The Treatment of Metastatic
`Breast Cancer
`
`Ernest J. Greenberg, MD
`
`Introduction
`Fifty percent of all women who have had
`breast cancer will eventually develop me(cid:173)
`tastases, a stage at which the disease is
`seldom curable. Metastatic breast cancer
`may affect any tissue in the body. I The
`duration of the' 'free interval, " the interval
`between the initial diagnosis of breast can(cid:173)
`cer and the detection of the first metastasis,
`is extremely variable. Adjuvant chemo(cid:173)
`therapy is frequently given as part of the
`primary treatment of breast cancer. As
`early as 1958, some of the first National
`Surgical Adjuvant Breast and Bowel
`Project (NSABP) trials demonstrated that
`adjuvant chemotherapy could increase both
`disease-free and overall survival. 2-4 Scan(cid:173)
`dinavian studies with more than 15 years of
`follow-up confirmed these findings. 5 In
`spite of this, the total mortality from meta(cid:173)
`static disease remains unchanged. Treat(cid:173)
`ment of advanced breast cancer is therefore
`of major importance in the management of
`this disease.
`The aspects to be considered in treating
`metastatic breast cancer are the timing and
`selection of therapy, based on both the dis(cid:173)
`ease and the individual patient, and the
`management of complications, both of the
`cancer and the treatment.
`
`Treatment Considerations
`
`Timing
`In selecting the best time to start treat(cid:173)
`ment, the clinician should evaluate the site
`of metastatic involvement, the patient's
`symptoms, the apparent growth rate of the
`tumor, the extent of disease, and the pa(cid:173)
`tient's hormone-receptor status. For exam(cid:173)
`ple,
`totally asymptomatic osteoblastic
`metastases found incidentally during the
`clinical evaluation of a postmenopausal
`woman with hormone-receptor-positive
`breast cancer may remain stable for
`months and sometimes years without any
`treatment.
`
`Characteristics of the Cancer
`Locoregional recurrences, solitary metas(cid:173)
`tases, and metastases involving particular
`organs or locations may require specific
`local treatment in addition to systemic ther(cid:173)
`apy. 6 Such local therapy may include
`surgery, radiotherapy, regional chemo(cid:173)
`therapy, and embolization, alone or in
`combination.
`Certain biological characteristics, such
`as the hormone-receptor status, free inter(cid:173)
`val, extent of tumor dissemination, major
`tissues affected, and estimated rate of
`growth, may also help in the selection of
`the treatment.
`
`Dr. Greenberg is Associate Attending Physician
`in the Department of Medicine at Memorial
`Sloan-Kettering Cancer Center in New York,
`New York.
`
`Patient Characteristics
`Certain preexisting medical problems may
`contraindicate specific treatment options or
`
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`
`indicate the need for very close monitoring.
`These include hypertension, diabetes mel(cid:173)
`litus, peptic ulcer, and certain psychiatric
`states that may be exacerbated by steroid
`agents. Cardiac and pulmonary conditions
`may increase the hazards associated with
`anthracyclines, cyclophosphamide, and
`methotrexate. Similarly, impaired renal or
`hepatic function may limit the dosage or
`even the use of certain cytotoxic agents.
`Advanced age and a frail general condition
`may impose limitations on the use or opti(cid:173)
`mal intensity of cytotoxic regimens, thus
`limiting treatment to palliation.
`
`Complications of the Disease
`Complications related to the disease can
`include mechanical problems, such as path(cid:173)
`ologic fractures of long bones; effusions in
`serous cavities (such as the pleura, pericar(cid:173)
`dium, and peritoneum); and compression
`or obstruction of important vascular,
`neurologic, gastrointestinal, urinary, or
`respiratory structures. Possible complica(cid:173)
`tions of the cancer also include metabolic
`problems, of which hypercalcemia is the
`most common in breast cancer.
`
`Complications of Treatment
`Bone marrow suppression with leukopenia
`and thrombocytopenia is the most common
`complication of chemotherapy and seldom
`requires specific management other than in
`the context of trials of intensive chemo(cid:173)
`therapy with autologous bone marrow
`transplantation rescue. The most common
`metabolic problems are those related to the
`exacerbation of diabetes and to electrolyte
`disturbances caused by corticosteroids.
