Hormones and Biological Agents

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Hormones and biological

agentsBy

Mosaad El Gammal

Lecturer of medical oncologyNCI

1/3/2010


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Hormones Several types of hormone-dependentcancer (especially breast, prostate,and endometrial cancer) respond to

treatment with their correspondinghormone antagonists. Other uses forsome hormonal therapies include thetreatment of paraneoplastic syndromes,such as carcinoid syndrome, andsymptoms caused by cancer, includinganorexia.


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Hormones

Estrogens:

Estrogens inhibit the effects of endogenous

androgens and androgen-dependent metastatic

prostatic carcinoma. Diethylstilbestrol is usually

the agent of choice.

Cardiac and cerebrovascular complications and

carcinoma of the male breast are potential adverseeffects.


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Hormones

Progenstins:

Progestins are useful in the management of

endometrial carcinoma and back-up therapy for

metastatic hormone-dependent breast cancer.


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Hormones

Androgens: Androgen activity in breast cancer is similar to

that of estrogens, perhaps for the same

mechanistic reasons. Virilizing effects and hepatic toxicity make them

unacceptable to most patients.

Fluoxymesterone is the most widely used agent.

Danazol has use in hematology in aplastic anemiaand congenital anemias.


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Hormones

Antiestrogen: Tamoxifen The only hormonal agent approved by the U.S. Food and

Drug Administration (FDA) for the prevention of

premenopausal breast cancer, the treatment of ductalcarcinoma in situ, and the treatment of surgically

resected premenopausal estrogen receptor (ER)positive

breast cancer. The most prominent toxicity from

tamoxifen is hot flashes, which affect approximately 50%

of women.


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Tamoxifen

Although the incidence of endometrial cancer in patients

receiving tamoxifen is increased, the absolute risk is

small and appears to be limited to mainly obese

postmenopausal women.Th

e annual incidence rate ofendometrial cancer in the United States is 1 per 1,000

postmenopausal women. For women receiving

tamoxifen, the increase in the incidence of endometrial

cancer is approximately 2.58 (ratio of incidence rates).

Uterine sarcoma, is also increased after tamoxifen use(approximately 15% of all uterine malignancies that

develop after tamoxifen use).


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Tamoxifen

Beneficial estrogenic effects fromtamoxifen include a decrease in totalcholesterol, the preservation of bone

density in postmenopausal women, andpossibly decreased cardiovasculardisease. In premenopausal women,however, tamoxifen has a negative effecton bone density, presumably because theestrogenic activity of tamoxifen on bone isless potent than that of natural estrogens.


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Tamoxifen Has Been the Standard of Care

1 year 2 years 5years

Recurrence reductions 21% 29% 47%

Mortality reductions 12% 17% 26%

Contra lateral breast

cancer reductions13% 26% 47%

MetaMeta--analysis ofanalysis of5555 trials and approximatelytrials and approximately 3030,,000000 women with ER+ tumors:women with ER+ tumors:

E B C T C G.E B C T C G. LancetLancet.. 19981998;;351351::14511451--14671467..

Fisher B et al.Fisher B et al. J Natl Cancer Inst.J Natl Cancer Inst. 20012001;;9393::684684--690690..


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Toremifene

Toremifene is an agent similar to tamoxifen.

It is available in the United States for the

treatment of patients with metastatic

breast cancer but is approved in other

countries for the adjuvant treatment of ER-

positive breast cancer.


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Fulvestrant

Fulvestrant is an ER antagonist that has no knownagonist activity and results in ER down-regulation.

Fulvestrant competitively binds to the ER but with amuch stronger affinity of approximately 100 times

greater than that of tamoxifen thus preventingendogenous estrogen from exerting its effect in targetcells.

Results from two phase III clinical trials have shownfulvestrant to be as effective as anastrozole in thetreatment of postmenopausal women with advancedhormone receptor positive breast cancer previouslytreated with antiestrogen therapy (mainly tamoxifen).


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Fulvestrant

In first-line hormone-responsive metastatic

breast cancer, a randomized phase III clinical

trial comparing tamoxifen to fulvestrant

demonstrated no differences in response or timeto progression.

Side effects; injection-site reactions and hot

flashes, asthenia, headache, and

gastrointestinal disturbances such as nausea,

vomiting, and diarrhea, with minor

gastrointestinal disturbances.


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Aromatase Inhibitors

Aromatase is the enzyme complex responsible for the

final step in estrogen synthesis via the conversion of the

androgens androstenedione and testosterone to the

estrogens estrone (E1) and E2.

