Clinical Study Chemotherapy 2014;60:129–134 DOI: 10.1159/000369781
Received: July 3, 2014 Accepted after revision: November 7, 2014 Published online: February 26, 2015
A Randomised Phase II Trial Comparing Docetaxel Plus Prednisone with Docetaxel Plus Prednisone Plus Low-Dose Cyclophosphamide in CastrationResistant Prostate Cancer Markus Porsch a Matthias Ulrich c Johann Jakob Wendler a Uwe-Bernd Liehr a Frank Reiher d Andreas Janitzky a Daniel Baumunk a Daniel Schindele a Florian Seseke e Anke Lux b Martin Schostak a a
Klinik für Urologie und Kinderurologie and b Institut für Biometrie und Medizinische Informatik, Medizinische Fakultät, Otto-von-Guericke-Universität, Magdeburg, c Klinik für Urologie und Kinderurologie, AMEOS Klinikum St. Salvator, Halberstadt, d Klinik für Urologie, Kinderurologie und Uroonkologie, AMEOS Klinikum, Haldensleben, and e Klinik für Urologie, Krankenhaus Martha-Maria, Halle-Doelau, Germany
Key Words Docetaxel · Prednisone · Cyclophosphamide · Prostate cancer · Castration-resistant prostate cancer
Abstract Background: Docetaxel plus prednisone is a standard treatment for castration-resistant prostate cancer. Cyclophosphamide may be an effective combination partner. Methods: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. Results: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered
© 2015 S. Karger AG, Basel 0009–3157/15/0602–0129$39.50/0 E-Mail [email protected] www.karger.com/che
to be cancer related. Conclusions: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results. © 2015 S. Karger AG, Basel
Introduction
Prostate carcinoma is the most frequent tumour among males [1] in industrialised countries. In spite of increasing incidence rates and a broad range of local curative therapeutic options in the early stages, the absolute mortality figures remain unchanged [2]. Although antiandrogenic measures and chemotherapy have substantially increased survival duration, castration-resistant prostate cancer (CRPC) remains incurable [3]. CRPC was long regarded as resistant to chemotherapy, with remission rates below 10% in monotherapy [4, 5]. This view began to change with the demonstration of objective remission rates of 19–69% for treatment with esDr. Markus Porsch Klinik für Urologie und Kinderurologie Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg Leipziger Strasse 44, DE–39120 Magdeburg (Germany) E-Mail markus.porsch @ med.ovgu.de
tramustine [6] and, since 2004, mitoxantrone (plus prednisone) and estramustine have been authorised by the FDA for palliative treatment of CRPC, albeit without a demonstrated survival advantage. In the past 2 decades, docetaxel, a member of the taxane family, has emerged as a potential therapeutic option for CRPC, as demonstrated by several studies, with objective response rates approaching or even exceeding 50% [7–12]. A later study of 1,006 patients showed a therapeutic advantage of docetaxel compared with mitoxantrone in terms of both survival and of prostate-specific antigen (PSA) level [13]; a 3-week docetaxel treatment cycle was marginally superior in respect of survival to a 1-week cycle, but was also associated with a higher incidence of severe neutropenia. Augmenting docetaxel with estramustine did not appear to increase its efficacy [14], while the additional use of estramustine also entailed a higher frequency of side effects (thromboembolic complications) [15], so that it is today regarded as obsolete. Docetaxel has received authorisation from the EMA and the FDA for treatment of CRPC. Nevertheless, some patients present with primary resistance, and a significant proportion of patients rapidly develop resistance [16], meaning the search for other antitumoural co-therapies continues. Of particular interest are agents with other mechanisms of action, as these could help in preventing or overcoming resistance to docetaxel. Cyclophosphamide, a member of the class of nitrogen mustards, has long been established as a chemotherapeutic agent for numerous carcinomas, both alone and in combination. Published studies of cyclophosphamide chemotherapy include prostate cancers and, specifically, CRPC. Cyclophosphamide alone showed a significant amelioration of symptoms [17], and a ‘vincristine + cyclophosphamide’ regimen led to a 50% PSA decrease in 29% of patients with an improvement in soft-tissue lesions [18]. Metronomic (i.e. continuous, low-dose) administration of cyclophosphamide to CRPC patients led to a substantive decrease in PSA levels: >80% in 29%, 50– 79% in 39% and 0.1 in each case). Haemoglobin decreased and leucocyte counts increased in both treatment groups, but no association with treatment was detected in the ANOVA (p > 0.1; see also Discussion). Porsch et al.