`Cardiovascular complications include in(cid:173)
`creased Jtypertension due to steroid hor(cid:173)
`mones and toxic cardiomyopathy due to
`anthracyclines. While hypertension is man(cid:173)
`ageable, cardiomyopathy can be progres(cid:173)
`sive and severely disabling. In dealing with
`treatment-related complications in general,
`anticipation, early detection, and, if possi(cid:173)
`ble, prevention constitute the best ap(cid:173)
`proach.
`Treatment selection requires the fol(cid:173)
`lowing preliminary information:
`
`• A complete chrono! gic history of the
`cancer. in luding e a.lu3tion of the free in(cid:173)
`terval; ioft rmali 0 nb UI the hormone(cid:173)
`tumor
`receptor status of the primary
`and, whenever available, of any recently
`biopsied metastatic tumor; and information
`about the menstrual status of the patient.
`• A detailed previous history and com(cid:173)
`plete systems review.
`• A careful evaluation of the patient's
`symptoms, including their location, dura(cid:173)
`tion, and progression.
`• An evaluation of the extent of metas(cid:173)
`tases based on physical examination; blood
`tests (including tumor markers such as car(cid:173)
`cinoembryonic antigen [CEA] and CAI5-
`3); chest x-ray; bone scan; and spot x-ray
`of areas seen as abnormal on the scan, liver
`scan, or computed tomography (CT). The
`value of routine initial brain CT, however,
`is still open to question.
`
`With the increasing
`effectiveness of systemic
`therapy more patient
`are ur " ring long enough lo
`manifest a late incidence of
`cerebral meta ta e '.
`
`• Careful questioning of the patient and
`review of records to obtain information
`about previous treatment, including re(cid:173)
`sponse and specific details about any radio(cid:173)
`therapy, such as the dose and the areas
`treated.
`This basic information oot only helps
`determine the choice of systemic therapy
`and prognosis but also establishes a base(cid:173)
`line for evaluation of the response to the
`next treatment. For example, a slow pro(cid:173)
`gression of symptoms in a postmenopausal
`woman with a hormone-receptor-positive
`cancer, which is mainly skeletal in distri(cid:173)
`bution, indicates a high likelihood of re(cid:173)
`sponse to hormonal treatment. In a pre(cid:173)
`menopausal woman, a slow progression of
`symptoms may be a good indication for
`bilateral oophorectomy.
`The use of bone x-ray films in addition
`to bone scan will help to evaluate the status
`
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`
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`of these metastatic lesions. While they may
`appear similar on bone scan, they may be
`either osteoblastic, osteolytic, or mixed on
`x-ray films. A change in appearance from
`osteolytic to osteoblastic under treatment
`usually signifies healing, although the le(cid:173)
`sions may look more intense on the bone
`scan. 7 Such an increase in intensity may
`also occur if the lesion progresses and be(cid:173)
`comes osteolytic on x-ray. Therefore,
`while bone scan is extremely sensitive for
`the detection of bony metastases, x-ray
`should be used as a complementary evalu(cid:173)
`ation technique.
`The blood tests performed reflect ab(cid:173)
`normalities of function of different tissue
`systems - the blood count reflecting the
`bone marrow; and the serum chemistries
`reflecting liver function, bone tissue activ(cid:173)
`ity, renal function, and other metabolic
`
`There i no single
`parameter that will b
`itself determine regres ion
`arre t, or progrc ion of
`metastatic brea l caD er.
`
`changes. These changes, however, are not
`specific for cancer and may only indicate
`the possibility that a problem exists in one
`or more given organs. Abnormal levels of
`CEA and CA 15-3 usually indicate the pres(cid:173)
`ence of active breast cancer. While the sen(cid:173)
`sitivity of these tests is limited, their speci(cid:173)
`ficity makes them useful in the evaluation
`and follow-up of the course ofthe disease.
