Background. Since postcastration progression of tumors to an androgen‐independent state appears to be linked to the cessation of androgen‐induced differentiation of tumorigenic stem cells, the authors hypothesized that the replacement of androgens at the end of a period of apoptotic regression might result in the regeneration of differentiated tumor cells with further apoptotic potential.
Methods and Results. To determine the effect of intermittent exposure of androgens on the androgen‐dependent Shionogi carcinoma, the tumor was transplanted into a succession of male mice, each of which was castrated when the estimated tumor weight became about 3 g. After the tumor had regressed to 30% of the original weight, it was transplanted into the next noncastrated male. This cycle of transplantation and castration‐induced apoptosis was repeated successfully four times before growth became androgen‐independent during the fifth cycle. In four of Stage C and three of Stage D patients with prostate cancer, androgen withdrawal was initiated with cyproterone acetate (100 mg/d) and diethylstilbestrol (0.1 mg/d) and then maintained with cyproterone acetate in combination with the luteinizing hormone‐releasing hormone agonist, goserelin acetate (3.6 mg/month). After 6 or more months of suppression of serum prostate‐specific antigen (PSA) into the normal range, treatment was interrupted for 2 to 11 months. After recovery of testicular function, androgen‐withdrawal therapy was resumed when serum PSA increased to a level of about 20 μg/l. This cycle was repeated sequentially to a total of two to four times over treatment periods of 21 to 47 months with no loss of androgen dependence.
Conclusions. These results demonstrate that intermittent androgen suppression can be used to induce multiple apoptotic regressions of a tumor; they also suggest that the cyclic effects of such treatment on prostate cancer can be followed by the sequential measurement of serum PSA levels.
Subsequent nonsteroidal antiandrogen therapies were effective against prostate cancer relapse after hormonal therapy. The response to third line therapy was more effective and survival was improved from the time of first line therapy relapse among second line responders than that in nonresponders. Our data support the notion that second line responders are androgen independent but still hormonally sensitive.
Abbreviations & Acronyms ADT = androgen deprivation therapy bNED = biological relapse free C-ion RT = carbon-ion radiotherapy CSS = cause-specific survival CT = computed tomography CTV = clinical target volume 3D-CRT = three-dimensional conformal radiation therapy DVH = dose-volume histogram Fr = fractions GHMC = Gunma Heavy Ion Medical Center GI = gastrointestinal GS = Gleason score GU = genitourinary Gy = gray GyE = gray equivalents HAMT = Highly Advanced Medical Technology HDR = high-dose-rate HIMAC = Heavy-Ion Medical Accelerator in Chiba IMRT = intensity modulated radiotherapy iPSA = initial serum prostate-specific antigen LET = linear energy transfer L/Q = linear-quadratic NIRS = National Institute of Radiological Sciences PSA = prostate-specific antigen PTV1 = initial planning target volume PTV2 = second planning target volume RBE = relative biological effectiveness RT = radiation therapy RTOG = Radiation Therapy Oncology Group SBRT = stereotactic body radiotherapy SOBP = spread-out Bragg peak UICC = Union for International Cancer Control Abstract: In 1994, carbon-ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy-Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phase I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon-ion radiotherapy for both early-and advance-stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon-ion radiotherapy, a phase II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5 weeks) obtained from the phase I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phase II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon-ion radiotherapy for prostate cancer was approved as "Highly Advanced Medical Technology" from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon-ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon-ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.
Treatment with SWL has a low morbidity and high effectiveness. The number and location of stones and a history of urolithiasis significantly influence recurrence. Further studies of prophylactic therapy are required, especially for patients with these factors.
For the treatment of patients with locally advanced prostate cancer, when combined with endocrine therapy, either radical prostatectomy or external beam radiotherapy demonstrated favorable long-term outcomes. The radiation dose of 60-70 Gy might not be enough for the local treatment of locally advanced prostate cancer.
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