Table 4. Patients’ body weight and BMI
The original target of 60 study patients was abandoned because of slow recruitment, which we attribute to the fact that many potential subjects had received prior therapy and thus met an exclusion criterion. Apart from this,
the study population corresponded to that planned, though a better balance of recruitment numbers between the three study centres would have been desirable. The two treatment arms did not show any relevant differences such as might have biased the study results. Apart from the reduction in patient numbers (to 33 instead of 60), there were no major deviations from the study protocol. The number of evaluable subjects (24 of 33) was acceptable in view of the complexity and seriousness of the study indication. Docetaxel was seen to be effective in PSA response. However, the results showed clearly that the study patients did not receive a therapeutic benefit from adding cyclophosphamide to docetaxel in the new combination therapy: neither a statistically significant difference in PSA reduction nor any non-significant trend in this direction was observed in a between-group comparison of changes in PSA level from the first to the sixth treatment cycle. The cogency of the study result, and thus the generalisability of its findings, are restricted on account of the small number of study patients. Nevertheless, there was no suggestion of the existence of a synergetic effect between the two chemotherapeutic agents, in spite of their different mechanisms of action (see Introduction). Pain scores were likewise not significantly improved by the additional use of cyclophosphamide. The safety assessment did not reveal any toxicity issues in connection with the additional use of cyclophosphamide. The patients’ quality of life was likewise not noticeably influenced by the use of the combination therapy rather than the monotherapy. The three fatalities were all considered to have been caused ultimately by the patients’ cancer disease. The thromboembolic events observed may be considered to be tumour related, as local tumour growth in the lesser pelvis can give rise to diversion of blood flow in this region and, in turn, to deep vein thrombosis and arterial pulmonary embolism. The portal thrombosis and extravasation may be regarded as procedure related. Pain-related and fatigue-related hospitalisation may be ascribed to disease progression. An increase in leucocyte counts, as seen in both treatment groups, is a known consequence of the administration of dexamethasone and prednisone [23], while the decreased haemoglobin levels observed may be attributed to the myelosuppressive docetaxel treatment and the generally advanced bone metastasis. We note that, although cyclophosphamide is often quoted as being associated with bladderrelated adverse events, no events of this type were recorded within the study. This we assume to be due to the relatively low cyclophosphamide dose level (50 mg daily)
Docetaxel, Prednisone and Cyclophosphamide in CRPC
Chemotherapy 2014;60:129–134 DOI: 10.1159/000369781
Arm A Body weight, kg Treatment before cycle 1 Mean ± SD 91.6 ± 18.6 Median 87 Range (min/max) 70/144 Treatment after cycle 6 Mean ± SD 89.8 ± 19.8 Median 85 Range (min/max) 68/148 Change from before cycle 1 to after cycle 6 Mean ± SD –1.8 ± 4.0 Median –2.0 Range (min/max) –8/+4 p 0.198 BMI Treatment before cycle 1 Mean ± SD 30.5 ± 6.9 Median 30.2 Range (min/max) 23.1/48.7 Treatment after cycle 6 Mean ± SD 29.9 ± 7.4 Median 28.1 Range (min/max) 23.0/50.0 Change from before cycle 1 to after cycle 6 Mean ± SD –0.61 ± 1.37 Median –0.7 Range (min/max) –2.7/+1.4 p 0.206
Arm B
86.2 ± 7.5 88 74/95 84.1 ± 7.5 84 75/95 –2.1 ± 3.1 –1.0 –10/+1 0.047
27.8 ± 2.8 27.7 22.1/32.7 27.0 ± 2.7 27.3 22.4/31.6 –0.75 ± 0.98 –0.7 –3.0/+0.3 0.047
For weight, n = 13 (arm A) and 11 (arm B). For BMI, n = 12 (arm A) and 10 (arm B). Percentage change in both variables (identical because body height was unchanged) was associated with p = 0.153 (arm A) and 0.047 (arm B).
Patient body weight and BMI are shown in table 4. Weight loss in the two treatment groups was approximately equal – the mean body weight in arm A decreased by 1.8 kg and in arm B by 2.1 kg. This difference lay just below the significance threshold for arm B only (p = 0.047), but no clinical relevance is attached to this small between-group difference.
