`
`Patients with Breast Cancer:
`
`Correlation with Clinical Data
`
`CAROL FABIAN, MD, LARRY STERNSON, PHD, MOUSTAFA EL-SERAFI, MD, LYN CAIN, RN, AND ERWIN HEARNE, PHD
`
`Blood tamoxifen levels were determined for patients with metastatic breast cancer following initial and
`chronic dosing at twice daily 10 mg/mg or a 20 mglmz single dose. Median time to response was six
`weeks. Blood tamoxifen levels at that time were ten-fold greater than those obtained after an initial single
`dose; however, steady-state values were not achieved until 16 weeks of chronic dosing. On a loading
`dose schedule of 40 mg/m2 twice daily for seven days and 20 mg/m2 daily thereafter, blood levels
`2 10 mg/m” twice daily steady-state values were reached in one week. Levels drawn at peak and
`trough times suggest that tamoxifen may be given on a once-daily basis. Tamoxifen half-life was 9-12
`hours after the initial dose and seven days after chronic dosing.
`Cancer 48:876—882, 1981.
`
`TAMOXIFEN is an antiestrogen currently being used
`
`in the treatment of breast cancer, particularly in
`the postmenopausal patient. The response rate of 37%
`achieved in postmenopausal women“"“"*“3"*3‘“Z” com-
`pares favorably with that of androgens (22%),*'5'“
`estrogens
`(26‘7?),‘-"” adrenalectomy (30%),"*7’2“‘ and
`hypophysectomy (30%)."~‘7~“ lts comparative effec-
`tiveness with oophorectomy with premenopausal pa-
`tients has yet to be fully delineated. A total of 70 such
`cases have been reported with a cumulative response
`rate of 27%.‘~”~““"‘*3"-3“’**’ Although this compares
`favorably with the 30% response rate reported for
`oophorectomy,”“'”’* a sizable proportion of patients
`were having some menopausal
`symptoms when
`tamoxifen therapy was begun. Side—effects appear to
`occur less frequently with tamoxifen than with the
`other common forms of treatment.“‘-“‘-‘“"»37
`
`Despite its current popularity, surprisingly little is
`known about the pharmacokinetics of tamoxifen be-
`cause of difficulties in developing a specific assay using
`a nonradiolabeled drug. Fromson er al.‘“ studied re-
`
`From the Division of Clinical Oncology. Department of Medicine
`University of Kansas Medical Center. Kansas City, Kansas, and the
`Department of Pharmaceutical Chemistry, University of Kansas,
`Lawrence, Kansas.
`Supported in part by lCl Americas NIH Grant nos. CA-12644 and
`RR-828.
`Address for reprints: Carol Fabian, MD: University of Kansas
`Medical Center: Division of Medical Oncology: 39th & Rainbow
`Blvd: Kansas City. Kansas 66103.
`Accepted for publication July 30. 1980.
`
`actions of a variety of animals (rats, mouse, dog, and
`monkey) to carbon—l4—labeled tamoxifen. Maximum
`serum levels appeared 1 to 6 hours after administra-
`tion with a prolonged half-life of greater than 24 hours.
`In rats and dogs, tamoxifen and its metabolites were
`conjugated and excreted into the bile. The majority
`of this pool was then reabsorbed after hydrolysis of
`the conjugates in the gut. The remainder was excreted
`in the feces. Urinary excretion was determined to be
`unimportant. Owing to the enterohepatic circulation,
`excretion was prolonged. A period often to 20 days was
`needed in order to eliminate 90% of the radioactivity
`from a single dose.
`Fromson“ also studied four female patients receiving
`tamoxifen, again using the carbon—l4 method.“ Feces
`and urine from two patients were collected. After a
`single dose equivalent to 12 mg/m2, maximum levels of
`tamoxifen were reached 4-7 hours after adminis-
`tration. An initial half-life of 7-14 hours was noted
`
`with a secondary half-life of more than seven days.
`Again,
`there was prolonged fecal excretion over
`several weeks.
