Platinum Levels Linked to Toxicity in Testicular Cancer Survivors

CHICAGO – Long-term platinum exposure may explain higher rates of certain late adverse effects in men who have undergone treatment for testicular cancer, investigators reported based on a longitudinal study.

Among 96 consecutive men treated with cisplatin for testicular cancer, serum platinum levels 5 years later were 14% higher in those with elevated versus normal blood pressure and 16% higher in those with paresthesia versus those without it.

Dr. Hink Boer and his colleagues collected two or three serum samples and a 24-hour urine sample from the men at various time points after chemotherapy out to 13 years (median, 5 years) for platinum measurement.

The men had a median age of 29 years at the start of treatment, according to results reported in a poster presentation at the annual meeting of the American Society of Clinical Oncology. The median absolute cumulative cisplatin dose was 809 mg.

The findings are especially important as these survivors are young men who "have their whole life ahead of them, actually. Survivor care is very much focused on relapse detection, of course. In the last decade, I think there is more attention on the delayed effects," Dr. Boer, a research fellow in medical oncology at the University of Groningen in the Netherlands, said in an interview.

A population pharmacokinetic model using measured serum platinum concentration and urinary excretion rate, as well as administered cisplatin dosage, age, body surface area, height, and weight, suggested that the mean terminal half-life of platinum in serum was 3.7 years, Dr. Boer reported.

Platinum levels fell steadily and in exponential fashion with time after chemotherapy but were still detectable 13 years later. Serum platinum levels at 3 years and at 5 years after chemotherapy were significantly higher in men administered a higher total dose of cisplatin and in men having lower renal clearance, he said.

Analyses of long-term toxicity showed that, compared with their counterparts with lower blood pressure, men with a blood pressure of at least 130/85 mm Hg or on antihypertensive medication had higher mean serum platinum levels at 3 years (420 vs. 366 pg/g, P = .045) and at 5 years (210 vs. 185 pg/g, P = .04), as well as a higher platinum area under the curve (AUC) for years 1-5 (1,071 vs. 945 pg/g × 10³ × day, P = .04).

Similarly, compared with their counterparts who did not have paresthesia, men having this adverse effect had higher mean serum platinum levels at 3 years (456 vs. 387 pg/g, P = .02) and at 5 years (227 vs. 195 pg/g, P = .02), as well as a higher platinum AUC for years 1-5 (1,144 vs. 996 pg/g × 10³ × day, P = .02).

In contrast, men with secondary Raynaud disease and men with endothelial damage as assessed from von Willebrand factor levels did not have significantly higher serum platinum levels than their respective counterparts, Dr. Boer said.

"It is a well-known problem now that the chemotherapy has its late effects, and we wanted to look to see if these very small concentrations ... have any relationship with these late toxicities," he said. "If you look at these data, you could assume that there is a relationship, a very small concentration but still, it might have an effect."

"The chemotherapy is very successful, of course; you don’t want to change it. The cure rates are very high in testicular cancer patients," he added. "At the moment it is not possible to get the platinum out of the body. It is not technically possible to chelate it or something.

"But you have to think about it – it could be a mechanism, so it is worthwhile to do more studies on this. Perhaps in the future, it will be possible to chelate it and get it out, if we can confirm that this is really an etiological mechanism," he said.

Current practice at his institution for these patients is regular examinations with special focus on cardiovascular risk factors such as blood pressure and cholesterol. "We are trying to bring more structure in this care and to pay more attention to the late effects. I think [the patients] deserve it because they are so young," Dr. Boer said.

Discussant Dr. Kim Allyson Margolin of the University of Washington, Seattle, noted that accumulating research is casting doubt on the view that this chemotherapy has minimal late effects. However, despite the finding of an association between persistent free platinum and late toxicity, "we don’t know whether the relationship of prior platinum exposure, just by doses given or something different about how the body handles the platinum related to renal function or metabolic polymorphisms, is responsible"

The study is "very interesting and provocative," Dr. Margolin concluded, "but we need more data. Pharmacologic investigations are still needed to enhance the quality of life for this growing number of germ cell tumor survivors."

Although the study focused on serum, Dr. Boer noted that platinum can be found in other tissues as well. "In the ganglia, for example, and also in bone, fat, and the liver ... it’s ... not really known if the platinum in these body compartments is reactive or not. It is really a topic that deserves more research," he said.

Dr. Boer disclosed that he had no relevant conflicts of interest. Dr. Margolin disclosed that she is a consultant to Bristol-Myers Squibb, Genentech, and Johnson & Johnson.