`With the increasing effectiveness of
`systemic therapy, more patients are surviv(cid:173)
`ing long enough to manifest late incidence
`of cerebral metastases. Some of these me(cid:173)
`tastases remain silent for undetermined pe(cid:173)
`riods of time before signs and symptoms
`become apparent, usually confirmed by a
`brain CT. It is not known, therefore,
`whether earlier detection and treatment of
`such lesions would favorably influence sur(cid:173)
`vival and quality of life.
`In summary, there is no single parame(cid:173)
`ter that will by itself determine regression,
`
`arrest, or progression of metastatic disease.
`The early detection of the metastatic spread
`of breast cancer must therefore be based on
`a multimodal diagnostic plan.
`While it stands to reason that the
`smaller the tumor burden (that is, the earlier
`the detection of metastatic disease), the
`more effective the treatment, proof of this
`thesis is lacking. 8
`There is still no valid evidence that
`treatment of asymptomatic metastatic
`breast cancer results in any advantage in
`quality of life or overall survival. It is un(cid:173)
`clear whether this is because the usual
`present method of search for metastases
`results in the detection of only the more
`advanced stages of this disease. The ques(cid:173)
`tions remain: Could more frequent, more
`intense, or more specific and sensitive diag(cid:173)
`nostic tests result in much earlier diagnosis,
`and could earlier treatment change the
`spectrum of this disease?
`Once metastatic disease is discovered
`and it is determined that treatment is indi(cid:173)
`cated, a decision must be made about the
`most appropriate therapy.
`Endocrine Therapy
`The growth and clinical course of breast
`cancer is frequently influenced by the hor(cid:173)
`monal milieu of the patient. This fact was
`known long before the discovery of hor(cid:173)
`mone receptors. Indeed, until the early
`1960s, endocrine treatment was the major
`effective therapy for metastatic breast can(cid:173)
`cer and its potential effectiveness was
`based entirely on clinical criteria: patients
`whose metastatic disease was limited in
`extent, was mostly osseous, and occurred
`after a long free interval were known to
`have a high likelihood of response.
`The development of methods that could
`determine the presence and concentration
`of estrogen receptor (ER) and progesterone
`receptor (PR) in breast cancer tissue9 im(cid:173)
`proved the selection of patients who could
`best benefit from endocrine therapy. It was
`observed that patients with breast cancer
`known to have a relatively high concen(cid:173)
`tration of ER and/or PR (i.e., who were
`hormone-receptor-positive) had a better
`prognosis. lO• 11 These women generally
`responded well to endocrine therapy, 12
`
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`while the converse was also true-i.e., pa(cid:173)
`tients whose breast cancers were hormone(cid:173)
`receptor-negative generally did not have
`much of a response to endocrine therapy.
`The higher the hormone-receptor concen(cid:173)
`tration, the greater the response. 13.14
`
`Tamoxifen
`Tamoxifen is the initial treatment of choice
`in postmenopausal patients with metastatic
`breast cancer that
`is either hormone(cid:173)
`receptor-positive or has a clinical course
`indicative of potential hormone responsive(cid:173)
`ness. Tamoxifen therapy induces remission
`in 40 to 80 percent of such patients. 13 Some
`reports indicate results in premenopausal
`women similar to those obtained with
`oophorectomy. 15,16
`The optimal dose in postmenopausal
`women is 10 mg orally twice a day. In
`premenopausal women, the optimal dose
`might be higher, since higher levels of es(cid:173)
`trogens may displace tamoxifen from the
`receptor sites in tumor tissue.
`The side effects of tamoxifen include
`initiation or worsening of the menopausal
`syndrome- hot flashes, atrophic vaginitis,
`dryness of mucous membranes (including
`dryness ofthe mouth and conjuctivae), and
`sometimes depression. Occasionally, vagi(cid:173)
`nal bleeding may occur. Tamoxifen has,
`however, been reported to have a protective
`effect against osteoporosis. 17 Anorexia and
`nausea are rare and, when they do occur,
`mild and transient. Rarely, prolonged ad(cid:173)
`ministration of tamoxifen has been reported
`to produce retinal changes with visual im(cid:173)
`pairment. There may be also an increased
`risk of venous thrombosis . 18
`Transient exacerbation of symptoms of
`metastases may occur during the first two
`to three weeks of treatment but should not
`cause it to be interrupted. Hypercalcemia is
`a rare complication of treatment with ta(cid:173)
`moxifen. An increased incidence of en(cid:173)
`dometrial cancer has been reported in
`women maintained on prolonged treatment
`with this medication. 19.20 These reports,
`however, have not been confirmed by any
`of the NSABP trials and should not limit
`the duration of use of tamoxifen in patients
`with metastatic breast cancer, where the
`
`actuality of the disease completely oversha(cid:173)
`dows the potential risk of the treatment.
