February 21, 2011 (Orlando, Florida) — In patients taking bleomycin for germ cell tumors, the use of lung function testing to monitor for drug-induced pneumonitis is controversial. A new study suggests that the 25% reduction in lung function scores currently used is too cautious a threshold for discontinuing bleomycin, especially in patients with lung metastases.
The study was presented here at the 2011 Genitourinary Cancers Symposium by Baerin Houghton, MD, from the University of Sydney, in News South Wales, Australia.
"This is an extremely important study," said Alan Horwich, MD, from the Royal Marsden Hospital in London, United Kingdom, who was approached for outside comment. "It takes a toxicity that everybody's anxious about — a common concern about a rare but serious complication — and it investigates it and confronts some of the blind prejudices that exist about the use of this important drug in testicular cancer, relative to its toxicity in the lung."
Dr. Horwich said that severe bleomycin lung toxicity is "terrifying to physicians and to patients alike," because it has the potential to cause toxic death in patients who would otherwise likely be cured of the disease at a young age. "It's a particularly unpleasant death, with progressive loss of respiratory function that seems to get worse, despite intensive ventilation support."
Lung Function Testing
"The use of lung function testing to monitor for drug-induced pneumonitis is controversial in patients taking bleomycin for germ cell tumors," study author Dr. Houghton explained to Medscape Medical News in an interview.
It's entirely understandable that clinicians are wary of overdosing patients with bleomycin, Dr. Houghton said, adding that "testicular cancers are generally very curable, so the last thing you want to do is kill someone with pulmonary toxicity."
Still, he noted, bleomycin is a key agent in combating testicular cancer, and when used, it's important to make the most of its therapeutic potential.
"Ours was a phase 2 feasibility study of accelerated bleomycin with etoposide and cisplatin in 30 patients [mean age, 28 years] with advanced germ cell tumors," Dr. Houghton said. Patients with measurable disease were stratified using International Germ Cell Cancer Consensus Classification criteria.
For patients deemed to have intermediate- or poor-risk disease, 12 weekly doses of bleomycin were planned. Patients assessed to be at good risk were scheduled to receive 9 doses.
Dr. Houghton conceded that in accelerating the chemotherapy regimen, he and his colleagues were acutely aware of the potential for triggering pulmonary toxicity. For that reason, patients were monitored very closely, with twice-weekly assessments.
"As part of the study design, bleomycin was to be stopped if patients exhibited clinical or x-ray evidence of pulmonary toxicity, or if they showed a 25% or greater reduction in lung function, as measured by DLCO [diffusion limitation for carbon monoxide] or [forced vital capacity]," Dr. Houghton said.
Therapy with bleomycin was also to be discontinued if glomerular filtration rates fell below 35 mL/min.
"We looked at the number of patients who were able to get two thirds of their planned bleomycin doses, as well as patients who were not," Dr. Houghton said. "Our reasoning was that patients who were not able to take at least two thirds of their doses might not be getting a sufficient dose to treat their disease."
A Third of Patients Undertreated
About 80% of planned bleomycin doses were administered. Of the 75 doses (20%) that were omitted in 15 patients, the omission in all cases was the result of a greater than 25% drop in DLCO.
The investigators report that 16 of the patients experienced a 10% to 24% reduction in DLCO, but in no case was the reduction greater than 35%. Declines in forced vital capacity were less than 10% in all patients.
Of particular note, Dr. Houghton said, no patient developed any other evidence of pulmonary toxicity.
Patients who had lung metastases (10 of 30) were 2.5 times as likely to have a greater than 25% drop in DLCO, and were 4 times as likely to receive less than two thirds of their planned dose of bleomycin.
"Of the 30 patients, a third received less than their planned dose of bleomycin," Dr. Houghton said. "In all cases, the reason for not reaching their therapeutic goals was because of an asymptomatic decline in their DLCO reading. Clinically isolated, however, there was no evidence of pneumonitis."
"The point of our study, I think, is that DCLO, used in isolation, may not be such a good tool to screen for development of bleomycin induced pneumonitis," he said. He stressed, however, that the results from this small study need to be validated in larger controlled trials.
Extremely Interesting
On reviewing the study, Dr. Horwich said that it's clear from these results that DLCO alone is not a reliable indicator of pulmonary toxicity.
"This is an extremely important study, because people all over the world are using DLCO to measure the pulmonary effects of bleomycin dosing. This study clearly shows that they're fooling themselves," he said.
