384 CANCER CHEMOTHERAPY
OESTROGENS
Oestrogens are little used in the current management of pro-
static carcinoma, because of the availability of gonadotrophin-
releasing hormone (GnRH) analogues to suppress testosterone.
ANTI-OESTROGENS
Therapy for hormone receptor-positive breast cancers includes
the use of selective oestrogen receptor modulators (SERM),
selective oestrogen receptor downregulators (SERD) and aro-
matase inhibitors.
Selective oestrogen receptor modulators (SERMs)
and selective oestrogen receptor downregulators
(SERDs)
Tamoxifen(Chapter 41) is the lead compound in the SERM
class (others include raloxifene). It is used to treat oestrogen
receptor-positive breast cancer and may be used as prophy-
laxis against breast cancer in high-risk patients. It is given
orally once or twice a day and metabolized by CYP2D6 and 3A
to active metabolites (e.g. endoxifen). Tamoxifenand its
metabolites are competitive inhibitors of oestrogen binding to
its receptor. Adverse effects include hot flushes, hair loss, nau-
sea and vomiting, menstrual irregularities, an increased inci-
dence of thrombo-embolic events, and a two- to three-fold
increased incidence of endometrial cancer in post-menopausal
women.
Fulvestrantis one example of the SERD class. It purport-
edly has an improved safety profile, faster onset and longer
duration of action than SERMs. It is given as a monthly injec-
tion. Common adverse effects are nausea, fatigue, injection
reactions and hot flushes.
Aromatase inhibitors
This class of agents, for example anastrazole(letrozole), is
used to treat early and advanced-stage oestrogen receptor-
positive breast cancer. Original members of this class were
aminoglutethimide andformestane.Anastrazoleis given
orally and metabolized by CYP3A and glucuronidation to
inactive metabolites. Anastrazoleacts by reversibly binding
to the haem moiety of the CYP19 gene product. This is the aro-
matase enzyme responsible in many tissues (including breast
tissue) for converting androstenedione and testosterone to
oestrogen. Adverse effects are less frequent than with tamoxi-
fen, but include hot flushes, menstrual irregularities,
thrombo-embolic events and endometrial cancer.
PROGESTOGENS
Endometrial cells normally mature under the influence of
progestogens and some malignant cells that arise from the
endometrium respond in the same way. About 30% of patients
with disseminated adenocarcinoma of the body of the uterus
respond to a progestogen, such as megestrol. Progestogen
bound to its receptor impairs the regeneration of oestrogen
receptors and also stimulates 17-β-oestradiol dehydrogenase,
the enzyme that metabolizes intracellular oestrogen. These
actions may deprive cancer cells of the stimulatory effects of
oestrogen. There is also probably a direct cytotoxic effect at high
concentrations. Other progestogens that are used include
norethisteroneandhydroxyprogesterone. There are no import-
ant toxic effects of progestogens that are relevant to cancer
chemotherapy (Chapter 41).GLUCOCORTICOSTEROIDS
Glucocorticosteroids (see Chapters, 33, 40 and 50) are cyto-
toxic to lymphoid cells and are combined with other cytotoxic
agents to treat lymphomas and myeloma, and to induce
remission in acute lymphoblastic leukaemia.HORMONAL MANIPULATION THERAPY IN ADVANCED
PROSTATE CANCER
In advanced prostate cancer, manipulation of the androgen
environment of the tumour cells can control the disease.
Gonadotrophin-releasing hormone (GnRH) analogues (long-
acting preparations of drugs, such as leuprolide/goserelin
(Chapter 42) initially stimulate and then reduce pituitary
FSH/LH release. These desensitize and suppress testosterone
production and have superseded the use of oestrogens to antag-
onize the androgen dependency of prostate cancer cells. They
are given with an androgen receptor antagonist (e.g. flutamide,
bicalutamide,cyproterone) to block the intracellular receptors
for dihydrotestosterone and prevent flare of the disease.
Aminoglutethimide(an aromatase inhibitor) and high-dose
ketoconazole (Chapter 45) block the synthesis of testicular
testosterone, adrenal androgens and other steroids. They are
given orally to patients with refractory prostate cancer.BIOLOGICAL RESPONSE MODIFIERSThese agents influence the biological response to the tumour.
They may act indirectly to mediate anti-tumour effects, e.g
stimulate the immune response against the transformed neo-
plastic cells or directly on the tumour (e.g. by modulating
tumour differentiation). Drugs with proven anti-cancer clinical
efficacy in this class are interleukin-2andinterferon-alfa 2b.INTERLEUKIN-2 (ALDESLEUKIN)
Interleukin-2(IL-2,aldesleukin) is a human recombinant form
of the native IL-2 produced by T helper cells. It differs from
nativeIL-2in that it is not glycosylated, has no terminal alanine
and a serine substituted at amino acid 125. It is used to treat
metastatic malignant melanoma and renal cell carcinoma. In
these patients with advanced cancer, response rates of as high as
20–30%, with durable complete responses in 5–10% have been
observed.IL-2is not a direct cytotoxic, but it induces/expands
cytolytic T cells against tumours. It is administered intra-
venously. Toxicity is the major determinant of the duration of
treatment. Common toxicities are often dose-limiting due to the
activation of T cells and release of other cytokines (TNF, inter-
leukins and interferon). They include hypotension, capillary
leak syndrome with pulmonary oedema, cardiac dysrhythmias,
prerenal uraemia, abnormal transaminases, anaemia-thrombo-
cytopenia, nausea, vomiting, diarrhoea, confusion, rashes and
fever.