Abstract
Background/Aim: Carbon ion radiotherapy is expected to be suitable to treat localized prostate cancer because it yields great biological and physical effects. The aim of this study was to examine long-term results and subsequent outcomes after biochemical failure. Patients and Methods: A total of 254 patients were treated from the beginning of 2003 and followed through 2009. Long-term hormone therapy was also used for some intermediate-risk and high-risk patients. Results: Among the patients examined, 54 patients experienced biochemical failure. Failure-free survival was 76%, 91% and 76% at eight years in low-risk, intermediate-risk and high-risk patients, respectively. Clinical progression occurred only in high-risk patients, with 89% progression-free survival at eight years. After biochemical failure, diseases of most patients were well controlled by salvage therapy but twelve high-risk patients (5%) died of prostate cancer. Conclusion: Carbon ion radiotherapy had an excellent effect on localized prostate cancer. Factors influencing salvage therapy included PSA kinetics and duration between radiation and failure.
In 2005 in Japan, 42,997 men were diagnosed with prostate cancer (an incidence of 42.0 per 100,000 men), and 9,264 men died of prostate cancer (1). The proportion of patients with cancer at a localized stage has increased and radiotherapy and surgery are critical curative treatments for such patients. Carbon ion beam is characterized by high cytocidal effects, high linear energy transfer and excellent radiation dose distribution. Based on its biological and physical effects, carbon ion radiotherapy is considered as a new treatment modality for solid tumors. The National Institute of Radiological Sciences in Japan constructed the Heavy Ion Medical Accelerator in Chiba (HIMAC) in 1993 and started to use carbon ion radiotherapy to treat localized and locally advanced prostate cancer in 1995. Preliminary short-term results have been reported (2-4). Since then, this is the first study to assess the long-term outcomes of patients who received carbon ion radiotherapy between 1995 and 2003. Because some patients experienced biochemical failure, the present study examined the influence of adjuvant therapy on the subsequent outcome.
Patients and Methods
Patients. Patients with confirmed histological adenocarcinoma and T1b-T3N0M0 cancer were enrolled in the study. Between the start of treatment (October 1995) and October 2003, 254 consecutive patients had received carbon ion radiotherapy. Patients had not received previous treatment for prostate cancer. Clinical records for all patients were collected in 2009. The follow-up period lasted for a mean of 98 months, with a median of 96 months and a range of 5-178 months. To establish the radiation modality, the three following Protocols were adapted sequentially (2): 35 cases used Protocol 9402 with a dose escalation of 54.0-72.0 Gy equivalent (GyE), 62 cases used Protocol 9703 with a dose escalation of 60.0-66.0 GyE and a fixed dose of 66.0 GyE, and 157 cases used Protocol 9904 with a fixed dose of 66.0 GyE in 20 fractions. Stages were defined using the UICC (2002). Before treatment, prostate biopsy with eight or more cores was performed and Gleason scores were estimated by a central pathologist (MH). Patients were divided into low-risk, intermediate-risk and high-risk groups using the NCCN classification system (5).
Hormone therapy was used according to risk classification as follows: no hormone therapy for low-risk and intermediate-risk patients with T2ab, and two to six months of neoadjuvant hormone therapy and one year or more of adjuvant hormone therapy for other intermediate-risk patients with T2c or with Gleason score of 7 and all high-risk patients. Hormone therapy generally consisted of a luteinizing hormone-releasing hormone agonist and a daily dose of 80 mg of bicalutamide. After biochemical failure, conventional hormone therapy, second-line hormone therapy and chemotherapy were successively employed.
Patients underwent digital rectal examinations and determination of prostate-specific antigen (PSA) every three to six months. If abnormal findings were suspected, an imaging examination including a bone scan and magnetic resonance imaging scan was carried out along with frequent PSA assays. The primary endpoint was biochemical failure, and overall and clinical progression-free survival rates were calculated.
Rates of acute and late morbidities were estimated using the RTOG/EORTG system (6).