`Careful regular gynecologic examinations
`should be maintained, and periodic endo(cid:173)
`metrial biopsies may be recommended in
`addition to the usual cytologic examina(cid:173)
`tions of the vaginal and cervical smears.
`
`Bilateral Oophorectomy
`Bilateral oophorectomy is mainly used for
`the initial treatment of hormone-receptor(cid:173)
`positive metastatic breast cancer in pre(cid:173)
`menopausal women. The surgery carries a
`low morbidity and mortality. Its effect is
`rapid. The procedure never exacerbates the
`metastatic disease, and its major side ef(cid:173)
`fects are due to the induction of premature
`menopause, which must be considered an
`expected effect of the surgery rather than a
`toxic side effect. Bilateral oophorectomy
`
`The earl detection of
`metastatic pread of
`breast cancer must be
`based on a muJtimodal
`diagnostic plan.
`
`induces a remission of metastatic disease in
`about 50 to 60 percent of appropriately se(cid:173)
`lected patients with ER-positive breast can(cid:173)
`cer.21 The combination of oophorectomy
`and cortisone has been reported to improve
`response,22 presumably through suppres(cid:173)
`sion of adrenocortical estrogen precursors.
`
`Progestins
`Two progestins have been used extensively
`in recent years: medroxyprogesterone ace(cid:173)
`tate (standard dose of 400 mg intramus(cid:173)
`cularly daily) and megesterol acetate
`(standard dose of 160 mg orally daily). In
`randomized trials, these agents appear to
`be equally effective23 when used as initial
`treatment. Larger doses may sometimes
`produce a response when standard doses
`remain ineffective. 24-26
`Progestins almost always cause weight
`gain27 and sometimes sodium and fluid re(cid:173)
`tention . These agents may also cause vagi-
`
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`nal bleeding while taken and, more fre(cid:173)
`quently, after cessation of treatment.
`Estrogens
`Since the advent of tamoxifen, estrogens
`are seldom used in the treatment of meta(cid:173)
`static breast cancer. The most common es(cid:173)
`trogen used was diethylstilbestrol. Estro(cid:173)
`gen therapy of breast cancer is associated
`with a high incidence of serious side ef(cid:173)
`fects-fluid retention, mastalgia, throm(cid:173)
`boembolic manifestations, vaginal bleed(cid:173)
`ing, and occasional stimulation of the
`growth of the metastases, sometimes with
`hypercalcemia. In a patient who has failed
`to respond to initial and secondary endo(cid:173)
`crine therapy for metastatic breast cancer,
`the markedly reduced response rate to ter(cid:173)
`tiary endocrine treatment no longer war-
`
`till no alid
`There i
`c\'idence that treatment of
`asymptomatic metastatic
`br a t cancer re ul
`in any
`adv8nta e in qualil nife or
`o\'eralJ urvival.
`
`rants the relatively high incidence of poten(cid:173)
`tially serious side effects associated with
`estrogens. This is particularly true of el(cid:173)
`derly postmenopausal women with late(cid:173)
`stage disease for whom estrogens had tra(cid:173)
`ditionally been the treatment of choice.
`Androgens
`Although less effective than other forms of
`endocrine therapy, androgens are still used
`for the treatment of women with hormone(cid:173)
`sensitive breast cancer. The use of andro(cid:173)
`gens, however, has also decreased mark(cid:173)
`edly since the development of tamoxifen.
`The most commonly used androgen is
`fluoxymesterone, which is administered
`mostly as a tertiary form of treatment in
`combination with cytotoxic agents
`in
`women with osseous metastases. It is also
`useful in myelophthisic anemia. The major
`side effects are related to masculiniza(cid:173)
`tion-loss of scalp hair, hirsutism of the
`body and face , deepening of the voice, cli-
`
`toral hypertrophy, and increased libido.