Discussion
133
compared with the much higher levels used in other indications (1–2 g daily) where bladder-related adverse events occurred [24]. From today’s standpoint it was justified to search for a suitable combination with docetaxel, rather than an entirely new substance to replace docetaxel. However, our study adds to the body of evidence that combination therapies with docetaxel do not benefit the patient and only increase the risk of (in some cases substantial) side effects [25, 26]. Radiological and survival efficacy criteria were originally planned but proved impossible to implement within the framework of the institutions involved. The use of
criteria such as RECIST was not possible as CRPC leads to bone metastases, for which there is still no workable definition of radiological progression. The limitations of the study were the small number of patients, which restricted the generalisability of the results, and the short observation period, which impeded the acquisition of survival data. In conclusion, the study results support the oncological effectiveness and tolerability of docetaxel plus prednisone, but an additional advantage of cyclophosphamide was not found. Thus, in the context of a lack of alternatives, the general use of docetaxel monotherapy, as set out in various guidelines, remains the logical consequence.
References 1 Gesundheitsberichterstattung des Bundes, Zentrum für Krebsregisterdaten: Krebs in Deutschland 2009/2010, ed 9. Berlin, Robert Koch-Institut, 2013, p 16. 2 Gesundheitsberichterstattung des Bundes, Zentrum für Krebsregisterdaten: Krebs in Deutschland 2009/2010, ed 9. Berlin, Robert Koch-Institut, 2013, p 17. 3 Gesundheitsberichterstattung des Bundes, Zentrum für Krebsregisterdaten: Krebs in Deutschland 2009/2010, ed 9. Berlin, Robert Koch-Institut, 2013, p 89. 4 Eisenberger MA, Abrams JS: Chemotherapy for prostatic carcinoma. Semin Urol 1988; 6: 303–310. 5 Yagoda A, Petrylak D: Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 1993;71:1098–1111. 6 Perry CA, McTravish D: Estramustine phosphate sodium: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging 1995;7:149–174. 7 Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormonerefractory prostate cancer: preliminary results. Semin Oncol 1999;26(suppl 17):14–18. 8 Friedland D, Cohen J, Miller R Jr, Voloshin M, Gluckman R, Lembersky B, Zidar B, Keating M, Reilly N, Dimitt P: A phase II trial of docetaxel (Taxotere) in hormone-refractory prostate cancer: correlation of antitumor effect to phosphorylation of Bcl-2. Semin Oncol 1999;26(suppl 17):19–23. 9 Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD: Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 2003;21:123–128. 10 Berry W, Dakhil S, Gregurich MA, Asmar L: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001;28(suppl 15):8–15.
134
11 Gravis G, Bladou F, Salem N, Macquart-Moulin G, Serment G, Camerlo J, Genre D, Bardou VJ, Maraninchi D, Viens P: Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma. Cancer 2003;98:1627–1634. 12 Schutz FA, Buzaid AC, Sartor O: Taxanes in the management of metastatic castration-resistant prostate cancer: efficacy and management of toxicity. Crit Rev Oncol Hematol 2014;91:248–256. 13 Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502– 1512. 14 Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson M, Small EJ, Raghaven D, Crawford ED: Docetaxel and Estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513– 1520. 15 Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard J-C, Logothetis CJ, Pignon J-P, Michiels S: Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a metaanalysis of individual patient data. Lancet Oncol 2007;8:994–1000. 16 Engels FK, Sparreboom A, Mathot RAA, Verweij J: Potential for improvement of docetaxel-based chemotherapy: a pharmacological review. Br J Cancer 2005;93:173–177. 17 Raghavan D, Cox K, Pearson BS, Coorey GJ, Rogers J, Watt WH, Coates AS, McNeil E, Grygiel JJ: Oral cyclophosphamide for the management of hormone-refractory prostate cancer. Br J Urol 1993;72:625–628.
Chemotherapy 2014;60:129–134 DOI: 10.1159/000369781
18 Daliani DD, Assikis V, Tu SM, Papandreou CN, Pagliaro LC, Holtkamp T, Wang X, Thall PF, Logothetis CJ: Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Cancer 2003;97:561–567. 19 Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R: Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer 2003;98:1643–1648. 20 Diaz JF, Andreu JM: Assembly of purified GDP-tubulin into microtubules induced by taxol and Taxotere: reversibility, ligand stoichiometry, and competition. Biochemistry 1993;32:2747–2755. 21 Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV: Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res 2005;11:6678–6685. 22 Nelius T, Klatte T, Reiher F, Filleur S, Yap R, Allhoff EP: Randomized study of docetaxel and dexamethasone with low or high dose estramustine for patients with advanced hormone-refractory prostate cancer (astract 4653). Proc Am Soc Clin Oncol 2006;24:254s. 23 Nakagawa M, Terashima T, D’yachkova Y, Bondy GP, Hogg JC, van Eeden SF: Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998; 98:2307–2313. 24 Cyclophosphamide: Fachinformation. Weiterstadt, Baxter Oncology, 2014. 25 Leo S, Accettura C, Lorusso V: Castration-resistant prostate cancer: targeted therapies. Chemotherapy 2011;57:115–127. 26 Loblaw DA, Walker-Dilks C, Winquist E, Hotte SJ: Systemic therapy in men with metastatic castration-resistant prostate cancer: a systematic review. Clin Oncol 2013; 25: 406– 430.