The nonsteroidal aromatase inhibitors include fadrozole

(second generation), and anastrozole, and letrozole

(third generation).

The steroidal aromatase inhibitors {irreversible enzyme

inhibition } include formestane (second generation) and

exemestane (third generation).


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Aromatase Inhibitors

When compared to tamoxifen, both letrozole and

anastrozole have demonstrated superior response rates

and progression-free survival in the metastatic setting.

In the adjuvant setting, two adjuvant trials havedemonstrated superiority in terms of relapse-free

survivals of both anastrozole (ATAC) and letrozole (BIG

1-98). Additionally, anastrozole has been studied in a

sequential approach, and the sequence of tamoxifen

followed by anastrozole is superior to 5 years oftamoxifen alone.

The side effects of both anastrozole and letrozole are

similar and include arthralgias and myalgias, higher rate

of fracture, compared with the tamoxifen


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Gonadotropin-Releasing Hormone

Analogues (goserelin and leuprolide)

Gonadotropin-releasing hormone (GnRH) analoguesresult in a medical orchiectomy in men and are used asa means of providing androgen ablation for metastaticprostate cancer. Because the initial agonist activity of

GnRH analogues can cause a tumor flare fromtemporarily increased androgen levels, concomitant useof the antiandrogen flutamide has been used to preventthis effect.

GnRH analogues can also cause tumor regressions in

hormonally responsive breast cancers and havereceived FDA approval for the treatment of metastaticbreast cancer in premenopausal women.

Side effects;hot flashes, sweating, and nausea


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Antiandrogens

The antiandrogen flutamide is used in men withmetastatic prostate cancer either as initial therapy,combined with GnRH analogue administration, or whenthe metastatic prostate cancer is unresponsive, despite

androgen ablation therapy. In patients whose prostatecancer is growing despite flutamide use, stoppingflutamide can clearly cause a flutamide-withdrawalresponse.

Side effects; diarrhea, with or without abdominal

discomfort. Gynecomastia and hepatotoxicity. Bicalutamide is another nonsteroidal antiandrogen that

has been approved by the FDA and relatively welltolerated and is associated with a lower incidence ofdiarrhea than is flutamide


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Octreotide

Octreotide is a somatostatin analogue that is

administered for the treatment of carcinoid syndrome

and otherhormonal excess syndromes associated with

some pancreatic islet cell cancers and acromegaly.

Response rates (measured in terms of reduction in

diarrhea and flushing) are high and, on average, last for

several months, sometimes for years. Occasionally,

antitumor responses temporarily related to octreotide are

seen with these tumors. Octreotide may be useful to alleviate 5-fluorouracil

associated diarrhea.


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HormonesGlucocorticoids: They are integral components of curative therapy

for acute lymphoblastic leukemia, non-Hodgkins

lymphoma, and Hodgkins disease. Glucocorticoids have essential roles in the

prevention of allergic reaction, emesis control,relief of intracranial hypertension or spinal cord

compression in neurologic complications, and painrelief.


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I

mmunomodulating DrugsI

mmunomodulating Drugs

Immunosuppressive Agents:

Act to suppress immune mechanisms and are used

to treat autoimmune diseases or to prevent graft

rejection following tissue transplantation.

Ciclosporin, Tacrolimus, adrenocortical hormones,

antimetabolites, alkylating agent, antilymphocyte

globulin, Mycophenolate Mofetil


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Immunomodulating DrugsImmunomodulating Drugs

Immunopotentiator :

Enhance antitumor immunity and are used to treat

neoplastic disease. Recombinant Interferons and Cytokines.


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Interleukin-2 Therapy

Clinical trials using high-dose IL-2 was found to result inobjective tumor regression in 10% to 20% of melanomaand renal cancer patients. Almost half of the responsesare complete, and over 80% of these are ongoingbeyond 10 years.

Although the frequency of response is relatively low,response durations can be substantial and in manycases curative. These results led to the approval of IL-2by the Food and Drug Administration for the treatment ofpatients with metastatic melanoma and renal cancer.


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Interferon-

Properties; Antitumor, antiproliferative activity, inhibition

of angiogenesis, antivial activity, NK cell activation,

cytotoxic T-lymphocyte activation.

Indications;hairy cell leukemia, CML, myeloproliferativedisorders, cutaneous T-cell lymphomas, low-grade

lymphomas, and multiple myeloma.

Side effects; flulike symptoms, malaise, headache,

depression, bone marrow suppression, chronic fatigue


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Thank you

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Hormones and Biological Agents