Metronomic Cyclophosphamide in Elderly Patients With Advanced, Castration‐resistant Prostate Cancer

Fontana, A.; Bocci, Guido; Galli, Luca; D’Arcangelo, M.; Derosa, Lisa; Fioravanti, Anna; Orlandi, Paola; Barletta, M. T.; Landi, Lorenza; Bursi, S.; Minuti, Gabriele; Bona, Eleonora; Grazzini, Ilaria; Danesi, Romano; Falcone, Alfredo

doi:10.1111/j.1532-5415.2010.02833.x

Cited by 27 publications

(23 citation statements)

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“…In that study, PSA levels decreased by 50% in 30% of patients, the median PFS and OS were 3 and 21 months, respectively, and no grade 3‐4 adverse events were observed. Similar results were also observed in a cohort of elderly (aged 78 years) CRPC patients . Based on our previous experiences, in the present study we tested for a therapeutic benefit from the combination of docetaxel plus prednisone with metronomic CTX plus CXB as a first‐line treatment for mCRPC.…”

Section: Introductionsupporting

confidence: 79%

“…Similar results were also observed in a cohort of elderly (aged 78 years) CRPC patients . Based on our previous experiences, in the present study we tested for a therapeutic benefit from the combination of docetaxel plus prednisone with metronomic CTX plus CXB as a first‐line treatment for mCRPC. The aims of this present study were to assess the response of mCRPC patients treated with the docetaxel plus prednisone standard treatment followed by an oral metronomic CTX regimen with CXB.…”

Section: Introductionsupporting

confidence: 79%

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Docetaxel plus oral metronomic cyclophosphamide: A phase II study with pharmacodynamic and pharmacogenetic analyses in castration‐resistant prostate cancer patients

Derosa

Galli

Orlandi

et al. 2014

Cancer

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BACKGROUND: Docetaxel plus prednisone is currently the standard first-line treatment in metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to assess the clinical activity and pharmacodynamic/pharmacogenetic profile of docetaxel plus prednisone in combination with metronomic cyclophosphamide in mCRPC patients. METHODS: Forty-one chemotherapynaive patients received docetaxel (60 mg/m 2 intravenously every 3 weeks up to 12 cycles) and, from day 2, prednisone 10 mg/day, celecoxib 400 mg/day, and metronomic cyclophosphamide 50 mg/day, continuously. Plasma VEGF and bFGF were detected by ELISA. Real-time PCR-SNP analysis of VEGF gene was performed using an ABI PRISM 7900HT SDS and TaqMan SNP genotyping. RESULTS: Eighty-seven percent of patients were free of progression at 6 months. A decrease in prostate-specific antigen 50% was observed in 82% of 39 evaluable patients, with a median time to progression of 12.3 months. Grade 3 adverse events were neutropenia (5%), thrombocytopenia, diarrhea, and stomatitis (2.5%). Median PFS and OS were 14.9 months (95% CI, 9.2-15.3 months) and 33.3 months (95% CI, 23-35.6 months), respectively. Of 11 patients (28%) with evaluable disease, 5 (44%) achieved a complete response, 2 (11%) a partial response, and 2 (11%) stable disease, whereas 2 showed disease progression. The 21154A/G VEGF polymorphism, plasma VEGF, and bFGF after the first cycle of chemotherapy may represent useful pharmacodynamic markers to predict better outcomes. CONCLUSIONS: The combination of docetaxel and oral metronomic chemotherapy is effective and well tolerated in mCRPC patients and may deserve further evaluation. Cancer 2014;120:3923-31.

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Section: Introductionsupporting

confidence: 79%

Section: Introductionsupporting

confidence: 79%

Docetaxel plus oral metronomic cyclophosphamide: A phase II study with pharmacodynamic and pharmacogenetic analyses in castration‐resistant prostate cancer patients

Derosa

Galli

Orlandi

et al. 2014

Cancer

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“…These characteristics, combined with the low cost, the good compliance of the oral administration, determine the possibility to treat subpopulations of patients. An example could be elderly patients [8,32],-who are generally vulnerable to chemotherapy-related toxicities because of their comorbidities, potential malnutrition and geriatric syndromes,-or the ones who refuse standard chemotherapy for its intrinsic possibility to induce severe adverse drug reactions. In this view, the use of CXB may have contributed both to a significant reduction of chemotherapy toxicity, such as haematological ones [33], and to the control of pain related to the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Both the low cost and the oral administration of the drugs are key characteristics of this schedule and may offer important social advantages [4]. Anecdotical case reports [5][6][7] and experiences in small subsets of patients enrolled in retrospective clinical studies [8][9][10] on metastatic cancers have been recently published about the use of metronomic therapy as a first-line treatment. These point out the possible importance of metronomic chemotherapy as an alternative approach to first-line therapy in frail patients requiring palliation or patients refusing the standard chemotherapy for its impact on the quality of life.…”