`
`Due to the long half-life of tamoxifen (demonstrated
`with the carbon-l4 label) we thought it possible that
`blood tamoxifen levels after initial administration might
`be quite different than those after chronic dosing and
`that this might having bearing on the length of time
`needed to achieve a therapeutic response. We were
`also interested in determining the half-life after chronic
`dosing. Kinetic data after chronic dosing might be
`
`0008-543X/81/0815/876l$0.90 © American Cancer Society
`
`876
`
`|nnoPharma Exhibit 1084.0001
`
`
`
`No. 4
`
`TAMoxiFi=.N PHARMACOLOGY IN BREAST CANCER
`
`Fabian et ca’.
`
`877
`
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`
`FIG. 1. Blood tamoxifen levels following a single dose of 10 mg/m2
`in 17 patients.
`
`tubes and samples were frozen until analysis was
`performed.The methodology for determining blood
`tamoxifen levels was developed by Mendenhall
`et al.,”’ using direct extraction, photochemical acti-
`vation, and chromatographic analysis as previously
`reported.” This methodology discriminates between
`the parent drug and the metabolite. Blood tamoxifen
`levels
`(parent drug) were reported in nanograms
`per milliliter of whole blood. Intraassay variability
`is :3% and interassay variability, i5%.
`The purpose of Phase II was to gain some pre-
`liminary information regarding blood tamoxifen levels
`on a single daily dose schedule as well as on several
`loading dose schedules. For two patients receiving
`single daily doses of 20 mg/m2, blood tamoxifen levels
`were measured at 3, 12, 24, and 48 hours after the
`
`initial dose, at weekly intervals for six weeks, and then
`at 3 and 24 hours post dose every four to eight weeks
`thereafter.
`
`Four patients each received a loading dose of 20
`mg/m2 twice daily for seven days and a 20 mg/m2 single
`daily dose thereafter. Four patients each received a
`loading dose of 40 mg/m2 twice daily for seven days
`and a 20 mg/m2 single daily dose thereafter. Two
`patients each received a loading dose of 80 mg/m2 twice
`daily for seven days and a 20 mg/m2 single daily
`dose changed thereafter. All doses on the loading dose
`schedule were to the nearest 10 mg. Time of blood
`
`|nnoPharma Exhibit 1084.0002
`
`in determining the appropriate
`potentially useful
`interval between discontinuation of tamoxifen therapy
`and biopsy sampling for estrogen receptor without
`running a substantial risk of obtaining a false—negative
`result. Using a specific analytic method for (non-
`radiolabeled) tamoxifen,” we investigated these pos-
`sibilities.
`
`Materials and Methods
`
`The study consisted of two phases. In Phase 1, blood
`tamoxifen levels for 25 patients with metastatic breast
`cancer were determined after the initial dose and
`
`during and after treatment at a commonly used dose
`schedule of 10 mg/m2 twice daily (to the nearest 10 mg).
`In Phase 11, similar pilot data were gathered regarding
`three loading dose schedules and a single daily dose
`schedule.
`
`A total of 37 patients with metastatic breast cancer
`participated in the study. Median performance status
`was I (symptomatic but ambulatory and capable of
`normal work activities). Eleven patients had had no
`prior systemic therapy. The remaining patients had had
`prior hormone therapy or chemotherapy or both. The
`median patient age was 57 years. Three patients were
`premenopausal and 34 patients were postmenopausal.
`Before entering the study, each patient was evalu-
`ated with x—rays of the chest, skull, spine, ribs, and
`pelvis, liver scan, complete blood count with differen-
`tial, calcium, phosphorus, SGOT, SGPT, alkaline phos-
`phatase, bilirubin, BUN, creatinine, and blood estra-
`diol levels. Estrogen receptor determinations were per-
`formed before treatment when possible with the dex-
`tran—coated charcoal technique. Specimens containing
`less than 3 fentomoles of receptor per milligram of
`cytosol protein were considered negative, 3-9 border-
`line, and those containing more than 10 fentomoles
`were considered positive. Complete blood counts and
`platelet counts were redone ten days after treatment
`was begun and every four to eight weeks thereafter,
`along with renal and liver function studies. Clinical
`follow—up examinations and x—rays of involved sites
`were performed at four to eight week intervals.
