Ask the Hematologist January-February 2009

A 24-year-old woman with stage IVB Hodgkin lymphoma was severely ill with pain, nausea, vomiting, weight loss, and massive retroperitoneal disease. She did not have pulmonary function testing performed at baseline despite being advised to do so. After four cycles of ABVD (therefore eight doses of bleomycin 10 U/m² ), she is totally asymptomatic (no cough, no dyspnea), but her carbon monoxide diffusing capacity (DL_CO) is now approximately 50 percent of the normal predicted value, with the other pulmonary function tests in the normal range. Her doctor felt the best course of action was to give her another two cycles, including bleomycin, if she is clinically well and then retest her pulmonary function tests. He then asked:

1. Would you consider dose reduction of bleomycin at this time? If so, by how much? Would you consider 20 percent dose reduction going forward unless her pulmonary function tests deteriorate further or she becomes symptomatic?

2. Would you consider stopping chemotherapy after six cycles based on current data? I will certainly repeat her PET/CT scan after six cycles for any evidence of residual disease. I want to save the option of a marrow transplant if she needs it in the future.

The management of this patient nicely demonstrates the major challenge confronting each clinician treating Hodgkin lymphoma: how best to balance maximizing the likelihood of curing the disease while minimizing acute and late toxicity. I will address two of these issues: when to drop bleomycin from the chemotherapy and how to decide how many cycles of chemotherapy are necessary. Neither has been directly addressed by randomized clinical trials, so we must rely on clinical experience and reasonable extrapolation from past observations.

I have found the measurement of carbon monoxide diffusing capacity (DL_CO) to be of limited use in monitoring for bleomycin toxicity. Even after correction for hemoglobin level, which is usually necessary in patients receiving chemotherapy, the correlation between DLCO and acute or chronic bleomycin toxicity is poor and unreliable, with very low sensitivity (< 20%) and specificity (~80%).¹  Taking a careful history and monitoring the plain chest radiograph are much more reliable. My personal approach is to ask patients specifically about the presence of a persistent cough at the time of each visit and to perform a plain chest radiograph with every other cycle of chemotherapy. I do not routinely perform pulmonary function testing. If either an otherwise unexplained cough or fine streaking in the peripheral lung fields develops, I stop the bleomycin. By using this approach, at least three-fourths of patients complete their planned course of ABVD receiving full doses of bleomycin. Even when bleomycin is dropped, patients have usually received more than half of the full planned total dose.

Following such an approach for the approximately 80 patients we see each year, my colleagues and I in British Columbia have seen severe bleomycin toxicity in less than 1 percent of patients. Of course, one should not lightly drop a potentially important agent from curative chemotherapy, because doing so risks reducing the effectiveness of the treatment. However, limited observations support the hypothesis that omission of bleomycin from the latter courses of chemotherapy for Hodgkin lymphoma has little impact on outcome.²  Fortunately, randomized trials addressing the necessity of including bleomycin in ABVD are currently being conducted.

How many cycles of chemotherapy are enough? Three bodies of evidence are relevant. First, over the past four decades randomized trials have demonstrated that the total number of cycles of chemotherapy for advanced-stage Hodgkin lymphoma can be reduced to six to eight without compromising effectiveness.³  Second, other randomized trials have shown that adding further treatment, such as radiation⁴  or even high-dose chemotherapy and hematopoietic stem cell transplantation (HDC/HSCT), after a complete response has been obtained does not improve long-term outcome.⁵  Finally, functional imaging with positron emission tomography (PET/CT) has been shown to reliably distinguish between residual fibronecrotic masses and persistent viable Hodgkin lymphoma.⁶  Thus, once a complete response has been clearly established, further chemotherapy is unnecessary, provided a minimum of at least six cycles have been delivered, and we now have a tool that allows reliable identification of complete response.

Continue the bleomycin only if, on direct questioning, the patient has no cough and the chest radiograph shows no new fibrotic streaking in the peripheral lung. Have a low threshold for omitting it. Perform a PET/CT scan after six cycles of the ABVD, along with other planned reassessments. If there is no persistent lymphoma, I would stop treatment. If the PET/CT scan is still abnormal, other measures, including: observation, if the PET/CT results are indeterminate; radiation, if disease appears limited in extent; or HDC/HSCT, if persistent disease is documented by biopsy, need to be considered.