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Background: The aim of this study is to analyze correlation between the tumor volume (TV) and the final pathological stage in patients undergoing neoadjuvant therapy., Patients and Methods: Twenty-six patients underwent radical prostatectomy alone (group S). The remaining 28 patients had undergone neoadjuvant therapy (group N) which mainly consisted of LH-RH agonist. TV and the final pathological stage were retrospectively reviewed., Results: The likelihood of positive surgical margin was statistically higher in group S than in group N (p = 0.009). The correlation between TV and the pathological stage was observed not only in group S (rho = 0.646, p = 0.0012) but also in group N (rho = 0.716, p = 0.0002). The mean TV was statistically smaller in group N in patients with baseline PSA level more than 10.1 ng/ml (p = 0.024)., Conclusion: A decrease in tumor volume caused by neoadjuvant therapy may play an important role in reducing the likelihood of positive surgical margin.

Since the discovery by Huggins and Hodges that androgen deprivation therapy is effective for prostatic cancer, surgical castration or the administration of exogenous estrogen has been the mainstay of treatment for advanced prostatic cancer. However, surgical castration is refused by some patients because of psychological impact and estrogen therapy is reported to be associated with significant morbidity and mortality. The chronic administration of superactive analogue of LHRH has been shown to suppress markedly gonadal steroidogenesis. Medical castration with LHRH analogue has been demonstrated to be safe and effective in patients with advanced prostatic cancer. But the traditional surgical castration still remains as another powerful option, because it is more excellent in the points of compliance and cost-benefit than a monthly injection of expensive LH-RH analogue.

The 5 year cancer specific survival rate of advanced prostate cancer, especially in metastatic cancer is less than 40%. Recently, maximum androgen blockade showed some beneficial effects in cases of minor disease but no additional usefulness in major cases. The treatment modality referred to as initial chemoendocrine, used to treat prostate cancer, seems to be a reasonable method because prostate cancer cells contain heterogeneity. This procedure means that the endocrine treatment is best suited to treat hormone sensitive cells, whereas chemotherapy is more appropriately used as a firstline therapy for hormone insensitive cells. We reported that the initial chemoendocrine method showed superiority in the 5 year cancer specific survival category than in the endocrine therapy analyzing non-randomized trials. From that stage on we reviewed the beneficial point of the treatment, and are now trying randomized control studies.

Neoadjuvant endocrine treatment prior to radical prostatectomy for prostate cancer confined to pelvis has of some value to prevent progression although there are many controversies. In order to improve the prognosis of locally advanced prostate cancer (stage B2 and C), definitive radiotherapy with neoadjuvant endocrine therapy has been investigated. Endocrine therapy reduces the volume of prostate, thus reduces the amount of side effect via reducing the area of irradiated normal tissue. Effect of radiation and that of endocrine therapy to induce apoptosis might be synergistic. The result is favorable although the follow-up period is too short. Further studies are needed to make conclusion.

Neoadjuvant androgen deprivation has been demonstrated to reduce the risk of surgical margin positivity and lymphnode metastasis, and facilitate a thorough prostatectomy. On the contrary, no long-term studies have proved the beneficial effects of preoperative therapy on patients' survival. A multicenter randomized study in Japan comparing neoadjuvant therapy and immediate surgery (control) was conducted. All the patients were to receive hormonal therapy for 2 years. The results confirmed the short-term efficacy of neoadjuvent hormonal treatment, and no significant difference in clinical relapse rate (5.6% (5/90) in neoadjuvant group versus 11.6% (10/86) in control group), nor PSA relapse rate (13.3% versus 17.4%) at 2 years posttreatment; however in stage C cancer there was a tendency of a lower clinical relapse rate in neoadjuvant group (9.5%: 2/21) than the control (30.4%: 7/23). These data provide no obvious evidence for favorable long-term outcomes in neoadjuvant group, although a possibility that stage C cancer benefits from the treatment remains to be explored.

There can be seen many investigations to examine the effects and benefits of total androgen blockade (TAB), combining an antiandrogen with surgical castration or a LH-RH analogue, for advanced prostate cancer. This review summarizes the concept, theory, method and clinical application of TAB. The concept of TAB was supported by reports that show a survival advantage using the combined blockade over LH-RH analogue alone. The theory of TAB proposes that suppression of all androgen production, adrenal and testicular androgen, should result in a better response than standard hormonal management such as castration and/or estrogens. In Japan, Chlormadinone acetate (100 mg twice daily) or Flutamide (375 mg three times daily) is orally administered and Leuprorelin acetate (3.75 mg every 4 weeks) or Goserelin acetate (3.6 mg every 4 weeks) is administered by hypodermic injection. There have been unresolved controversies surrounding this therapeutic modality, therefore future studies should help to define the role of TAB.

Of 156 patients, 111 (clinical stage T1a-b; 21, T1c; 17, T2a-b; 36, T2c; 27, T3; 10) immediately underwent radical prostatectomy (surgery group), and 45 (clinical stage T1a-b; 8, T1c; 4, T2a-b; 10, T2c; 9, T3; 14) received neoadjuvant hormonal therapy (NHT group). NHT offered probability of increasing organ-confined cancer(OCC; pathological stage pT2 or lower N0M0) in the following group, which contains (a) patients who had moderately differentiated adenocarcinoma in the biopsy specimen and T2b or lower diseases, and (b) those who had well differentiated adenocarcinoma, T2c diseases and PSA levels of 10 ng/ml or higher, referred to as "OCC suitable criteria". Of 156 patients, 51 (33%) met OCC suitable criteria. In those cases, the proportion of OCC in NHT group was significantly higher than that in surgery group (11/12 (92%) vs. 16/39 (41%), p = 0.002). NHT is useful for increasing OCC in patients who meet OCC suitable criteria.

Endocrine therapy, which consists of orchiectomy followed by administration of large doses of estrogen, then a reduced amount of estrogen, has been applied as the main treatment for stage D2 prostatic cancer. Alternatively, anti-androgen is used for elderly patients or those with cardiovascular disorders. Survival rate with endocrine therapy at 5 and 10 years was 35% and 16%, respectively. Therefore, in Japan, a better survival is shown than that reported in western countries using much smaller doses of estrogen. Most of the side effects caused by estrogen are not serious. Side effects caused by anti-androgen are few except for loss of libido. At the start of treatment, more than 80% of patients showed a response, but gradually relapse occurred and only 20% were well controlled 5 years after the start. Factors influencing the survival were pathological grade, response to endocrine therapy judged by the level of prostatic acid phosphatase 4 weeks after the start, and R1881 (methyltrienolone)-binding protein observed histochemically. The latter protein was also correlated with the grade and response to endocrine therapy. Relapse after endocrine therapy might be attributable to adaptation or mutation progressing to androgen-independent cells. Using SC 115, an androgen-dependent mouse tumor, these two types of relapse were demonstrated. Gradual progression to undifferentiated cancer was noticed between pretreatment biopsy and autopsy. Relapse in human prostatic cancer may thus be partly due to genetic change to a resistant clone.

We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.