Neoadjuvant therapy preceding prostatectomy for prostate cancer: rationale and current trials

Neoadjuvant therapy improves outcomes for a number of malignancies and provides intermediate pathologic outcomes, which correlate with long-term outcomes. Neoadjuvant androgen-deprivation therapy, alone or with docetaxel chemotherapy, preceding prostatectomy for localized prostate cancer is feasible and demonstrates pathologic activity, but evidence for improved long-term outcomes is lacking. Data in support of the further exploration of neoadjuvant therapy for localized prostate cancer preceding prostatectomy are reviewed. Ongoing randomized trials are elucidating the impact of neoadjuvant androgen deprivation combined with docetaxel chemotherapy on pathologic and long-term outcomes. The correlation of pathologic and biologic outcomes with long-term outcomes in this setting is unknown. The neoadjuvant therapy approach followed by prostatectomy is feasible with a wide array of agents and provides a paradigm for evaluating the activity, and mechanism of action and resistance to new treatments. This promising modality may aid the rapid development of novel therapeutic agents. A multidisciplinary approach involving oncologists, urologists and pathologists is critical to the success of this model.     

免疫治疗在胃癌新辅助治疗中的研究进展

胃癌（GC）在我国发病的重要特点是中晚期确诊病例占确诊人数的大多数,早期诊断的患者不足10%。对于进展期的GC患者来说,标准治疗策略是手术联合术后辅助治疗或者术前新辅助+手术联合术后辅助治疗,而近年来免疫治疗成为一种治疗肿瘤的创新方法。如何在新辅助治疗中最大程度地利用免疫治疗,从而取得更好的临床获益值得探讨。本文综述了免疫治疗在GC新辅助治疗中的研究进展,进一步研究新辅助治疗联合免疫治疗对免疫系统功能的影响将有助于提高对GC的治疗水平。     

Neoadjuvant hormonal therapy for prostate cancer

There have been expectations that neoadjuvant hormonal therapy would decrease the rate of positive surgical margins and, therefore, to improve the patient's survival rate after radical prostatectomy for clinically localized prostate cancer. A review of seven prospective randomized studies for clinically localized prostate cancer revealed a significant decrease in the positive surgical margin rate in cases of clinical T2 disease after neoadjuvant hormonal therapy with prostatectomy. However, this treatment did not alter the rate of seminal vesicle invasion or lymph node metastasis after radical prostatectomy. There was no difference in operative blood loss, operating time, complication rate or hospital stay between patients treated with neoadjuvant hormonal therapy and controls. Furthermore, there was no improvement in prostate specific antigen-free survival rate after a maximum of 4 years follow-up. Further research is required to determine the optimal duration of neoadjuvant hormonal therapy and whether this therapy increases the survival rate. Neoadjuvant hormonal therapy before radical prostatectomy is not supported by any outcome at this point and its use remains in the investigational stage.     

Prostate cancer

Localized prostate cancer is generally treated with radical prostatectomy or radiation therapy (external beam or brathytherapy). However, the primary treatment failure rate is especially high in so-called high-risk patients. Therefore, many clinical trials of neoadjuvant therapy before radiation therapy or prostatectomy have been conducted. We reviewed randomized controlled studies of neoadjuvant therapy combined with surgery or radiotherapy in localized or locally advanced prostate cancer. In some prospective studies, neoadjuvant hormones prior to external beam radiation therapy have been shown to significantly improve disease-free, disease-specific and overall survival as well as to reduce local recurrence or metastases. By contrast, neoadjuvant hormonal therapy prior to prostatectomy did not improve recurrence-free and overall survival, although there was a significant reduction in the positive surgical margin rates and a significant improvement in other pathological variables such as lymph node involvement, pathological staging and organ confined rates. However, the use of neoadjuvant hormones for a longer time, either 6 or 8 months prior to prostatectomy, was associated with a further reduction in positive surgical margins, and might improve the treatment outcome of the patients. More research is needed to guide patient selection, choice, duration and schedule of hormonal therapy prior to radiation therapy or surgery. A large Phase III study of neoadjuvant chemotherapy using docetaxel before prostatectomy is ongoing, and the results of this study are much awaited.     

