Page 985 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 54 Cancer Chemotherapy 971

immunoglobulin) that allows the total body burden of tumor cells BREAST CANCER
to be quantified. Multiple myeloma principally involves the bone
marrow and bone, causing bone pain, lytic lesions, bone fractures, STAGE I & STAGE II DISEASE
and anemia as well as an increased susceptibility to infection.
Most patients with multiple myeloma are symptomatic at the The management of primary breast cancer has undergone a
time of initial diagnosis and require treatment with cytotoxic remarkable evolution as a result of major efforts at early diagnosis
chemotherapy. Treatment with the combination of the alkylating (through encouragement of self-examination as well as through
agent melphalan and prednisone (MP protocol) has been a stan- the use of cancer detection centers) and the implementation of
dard regimen for nearly 30 years. About 40% of patients respond combined modality approaches incorporating systemic chemo-
to the MP combination, and the median duration of remission is therapy as an adjuvant to surgery and radiation therapy. Women
2–2.5 years. with stage I disease (small primary tumors and negative axillary
In patients who are considered candidates for high-dose ther- lymph node dissections) are currently treated with surgery alone,
apy with stem cell transplantation, melphalan and other alkylating and they have an 80% chance of cure.
agents are to be avoided, as they can affect the success of stem cell Women with node-positive disease have a high risk of both
harvesting. local and systemic recurrence. Thus, lymph node status directly
Thalidomide is a well-established agent for treating refractory or indicates the risk of occult distant micrometastasis. In this situa-
relapsed disease, and about 30% of patients will achieve a response tion, postoperative use of systemic adjuvant chemotherapy with
to this therapy. More recently, thalidomide has been used in com- six cycles of cyclophosphamide, methotrexate, and fluorouracil
bination with dexamethasone, and response rates approaching 65% (CMF protocol) or of fluorouracil, doxorubicin, and cyclo-
have been observed. Studies are now under way to directly compare phosphamide (FAC) has been shown to significantly reduce
the combination of vincristine, doxorubicin, and dexamethasone the relapse rate and prolong survival. Alternative regimens with
(VAD protocol) with the combination of thalidomide and dexa- equivalent clinical benefit include four cycles of doxorubicin
methasone. In some patients, especially those with poor perfor- and cyclophosphamide and six cycles of fluorouracil, epirubicin,
mance status, single-agent pulse dexamethasone administered on a and cyclophosphamide (FEC). Each of these chemotherapy
weekly basis can be effective in palliating symptoms. Lenalidomide regimens has benefited women with stage II breast cancer with
and pomalidomide are two immunomodulatory analogs (IMiDs) one to three involved lymph nodes. Women with four or more
of thalidomide. Lenalidomide is approved in combination with involved nodes have had limited benefit thus far from adjuvant
dexamethasone for multiple myeloma patients who have received at chemotherapy. Long-term analysis has clearly shown improved
least one prior therapy, and clinical data show that this combination survival rates in node-positive premenopausal women who have
is effective as first-line therapy. Pomalidomide is the most recent been treated aggressively with multiagent combination chemo-
IMiD to receive approval, and this drug may be able to overcome therapy. The results from three randomized clinical trials clearly
resistance to thalidomide and lenalidomide. The side-effect profiles show that the addition of trastuzumab, a monoclonal antibody
of these IMiDs appear to be similar, although neurotoxicity is directed against the HER-2/neu receptor, to anthracycline- and
observed more commonly with thalidomide, somewhat less often taxane-containing adjuvant chemotherapy benefits women with
with pomalidomide, and rarely with lenalidomide. HER-2-overexpressing breast cancer with respect to disease-free
Bortezomib was first approved for use in relapsing or refractory and overall survival.
multiple myeloma and is now widely used as first-line therapy. This Breast cancer was the first neoplasm shown to be responsive
agent is thought to exert its main cytotoxic effects through inhibition to hormonal manipulation. Tamoxifen is beneficial in postmeno-
of the 26S proteosome, resulting in downregulation of the nuclear pausal women when used alone or in combination with cytotoxic
factor kappa B (NF-κB) signaling pathway, which is thought to be chemotherapy. The present recommendation is to administer
a major signaling pathway for this disease. Of note, inhibition of tamoxifen for 5 years of continuous therapy after surgical resec-
NF-κB has also been shown to restore chemosensitivity. One poten- tion. Longer durations of tamoxifen therapy do not appear to offer
tial advantage of bortezomib is that it can be administered by the additional clinical benefit. Postmenopausal women who complete
intravenous or subcutaneous route. Carfilzomib is an epoxyketone 5 years of tamoxifen therapy should be placed on an aromatase
26S proteosome inhibitor that is approved for patients with multi- inhibitor such as anastrozole for at least 2.5 years, although the
ple myeloma who have received at least two prior therapies, includ- optimal duration is unknown. In women who have completed
ing bortezomib and an immunomodulatory agent. This agent is 2–3 years of tamoxifen therapy, treatment with an aromatase
important as it is able to overcome resistance to bortezomib, and inhibitor for a total of 5 years of hormonal therapy is now recom-
preclinical and clinical studies suggest that it has broad-spectrum mended (see Chapter 40).
activity in hematologic malignancies and solid tumors. Ixazomib Results from several randomized trials for breast cancer
is the newest proteosome inhibitor to be approved in multiple have established that adjuvant chemotherapy for premenopausal
myeloma, and in contrast to the other proteosome inhibitors, it women and adjuvant tamoxifen for postmenopausal women are
is orally administered with good oral bioavailability. This agent of benefit to women with stage I (node-negative) breast cancer.
can cause peripheral sensory neuropathy, but it is also associated While this group of patients has the lowest overall risk of recur-
with GI toxicity in the form of diarrhea and nausea and vomiting, rence after surgery alone (about 35–50% over 15 years), this risk
thrombocytopenia, and hepatotoxicity. can be further reduced with adjuvant therapy.