PSA kinetics. Total PSA (PSA) was determined using commercial kits (AxSYM PSA Dainapack; Abbot, Chiba Japan). Biochemical failure was judged by Phoenix criteria, when PSA was elevated by 2 ng/ml or more over baseline (7). PSA-doubling time (PSA-DT) and velocity before biochemical failure were calculated by linear regression. A slope was obtained from three or more points by the least-squares fitting method using the natural logarithm (ln) of PSA (for calculation of PSA-DT) or PSA (for calculation of velocity). Consequently, PSA-DT was calculated as ln 2/slope (8) and velocity was determined as the difference in PSA increase per year (9). The response to salvage hormone therapy was evaluated as follows: a partial response (PR) was defined as a decrease in PSA ≥50% from baseline, progressive disease (PD) was designated as an increase in PSA ≥25% over baseline, and no change (NC) was denoted as any change between PR and PD.
Carbon ion radiotherapy. The technique of carbon ion radiotherapy was previously reported (2). Briefly, the head and feet of the patients were positioned in a customized cradle and the pelvis was immobilized with a thermoplastic sheet. The bladder was filled with 100 ml of sterilized water in the anterior direction at a computed tomography (CT) planning and at each session from the anterior direction. The rectum was emptied with a laxative or enema, if necessary.
The clinical target volume was designed for the prostate and seminal vesicle after referring to a 5-mm thick CT scan. The initial planning target volume was created by adding 10-mm anterior and lateral margins and 5-mm posterior margin. After the first 10 fractions, the posterior margin was set on the anterior wall of the rectum to limit the dose received by the rectum to <50 GyE. Radiation was performed with one anterior-posterior port and a pair of lateral ports which were alternated at each session once a day in four fractions per week for five weeks.
Statistical analysis. Survival was calculated with the Kaplan-Meier method. Statistical differences were determined by the unpaired two-group t-test and p-value of ≤0.05 was considered statistical significant. All calculations were performed with SPSS statistical computer program (SPSS Inc, Tokyo, Japan).
Results
Risk groups and outcomes. The risk distribution of the patients was 11%, 26% and 63% in the low-risk, intermediate-risk and high-risk groups, respectively (Table I).
Five patients showed local recurrences (2%), some of which were due to insufficient radiation doses in the initial protocols. Distant metastases were detected in a total of 15 patients (6%) distributed as follows: ten in bone, three in abdominal lymph nodes, one in liver and one in lung. Twelve patients (5%) died of cancer-specific causes, all of them were high-risk patients (8% of the high-risk group). Forty-three patients (17%) died of other diseases: four (14%), nine (14%) and thirty (19%) belonged to the low-, intermediate- and high-risk groups, respectively. These patients showed no signs of biochemical failure until death.
Risk classification. The number of patients with biochemical failure is shown in parentheses.
The rates of overall survival in all patients at five and eight years after radiotherapy were 90% and 84%, respectively, while the respective rates of biochemical failure-free survival were 85% and 79%. Three-, five- and eight-year overall survival rates were 93%, 93% and 93% in the low-risk group, 96%, 94% and 90% in the intermediate-risk group, and 95%, 88% and 79% in the high-risk group, respectively (Figure 1). The respective rates for biochemical failure-free survival were 93%, 85% and 76% in the low-risk group, 97%, 95% and 91% in the intermediate-risk group and 85%, 79% and 76% in the high-risk group, respectively (Figure 2). No clinical progression was detected in the low-risk and intermediate-risk groups. Three-, five- and eight-year progression-free survival rates in the high-risk group were 96%, 93% and 89% (Figure 3, p=0.005).
At G0, G1, G2, G3 and G4, the incidence of morbidities in the bladder/urethra were 70%, 27%, 3%, 0% and 0% (acute morbidities) and 70%. 21%, 6%, 3% and 0% (late morbidities), respectively, and the incidence of morbidities in the rectum were 97%. 3%, 0%, 0% and 0% (acute morbidities) and 85%. 9%, 4%, 2% and 0% (late morbidies), respectively.
Overall survival rates of prostate cancer patients treated with carbon ion radiotherapy. The patients are separated into the following risk groups: L, low-risk (29 patients); I, intermediate-risk (66 patients); H, high-risk (159 patients). The vertical axis indicates overall survival probability.