`In Phase I of the study, blood samples for determina-
`tion of blood tamoxifen levels were drawn at 0, ‘/2, 3,
`6, 9, and 12 hours after the initial dose, and then at 3 and
`12 hours post dose on a monthly basis. For two patients
`receiving 10 mg/m‘3 twice daily, blood tamoxifen levels
`were measured at weekly intervals for six weeks after
`tamoxifen was begun;
`in addition to blood samples
`taken at 3, 12, 24, and 48 hours after the first dose.
`After the initial six weeks, samples were obtained at
`3 and 12 hours post close every four to eight weeks.
`Blood samples were collected in heparinized glass
`
`
`
`878
`
`CANCER August 15 1981
`
`Vol. 48
`
`400
`
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`50
`
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`
`60
`
`WEEKS ON TAMOXIFEN
`
`FIG. 2. Mean blood tamoxifen levels : 1 S.D. in 12 patients at a
`dose of 10 mg/m” twice daily using both the 3-hour and 12-hour post-
`dose values.
`
`sampling varied slightly for patients on the loading
`dose schedule, but at minimum, samples were drawn
`at 3 and 12 hours post dose on days 1, 4, (96 hours),
`and 7, and then at 3 and 24 hours post dose weekly for
`eight weeks. After the first eight weeks on study, blood
`samples were drawn at 3 and 24 hours post dose every
`two months.
`
`In both phases of the study, blood samples were
`also obtained after treatment had failed and tamoxifen
`
`therapy was terminated. The first sample was always
`drawn 3 hours after the last dose was given. Samples
`were then drawn at 24, 48, and 72 hours and weekly for
`six weeks after the last dose.
`
`Criteria for response were those recommended by
`the Breast Cancer Task Force.” An improvement
`category was also added, defined as a less than 50%
`
`but greater than 25% decrease in the sum of the prod-
`ucts of the diameters of measured lesions. The re-
`
`sponse duration was defined as the time from onset of
`response to relapse or increasing disease. For analysis
`pertaining to two groups, a one sided t—test was used.
`For analysis pertaining to three groups, a one way
`analysis of variance was used.
`
`Results
`
`Blood Tamoxifen Levels: Phase I
`
`Twenty—three patients each received a dose of 10
`mg/m2 twice daily and blood tamoxifen levels were
`determined at 0, 1/2, 3, 6, 9, and 12 hours after the initial
`dose and every four weeks thereafter.
`Single-dose kinetic data (Fig. 1) were available for
`17 patients in Phase 1. The median peak level after a
`single dose was reached in a median time of 6 hours.
`The median half-life was greater than 6 hours and could
`not accurately be determined. For four additional pa-
`tients (two at 10 mg/M2 twice—daily BID and two at
`20 mg/m2 single dose), blood samples were drawn at
`1/2, 3, 12, 24, and 48 hours after the first dose. The half-
`
`life appeared to be between 9 and 12 hours (after peak
`levels were reached).
`
`Twelve patients received tamoxifen for prolonged
`periods of time. Figure 2 gives mean tamoxifen values
`:1 SD after chronic dosing, utilizing both the 3-hour
`and 6-hour post-dose values. After four weeks, the
`mean blood tamoxifen level was 144 which was ten
`
`times higher than that obtained after a single dose. Mean
`steady-state values were not obtained, however, until
`patients had received drug for 16 weeks. The median
`time to response was six weeks. The lowest tamoxifen
`level at this time in a responder was 70 ng/ml. The
`lowest steady-state value in a responder was 150 ng/ml.
`Nineteen patients received drug for four or more
`weeks and were thought to have consistently taken
`their tamoxifen. In this group, 58 sets of 3-hour post-
`dose and 12-hour post-dose blood samples were drawn
`on the same day. Values at 3 hours post dose (median,
`206 ng/ml) were not different from those measured at
`
`12 hours post dose (median, 182 ng/ml). Levels at 3
`and 12 hours in responders were not significantly dif-
`ferent from those in nonresponders (Fig. 3).
