According to data from three major retrospective studies, it appears that some Hodgkin's lymphoma patients who are on bleomycin‐containing chemotherapy regimens are at high risk for pulmonary toxicity. When the lung problems appear, these patients' overall survival decreases and they die sooner than patients who have not had bleomycin.
But if bleomycin is deleted from the chemotherapy regimen, patients' chances of overall and progression‐free survival return to that of those not on the drug.
‘The major impact on outcome was related to acute pulmonary death, with six out of seven deaths in the bleomycin pulmonary toxicity group resulting from the pulmonary toxicity. All six patients died within nine months of their Hodgkin's diagnosis’
In 1964, the outlook for Hodgkin's lymphoma patients took a sharp turn upward with the discovery of an effective chemotherapy combination: mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). When it became the standard treatment, complete response rates were 84%, with long‐term survival rates of 66%.
This was good but not good enough, so in the early 1970s, relapsed and refractory patients were given the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Trials showed that this regimen as first‐line treatment was at least as effective as MOPP or MOPP/ABV(D) combinations ‐ but with a better long‐term toxicity profile. ABVD is now the standard treatment for Hodgkin's lymphoma.
Dr Stephen Ansell, associate professor at Mayo College of Medicine, and senior author of a study in the October 20 issue of Journal of Clinical Oncology (2005; 23: 7614‐7620), explains that using bleomycin, an anti‐tumour antibiotic, in the combination was based on singleagent activity in previous lymphoma trials
But the drug has significant adverse events, especially bleomycin pulmonary toxicity (BPT) in Hodgkin's lymphoma, which can occur in up to 46% of patients, with mortality as high as 27%.
Previous studies reported that certain factors increased the risk of this toxicity: being over the age of 40 (a rate three times higher for patients over 40 compared with younger ones), renal insufficiency, radiation, underlying lung disease, a history of smoking, and first‐line support with granulocyte colony‐stimulating factor (G‐CSF).
‘We therefore specifically studied these factors but did not find them to be significant as a risk for BPT in our patient cohort’, Dr Ansell says.
Neither did any of these factors have an effect on other clinical outcomes such as complete response, overall survival, and progression‐free survival.
Bleomycin increases costs
The distinct possibility of bleomycin toxicity, even if it never occurs, significantly increases the cost of treating Hodgkin's lymphoma. This is because of the pulmonary function studies and other surveillance techniques that need to be used to detect this toxic effect early enough for treatment to be effective, Dr Ansell points out.
There is no specific treatment for bleomycin pulmonary toxicity, but corticosteroids are generally given and bleomycin is removed from the chemotherapy regimen.
If the toxicity does develop, chemotherapy dose intensity can be compromised, and treatment might have to be delayed. The effect this has on outcome is unclear, which is why Dr Ansell and colleagues set about their study.
In the study (first author William Martin), the researchers searched the Mayo Clinic database for all patients with a diagnosis of Hodgkin's lymphoma between 1986 and 2003. Of the 942 patients found, 141 were treated with bleomycin‐containing chemotherapy. The mean bleomycin dose was 84 mg/m2, with a range of 20 to 180 mg/m2. However, the dose had no effect on overall or progression‐free survival.
Of the 141 patients treated with bleomycin, 25 of them (18%) developed bleomycin pulmonary toxicity. Seven died (6 from BPT, and one from the Hodgkin's itself).
There was no significant difference in the treatment of BPT between the patients who died of it and those who survived, but it is noteworthy that all who died were over the age of 40, and they all died quickly ‐ within nine months of the Hodgkin's diagnosis.
It is also worth pointing out that patients who survived bleomycin toxicity were as likely as patients who did not get it to survive their Hodgkin's lymphoma.
When 31 of the 141 patients (22%) had bleomycin omitted from their chemotherapy regimen at any time, their response and survival rates were the same as all other patients.
