Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study

Taplin, Mary Ellen; Montgomery, Bruce; Logothetis, Christopher J.; Bubley, Glenn J.; Richie, Jerome P.; Dalkin, Bruce L.; Sanda, Martin G.; Davis, John W.; Loda, Massimo; True, Lawrence D.; Troncoso, Patricia; Ye, Huihui; Lis, Rosina T.; Marck, Brett T.; Matsumoto, Alvin M.; Balk, Steven P.; Mostaghel, Elahe A.; Penning, T.M.; Nelson, Peter S.; Xie, Wanling; Jiang, Zhenyang; Haqq, Christopher M.; Tamae, Daniel; Tran, Ngoc Nguyen; Peng, Weimin; Kheoh, Thian; Molina, Arturo; Kantoff, Philip W.

doi:10.1200/jco.2013.53.4578

Cited by 222 publications

(238 citation statements)

References 28 publications

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“…The authors have to be commended for their efforts to raise awareness of the need for concerted cancer registries and centralised treatments. They corroborated previous studies on the relationship between hospital volume and perioperative outcomes, such as in-hospital mortality, complications and length of stay [4]. They also found an improvement in perioperative outcomes over time.…”

Section: How Can We Improve Surgical Outcomes?supporting

confidence: 80%

“…Finally, centralisation of care may have played an important role in the decreasing rates of adverse outcomes after RP. Although the authors specify that there was no policy-driven regionalisation of RP care in Italy (relative to the UK, for example), the increase in average hospital volume should translate into better outcomes, as discussed above [4]. Further regionalisation should be expected in Italy with the adoption of robotic surgery, as only a few centres have the means and logistics to support a da Vinci system [5].…”

Section: How Can We Improve Surgical Outcomes?mentioning

confidence: 99%

“…At the very minimum, we should be keeping accurate surgical registries to determine how many of these men subsequently progress to radiation. We have learned that preoperative anti-androgen therapy does not improve survival, but is there a role for some of the new chemotherapies to be used in a neoadjuvant setting [4]? We do this for older men with aggressive bladder cancers.…”

mentioning

confidence: 99%

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Surgery is possible: now let's prove its superior efficacy!

Albertsen

2015

BJU International

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The appropriate treatment of prostate cancer remains controversial. Younger men are often advised to undergo surgery, while older men are often steered towards radiation therapy. Brachytherapy and cryotherapy are offered to men of all ages, while several centres have recently begun promoting new focal therapies. The appropriate role for androgen deprivation therapy also garners considerable discussion. One thing most urologists agree on is that surgery should be offered only to men with a life expectancy > 10 years, but who are these men?In the accompanying review article, Everaerts et al. [1] argue that many elderly men are being denied appropriate therapy simply because of their age. Prostate cancer prevalence increases with age and many men aged > 70 years are diagnosed with intermediate and high grade prostate cancers. Should these men be offered surgery? Everaerts et al. believe they should and with good reason. Fit, older men tolerate radical prostatectomy well. The primary complication from surgery is erectile dysfunction, but for many older men this is not a major issue impacting quality of life. Incontinence rates are slightly higher among older men compared with younger men, but the rates are still modest in the hands of good surgeons.Everaerts et al. advocate a full geriatric evaluation for those men described as 'vulnerable' and frail. Many older men have comorbidities that can be improved before surgery. Everaerts et al. cite the G8 Health Status Screening tool, a validated instrument, as being particularly helpful to assess health status among older men. To change the treatment paradigm, however, urologists must consider fit older men as appropriate candidates for surgery.Simply advocating surgery, however, is insufficient. Ideally, we should be advising our patients to undergo the therapies that provide the greatest longevity with the least morbidity. The Scandinavian Prostate Cancer Group 4 trial has suggested that older men may not receive any survival advantage from surgery, but surgery does control the risk of metastatic disease in a larger proportion of men when compared with a more conservative approach of androgen deprivation therapy [2]. Next year, results from the ProtecT trial will provide information on the relative benefits of surgery vs radiation in a randomized trial setting [3]. This information is important, but insufficient.The growing population of older men provides urologists with both a challenge and an opportunity. Historically, men aged > 70 years have been excluded from randomized trials concerning prostate cancer screening and treatment. This is no longer defensible. Everaerts et al. have highlighted a critical point. We now have the tools to assess overall health in older men. Those who are fit and have clinically significant disease should be encouraged to participate in clinical trials evaluating surgery and radiation therapy. Men with high grade disease are at a particularly high risk of disease progression. At the very minimum, we should be keeping accurate surgical r...

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Section: How Can We Improve Surgical Outcomes?supporting

confidence: 80%

Section: How Can We Improve Surgical Outcomes?mentioning

confidence: 99%

mentioning

confidence: 99%

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Surgery is possible: now let's prove its superior efficacy!