`Auid retention and hypercholesterolemia
`are frequent. When fluoxymesterone is ef(cid:173)
`fective in causing regression of metastases,
`it also increases the feeling of well-being
`associated with a slight rise in the red blood
`cell count and an increase in muscle mass.
`This agent is effective in about 20 percent
`of patients but is also associated with a risk
`of occasional stimulation of the growth of
`metastases and of hypercalcemia.
`Aminoglutethimide
`Aminoglutethimide inhibits steroidogene(cid:173)
`sis in the adrenal cortex as well as aromati(cid:173)
`zation of androgens to estrogens in periph(cid:173)
`eral tissues. 28 Because the optimal dose of
`250 mg four times daily causes adrenocor(cid:173)
`tical insufficiency, patients must therefore
`receive replacement doses of hydrocorti(cid:173)
`sone of either 20 to 40 mg per day or the
`maximum that would not cause the devel(cid:173)
`opment of Cushing's syndrome . Lesser
`doses of aminoglutethimide (250 mg twice
`a day) without hydrocortisone have been
`reported to be as effective as the larger
`doses in inducing remission of metastatic
`breast cancer.29 This may indicate that the
`agent's major mode of action is through
`aromatase inhibition in peripheral tissues .
`is used
`While amino glutethimide
`mostly as second-line hormonal treatment
`in postmenopausal women, it has been re(cid:173)
`ported to be as effective as tamoxifen as
`primary therapy. 30 Because of its toxic side
`effects, however, aminoglutethimide can(cid:173)
`not be considered a primary treatment in
`the sequence of endocrine therapies. These
`side effects include somnolence, some(cid:173)
`times severe, and a drug rash that occurs in
`about 30 percent of patients and may be
`transient but is sometimes persistent, pro(cid:173)
`gressive, and increasingly severe enough to
`necessitate cessation of treatment. Nausea
`and hepatic dysfunction can also some(cid:173)
`times limit the use of this agent. The effec(cid:173)
`tiveness of aminoglutethimide is markedly
`decreased in postmenopausal women when
`it follows a previous treatment that in(cid:173)
`cluded prolonged administration of predni(cid:173)
`sone with resultant marked suppression of
`adrenocortical function and very low cir(cid:173)
`culating levels of estrogen. 31
`
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`Ketoconazole
`Ketoconazole is an antifungal agent that
`was also found to reversibly suppress
`adrenocortical function. 32 This drug has
`been reported to be capable of inducing
`remissions of metastatic breast cancer. The
`major side effects are nausea and vomiting.
`Hepatic toxicity does occur but has not
`been a significant problem when ketocona(cid:173)
`zole is used for adrenocortical suppres(cid:173)
`sion. 33
`
`LHRH Analogues
`The two major luteinizing hormone-releas(cid:173)
`ing hormone (LHRH) analogues employed
`are leuprolide and buserelin. These agents
`inhibit the production of luteinizing hor(cid:173)
`mone (LH) and follicle-stimulating hor(cid:173)
`mone (FSH) and consequently inhibit ovar(cid:173)
`ian function. Leuprolide and buserelin have
`been reported to be capable of inducing
`remission of metastatic breast cancer. 34- 36
`The use of leuprolide was shown to induce
`remissions of metastatic breast cancer in 44
`percent of premenopausal women in one
`study35 and 39 percent of postmenopausal
`women in another. 36 Since leuprolide may
`initially cause transient ovarian stimula(cid:173)
`tion, combination with tamoxifen may in(cid:173)
`crease estrogenic blockade and be the
`equivalent of oophorectomy in premeno(cid:173)
`pausal women.