Patient-reported outcomes after neoadjuvant therapy for rectal cancer: a systematic review

Neoadjuvant therapy followed by total mesorectal excision is standard of care for locally advanced rectal cancer. However, this approach has been previously shown to be associated with high rate of morbidity and it may have a negative effect on patients’ reported outcomes (PROs). In order to summarize findings on the effect of the neoadjuvant approach on PROs, we systematically reviewed articles published in the last five years. Thirty-five articles met the inclusion criteria. Ten articles compared the effect of surgery with and without neoadjuvant therapy, six articles compared different neoadjuvant therapies, ten articles reported on patients who were all treated with neoadjuvant therapy, and nine articles examined the effect of neoadjuvant therapy in the analyses. The results are summarized by function investigated and critically commented.     

Neoadjuvant therapy for localized pancreatic cancer: guiding principles

The management of localized pancreatic cancer (PC) remains controversial. Historically, patients with localized disease have been treated with surgery followed by adjuvant therapy (surgery-first approach) under the assumption that surgical resection is necessary, even if not sufficient for cure. However, a surgery-first approach is associated with a median overall survival of only 22-24 months, suggesting that a large proportion of patients with localized PC have clinically occult metastatic disease. As a result, adjuvant therapy has been recommended for all patients with localized PC, but in actuality, it is often not received due to the high rates of perioperative complications associated with pancreatic resections. Recognizing that surgery may be necessary but usually not sufficient for cure, there has been growing interest in neoadjuvant treatment sequencing, which benefits patients with both localized and metastatic PC by ensuring the delivery of oncologic therapies which are commensurate with the stage of disease. For patients who have clinically occult metastatic disease, neoadjuvant therapy allows for the early delivery of systemic therapy and avoids the morbidity and mortality of a surgical resection which would provide no oncologic benefit. For patients with truly localized disease, neoadjuvant therapy ensures the delivery of all components of the multimodality treatment. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable (BLR) disease.     

前列腺癌术前新辅助治疗的研究进展

根治性前列腺切除术是治疗局限性前列腺癌的重要方法,但前列腺癌患者术前准确临床分期较困难,常出现肿瘤切除不彻底、术后肿瘤易复发和转移.研究证实术前新辅助内分泌治疗(NHT)能缩小前列腺体积,降低PSA水平,降低手术切缘阳性率,但精囊受侵率及盆腔淋巴结转移无减少,未发现无PSA进展率及肿瘤特异性生存率方面的优势.目前的资料尚不能证实所有患者术前都必须进行新辅助内分泌治疗.     

Neoadjuvant chemotherapy for operable breast cancer

Adjuvant systemic chemotherapy has been shown to prolong survival in all subsets of patients with breast cancer. In addition, among patients with locally advanced breast cancer, neoadjuvant orpreoperative chemotherapy has improved the ability to perform breast-conserving therapy. This observation, combined with multiple preclinical hypotheses and the results of laboratory studies, has prompted investigation of neoadjuvant chemotherapy as a treatment strategy for operable breast cancer. In this article, both the evidence supporting this treatment approach and some of the problems associated with it are reviewed. Currently, seven randomized studies comparing neoadjuvant chemotherapy followed by surgery or surgery followed, in turn, by adjuvant chemotherapy have been completed and their results analyzed. Despite exciting preclinical evidence, no trial to date has shown a survival advantage for the neoadjuvant treatment approach. Nonetheless, evidence from more recent phase III trials and the fact that neoadjuvant chemotherapy is not harmful topatients validate its use in operable breast cancer.     

Gastric cancer--surgical approach.

Although the incidence of carcinoma of the stomach has steadily declined over the last 50 years, approximately 23,000 new cases will be diagnosed in the United States this year and 13,700 patients will die. Despite marked improvement in operative techniques, fewer than 20 per cent of those diagnosed with gastric cancer beyond the most superficial levels of invasion will survive for over five years. Gastric tumours spread by local, lymphatic, and aggressive intra-peritoneal routes as well as hematogenous dissemination. Over 87 per cent of recurrences have local or regional components. Radiation therapy may decrease local and regional recurrences in those patients with transmural tumours. The neoadjuvant use of etoposide, adriamycin, and platinum may yield complete clinical and pathologic responses in patients found to have 'unresectable' tumours. Other chemotherapy regimens have been shown to have some effect on advanced disease and may have a role in the neoadjuvant setting. Our current recommendations for the treatment of gastric cancer in a controlled trial setting would be neoadjuvant chemotherapy followed by R2 resection, postoperative +/- intraoperative radiation therapy with the possibility of postoperative chemotherapy. Hopefully, this aggressive multimodality approach will significantly improve the five year survival for this disease.     

