A Textbook of Clinical Pharmacology and Therapeutics

INTERFERON-ALFA 2B
Interferon-alfa 2b is a glycoprotein (molecular weight
15–27.6 kDa) produced by recombinant expression in E. coli.
It is used in the treatment of hairy cell leukaemia, refractory
chronic myeloid leukaemia, advanced malignant melanoma
and follicular lymphoma. Interferons bind to specific cell surface
receptors which initiate intracellular events relating to
effects on RNA and protein synthesis. Such processes include
enzyme induction, inhibition of cell proliferation enhancement
of immune effector cells, such as macrophage phagocytic activity
and cytotoxic T lymphocytes. Interferons are administered
subcutaneously. Pegylated formulations allow once weekly
administration. Common adverse effects include flu-like illnesses,
fatigue, myalgias and arthralgias, injection site reactions,
rashes. Less frequent side effects are hypotension, cardiac
failure and CNS effects (memory loss and depression). Chronic
interferon therapy may downregulate CYP450s involved in
drug metabolism and lead to drug toxicity, e.g to theophylline.
Other immunostimulatory drugs that have been used with
some success include thalidomide, which has anti-angiogenesis
properties and decreases TNF production (effective in refractory
malignant myeloma), and levamisole (as an adjuvant for
colon cancer). The optimal use of tumour vaccines is still being
actively researched.
Case history
A 19-year-old white male presented with palpable lumps
on both sides of his neck and profuse sweating at night.
Lymph node biopsy and computed tomography (CT) scanning
yielded a diagnosis of stage IVb Hodgkin’s disease. He
was started on combination chemotherapy with doxorubicin
60 mg/m 2 , bleomycin 10 units/m 2 , vinblastine 5 mg/m 2
and dacarbazine 100 mg (ABVD). After four cycles of
chemotherapy, he developed abdominal pain that was
found to be due to acute appendicitis and he underwent
emergency appendicectomy and made a good recovery.
Four days after completing his fifth cycle of ABVD treatment
he noted increased dyspnoea on exertion. This progressed
over 48 hours to dyspnoea at rest. Physical
examination revealed cyanosis. There was no palpable cervical
lymphadenopathy, but he had a sinus tachycardia and
bilateral basal and mid-zone late inspiratory crackles.
Further investigations revealed normal haemoglobin,
white blood count and platelets, normal coagulation
screen, PO 2 on air 50 mmHg and fluffy interstitial infiltrates
in both lower- and mid-lung fields on chest x-ray.
Pulmonary function tests showed an FEV 1/FVC ratio of
80%, reduced FVC and a DL CO of 25% of the predicted
value. Bronchoalveolar lavage fluid was negative for bacterial,
viral and fungal pathogens, including Pneumocystis
carinii.
DRUGS USED IN CANCER CHEMOTHERAPY 385
Question
What was the cause of this patient’s respiratory problems?
How should he be treated?
Answer
In this patient, the possible causes of such pulmonary symptoms
and radiographic findings include opportunistic infection,
pulmonary oedema (secondary to fluid overload),
pulmonary haemorrhage, progression of disease or druginduced
interstitial alveolitis. Here, with the exclusion of a
haemorrhagic diathesis and pulmonary infection, no fluid
overload and apparent regression of his cervical lymphadenopathy,
the probable diagnosis is bleomycin-induced
interstitial pneumonitis. Although the patient had not
received more than 300 units of bleomycin, it is likely that
during his operation he received high inspired oxygen
concentrations, and this could have put him at higher
risk of developing ‘bleomycin lung’. Currently, he should
receive the lowest inspired oxygen concentration that
will yield a PO 2 of �60 mmHg. Glucocorticosteroid therapy
may be of benefit, but the syndrome may not be fully
reversible. Bleomycin, and other cytotoxic agents which
cause a pneumonitis (e.g. cyclophosphamide, busulfan,
carmustine, methotrexate and mitomycin) and radiation
therapy (which can exacerbate bleomycin pulmonary
toxicity), should not be used for this patient’s future
therapy.
FURTHER READING AND WEB MATERIAL
Baker SD, Grochow LB. Pharmacology of cancer chemotherapy in the
older person. Clinics in Geriatric Medicine 1997; 13: 169–83.
Chabner BA, Longo DL. Cancer chemotherapy and biotherapy, 2nd edn.
Philadelphia: Lippincott-Raven, 1996.
Douglas JT. Cancer gene therapy. Technology in Cancer Research and
Treatment 2003; 2: 51–64.
Frei E. Curative cancer chemotherapy. Cancer Research 1985; 45:
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Kim R, Emi M, Tanabe K et al. The role of apoptotic or nonapoptotic
cell death in determining cellular response to anticancer treatment.
European Journal of Surgical Oncology 2006; 32: 269–77.
Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy.
New England Journal of Medicine 2005; 353: 172–87.
Mooi WJ, Peeper DS. Oncogene-induced cell senescence – halting on
the road to cancer. New England Journal of Medicine 2006; 355:
1037–46.
O’Driscoll L, Clynes M. Biomarkers and multiple drug resistance in
breast cancer. Current Cancer Drug Targets 2006; 6: 365–84.
Yong WP, Innocenti F, Ratain MJ. The role of pharmacogenetics in
cancer therapeutics. British Journal of Clinical Pharmacology 2006;
62: 35–46.
Useful websites: American Society of Clinical Oncology, www.asco.org;
National Cancer Institute of America, www.cancer.gov.