`
`Bilateral Adrenalectomy and
`Hypophysectomy
`Bilateral adrenalectomy and hypophysec(cid:173)
`tomy have been very effective in the past
`for the treatment of metastatic breast can(cid:173)
`cer, with response rates ranging from 20 to
`50 percent depending on the sites of in(cid:173)
`volvement. 37 .38 These procedures, how(cid:173)
`ever, have now been replaced by the non(cid:173)
`surgical forms of adrenal and pituitary
`suppression described above, which have
`increased response rates due to better pa(cid:173)
`tient selection and with neither the opera(cid:173)
`tive risk nor the risks and problems associ(cid:173)
`ated with the sequelae of permanent, major
`endocrine deprivation.
`
`Combination of Hormonal Agents
`With the exception of combined tamoxifen
`and prednisone, combinations of hormonal
`agents have not generally improved the re(cid:173)
`sults of hormonal therapy in metastatic
`breast cancer. 39.40
`
`Cytotoxic Chemotherapy
`Cytotoxic agents kill cells by interfering
`with DNA synthesis. Consequently, they
`should be most effective against rapidly
`proliferating cancer cells. The best indica(cid:173)
`tions for their initial application should be
`for the treatment of non-hormone-depend(cid:173)
`ent breast cancer, in patients who have
`failed to respond to or have exhausted their
`response to hormonal therapy, and in those
`
`Tamo ifen i the initiaJ treatment
`of h ice in p
`tmcDopau al
`pati nt with metasC.atic bre
`cancer that is either hormone(cid:173)
`recepLor-positi e or that has a
`clinical cour e indicati,'e of
`potential hormone re pon i\'en
`
`t
`
`with rapidly progressive visceral involve(cid:173)
`ment by metastases. The best responses,
`however, have been in patients with a long
`free interval, limited extent of disease, and
`a good performance index. The most effec(cid:173)
`tive cytotoxic drugs are cyclophospha(cid:173)
`mide, methotrexate, 5-fiuorouracil (5FU),
`and doxorubicin. The treatment proto(cid:173)
`cols most commonly used are outlined in
`Table 1.
`Each of these agents given alone is ca(cid:173)
`pable of inducing regression of metastatic
`breast cancer. 41 - 45 Methotrexate has a par(cid:173)
`ticular application in the treatment of men(cid:173)
`ingeal carcinomatosis from breast cancer. 46
`In this clinical setting, methotrexate is ad(cid:173)
`ministered intrathecally via an indwelling
`reservoir.
`The feasibility and improved effective(cid:173)
`ness of combinations of cytotoxic drugs
`was first reported in 1963 by Greenspan
`et a1. 47 In 1969, Cooper reported the re-
`
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`
`TABLE 1
`CYTOTOXIC CHEMOTHERAPY REGIMENS COMMONLY USED
`IN METASTATIC BREAST CANCER
`
`CMF
`
`Cyclophosphamide
`Methotrexate
`5-FU
`
`CAF
`
`Cyclophosphamide
`Doxorubicin
`5-FU
`
`FAC
`
`5-FU
`Doxorubicin
`Cyclophosphamide
`
`100 mg/m2/day orally days 1-14/28 days
`40 mg/m2 IV days 1 and 8128 days
`500 mg/m21V days 1 and 8128 days
`
`100 mg/m2/day orally days 1-14/28 days
`30 mg/m2 IV days 1 and 8128 days
`500 mg/m2 IV days 1 and 8128 days
`
`400 mg/m2 IV days 1 and 8128 days
`40 mg/m21V day 1128 days
`400 mg/m2 IV day 1128 days
`
`CMFVP ("Cooper")
`
`(Many modifications of this regimen)
`
`Cyclophosphamide
`Methotrexate
`5-FU
`Vincristine
`Prednisone
`
`VATH
`Vinblastine
`Doxorubicin
`Thiotepa
`Ha!otestin
`
`2 mg/kg/day orally
`0.7 mglkg/week IV X 8 weeks, then every other week
`12 mglkgiweek IV X 8 weeks, then every other week
`35 mcglkg/weeK IV X 4-5 weeks, Ihen every other week
`0.75 mglkg/day reduced gradually
`
`4.5 mg/m2 IV every 21 days
`45 mg/m2 IV every 21 days
`12 mg/m2 IV every 21 days
`30 mg orally dally
`
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`
`suits of treatment with a combination that
`included cyclophosphamide, methotrex(cid:173)
`ate, 5FU, vincristine, and prednisone
`(CMFVP) ,48 which became a standard
`combination from which other variations
`were developed. At present, the two major
`groups of cytotoxic drug combinations
`used in the treatment of metastatic breast
`cancer are those including doxorubicin,
`such as CAF (cyclophosphamide-doxorub(cid:173)
`icin-5FU) or CAFVP (CAF-vincristine(cid:173)
`prednisone), and those that do not, such as
`CMF or CMFVP. Combinations that in(cid:173)
`clude doxorubicin have been reported to be
`more effective than those that do not. 49 This
`occurs, however, at the price of potential
`myocardial toxicity, which limits the total
`dose of the drug that can be safely admin(cid:173)
`istered.