Cost-effectiveness comparison between neoadjuvant chemohormonal therapy and extended pelvic lymph node dissection in high-risk prostate cancer patients treated with radical prostatectomy: a multi-institutional analysis

The aim of the present study was to assess the cost-effectiveness of extended pelvic lymph node dissection (ePLND) compared to neoadjuvant chemohormonal therapy using gonadotropin-releasing hormone agonist/antagonist and estramustine. We retrospectively analyzed data within Michinoku Urological Cancer Study Group database containing 2971 PC patients treated with radical prostatectomy (RP) at four institutes between July 1996 and July 2017. We identified 237 and 403 high-risk patients who underwent RP and ePLND (ePLND group), and neoadjuvant chemohormonal therapy followed by RP and limited PLND (neoadjuvant group), respectively. The oncological outcomes and cost-effectiveness were compared between groups. Medical cost calculation focused on PC-related medication and adjuvant radiotherapy. Biochemical recurrence-free and overall survival rates in the neoadjuvant group were significantly higher than those in the ePLND group. Significantly higher number of patients progressed to castration-resistant PC in the ePLND group than in the neoadjuvant group. Background-adjusted multivariate Cox regression analysis using inverse probability of treatment weighting (IPTW) revealed that neoadjuvant chemohormonal therapy independently reduced the risk of biochemical recurrence after RP. The 5-year cost per person was significantly higher in the ePLND group than in the neoadjuvant group. Although the present study was retrospective, neoadjuvant chemohormonal therapy followed by RP as a concurrent strategy has potential to improve oncological outcome and cost-effectiveness.     

Neoadjuvant chemotherapy in ovarian cancer

Primary radical tumor debulking followed by platinum/taxane-based chemotherapy is considered standard for advanced stage ovarian carcinomas. The extent of postoperative residual disease is the most important prognostic factor. However, complete tumor resection is achieved in only 40–50% of advanced ovarian cancers. For the remaining patients, who have an unfavorable prognosis, the concept of neoadjuvant or primary chemotherapy followed by interval laparotomy has emerged. Two different strategies are pursued. One is to administer several courses of neoadjuvant chemotherapy in order to downstage the tumor prior to primary debulking surgery. The other is to administer chemotherapy after suboptimal debulking surgery to optimize cytoreduction during interval laparotomy. Numerous retrospective studies demonstrated that neoadjuvant chemotherapy followed by primary debulking surgery is a feasible and safe approach. It is becoming increasingly evident that the selection of appropriate patients is crucial. Some studies demonstrated that the volume of ascites proved to be an easily measurable biomarker that allowed prediction of tumor resectability. However, further investigations are needed to better define patients who will benefit from neoadjuvant chemotherapy. Despite promising results, neoadjuvant chemotherapy must still be considered experimental. Therefore, the potential advantages of neoadjuvant chemotherapy need to be confirmed in prospective randomized studies.     

Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: feasibility and preliminary results.

PURPOSE: We assessed the feasibility and efficacy of integrating chemotherapy and androgen ablation with radical prostatectomy in patients with locally advanced prostate cancer. The neoadjuvant approach was adopted because it allows an in situ assessment of antitumoral activity. PATIENTS AND METHODS: Thirty-three patients were enrolled who met the clinical criteria of stage T1-2, Gleason score of >/= 8 or T2b-T2c, Gleason score of 7 and prostate-specific antigen (PSA) level greater than 10 ng/mL (n = 15), or clinical stage T3 (n = 18). Therapy consisted of 12 weeks of ketoconazole and doxorubicin alternating with vinblastine, estramustine, and androgen ablation followed by prostatectomy. The ability of neoadjuvant chemotherapy and hormonal therapy to induce a 20% rate of pT0 in the prostatectomy specimen as well as surgical feasibility were assessed. RESULTS: Chemotherapy complications were comparable to those reported with this regimen previously. No major intraoperative complications occurred. Postoperative complications occurred in 10 (33%) of 30 patients. One patient died at home after discharge (postoperative day 17; no autopsy was performed). Ten (33%) of the 30 patients had organ-confined disease, and 20 (70%) of 30 had extraprostatic extension; 11 (37%) of the 30 had positive lymph nodes. Only five (17%) of 30 exhibited positive surgical margins. All patients achieved an undetectable PSA level postoperatively, and 20 of the surviving 29 patients remain without disease recurrence with a median follow-up of 13 months (range, 9 to 18 months). CONCLUSION: Chemotherapy and androgen ablation followed by radical prostatectomy was feasible in patients with locally advanced prostate cancer. Although the goal of achieving a 20% rate for pT0 status was not achieved, we believe this type of integrated therapeutic strategy should be investigated further for its ability to alter the course of regionally advanced prostate cancer.     