Effect of hormone therapy. Patients were treated with hormone therapy or left untreated according to the risk classification (Table II). Of 254 patients, 54 (21%) experienced biochemical failure; 24%, 11% and 25% in the low-, intermediate- and high-risk groups, respectively. The relatively high rate of biochemical failure in the low-risk patients may be partially due to the small number of patients in this group compared to the others; moreover, the low-risk group may contain underdiagnosed cases without adjuvant hormone therapy. Biochemical failure occurred infrequently in the intermediate-risk patients, due perhaps to the long-term adjuvant hormone therapy provided to T2c patients. In contrast, no hormone therapy was scheduled for T2ab patients. As the failure rate was rather low in the high-risk patients, hormone therapy seemed to be beneficial and a two-year treatment duration appeared to be better for avoiding biochemical failure compared to shorter treatments.
After biochemical failure, the patients without or after adjuvant hormone therapy were treated with conventional hormone therapy for two years or more. Most patients in the low- and intermediate-risk groups responded well with PR. No cancer deaths were observed in these groups.
Of 159 high-risk patients, 40 (25%) experienced biochemical failure. Twenty-six patients showed failure without or after adjuvant hormone therapy. These patients were treated with conventional hormone therapy repeatedly and 23 patients showed PR and three showed PD. Of these patients, three died of prostate cancer after an average period of 62 months (range 32-106 months) after radiotherapy.
Biochemical failure-free survival rates of prostate cancer patients treated with carbon ion radiotherapy. The patients are separated into the following risk groups: L, low-risk (29 patients); I, intermediate-risk (66 patients); H, high-risk (159 patients). The vertical axis indicates biochemical failure-free survival probability
Clinical progression-free survival rates of prostate cancer patients treated with carbon ion radiotherapy. The patients are separated into the following risk groups: L, low-risk (29 patients); I, intermediate-risk (66 patients); H, high-risk (159 patients). The vertical axis indicates clinical progression-free survival probability.
Relationship between hormone therapy and biochemical failure. Other failures occurred after termination of hormone treatment.
Response to salvage therapy after biochemical failure. Data are shown as mean, median (range).
Fourteen high-risk patients progressed to a castration-resistant state despite continuous hormone treatment, nine of whom died of prostate cancer after an average period of 43 months (range 16-91 months) from radiotherapy (Figure 4). The period between radiotherapy and biochemical failure was shorter for these patients (average 20 months: range 6-38 months) than for the other high-risk patients who experienced biochemical failure (average 42 months: range 6-95 months; p=0.0002).
The factors influencing the salvage therapy for biochemical failure were examined (Table III). PSA-DT was found to significantly affect response, and a PSA-DT greater than ten months indicated a good response to salvage hormone therapy (data not shown).
Discussion
Radiotherapy for prostate cancer in Japan is generally reserved for rather advanced stages of the disease. Based on the results determined from 162 patients with prostate cancer at 50 facilities in 1999-2000, 80% of the patients were high-risk, and overall and biochemical failure-free survival rates at three years were 86.7% and 86.1%, respectively. Two-thirds of patients received hormone therapy (10). In the present study, 63% of patients were high-risk.
Cause-specific survival of fourteen high-risk patients with disease progression under continuous hormone treatment after radiotherapy.
Low-risk patients are candidates for radiotherapy alone, and such patients achieved favorable outcomes. Treatment for intermediate-risk patients involves consideration of whether or not radiotherapy alone is sufficient. Some of the patients experienced biochemical failure with carbon ion radiotherapy alone. However, patients with more advanced stage disease in the intermediate-risk group, namely T2c, showed favorable outcomes after the addition of hormone therapy. This suggests that hormone therapy may be advisable as a supplement for certain intermediate-risk patients.