CHICAGO – Long-term platinum exposure may explain higher rates of certain late adverse effects in men who have undergone treatment for testicular cancer, investigators reported based on a longitudinal study.

Among 96 consecutive men treated with cisplatin for testicular cancer, serum platinum levels 5 years later were 14% higher in those with elevated versus normal blood pressure and 16% higher in those with paresthesia versus those without it.

Dr. Hink Boer and his colleagues collected two or three serum samples and a 24-hour urine sample from the men at various time points after chemotherapy out to 13 years (median, 5 years) for platinum measurement.

The men had a median age of 29 years at the start of treatment, according to results reported in a poster presentation at the annual meeting of the American Society of Clinical Oncology. The median absolute cumulative cisplatin dose was 809 mg.

The findings are especially important as these survivors are young men who "have their whole life ahead of them, actually. Survivor care is very much focused on relapse detection, of course. In the last decade, I think there is more attention on the delayed effects," Dr. Boer, a research fellow in medical oncology at the University of Groningen in the Netherlands, said in an interview.

A population pharmacokinetic model using measured serum platinum concentration and urinary excretion rate, as well as administered cisplatin dosage, age, body surface area, height, and weight, suggested that the mean terminal half-life of platinum in serum was 3.7 years, Dr. Boer reported.

Platinum levels fell steadily and in exponential fashion with time after chemotherapy but were still detectable 13 years later. Serum platinum levels at 3 years and at 5 years after chemotherapy were significantly higher in men administered a higher total dose of cisplatin and in men having lower renal clearance, he said.

Analyses of long-term toxicity showed that, compared with their counterparts with lower blood pressure, men with a blood pressure of at least 130/85 mm Hg or on antihypertensive medication had higher mean serum platinum levels at 3 years (420 vs. 366 pg/g, P = .045) and at 5 years (210 vs. 185 pg/g, P = .04), as well as a higher platinum area under the curve (AUC) for years 1-5 (1,071 vs. 945 pg/g × 10³ × day, P = .04).

Similarly, compared with their counterparts who did not have paresthesia, men having this adverse effect had higher mean serum platinum levels at 3 years (456 vs. 387 pg/g, P = .02) and at 5 years (227 vs. 195 pg/g, P = .02), as well as a higher platinum AUC for years 1-5 (1,144 vs. 996 pg/g × 10³ × day, P = .02).

In contrast, men with secondary Raynaud disease and men with endothelial damage as assessed from von Willebrand factor levels did not have significantly higher serum platinum levels than their respective counterparts, Dr. Boer said.

"It is a well-known problem now that the chemotherapy has its late effects, and we wanted to look to see if these very small concentrations ... have any relationship with these late toxicities," he said. "If you look at these data, you could assume that there is a relationship, a very small concentration but still, it might have an effect."

"The chemotherapy is very successful, of course; you don’t want to change it. The cure rates are very high in testicular cancer patients," he added. "At the moment it is not possible to get the platinum out of the body. It is not technically possible to chelate it or something.

"But you have to think about it – it could be a mechanism, so it is worthwhile to do more studies on this. Perhaps in the future, it will be possible to chelate it and get it out, if we can confirm that this is really an etiological mechanism," he said.

Current practice at his institution for these patients is regular examinations with special focus on cardiovascular risk factors such as blood pressure and cholesterol. "We are trying to bring more structure in this care and to pay more attention to the late effects. I think [the patients] deserve it because they are so young," Dr. Boer said.

Discussant Dr. Kim Allyson Margolin of the University of Washington, Seattle, noted that accumulating research is casting doubt on the view that this chemotherapy has minimal late effects. However, despite the finding of an association between persistent free platinum and late toxicity, "we don’t know whether the relationship of prior platinum exposure, just by doses given or something different about how the body handles the platinum related to renal function or metabolic polymorphisms, is responsible"

The study is "very interesting and provocative," Dr. Margolin concluded, "but we need more data. Pharmacologic investigations are still needed to enhance the quality of life for this growing number of germ cell tumor survivors."

Although the study focused on serum, Dr. Boer noted that platinum can be found in other tissues as well. "In the ganglia, for example, and also in bone, fat, and the liver ... it’s ... not really known if the platinum in these body compartments is reactive or not. It is really a topic that deserves more research," he said.

Dr. Boer disclosed that he had no relevant conflicts of interest. Dr. Margolin disclosed that she is a consultant to Bristol-Myers Squibb, Genentech, and Johnson & Johnson.

