Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: A meta-analysis of individual patient data

Department of Medicine, Institut Gustave Roussy, Villejuif, France.
The Lancet Oncology (Impact Factor: 24.69). 12/2007; 8(11):994-1000. DOI: 10.1016/S1470-2045(07)70284-X
Source: PubMed


Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer.
We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used.
The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275).
In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

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Available from: William R Berry, Oct 21, 2014
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    • "Bone pain can be relieved using bisphosphonate, denosumab, or radiopharmaceutical radium-223 chloride treatment [10– 12]. Until recently, chemotherapy has not been considered an effective treatment against prostate cancer; however, studies with docetaxel alone or combined with the estradiol derivative estramustine, the CYP17 inhibitor abiraterone acetate, and the androgen receptor (AR) antagonist enzalutamide demonstrated promising results against castration-resistant prostate cancer (CRPC) [13] [14] [15] [16]. New investigational drug compounds such as the AR inhibitor ODM-201 and the taxane analog cabazitaxel have also shown promising results in clinical trials [17] [18]. "
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    • "The significance of addition of EMP to DTX therapy in CRPC patients is still controversial in clinical trials [3-6] as well as preclinical studies [7-9]. Therefore, it is reasonable to compare the clinical efficacy of DTX + EMP combination with DTX alone in EMP-refractory CRPC patients in order to elucidate the significance of addition of EMP to DTX therapy. "
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    ABSTRACT: The purpose of this study was to deepen our knowledge of the combined use of estramustine and radiotherapy in the treatment of prostate cancer. Prostate cancer is a common disease, with a high variability between subjects in its malignant potential. In many cases, the disease is an incidental finding with little or no clinical significance. In other cases, however, prostate cancer may be an aggressive malignant disease, which, if the initial treatment fails, lacks an effective cure and may lead to severe symptoms, metastasis, and death despite all treatment. In many cases, the methods of treatment available at the moment provide cure or significant regression of symptoms, but often at the cost of considerable side effects. Estramustine, a cytostatic drug used for treating advanced cancer of the prostate, has been shown to inhibit prostate cancer progression and also to increase the sensitivity of cancer cells to radiotherapy. The goals of this study were, first, to find out whether it is possible to use either estramustine or an antibody against estramustine binding protein as carrier molecules for bringing therapeutic radioisotopes into prostate cancer cells, and, secondly, to gain more understanding of the mechanisms behind the known radiosensitising effect of estramustine. Estramustine and estramustine binding protein antibody were labelled with iodine-125 to study the biodistribution of these substances in mice. In the first experiment, both of the substances accumulated in the prostate, but radioiodinated estramustine also showed affinity to the liver and the lungs. Since the radiolabelled antibody was found out to accumulate more selectively to the prostate, we studied its biodistribution in nude mice with DU-145 human prostate cancer implants. In this experiment, the prostate and the tumour accumulated more radioactivity than other organs, but we concluded that the difference in the dose of radiation compared to other organs was not sufficient for the radioiodinated antibody to be advocated as a carrier molecule for treating prostate cancer. Mice with similar DU-145 prostate cancer implants were then treated with estramustine and external beam irradiation, with and without neoadjuvant estramustine treatment. The tumours responded to the treatment as expected, showing the radiation potentiating effect of estramustine. In the third experiment, this effect was found without an increase in the amount of apoptosis in the tumour cells, despite previous suggestions to the contrary. In the fourth experiment, we gave a similar treatment to the mice with DU-145 tumours. A reduction in proliferation was found in the groups treated with radiotherapy, and an increased amount of tumour hypoxia and tumour necrosis in the group treated with both neoadjuvant estramustine and radiation. This finding is contradictory to the suggestion that the radiation sensitising effect of estramustine could be attributed to its angiogenic activity. Tässä työssä tutkittiin estramustiinin ja sädehoidon yhteisvaikutusta eturauhassyövän hoidossa. Eturauhassyöpä on yleinen sairaus, joka usein ilmenee sattumalöydöksenä eikä aiheuta oireita tai lyhennä elinaikaa. Tauti on kuitenkin luonteeltaan hyvin vaihteleva, ja joillakin potilailla se on agressiivinen sairaus, joka etenee kaikesta hoidosta huolimatta ja johtaa vaikeisiin oireisiin ja kuolemaan. Nykyaikainen hoito auttaa osassa tapauksista, mutta voi aiheuttaa vaikeita sivuvaikutuksia. Estramustiini on sytostaatti, jota on aiemmin käytetty hormonihoidolle reagoimattoman eturauhassyövän hoidossa. Sen on myös todettu herkistävän syöpäsoluja sädehoidon vaikutukselle. Estramustiini kertyy mm. eturauhassyöpäsolujen sisään sitojaproteiinin ansiosta. Tämän tutkimuksen tavoitteena oli selvittää, voidaanko estramustiinia tai sen sitojaproteiinin vasta-ainetta käyttää kantajamolekyyleinä viemään hoidossa käytettävää radioaktiivsta ainetta eturauhassyöpäsolujen sisään. Toisena tavoitteena oli saada lisätietoa sädeherkistävän vaikutuksen mekanismeista. Estramustiini- ja estramustiinin sitojaproteiinimolekyyleihin liitettiin radioaktiivista jodia ja tutkitiin aineiden kertymistä eri elimiin hiirillä. Molemmat aineet kertyivät eturauhaseen, radiojoditettu estramustiini myös maksaan ja keuhkoon. Radiojoditettu estramustiinin sitoja-aine kertyi selektiivisemmin eturauhaseen joten se valittiin jatkotutkimukseen. Kertymistä tutkittiin hiirillä, joilla oli DU-145-eturauhassyöpäsiirteet. Vasta-aineen kertyminen eturauhassyöpäsiirteeseen ei ollut muihin elimiin verrattuna niin voimakasta, että sitä voitaisiin suositella kantaja-aineeksi eturauhassyövän hoidossa. Samanlaisia hiirten DU-145-eturauhassyöpäsiirteitä hoidettiin sitten ulkoisella sädehoidolla, estramustiinilla ja näiden yhdistelmällä. Kasvaimien todettiin reagoivan hoidolle ja estramustiini tehosti sädehoidon vaikutusta. Toisin kuin odotettiin, tehon lisääntyminen ei liittynyt apoptoosin eli ohjelmoidun solukuoleman lisääntymiseen. Lisätutkimuksissa selvisi, että sädehoito vähensi kasvaimien solunjakautumista ja sädehoidon ja estramustiinin yhdistelmä aiheutti kasvaimiin hapenpuutetta ja lisäsi kuolioon menneiden solujen määrää. Tämä ei mielestämme tue aiempaa oletusta, jonka mukaan estramustiinin verenkiertoa parantava vaikutus kasvaimessa olisi osallisena sädeherkistyksessä.
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