Albertsen

2015

BJU International

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“…Serum and tissue progesterone level slightly increases through AA administration (11). Progesterone can also activate several mARs (11).…”

Section: Discussionmentioning

confidence: 99%

Abiraterone acetate withdrawal syndrome: Speculations on the underlying mechanisms

Kato¹,

Komiya

Yuasa³

et al. 2017

Oncol Lett

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Abstract.A 72-year-old man initially presented with lumbar and right chest pain, but was later found out to also have an elevated prostate-specific antigen (PSA) level at 2,000.0 ng/ml. Further evaluation disclosed metastatic prostate cancer involving the bones and lymph nodes. The patient was initially treated with combined androgen blockade (CAB) with leuprolide acetate and bicalutamide. After 6 months of CAB, the patient's PSA level began to rise from the nadir (85.1 ng/ml) to 113.3 ng/ml. Bicalutamide was withdrawn in anticipation of anti-androgen withdrawal syndrome and the PSA level declined temporally. However, it increased up to 517.0 ng/ml thereafter. Consequently, a year after CAB, abiraterone acetate (AA) was initiated at a standard dose of 1,000 mg daily in combination with 10 mg of prednisolone. PSA rapidly decreased to the nadir of 20.1 ng/ml thereafter. The PSA level remained stable until 2 years after AA administration. However, he decided to reduce the dose of AA to half of the standard dose (500 mg daily). Contrary to our expectations, the serum PSA level promptly decreased to a nadir of 8.1 ng/ml. Thereafter, the PSA level remained stable until 3 years and 9 months after AA administration. Subsequently, the patient stopped taking AA and prednisolone. However, to our surprise, the patient's serum PSA level decreased further to <1.0 ng/ml after AA discontinuation. His PSA remained <1.0 ng/ml without clinical or radiological progression for 1 year after AA withdrawal. Recently, it was reported that cessation of AA is associated with AA withdrawal syndrome in metastatic castration-resistant prostate cancer, defined as a PSA decrease after AA discontinuation, mimicking anti-androgen withdrawal syndrome. In the present study, explanations of the mechanisms underlying this phenomenon were explored, including mutant AR activation by alternative ligands.

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“…Given the lack of any observed down-staging or down-grading of disease, there is no strong impetus to move forward with further assessment of neoadjuvant monotherapy with axitinib, especially with more encouraging data using novel endocrine therapies in a similar fashion. For instance, complete and near complete pathologic responses have been observed in a neoadjuvant assessment of enzalutamide in high-risk localized prostate cancer-certainly these agents may be more appropriate for further study (13). VEGF-directed therapies have been rigorously assessed in the setting of metastatic castration-resistant prostate cancer (mCRPC).…”

Section: Discussionmentioning

confidence: 99%

Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer

Pal

Vuong

Zhang³

et al. 2015

Molecular Cancer Therapeutics

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Preclinical studies have suggested that VEGFR1-positive cells potentially foster the development of metastases by establishing a "premetastatic niche." We sought to test this hypothesis in highrisk localized prostate cancer and assess potential niche modulation by the VEGFR1-targeting drug axitinib. Formalin-fixed, paraffinembedded tissue derived from benign lymph nodes was collected and VEGFR1-positive cell clustering was assessed in benign lymph nodes via IHC. Recursive partitioning was used to define a threshold for VEGFR1 clustering that could segregate patients based on time to biochemical recurrence (TTBR). Multivariate analyses were used to determine whether VEGFR1 clustering, age, pathologic Tstage, Gleason score, or baseline PSA could independently predict TTBR. A randomized, phase II clinical trial comparing axitinib for 28 days followed by radical prostatectomy and pelvic lymph node dissection (RP/PLND) to RP/LND alone was then conducted, with the primary endpoint of demonstrating downregulation of VEGFR1-positve cell clustering in benign lymph nodes. Our retrospective analysis assessed a cohort of 46 patients. A threshold of 1.65 VEGFR1-positive cells per high power field was identified, below which TTBR was delayed. VEGFR1 clustering was an independent predictor of TTBR in a multivariate analysis. Only 11 out of the planned 44 patients were accrued to the phase II trial. While preoperative axitinib was safe and well tolerated, there was no sign of clinical activity or VEGFR1 downregulation. Our results validate previous findings that suggest VEGFR1-positive cells in benign lymph nodes can predict clinical outcome. Further work is needed to develop a viable clinical strategy for modulating VEGFR1 in these tissues.

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Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study

Cited by 222 publications

References 28 publications

Surgery is possible: now let's prove its superior efficacy!

Surgery is possible: now let's prove its superior efficacy!

Abiraterone acetate withdrawal syndrome: Speculations on the underlying mechanisms

Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer

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