Porsch et al.
Copyright: S. Karger AG, Basel 2015. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: July 3, 2014 Accepted after revision: November 7, 2014 Published online: February 26, 2015
A Randomised Phase II Trial Comparing Docetaxel Plus Prednisone with Docetaxel Plus Prednisone Plus Low-Dose Cyclophosphamide in CastrationResistant Prostate Cancer Markus Porsch a Matthias Ulrich c Johann Jakob Wendler a Uwe-Bernd Liehr a Frank Reiher d Andreas Janitzky a Daniel Baumunk a Daniel Schindele a Florian Seseke e Anke Lux b Martin Schostak a a
Klinik für Urologie und Kinderurologie and b Institut für Biometrie und Medizinische Informatik, Medizinische Fakultät, Otto-von-Guericke-Universität, Magdeburg, c Klinik für Urologie und Kinderurologie, AMEOS Klinikum St. Salvator, Halberstadt, d Klinik für Urologie, Kinderurologie und Uroonkologie, AMEOS Klinikum, Haldensleben, and e Klinik für Urologie, Krankenhaus Martha-Maria, Halle-Doelau, Germany
Key Words Docetaxel · Prednisone · Cyclophosphamide · Prostate cancer · Castration-resistant prostate cancer
Abstract Background: Docetaxel plus prednisone is a standard treatment for castration-resistant prostate cancer. Cyclophosphamide may be an effective combination partner. Methods: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. Results: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered
© 2015 S. Karger AG, Basel 0009–3157/15/0602–0129$39.50/0 E-Mail [email protected] www.karger.com/che
to be cancer related. Conclusions: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results. © 2015 S. Karger AG, Basel
Introduction
Prostate carcinoma is the most frequent tumour among males [1] in industrialised countries. In spite of increasing incidence rates and a broad range of local curative therapeutic options in the early stages, the absolute mortality figures remain unchanged [2]. Although antiandrogenic measures and chemotherapy have substantially increased survival duration, castration-resistant prostate cancer (CRPC) remains incurable [3]. CRPC was long regarded as resistant to chemotherapy, with remission rates below 10% in monotherapy [4, 5]. This view began to change with the demonstration of objective remission rates of 19–69% for treatment with esDr. Markus Porsch Klinik für Urologie und Kinderurologie Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg Leipziger Strasse 44, DE–39120 Magdeburg (Germany) E-Mail markus.porsch @ med.ovgu.de
tramustine [6] and, since 2004, mitoxantrone (plus prednisone) and estramustine have been authorised by the FDA for palliative treatment of CRPC, albeit without a demonstrated survival advantage. In the past 2 decades, docetaxel, a member of the taxane family, has emerged as a potential therapeutic option for CRPC, as demonstrated by several studies, with objective response rates approaching or even exceeding 50% [7–12]. A later study of 1,006 patients showed a therapeutic advantage of docetaxel compared with mitoxantrone in terms of both survival and of prostate-specific antigen (PSA) level [13]; a 3-week docetaxel treatment cycle was marginally superior in respect of survival to a 1-week cycle, but was also associated with a higher incidence of severe neutropenia. Augmenting docetaxel with estramustine did not appear to increase its efficacy [14], while the additional use of estramustine also entailed a higher frequency of side effects (thromboembolic complications) [15], so that it is today regarded as obsolete. Docetaxel has received authorisation from the EMA and the FDA for treatment of CRPC. Nevertheless, some patients present with primary resistance, and a significant proportion of patients rapidly develop resistance [16], meaning the search for other antitumoural co-therapies continues. Of particular interest are agents with other mechanisms of action, as these could help in preventing or overcoming resistance to docetaxel. Cyclophosphamide, a member of the class of nitrogen mustards, has long been established as a chemotherapeutic agent for numerous carcinomas, both alone and in combination. Published studies of cyclophosphamide chemotherapy include prostate cancers and, specifically, CRPC. Cyclophosphamide alone showed a significant amelioration of symptoms [17], and a ‘vincristine + cyclophosphamide’ regimen led to a 50% PSA decrease in 29% of patients with an improvement in soft-tissue lesions [18]. Metronomic (i.e. continuous, low-dose) administration of cyclophosphamide to CRPC patients led to a substantive decrease in PSA levels: >80% in 29%, 50– 79% in 39% and 0.1 in each case). Haemoglobin decreased and leucocyte counts increased in both treatment groups, but no association with treatment was detected in the ANOVA (p > 0.1; see also Discussion). Porsch et al.