In the case of high-risk patients, radiotherapy alone is considered to be insufficient. The five-year biochemical failure-free survival rate after radiotherapy with 66 Gy was approximately 30% (11). Increasing the radiation dose to 78 Gy using three-dimensional conformal radiotherapy or intensity-modulated radiation therapy improved biochemical failure-free survival rates compared to radiation with less than 72 Gy for high-risk patients (12-13). A radiation dose of 74 Gy for T3 patients with hormone therapy for 1-6 months yielded a biochemical failure-free survival rate of 46% after four years (14). For high-risk prostate cancer, therefore, high radiation doses greater than 72 Gy may be required for treatment, and such high doses may be used without serious adverse effects (15). The extension of the target volume to the pelvic area has been proposed (16), but because of the possible adverse effects on the neighboring organs, this technique is still controversial (17). Proton beam radiotherapy resulted in five-year biochemical-free survival rate of 48% in high-risk patients (18). Establishment of radiation modality was arranged from the results of initial protocols referring to carbon ion beam properties (19). After the initial protocols, the appropriate radiation dose was set at 66.0 GyE in 20 fractions. The cytocidal effect of this dose was assumed to be comparable to that of high doses of photons. Taking into account other beneficial properties, carbon ion radiotherapy may be considered to be one of the best treatment methods for prostate cancer. Acute and late morbidities associated with treatment are only minor and comparable to those associated with photon radiation (20).
The addition of hormone therapy has generally been recommended before, during and/or after radiotherapy to improve results for high-risk patients (21). In the literature, the reported durations of hormone therapy range between four months and five years (22). A consensus on the optimal duration has not yet been achieved. Hormone therapy for four months led to improved biochemical failure (22), but longer durations of hormone therapy, ranging from eight to thirty-six months, showed increased biochemical failure-free survival compared to either radiation alone or short-term hormone therapy (23-25). The RTOG 92-02 Trial showed that for high-risk patients 70 Gy of radiation with two years of hormone therapy led to 67% and 44% of biochemical failure-free rates at five and ten years, respectively (26-27). External beam radiotherapy with hormone therapy showed outcomes similar to those achieved with surgery (28-29). In the present study, high-risk patients were treated with adjuvant hormone therapy and this treatment seems to have achieved considerable biochemical failure-free outcomes in conjunction with carbon ion radiotherapy. Hormone therapy for two years may be sufficient. It is claimed that the addition of hormone therapy is generally credited with improving biochemical failure-free and clinical progression-free survivals, but has no benefit on overall survival. This is an important issue that needs to be further clarified. Recently, studies have reported adverse effects of hormone therapy (30), and trivialized its beneficial effects (31). On the contrary, the addition of hormone therapy is protective to the genitourinary and gastrointestinal tracts (32). Based on these findings, careful use of adjuvant hormone therapy may be beneficial. After biochemical failure, early induction of hormone therapy is more effective than delayed therapy (33). Salvage hormone treatment after failure as judged by the Phoenix criteria was also effective as shown in the present cohort. Factors influencing the response to hormone therapy included PSA-DT before the time of failure and the duration between radiotherapy and biochemical failure, suggesting a correlation with rapidly growing tumors.
A subset of high-risk patients progressed to a castration-resistant state, despite radiotherapy to the prostate and continuous hormone treatment. Most of these patients scarcely showed response to second-line hormone therapy. Clinically distant metastases may occur at certain times after biochemical failure (34, 35). Treatments for these patients were performed following EAU guidelines (36), but the patients progressed to a more severe disease state in general. The duration from the start of hormone therapy to biochemical failure in highly advanced prostate cancer patients, such as those at the metastatic stage, was generally one to two years and similar disease progression intervals were observed after radiotherapy. Factors affecting the rapid progression to a castration-resistant state included the time between radiotherapy and biochemical failure, and PSA kinetics including velocity and PSA-DT (37, 38), but other influencing factors have not been determined yet (39). Further advances are awaited in the development of treatment strategies for rapidly growing prostate cancer.
In summary, carbon ion radiotherapy is suitable and tolerable for the treatment of localized prostate cancer, especially for locally advanced stages.
Acknowledgements
The Authors acknowledge co-investigators from the Working Group for Genitourinary Tumors, the National Institute of Radiological Sciences of Japan. This work was partially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
- Received October 3, 2010.
- Revision received November 6, 2010.
- Accepted November 9, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