`Other toxic manifestations of cytotoxic
`drugs (Table 2) are similar for most com(cid:173)
`binations and include possible amenorrhea
`in premenopausal women, bone marrow
`depression, nausea, vomiting, diarrhea,
`mucositis, and hair loss to the point of alo(cid:173)
`pecia, particularly with doxorubicin. Cy(cid:173)
`clophosphamide may cause chemical cys(cid:173)
`titis. The vinca alkaloids, vincristine and
`vinblastine, may cause peripheral and auto(cid:173)
`nomic neuropathy. Weight gain is very
`common during chemotherapy in spite of
`gastrointestinal toxicity. Most of these
`toxic side effects are controllable with
`proper oral hygiene, antiemetics, high in(cid:173)
`take of fluids, properly selected diet, and
`antidiarrheals. Cardiac and pulmonary
`toxicities from doxorubicin, cyclophos(cid:173)
`phamide, and methotrexate are best pre(cid:173)
`vented by attention to dosage and treatment
`schedule, or controlled by early recognition
`of the problem and timely cessation of the
`causative agent. As noted, certain degrees
`of renal, hepatic, or cardiac dysfunctions
`may preclude the use or limit the dosage of
`one or more of these drugs. Previous irra(cid:173)
`jiation to the left side of the chest wall may
`also require dose limitation of doxorubicin
`jue to the increased potential for cardio(cid:173)
`myopathy.
`Prednisone, when included in any of
`:he above-mentioned treatment regimens,
`Ippears to slightly improve the response
`'ate and duration. 50.51 A previous history of
`
`peptic ulcer, diabetes, hypertension, or
`psychosis, however, may limit the use of
`prednisone. A previous history or evidence
`of prior tuberculous infection may require
`tuberculosis prophylaxis. The advantage of
`combining cytotoxic chemotherapy with
`hormonal treatment has been investigated.
`There is some indication that the addition
`of tamoxifen may improve treatment re(cid:173)
`sults,52 but these findings have not been
`universally confirmed.
`
`Duration of Treatment
`It is generally agreed that treatment,
`whether with hormonal or nonhormonal
`agents, should be maintained long enough
`to establish either a favorable response or a
`failure to respond. This may take eight to
`
`Bilateral oophor ctomy
`ion of meta tatic
`iodu
`a remi
`disea e inabout SO t 60
`percent of appropriately
`leeted premenopnu aJ
`ith ER-positive
`women
`breast cancer.
`
`12 weeks. In case offailure-i.e., progres(cid:173)
`sion of the metastatic process-the treat(cid:173)
`ment should be changed. In case of arrest,
`symptomatic control, and/or regression of
`metastatic lesions, treatment should be
`maintained at least until all evidence of
`disease has resolved (complete response)
`or until the disease has stabilized after re(cid:173)
`gressing (partial response).
`Thereafter, there is no uniform agree(cid:173)
`ment on how to proceed, how long to main(cid:173)
`tain treatment, or when or whether to stop.
`The results of one study suggest that, in
`those who respond to chemotherapy, con(cid:173)
`tinued treatment for six months may be
`sufficient if the disease has stabilized. 53
`Treatment may be resumed when the dis(cid:173)
`ease shows evidence of reactivation. The
`alternative would be to maintain treatment
`until relapse and then to change to another
`
`IOL. 41, NO.4 JULY/AUGUST 1991
`
`249
`
`NOVARTIS EXHIBIT 2068
`Par v Novartis, IPR 2016-00084
`Page 8 of 15
`
`

`
`~
`
`()
`
`~ ,.