Dr. Houghton and Dr. Horwich have disclosed no relevant financial relationships.
2011 Genitourinary Cancers Symposium (GUCS): Abstract 227. Presented February 18, 2011.
The study was presented here at the 2011 Genitourinary Cancers Symposium by Baerin Houghton, MD, from the University of Sydney, in News South Wales, Australia.
"This is an extremely important study," said Alan Horwich, MD, from the Royal Marsden Hospital in London, United Kingdom, who was approached for outside comment. "It takes a toxicity that everybody's anxious about — a common concern about a rare but serious complication — and it investigates it and confronts some of the blind prejudices that exist about the use of this important drug in testicular cancer, relative to its toxicity in the lung."
Dr. Horwich said that severe bleomycin lung toxicity is "terrifying to physicians and to patients alike," because it has the potential to cause toxic death in patients who would otherwise likely be cured of the disease at a young age. "It's a particularly unpleasant death, with progressive loss of respiratory function that seems to get worse, despite intensive ventilation support."
Lung Function Testing
"The use of lung function testing to monitor for drug-induced pneumonitis is controversial in patients taking bleomycin for germ cell tumors," study author Dr. Houghton explained to Medscape Medical News in an interview.
It's entirely understandable that clinicians are wary of overdosing patients with bleomycin, Dr. Houghton said, adding that "testicular cancers are generally very curable, so the last thing you want to do is kill someone with pulmonary toxicity."
Still, he noted, bleomycin is a key agent in combating testicular cancer, and when used, it's important to make the most of its therapeutic potential.
"Ours was a phase 2 feasibility study of accelerated bleomycin with etoposide and cisplatin in 30 patients [mean age, 28 years] with advanced germ cell tumors," Dr. Houghton said. Patients with measurable disease were stratified using International Germ Cell Cancer Consensus Classification criteria.
For patients deemed to have intermediate- or poor-risk disease, 12 weekly doses of bleomycin were planned. Patients assessed to be at good risk were scheduled to receive 9 doses.
Dr. Houghton conceded that in accelerating the chemotherapy regimen, he and his colleagues were acutely aware of the potential for triggering pulmonary toxicity. For that reason, patients were monitored very closely, with twice-weekly assessments.
"As part of the study design, bleomycin was to be stopped if patients exhibited clinical or x-ray evidence of pulmonary toxicity, or if they showed a 25% or greater reduction in lung function, as measured by DLCO [diffusion limitation for carbon monoxide] or [forced vital capacity]," Dr. Houghton said.
Therapy with bleomycin was also to be discontinued if glomerular filtration rates fell below 35 mL/min.
"We looked at the number of patients who were able to get two thirds of their planned bleomycin doses, as well as patients who were not," Dr. Houghton said. "Our reasoning was that patients who were not able to take at least two thirds of their doses might not be getting a sufficient dose to treat their disease."
A Third of Patients Undertreated
About 80% of planned bleomycin doses were administered. Of the 75 doses (20%) that were omitted in 15 patients, the omission in all cases was the result of a greater than 25% drop in DLCO.
The investigators report that 16 of the patients experienced a 10% to 24% reduction in DLCO, but in no case was the reduction greater than 35%. Declines in forced vital capacity were less than 10% in all patients.
Of particular note, Dr. Houghton said, no patient developed any other evidence of pulmonary toxicity.
Patients who had lung metastases (10 of 30) were 2.5 times as likely to have a greater than 25% drop in DLCO, and were 4 times as likely to receive less than two thirds of their planned dose of bleomycin.
"Of the 30 patients, a third received less than their planned dose of bleomycin," Dr. Houghton said. "In all cases, the reason for not reaching their therapeutic goals was because of an asymptomatic decline in their DLCO reading. Clinically isolated, however, there was no evidence of pneumonitis."
"The point of our study, I think, is that DCLO, used in isolation, may not be such a good tool to screen for development of bleomycin induced pneumonitis," he said. He stressed, however, that the results from this small study need to be validated in larger controlled trials.
Extremely Interesting
On reviewing the study, Dr. Horwich said that it's clear from these results that DLCO alone is not a reliable indicator of pulmonary toxicity.
"This is an extremely important study, because people all over the world are using DLCO to measure the pulmonary effects of bleomycin dosing. This study clearly shows that they're fooling themselves," he said.
Dr. Houghton and Dr. Horwich have disclosed no relevant financial relationships.
2011 Genitourinary Cancers Symposium (GUCS): Abstract 227. Presented February 18, 2011.
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