By Joseph M. Connors, MD
Dr. Connors is Clinical Professor and Chair of the Lymphoma Tumor Group at the British Columbia Cancer Agency.
(Note: The original question was submitted to the Consult-a-Colleague Program and was adapted for print by Dr. Connors.)
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 (DLCO)
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:
- 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?
- 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
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 (DLCO)
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.
What Do I Recommend for the Described Patient?
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.
1. McKeage MJ, Evans BD, Atkinson C, et al. Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin lung. New Zealand Clinical Oncology Group. J Clin Oncol. 1990;8:779-83.
2. Canellos GP, Duggan D, Johnson J, et al. How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol. 2004;22:1532-3.
3. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327:1478-84.
4. Aleman BM, Raemaekers JM, Tirelli U, et al. Involved-field radiotherapy for advanced Hodgkin's lymphoma. New England Journal of Medicine. 2003;348:2396-406.
5. Carella AM, Bellei M, Brice P, et al. High-dose
therapy and autologous stem cell transplantation versus conventional
therapy for patients with advanced Hodgkin's lymphoma responding to
front-line therapy: long term results. Haematologica. 2008. [Epub ahead of print]
6. Panizo C, Pérez-Salazar M, Bendandi M, et al. Positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual Hodgkin's disease mediastinal masses. Leuk Lymphoma. 2004;45:1829-33.
does not recommend or endorse any specific tests, physicians, products,
procedures, or opinions, and disclaims any representation, warranty, or
guaranty as to the same. Reliance on any information provided in this
article is solely at your own risk.
back to top