Regardless of the chemotherapy regimen used to treat Hodgkin's lymphoma, bleomycin has almost always been a component, Dr Ansell points out.
The response rates, regardless of regimen, are more than 90%, and the five‐year survival rate exceeds 70%. Serious toxicity is thus a major issue.
Detrimental effect on survival
This JCO study was the first to demonstrate a detrimental effect on five‐year survival rates in Hodgkin's patients who develop BPT ‐ a reduction from 90% to 63%. The authors did observe a higher rate of bleomycin pulmonary toxicity in patients on first‐line ABVD compared with those receiving MOPP‐ABV(D), although the reasons are unknown.
‘To definitively prove that bleomycin can be excluded from these regimens, you would have to do a randomised study comparing a regimen with bleomycin with one without it. The data in our manuscript provide the rationale for doing such a trial’
‘One could hypothesize that a larger exposure to bleomycin in patients treated with ABVD alone might incite more pulmonary toxicity’, Dr Ansell says. ‘Alternatively, drugs incorporated in MOPP, such as prednisone, might be protective in patients treated with the combination.’
Dr Ansell also points out a possible synergistic effect between bleomycin and G‐CSF in promoting pulmonary toxicity. Bleomycin binds to DNA and produces free radicals which then cause DNA strand leaks and cell death.
Although the exact mechanism is unknown, it seems that bleomycininduced cell injury in the lung stimulates an inflammatory response and an increase in cytokine production, he says, and thus, a statistically significant increase in risk of the toxicity in Hodgkin's patients treated with G‐CSF.
Leaving bleomycin out of the therapy had no effect on outcome in this study.
‘In 31 patients who had bleomycin omitted from their chemotherapy, response rates remained equal to the rates for patients administered full‐dose bleomycin,’ Dr Ansell and his team report.
Thus, in terms of Hodgkin's lymphoma outcome, it does not seem to matter whether or not patients take bleomycin.
Two Cancer and Leukaemia Group B trials reported similar results. Forty out of 363 patients in both trials received bleomycin as part of standard treatment, but discontinued it because of bleomycin toxicity.
Of those 40 patients, five discontinued in the first two cycles, nine in the third, 12 in the fourth, 11 in the fifth, and three after the fifth cycle.
The response to Hodgkin's lymphoma therapy was the same as for those who received bleomycin: 90% and 91%, respectively.
‘Dr Ansell also points out a possible synergistic effect between bleomycin and G‐CSF in promoting pulmonary toxicity. Bleomycin binds to DNA and produces free radicals which then cause DNA strand leaks and cell death’
Why use bleomycin at all?
In a letter published in an earlier issue of JCO (2004; 22: 1532‐1533), Dr George Canellos and three colleagues also point out the pulmonary toxicity caused by bleomycin. The risk necessitates frequent assessment of pulmonary function during the course of treatment, and there is also an increased cost and inconvenience, they write.
They recommend that when pulmonary symptoms are found, bleomycin should be stopped.
‘This suggests that bleomycin may have a limited role in the ABVD regimen and can be discontinued with impunity in the event of pulmonary complications,’ the letter points out.
Dr George Canellos, founding chief of medical oncology and senior physician at Dana‐Farber Cancer Institute, questions the benefit of using bleomycin in Hodgkin's lymphoma therapy and says that bleomycin's role in treatment is diminishing ‐ and should be. ‘It would be good just to eliminate it’, he said.
When OT asked Dr Ansell a similar question, he replied that this study was a retrospective analysis. ‘To definitively prove that bleomycin can be excluded from these regimens, you would have to do a randomized study comparing a regimen with bleomycin with one without it. The data in our manuscript provide the rationale for doing such a trial.’
‘In terms of Hodgkin's lymphoma outcome, it does not seem to matter whether or not patients take bleomycin’
But he said he knows of no such trial now ongoing or planned for the near future.
© 2005 Lippincott Williams & Wilkins, Inc.