Section: Introductionmentioning

confidence: 98%

First-line metronomic chemotherapy in a metastatic model of spontaneous canine tumours: a pilot study

et al. 2011

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Metronomic chemotherapy—the low-dose, long term and\ud \ud frequently administered chemotherapy—has revealed in\ud \ud these years an important impact on the stabilization of\ud \ud cancer disease for its known antiangiogenic effects,\ud \ud prolonged clinical benefits and the improved quality of life\ud \ud of several cancer patients, without any high grade toxicity\ud \ud [1–3]. Both the low cost and the oral administration of the\ud \ud drugs are key characteristics of this schedule and may offer\ud \ud important social advantages [4]. Anecdotical case reports\ud \ud [5–7] and experiences in small subsets of patients enrolled\ud \ud in retrospective clinical studies [8–10] on metastatic cancers\ud \ud have been recently published about the use of metronomic\ud \ud therapy as a first-line treatment. These point out the\ud \ud possible importance of metronomic chemotherapy as an\ud \ud alternative approach to first-line therapy in frail patients\ud \ud requiring palliation or patients refusing the standard\ud \ud chemotherapy for its impact on the quality of life. However,\ud \ud no data of prospective clinical trials on first line metronomic\ud \ud chemotherapy are currently available in metastatic\ud \ud cancer human patients.\ud \ud The veterinary medical oncology has advanced dramatically\ud \ud over the past few decades, because of the successful\ud \ud application of a number of conventional chemotherapeutic\ud \ud drugs to the cancer conditions diagnosed in veterinary\ud \ud patients [11]. Veterinary oncology cases often present a\ud \ud unique opportunity to investigate novel drugs and treatment\ud \ud schedules providing many in vivo information to the larger\ud \ud medical community and giving new effective options for\ud \ud dogs themselves [12]. As well recently pointed out by\ud \ud Paoloni and Khanna [13], these studies may also have a\ud \ud great translational relevance, predicting new therapies and\ud \ud related surrogate markers in human beings because pet dogs\ud \ud with cancers might assist the transition between mouse\ud \ud models and human patients. Moreover, in the clinical\ud \ud practice, veterinarians and their clients are generally less\ud \ud willing to accept a high degree of side effects, which most\ud \ud often results in lower drug doses than the ones that are used\ud \ud in human oncology.\ud \ud The aim of the present pilot study was to test a first-line\ud \ud metronomic oral combination of cyclophosphamide (CTX)\ud \ud and celecoxib (CXB) in canine metastatic spontaneous\ud \ud tumours, characterizing possible biomarkers to translate in\ud \ud human clinical research

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“…Furthermore, depending on the type of drug that is administered metronomically, direct cytotoxic effects on tumour cells and stimulation of the immune system also have been reported (Rozados et al , 2010). Metronomic oral CTX, as well as its combination with other drugs such as celecoxib (CXB) or dexamethasone (DEX), is a promising clinical approach to treat castration-resistant metastatic prostate cancer (Fontana et al , 2010a, 2010b; Nelius et al , 2011; Penel et al , 2012). In addition, the antitumour and antiangiogenic activity of metronomic CTX has been demonstrated in various experimental models of human prostate cancer (Man et al , 2002; Emmenegger et al , 2007, 2010, 2011).…”

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confidence: 99%

VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide

et al. 2013

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Background:No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone.Methods:Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (−2578A/C, −634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy–Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan–Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant.Results:Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the −2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the −634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the −634CC genotype had a median PFS of 2.2 months whereas patients with the genotype −634CG/GG had a median PFS of 6.25 months (P=0.0042).Conclusion:The −634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule.

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Metronomic Cyclophosphamide in Elderly Patients With Advanced, Castration‐resistant Prostate Cancer

Cited by 27 publications

References 8 publications

Docetaxel plus oral metronomic cyclophosphamide: A phase II study with pharmacodynamic and pharmacogenetic analyses in castration‐resistant prostate cancer patients

Docetaxel plus oral metronomic cyclophosphamide: A phase II study with pharmacodynamic and pharmacogenetic analyses in castration‐resistant prostate cancer patients

First-line metronomic chemotherapy in a metastatic model of spontaneous canine tumours: a pilot study

VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide

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