Table 4. Patients’ body weight and BMI
The original target of 60 study patients was abandoned because of slow recruitment, which we attribute to the fact that many potential subjects had received prior therapy and thus met an exclusion criterion. Apart from this,
the study population corresponded to that planned, though a better balance of recruitment numbers between the three study centres would have been desirable. The two treatment arms did not show any relevant differences such as might have biased the study results. Apart from the reduction in patient numbers (to 33 instead of 60), there were no major deviations from the study protocol. The number of evaluable subjects (24 of 33) was acceptable in view of the complexity and seriousness of the study indication. Docetaxel was seen to be effective in PSA response. However, the results showed clearly that the study patients did not receive a therapeutic benefit from adding cyclophosphamide to docetaxel in the new combination therapy: neither a statistically significant difference in PSA reduction nor any non-significant trend in this direction was observed in a between-group comparison of changes in PSA level from the first to the sixth treatment cycle. The cogency of the study result, and thus the generalisability of its findings, are restricted on account of the small number of study patients. Nevertheless, there was no suggestion of the existence of a synergetic effect between the two chemotherapeutic agents, in spite of their different mechanisms of action (see Introduction). Pain scores were likewise not significantly improved by the additional use of cyclophosphamide. The safety assessment did not reveal any toxicity issues in connection with the additional use of cyclophosphamide. The patients’ quality of life was likewise not noticeably influenced by the use of the combination therapy rather than the monotherapy. The three fatalities were all considered to have been caused ultimately by the patients’ cancer disease. The thromboembolic events observed may be considered to be tumour related, as local tumour growth in the lesser pelvis can give rise to diversion of blood flow in this region and, in turn, to deep vein thrombosis and arterial pulmonary embolism. The portal thrombosis and extravasation may be regarded as procedure related. Pain-related and fatigue-related hospitalisation may be ascribed to disease progression. An increase in leucocyte counts, as seen in both treatment groups, is a known consequence of the administration of dexamethasone and prednisone [23], while the decreased haemoglobin levels observed may be attributed to the myelosuppressive docetaxel treatment and the generally advanced bone metastasis. We note that, although cyclophosphamide is often quoted as being associated with bladderrelated adverse events, no events of this type were recorded within the study. This we assume to be due to the relatively low cyclophosphamide dose level (50 mg daily)
Docetaxel, Prednisone and Cyclophosphamide in CRPC
Chemotherapy 2014;60:129–134 DOI: 10.1159/000369781
Arm A Body weight, kg Treatment before cycle 1 Mean ± SD 91.6 ± 18.6 Median 87 Range (min/max) 70/144 Treatment after cycle 6 Mean ± SD 89.8 ± 19.8 Median 85 Range (min/max) 68/148 Change from before cycle 1 to after cycle 6 Mean ± SD –1.8 ± 4.0 Median –2.0 Range (min/max) –8/+4 p 0.198 BMI Treatment before cycle 1 Mean ± SD 30.5 ± 6.9 Median 30.2 Range (min/max) 23.1/48.7 Treatment after cycle 6 Mean ± SD 29.9 ± 7.4 Median 28.1 Range (min/max) 23.0/50.0 Change from before cycle 1 to after cycle 6 Mean ± SD –0.61 ± 1.37 Median –0.7 Range (min/max) –2.7/+1.4 p 0.206
Arm B
86.2 ± 7.5 88 74/95 84.1 ± 7.5 84 75/95 –2.1 ± 3.1 –1.0 –10/+1 0.047
27.8 ± 2.8 27.7 22.1/32.7 27.0 ± 2.7 27.3 22.4/31.6 –0.75 ± 0.98 –0.7 –3.0/+0.3 0.047
For weight, n = 13 (arm A) and 11 (arm B). For BMI, n = 12 (arm A) and 10 (arm B). Percentage change in both variables (identical because body height was unchanged) was associated with p = 0.153 (arm A) and 0.047 (arm B).