`() ,.
`z
`m " ~ o c
`~ ,.
`r
`Cl
`" () c z
`ij
`j;
`i1i
`
`TABLE 2
`TOXICITY OF COMMONLY USED CYTOTOXIC AGENTS
`IN METASTATIC BREAST CANCER
`
`Dermatologlc
`
`Oral
`
`Eye
`
`Heart
`
`Lungs
`
`Gastro-
`intestinal
`
`liver
`
`Genlto-
`urinary
`
`Hemato-
`logic
`
`Neurologic Hormonal
`
`Radiation
`Recall
`
`Poss
`
`Poss
`
`Pass
`
`Poss
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Cll(
`
`MTX
`
`5-FU
`
`Do,
`
`VCR
`
`VLB
`
`TT
`
`M~o
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`CTX: Cyclophosphamide
`MTX: Methotrexate
`5-FU: S·Auorouracil
`Dox: Doxorubicin
`VCR: VIncristine
`
`VLB: Vinblastine
`TT: Thiotepa
`M~o : Mitomycin C
`Pass: Possibly
`
`NOVARTIS EXHIBIT 2068
`Par v Novartis, IPR 2016-00084
`Page 9 of 15
`
`

`
`combination of antineoplastic drugs. While
`this is relatively well tolerated with hor(cid:173)
`monal agents, the continuous administra(cid:173)
`tion of some cytotoxic agents may increase
`the rate and severity of some toxic compli(cid:173)
`cations and interfere with the patient's
`quality of life. Such decisions should be
`individualized based upon the patient's
`clinical course.
`
`Secondary and Later Therapy
`A response to secondary chemotherapy can
`be induced after relapse. If the relapse oc(cid:173)
`curs while the patient is under treatment, a
`different drug regimen must be used. If the
`relapse occurs more than six months after
`cessation of chemotherapy, the same drugs
`may induce another remission.
`Secondary and subsequent treatment
`regimens may be administered as a single
`drug or as combinations of several cyto(cid:173)
`toxic agents. In patients not previously
`treated with doxorubicin, that drug alone or
`in combination with cyclophosphamide
`and 5FU (CAF), or with vinblastine, thi(cid:173)
`otepa, and fluoxymesterone (H = Halotes(cid:173)
`tin) (V A TH)54 have been reported to be
`very effective ill inducing another remis(cid:173)
`sion. Other medications that may be given
`alone or in combination, by rapid or contin(cid:173)
`uous infusion, are mitomycin C, vinblas(cid:173)
`tine, mitoxantrone, vindesine, and cispla(cid:173)
`tin. 55-60 More intensive chemotherapy with
`increased dosages,61.62 as well as such
`combinations with citrovorum rescue and
`close supportive care, have resulted in fur(cid:173)
`ther remissions of metastatic disease.
`Several trials are under way combining
`intensive cytotoxic drug therapy and au(cid:173)
`tologous bone marrow
`transfusion . 63
`While these combinations hold the poten(cid:173)
`tial for greater cytocidal effect on the neo(cid:173)
`plastic tissue, they are still associated with
`severe toxicity and significant mortality.
`The response rates are high, but the long(cid:173)
`term results are unknown. In order to be
`effective, this form of treatment must be
`applied early in the course of the disease
`when it would greatly disturb quality of
`life. Nevertheless, such trials deserve fur(cid:173)
`ther investigation. A longer follow-up of
`the patients thus treated may help establish
`
`the role of such therapy in the total arma(cid:173)
`mentarium against breast cancer.
`The combination of leucovorin and
`5FU as a tertiary form of treatment has
`likewise induced further remissions in 20
`percent of patients already pretreated with
`5FU as part of a previous CMF or CAF
`combination. 64
`The probability of response decreases
`after each relapse and particularly after re(cid:173)
`lapse from secondary therapy. Tertiary and
`later treatment regimens should be in the
`context of investigational study protocols.
`Several drugs other than those already men(cid:173)
`tioned have been reported to be active in
`this clinical setting. There is no consensus
`