Effect of neoadjuvant epirubicin and total androgen blockade on complete pathological response in patients with clinical stage T3/T4 prostate cancer

Aims

Most patients with stage T3–T4 prostate cancer experience disease relapse despite radiation and/or hormonal therapy, and their management remains controversial. We investigated the feasibility of, and the pathological response induced by neoadjuvant chemo-hormonal treatment in men with clinical stage T3/T4.

Methods

Fifteen patients underwent neoadjuvant therapy consisting of weekly intravenous infusions of epirubicin 30 mg/m² and total androgen blockade (TAB) for three months before undergoing radical prostatectomy, after which all received locoregional conformal radiotherapy (66 Gy) and then continued with TAB and three additional months of epirubicin.

Results

After neoadjuvant therapy, PSA levels decreased in all 15 patients and became undetectable in two. None of the patients achieved a complete pathological response, but a 35–75% reduction in tumour size was observed in all cases, and all the patients were able to undergo successful prostatectomy. Pathological assessments of the surgical specimens revealed negative margins in 13 patients. After a median follow-up of 34 months (range 11–62), 14 patients (93%) are still clinically and biochemically disease free. No grade 3 or 4 complications occurred.

Conclusion

This study suggests that neoadjuvant treatment with epirubicin and TAB is feasible and well tolerated in patients with clinical stage T3–T4 prostate cancer.     

Additional therapy for high-risk prostate cancer treated with surgery: what is the evidence?

Single-modality approaches to the treatment of high-risk prostate cancer, whether radical prostatectomy or external-beam radiotherapy, have yielded disappointing results. Treatment intensification has, thus, been the subject of considerable research activity in recent years. This review will discuss the evidence for neoadjuvant and adjuvant treatment approaches when surgery is chosen as the definitive therapy for high-risk prostate cancer. Particular emphasis will be placed on the randomized trials, both completed and in progress. Trials investigating adjuvant radiotherapy, androgen-deprivation therapy and chemotherapy will each be discussed in turn. Among these, only adjuvant radiotherapy has been shown to prolong survival after surgery, and the recently published evidence for this benefit will be discussed in detail.     

Robot-Assisted Radical Prostatectomy for Potential Cancer Control in Patients with Metastatic Prostate Cancer

Recently, cytoreductive prostatectomy for metastatic prostate cancer (mPCa) has been associated with improved oncological outcomes. This study was aimed at evaluating whether robot-assisted radical prostatectomy (RARP) as a form of cytoreductive prostatectomy can improve oncological outcomes in patients with mPCa. We conducted a retrospective study of twelve patients with mPCa who had undergone neoadjuvant therapy followed by RARP. The endpoints were biochemical recurrence-free survival, treatment-free survival, and de novo metastasis-free survival. At the end of the follow-up period, none of the enrolled patients had died from PCa. The 1- and 2-year biochemical recurrence-free survival rates were 83.3% and 66.7%, respectively, and treatment-free survival rates were 75.0% and 56.3%, respectively. One patient developed de novo bone metastases 6.4 months postoperatively, and castration-resistant prostate cancer 8.9 months postoperatively. After RARP, the median duration of recovery of urinary continence was 5.2 months. One patient had severe incontinence (>2 pads/day) 24 months postoperatively. RARP may be a treatment option in patients with mPCa who have achieved a serum prostate-specific antigen level < 0.2 ng/mL, and present without new lesions on imaging.     