CHICAGO – Long-term platinum exposure may explain higher rates of certain late adverse effects in men who have undergone treatment for testicular cancer, investigators reported based on a longitudinal study.

Among 96 consecutive men treated with cisplatin for testicular cancer, serum platinum levels 5 years later were 14% higher in those with elevated versus normal blood pressure and 16% higher in those with paresthesia versus those without it.

Dr. Hink Boer and his colleagues collected two or three serum samples and a 24-hour urine sample from the men at various time points after chemotherapy out to 13 years (median, 5 years) for platinum measurement.

The men had a median age of 29 years at the start of treatment, according to results reported in a poster presentation at the annual meeting of the American Society of Clinical Oncology. The median absolute cumulative cisplatin dose was 809 mg.

The findings are especially important as these survivors are young men who "have their whole life ahead of them, actually. Survivor care is very much focused on relapse detection, of course. In the last decade, I think there is more attention on the delayed effects," Dr. Boer, a research fellow in medical oncology at the University of Groningen in the Netherlands, said in an interview.

A population pharmacokinetic model using measured serum platinum concentration and urinary excretion rate, as well as administered cisplatin dosage, age, body surface area, height, and weight, suggested that the mean terminal half-life of platinum in serum was 3.7 years, Dr. Boer reported.

Platinum levels fell steadily and in exponential fashion with time after chemotherapy but were still detectable 13 years later. Serum platinum levels at 3 years and at 5 years after chemotherapy were significantly higher in men administered a higher total dose of cisplatin and in men having lower renal clearance, he said.

Analyses of long-term toxicity showed that, compared with their counterparts with lower blood pressure, men with a blood pressure of at least 130/85 mm Hg or on antihypertensive medication had higher mean serum platinum levels at 3 years (420 vs. 366 pg/g, P = .045) and at 5 years (210 vs. 185 pg/g, P = .04), as well as a higher platinum area under the curve (AUC) for years 1-5 (1,071 vs. 945 pg/g × 10³ × day, P = .04).

Similarly, compared with their counterparts who did not have paresthesia, men having this adverse effect had higher mean serum platinum levels at 3 years (456 vs. 387 pg/g, P = .02) and at 5 years (227 vs. 195 pg/g, P = .02), as well as a higher platinum AUC for years 1-5 (1,144 vs. 996 pg/g × 10³ × day, P = .02).

In contrast, men with secondary Raynaud disease and men with endothelial damage as assessed from von Willebrand factor levels did not have significantly higher serum platinum levels than their respective counterparts, Dr. Boer said.

"It is a well-known problem now that the chemotherapy has its late effects, and we wanted to look to see if these very small concentrations ... have any relationship with these late toxicities," he said. "If you look at these data, you could assume that there is a relationship, a very small concentration but still, it might have an effect."

"The chemotherapy is very successful, of course; you don’t want to change it. The cure rates are very high in testicular cancer patients," he added. "At the moment it is not possible to get the platinum out of the body. It is not technically possible to chelate it or something.

"But you have to think about it – it could be a mechanism, so it is worthwhile to do more studies on this. Perhaps in the future, it will be possible to chelate it and get it out, if we can confirm that this is really an etiological mechanism," he said.

Current practice at his institution for these patients is regular examinations with special focus on cardiovascular risk factors such as blood pressure and cholesterol. "We are trying to bring more structure in this care and to pay more attention to the late effects. I think [the patients] deserve it because they are so young," Dr. Boer said.

Discussant Dr. Kim Allyson Margolin of the University of Washington, Seattle, noted that accumulating research is casting doubt on the view that this chemotherapy has minimal late effects. However, despite the finding of an association between persistent free platinum and late toxicity, "we don’t know whether the relationship of prior platinum exposure, just by doses given or something different about how the body handles the platinum related to renal function or metabolic polymorphisms, is responsible"

The study is "very interesting and provocative," Dr. Margolin concluded, "but we need more data. Pharmacologic investigations are still needed to enhance the quality of life for this growing number of germ cell tumor survivors."

Although the study focused on serum, Dr. Boer noted that platinum can be found in other tissues as well. "In the ganglia, for example, and also in bone, fat, and the liver ... it’s ... not really known if the platinum in these body compartments is reactive or not. It is really a topic that deserves more research," he said.

Dr. Boer disclosed that he had no relevant conflicts of interest. Dr. Margolin disclosed that she is a consultant to Bristol-Myers Squibb, Genentech, and Johnson & Johnson.