A validated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate‐resistant prostate cancer

Shamash, Jonathan; Stebbing, Justin; Sweeney, C. J.; Sonpavde, Guru; Harland, Steve; Dawkins, G.P.C.; Brock, Cathryn; Abelman, Walter; Wilson, Peter; Sanitt, Adam; Oliver, R. T. D.; Powles, Thomas

doi:10.1002/cncr.25194

Cited by 20 publications

(13 citation statements)

References 19 publications

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“…CTCs may be useful in future to help decide which patients should stop this therapy early as their changes were much more rapid than PSA. This supports our previous work in which we developed an easy to use prognostic index to identify those individuals with a prolonged survival within 1 month of starting therapy using PSA (21), however in this case the use of intensive chemotherapy followed by reintroduction of hormonal treatment made early changes in PSA much less useful. The principle of early identification of response to a therapy is of particular importance in managing CRPC-in which the number of options has expanded, allowing a change to an alternative and minimizing toxicity.…”

Section: Discussionsupporting

confidence: 85%

“…Following our recent data, we also wished to specifically observe whether changes in biomarkers (PSA or CTCs) at 1 month could predict survival (21). We found that responses in patients with heavily pretreated CRPC could be induced by our protocol, and that in those individuals with increased CTCs at the start of therapy, a rapid clincancerres.aacrjournals.org Downloaded from decrease was associated with a survival benefit.…”

Section: Discussionmentioning

confidence: 86%

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Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

Shamash¹,

Jacob²,

Agrawal³

et al. 2012

Clinical Cancer Research

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Purpose: Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response.Experimental Design: Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred.Results: Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P ¼ 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high.Conclusions: Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 86%

Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

Shamash¹,

Jacob²,

Agrawal³

et al. 2012

Clinical Cancer Research

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“…Notably, the Gleason grade was highly predictive of the TDP under LH-RH analogs but not so of the TDP under DES therapy, suggesting important differences in the anticancer mechanism of action of both agents. In the study of Shamash et al (19), a PSA decrease >50% within 1 month of treatment with DES and corticosteroids was found to predict a favourable prognosis with median TDP greater than 1 year and median survival greater than 2 years.…”

Section: Discussionmentioning

confidence: 96%

Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

et al. 2013

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Abstract. The aim of the present retrospective study was to evaluate the efficacy and safety of diethylstilbestrol (DES) as treatment for patients with castration-resistant prostate cancer (CRPC) and to identify predicting factors of response to DES. Patients treated with DES during the castration-resistant phase following the failure of prior treatment with LH-RH analogs during the castration-sensitive phase were retrieved from a prostate cancer database of our institution. Patients were treated with a daily dose of DES of 1-4 mg (mean, 2.6 mg) and anticoagulants for thromboembolic prophylaxis until disease progression. We analyzed their medical records, biochemical prostate-specific antigen (PSA) response and time to disease progression (TDP). Disease response and progression were identified according to the PCWG2 criteria. Patient data were examined using Kaplan-Meier survival analysis and statistical correlation tests with intra-patient comparison of the LH-RH and DES treatment phases. Fortythree DES-treated CRPC patients were found in our database through July 2011. The median age was 66 years. Sixty-three percent of the patients achieved a ≥50% decline in their serum PSA levels during DES therapy. Median TDP was 20.4 months for LH-RH analog treatment in the castration-sensitive phase, and 7.1 months for DES treatment in the castration-resistant phase. Durable responses (>1 year) were observed in 31% of the patients. Median overall survival was 57 months from the start of the DES therapy. There was no significant correlation between the TDP under LH-RH analogs and under DES therapy among the 38 patients eligible for correlation analysis. However, the magnitudes of serum PSA responses under DES and LH-RH analogs were significantly correlated with each other, and with the TDP under DES therapy. There were no treatment-related deaths. Four patients (9%) developed thromboembolic complications while under treatment, some of which appeared to be related to a discontinuation of thromboprophylaxis. In conclusion, DES confers substantial clinical benefit in the treatment of CRPC, with a relatively good safety profile when administered with thromboprophylaxis. The use of DES may be effective in CRPC, irrespective of the length of the hormone-sensitive period with LH-RH treatment. The magnitude of PSA response to previous treatment with LH-RH analogs, as well as to DES, was predictive of the duration of response to DES.

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“…More recently a study performed by Clemons et al [8] showed PSA response in 39% of patients with median TTP of 30 weeks (95% CI, 21.9-68.7). An interesting study conducted by Shamash et al [9] found that the level of PSA response 1 month after DES induction might serve as a surrogate marker for prediction of prolonged response to treatment. They constructed a prognostic index and demonstrated in 145 individuals with CRPC that only two factors were significant in predicting which patients will maintain a prolonged response to DES therapy.…”

Section: Discussionmentioning

confidence: 99%

Diethylstilboestrol (1 mg) in the Management of Castration-Resistant Prostate Cancer

et al. 2014

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Objective: To investigate the efficacy of diethylstilboestrol (DES) in patients with advanced prostate cancer refractory to androgen suppression. Methods: This retrospective study comprises 194 patients with prostate cancer treated with DES (1 mg daily) between 1976 and 2010. Study outcome parameters included demographic data, tumour characteristics, treatment history, prostate-specific antigen (PSA) responses, radiologic studies, adverse events and overall survival. Results: At initiation of oestrogen therapy the mean patient age was 69 years (range: 48-89) and the median PSA was 96 ng/ml (range: 1.9-9,500). The median duration of prior prostate cancer treatment was 29 months (range: 1-365). DES was the second-line treatment in 58 patients and the third/fourth-line therapy in 136 men. A formal (≥50%) PSA response was observed in 95 patients (48.9%) and the median time to progression (TTP) was 250 days (95% CI, 180-360) for this group. An additional 62 patients (31.9%) had a partial PSA response with a median TTP of 150 days (95% CI, 92-180). Thirty-seven patients (19.1%) did not have a PSA response and the median TTP was 90 days (95% CI, 90-97). The median overall survival from the start of oestrogen therapy for the entire cohort was 576 days (95% CI, 482-690). The median overall survival of patients who had a formal (≥50%), partial (<50%) and no PSA response was 756 (95% CI, 670-1,429), 428 (95% CI, 340-630) and 329 (95% CI, 287-510) days, respectively. Thirty-nine patients (20.1%) were still alive at the end of the study. No treatment-related deaths occurred. Conclusions: In the age of chemotherapy this study highlights the efficacy of oestrogen therapy in castration-refractory prostate cancer. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.

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A validated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate‐resistant prostate cancer

Abstract: The easy-to-use prognostic index that the authors developed was able to identify a subgroup of patients with CRPC who had prolonged survival only 1 month after starting DS therapy.

Cited by 20 publications

References 19 publications

Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

Diethylstilboestrol (1 mg) in the Management of Castration-Resistant Prostate Cancer

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