disputable whether upgrading is a profile of radio-resistant cells or represents radiation effect. Grading the histological pattern after radiation with the Gleason system may be different from that of untreated structure. Further histological examination will confirm the effect of monotherapy with carbon ion radiation for patients with low-risk prostate cancer.
In conclusion, risk assessment of patients is the first step in applying monotherapy with carbon ion radiation, and low-risk patients appear to be the appropriate candidates for this treatment.
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Acknowledgments |
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The authors deeply thank the Working Group on Genitourinary Tumors, National Institute of Radiological Sciences, for their kind support.
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References |
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