Patient body weight and BMI are shown in table 4. Weight loss in the two treatment groups was approximately equal – the mean body weight in arm A decreased by 1.8 kg and in arm B by 2.1 kg. This difference lay just below the significance threshold for arm B only (p = 0.047), but no clinical relevance is attached to this small between-group difference.
Discussion
133
compared with the much higher levels used in other indications (1–2 g daily) where bladder-related adverse events occurred [24]. From today’s standpoint it was justified to search for a suitable combination with docetaxel, rather than an entirely new substance to replace docetaxel. However, our study adds to the body of evidence that combination therapies with docetaxel do not benefit the patient and only increase the risk of (in some cases substantial) side effects [25, 26]. Radiological and survival efficacy criteria were originally planned but proved impossible to implement within the framework of the institutions involved. The use of
criteria such as RECIST was not possible as CRPC leads to bone metastases, for which there is still no workable definition of radiological progression. The limitations of the study were the small number of patients, which restricted the generalisability of the results, and the short observation period, which impeded the acquisition of survival data. In conclusion, the study results support the oncological effectiveness and tolerability of docetaxel plus prednisone, but an additional advantage of cyclophosphamide was not found. Thus, in the context of a lack of alternatives, the general use of docetaxel monotherapy, as set out in various guidelines, remains the logical consequence.
References 1 Gesundheitsberichterstattung des Bundes, Zentrum für Krebsregisterdaten: Krebs in Deutschland 2009/2010, ed 9. Berlin, Robert Koch-Institut, 2013, p 16. 2 Gesundheitsberichterstattung des Bundes, Zentrum für Krebsregisterdaten: Krebs in Deutschland 2009/2010, ed 9. Berlin, Robert Koch-Institut, 2013, p 17. 3 Gesundheitsberichterstattung des Bundes, Zentrum für Krebsregisterdaten: Krebs in Deutschland 2009/2010, ed 9. Berlin, Robert Koch-Institut, 2013, p 89. 4 Eisenberger MA, Abrams JS: Chemotherapy for prostatic carcinoma. Semin Urol 1988; 6: 303–310. 5 Yagoda A, Petrylak D: Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 1993;71:1098–1111. 6 Perry CA, McTravish D: Estramustine phosphate sodium: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging 1995;7:149–174. 7 Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormonerefractory prostate cancer: preliminary results. Semin Oncol 1999;26(suppl 17):14–18. 8 Friedland D, Cohen J, Miller R Jr, Voloshin M, Gluckman R, Lembersky B, Zidar B, Keating M, Reilly N, Dimitt P: A phase II trial of docetaxel (Taxotere) in hormone-refractory prostate cancer: correlation of antitumor effect to phosphorylation of Bcl-2. Semin Oncol 1999;26(suppl 17):19–23. 9 Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD: Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 2003;21:123–128. 10 Berry W, Dakhil S, Gregurich MA, Asmar L: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001;28(suppl 15):8–15.
134
11 Gravis G, Bladou F, Salem N, Macquart-Moulin G, Serment G, Camerlo J, Genre D, Bardou VJ, Maraninchi D, Viens P: Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma. Cancer 2003;98:1627–1634. 12 Schutz FA, Buzaid AC, Sartor O: Taxanes in the management of metastatic castration-resistant prostate cancer: efficacy and management of toxicity. Crit Rev Oncol Hematol 2014;91:248–256. 13 Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502– 1512. 14 Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson M, Small EJ, Raghaven D, Crawford ED: Docetaxel and Estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513– 1520. 15 Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard J-C, Logothetis CJ, Pignon J-P, Michiels S: Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a metaanalysis of individual patient data. Lancet Oncol 2007;8:994–1000. 16 Engels FK, Sparreboom A, Mathot RAA, Verweij J: Potential for improvement of docetaxel-based chemotherapy: a pharmacological review. Br J Cancer 2005;93:173–177. 17 Raghavan D, Cox K, Pearson BS, Coorey GJ, Rogers J, Watt WH, Coates AS, McNeil E, Grygiel JJ: Oral cyclophosphamide for the management of hormone-refractory prostate cancer. Br J Urol 1993;72:625–628.
Chemotherapy 2014;60:129–134 DOI: 10.1159/000369781
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