晚期骨转移前列腺癌63例诊治分析

目的：总结晚期骨转移前列腺癌诊治经验。方法：63例前列腺癌骨转移患者行姑息性前列腺切除或内分泌治疗．其中1例辅助治疗后行根治手术。结果：52例（82．5％）随访6～72个月，平均30个月。15例治疗后12-48个月（平均21个月）转移死亡；1例因脑血管意外治疗6个月后死亡。生存36例中，随访至少1年（平均34个月），均无症状生存．内分泌治疗6个月PSA反应率达100％。结论：前列腺癌骨转移患者行内分；强治疗早期效果明确，对梗阻症状明显者加姑息性前列腺切除能提高生活质量。     

A randomized phase III study of neoadjuvant hormonal therapy in patients with localized prostate cancer

The primary objective of this randomized trial is to evaluate the benefit of the addition of neoadjuvant hormonal therapy to escalated-dose external-beam radiation therapy in the treatment of patients with intermediate-risk carcinoma of the prostate. A secondary objective of this study is to determine prognostic factors for radiation response. All patients will have tissue oxygenation measured and biopsies taken before treatment at the time of fiducial marker insertion for radiation treatment planning and daily monitoring. In addition, patients randomized to the neoadjuvant bicalutamide arm will be asked to consider having these studies repeated before initiation of radiation therapy (after 3 months of hormonal therapy).     

Early use of chemotherapy in conjunction with radical prostatectomy

Since the advent of prostate-specific antigen testing, most prostate cancers are now detected in an early, organ-confined stage. Because of this, local therapies including radical prostatectomy and irradiation have become more common in the treatment of men with prostate cancer. Nonetheless, relapse of disease remains a major problem. In the past decade, many groups have studied the early use of chemotherapy with or without hormonal therapy after radical prostatectomy, specifically, and found it to be safe. In this article, we will summarize the data for neoadjuvant and adjuvant chemotherapy and chemohormonal therapy in conjunction with radical prostatectomy. We will also highlight more recent clinical trial designs, including a multicenter pilot study of adjuvant docetaxel therapy, which has several important distinctions when compared with previous studies, including the active chemotherapeutic agent docetaxel, better risk-adapted patient accrual, and higher statistical power. Although data for this study are not yet mature, these differences in clinical trial design make such studies in adjuvant chemotherapy for patients with high-risk prostate cancer novel and promising.     

Combining radiation therapy and androgen deprivation for localized prostate cancer-a critical review

Interest has been increasing in the use of androgen deprivation therapy (ADT) combined with radiation therapy (RT) in the management of localized prostate cancer. Preclinical studies have provided some rationale for the use of this combination. In patients with high-risk disease, the benefit of a combined approach, with the addition of adjuvant hormonal therapy, is supported by results of randomized trials. In contrast, for patients with low-risk disease, there is no obvious therapeutic advantage except for cytoreduction. The usefulness of short-term hormonal therapy in association with rt for intermediate-risk patients is still debatable, particularly in the context of doseescalated RT. The optimal timing and duration of ADT, in the neoadjuvant and adjuvant settings alike, are still under investigation. In view of the potential side effects with ADT, further studies are being performed to better identify subsets of patients who will definitely benefit from this therapy in combination with rt.     

Recent advances in the treatment of prostate cancer

As new evidence for prostate cancer treatment has emerged in the last few years, longstanding controversies in the treatment of prostate cancer have resurfaced. A number of long-held tenets of prostate cancer therapy have been revisited, sometimes with surprising and challenging results. Although neoadjuvant hormonal therapy prior to radical prostatectomy decreases positive surgical margin rates, longer follow-up is needed to support survival improvement of this combined modality therapy. Androgen deprivation combined with radiation therapy appears to improve disease-free survival (and survival in one series) in patients with locally advanced cancer. Another approach to locally advanced prostate cancer using three-dimensional conformal radiation therapy may improve long term outcome. The data are currently insufficient to conclude that interstitial low dose rate brachytherapy is equivalent to conventional treatments: patients with small tumor volumes and low Gleason grade seem to obtain more benefit, whereas for large tumors with higher gleason grades this approach seems inferior to conventional treatments. In advanced prostate cancer recent data suggest that immediate hormonal therapy improves survival. In this group of patients the use of maximum androgen blockade remains controversial but may adversely affect quality of life compared to orchiectomy alone. Intermittent hormonal therapy may improve quality of life, although effect upon survival is unknown. Chemotherapy in combination with androgen deprivation is currently being studied as front-line therapy in advanced prostate cancer. Palliative benefit of chemotherapy for hormone refractory prostate cancer remains an important endpoint; survival advantage has not been seen in any randomized trials. Suramin may delay disease progression in hormone refractory prostate cancer. Many aspects of prostate cancer treatment will remain controversial until results of large, randomized trials with longer follow-up are available.