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Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study.

Brodin O, Eksborg S, Wallenberg M, Asker-Hagelberg C, Larsen EH, Mohlkert D, Lenneby-Helleday C, Jacobsson H, Linder S, Misra S, Björnstedt M - Nutrients (2015)

Bottom Line: The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite.In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol.Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Karolinska Institutet, Karolinska University Hospital Södersjukhuset, SE-118 83 Stockholm, Sweden. ola.brodin@karolinska.se.

ABSTRACT

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients' refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits.

Materials and methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation.

Results and conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

No MeSH data available.


Related in: MedlinePlus

(A) Waterfall plot showing tumor response following selenite treatment (top panel) and subsequent administration of chemotherapeutic drugs (bottom panel). In the waterfall plot, a positive value indicates increase in tumor volume and vice versa. (B) Anterior-posterior Maximum Intensity Projection (MIP) PET images of a 48 year old man with multiple metastases from a carcinoma of the left sinus ethmoidalis, acquired 60 min after iv administration of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) (4 MBq/kg body weight); left panel, baseline examination; and right panel, examination after 17 days following stopping his selenite treatment (three treatments with 28.2 mg selenite a day). A few hours after the first treatment, his primary tumor, localized behind his left eye, started to swell, producing a massive increase of his earlier modest exophthalmos. However, it returned to the earlier status after 1–2 days. This examination shows a general decrease of the FDG-uptake of the metastases, most evident in a large metastasis of the left liver lobe (arrow). (C) Toxicity of single or combined exposure of carboplatin and gemcitabine for 48 h to cells collected from pleural exudates from a patient. Fraction 1 indicates before selenite treatment and Fraction 2 indicates after selenite treatment. Data are presented as mean ± S.D. 160 × 143 mm (300 × 300 DPI).
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nutrients-07-04978-f004: (A) Waterfall plot showing tumor response following selenite treatment (top panel) and subsequent administration of chemotherapeutic drugs (bottom panel). In the waterfall plot, a positive value indicates increase in tumor volume and vice versa. (B) Anterior-posterior Maximum Intensity Projection (MIP) PET images of a 48 year old man with multiple metastases from a carcinoma of the left sinus ethmoidalis, acquired 60 min after iv administration of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) (4 MBq/kg body weight); left panel, baseline examination; and right panel, examination after 17 days following stopping his selenite treatment (three treatments with 28.2 mg selenite a day). A few hours after the first treatment, his primary tumor, localized behind his left eye, started to swell, producing a massive increase of his earlier modest exophthalmos. However, it returned to the earlier status after 1–2 days. This examination shows a general decrease of the FDG-uptake of the metastases, most evident in a large metastasis of the left liver lobe (arrow). (C) Toxicity of single or combined exposure of carboplatin and gemcitabine for 48 h to cells collected from pleural exudates from a patient. Fraction 1 indicates before selenite treatment and Fraction 2 indicates after selenite treatment. Data are presented as mean ± S.D. 160 × 143 mm (300 × 300 DPI).

Mentions: The antitumor effect was a secondary endpoint. Any antitumor effect described herein should be interpreted with precaution due inherent uncertainty associated with the limited number of patients on each dose level. Tumor size (RECIST) was evaluated before and after the selenite treatment and following subsequent chemotherapy treatment. The results from these measurements are presented in the waterfall plot (Figure 4A), suggesting no consistent effect of selenite treatment on the tumor volume. None of the patients had a complete or partial response immediately after respective treatments but 13 patients had a stable disease after selenite treatment and 16 patients after subsequent chemotherapy. Patient 4, who received a stent in the trachea and main bronchus to get relieved from the risk of compression-associated breathing difficulties a week before starting selenite treatment, had a stable disease with gradually improved response during the following six months. The tumor was undetectable half a year later as revealed by CT and a PET-CT examination. She is still alive without any recurrent tumor for more than six years.


Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study.

Brodin O, Eksborg S, Wallenberg M, Asker-Hagelberg C, Larsen EH, Mohlkert D, Lenneby-Helleday C, Jacobsson H, Linder S, Misra S, Björnstedt M - Nutrients (2015)

(A) Waterfall plot showing tumor response following selenite treatment (top panel) and subsequent administration of chemotherapeutic drugs (bottom panel). In the waterfall plot, a positive value indicates increase in tumor volume and vice versa. (B) Anterior-posterior Maximum Intensity Projection (MIP) PET images of a 48 year old man with multiple metastases from a carcinoma of the left sinus ethmoidalis, acquired 60 min after iv administration of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) (4 MBq/kg body weight); left panel, baseline examination; and right panel, examination after 17 days following stopping his selenite treatment (three treatments with 28.2 mg selenite a day). A few hours after the first treatment, his primary tumor, localized behind his left eye, started to swell, producing a massive increase of his earlier modest exophthalmos. However, it returned to the earlier status after 1–2 days. This examination shows a general decrease of the FDG-uptake of the metastases, most evident in a large metastasis of the left liver lobe (arrow). (C) Toxicity of single or combined exposure of carboplatin and gemcitabine for 48 h to cells collected from pleural exudates from a patient. Fraction 1 indicates before selenite treatment and Fraction 2 indicates after selenite treatment. Data are presented as mean ± S.D. 160 × 143 mm (300 × 300 DPI).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488827&req=5

nutrients-07-04978-f004: (A) Waterfall plot showing tumor response following selenite treatment (top panel) and subsequent administration of chemotherapeutic drugs (bottom panel). In the waterfall plot, a positive value indicates increase in tumor volume and vice versa. (B) Anterior-posterior Maximum Intensity Projection (MIP) PET images of a 48 year old man with multiple metastases from a carcinoma of the left sinus ethmoidalis, acquired 60 min after iv administration of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) (4 MBq/kg body weight); left panel, baseline examination; and right panel, examination after 17 days following stopping his selenite treatment (three treatments with 28.2 mg selenite a day). A few hours after the first treatment, his primary tumor, localized behind his left eye, started to swell, producing a massive increase of his earlier modest exophthalmos. However, it returned to the earlier status after 1–2 days. This examination shows a general decrease of the FDG-uptake of the metastases, most evident in a large metastasis of the left liver lobe (arrow). (C) Toxicity of single or combined exposure of carboplatin and gemcitabine for 48 h to cells collected from pleural exudates from a patient. Fraction 1 indicates before selenite treatment and Fraction 2 indicates after selenite treatment. Data are presented as mean ± S.D. 160 × 143 mm (300 × 300 DPI).
Mentions: The antitumor effect was a secondary endpoint. Any antitumor effect described herein should be interpreted with precaution due inherent uncertainty associated with the limited number of patients on each dose level. Tumor size (RECIST) was evaluated before and after the selenite treatment and following subsequent chemotherapy treatment. The results from these measurements are presented in the waterfall plot (Figure 4A), suggesting no consistent effect of selenite treatment on the tumor volume. None of the patients had a complete or partial response immediately after respective treatments but 13 patients had a stable disease after selenite treatment and 16 patients after subsequent chemotherapy. Patient 4, who received a stent in the trachea and main bronchus to get relieved from the risk of compression-associated breathing difficulties a week before starting selenite treatment, had a stable disease with gradually improved response during the following six months. The tumor was undetectable half a year later as revealed by CT and a PET-CT examination. She is still alive without any recurrent tumor for more than six years.

Bottom Line: The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite.In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol.Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Karolinska Institutet, Karolinska University Hospital Södersjukhuset, SE-118 83 Stockholm, Sweden. ola.brodin@karolinska.se.

ABSTRACT

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients' refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits.

Materials and methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation.

Results and conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

No MeSH data available.


Related in: MedlinePlus