`
`Blood Tamoxifen Levels.‘ Phase 11
`
`Blood tamoxifen levels after four weeks and steady-
`state values were at least 1 log higher than those ob-
`tained after a single dose, but it was unknown how
`quickly the steady-state values were being reached.
`Also, since there was no difference between values ob-
`tained at 3 hours and those obtained at 12 hours on
`
`|nnoPharma Exhibit 10840003
`
`
`
`
`
`
`
`TAMOXIFENBLOODLEVELSng/ml
`
` CI RESPONDERS
`
`I IMPROVED + STABLE DISEASE
`A PROGRESSIVE DISEASE
`
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`FIRST DOSE
`
`FR]. 3. Comparison of blood tamoxifen levels in responding and
`nonresponding patients at a dose of 10 mg/m2 twice daily using both
`the 3-hour and 12-hour post-dose values.
`
`
`
`No. 4
`
`TAMox1FEN PHARMACOLOGY IN BREAST CANCER
`
`Fabian et al.
`
`879
`
`chronic dosing, it was possible that a single daily dosage
`would be adequate.
`In order to clarify these points, we studied four pa-
`tients receiving 10 mg/m2 twice daily or 20 mg/m2
`once daily with interval samplings between 12 hours
`and four weeks on study. The median steady-state
`value for this group was 333 ng/ml. Steady—state values
`were not achieved until four weeks had passed and then
`in only three or four patients. Average values after one,
`two, three, and four weeks were 107, 156, 158, and
`375 ng/ml, respectively. Values were below 150 ng/ml
`in two of four patients after one and two weeks, in one
`of two patients after three weeks, and in one of four
`patients after four weeks (Fig. 4).
`In an effort to quickly achieve a steady state as well
`as a level of tamoxifen which was known to be thera-
`
`peutic, ten patients were given loading doses of tamoxi-
`fen for seven days. Four patients received 20 mg/m2
`twice daily; four patients, 40 mg/m2 twice daily; and
`two patients, 80 mg/m2 twice daily. After the initial
`seven days, each patient was given a single daily dose of
`20 mg/m2. At 20 mg/m2 twice daily, three of four pa-
`tients reached the median steady—state value for the
`group (241 ng/ml) within a week (Fig. 5). At the 40
`mg/m2 BID level, all four patients reached the median
`steady—state value for the group (328 ng/ml) within a
`week, and all were within the range known to be asso-
`ciated with response in our patients (>150 ng/ml) by
`72 hours as all had blood tamoxifen levels of at least
`
`225 ng/ml (Fig. 6). In two cases, increasing the initial
`dose to 80 mg/m2 twice daily for seven days resulted
`in blood tamoxifen levels of 225 : 15 ng/ml (levels
`known to be associated with response) within 3 hours
`following the initial dose.
`In order
`to determine whether adequate blood
`tamoxifen levels could be sustained if tamoxifen were
`
`given once daily, two patients were given 20 mg/m”
`orally once a day. Ten patients were given 20 mg/m2
`orally once daily after being given initial seven day
`loading doses of 20-80 mg/m2 (as described earlier).
`Blood tamoxifen levels were determined at 3 and 24
`
`hours post close weekly for the first six to eight weeks
`and then every four to eight weeks thereafter. Median
`blood tamoxifen levels after chronic closing (at least
`4 weeks on study) at the 20 mg/ml single daily dose
`level were 376 ng/ml at 3 hours and 262 ng/ml at 24 hours
`post dose. The analysis was done on 14 sets of 3-hour
`and 24-hour samples drawn in the same day. Although
`there was a greater spread in these values than with
`twice daily dosing, the 24-hour value was still well
`above a level shown to be associated with response.
`Serial blood levels were determined for 17 patients
`after discontinuation of tamoxifen (Fig. 7). The median
`half-life was seven days (range, three to 21 days). The
`
`400
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`TAMLEVELng/ml
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`FDAYS wEEKS
`TIME ow STUDY AFTER 1st DOSE
`
`F10. 4. Blood tamoxifen levels in patients receiving 10 mg/m2
`twice daily or 20 mg/m? single daily dose.
`
`median time to reach blood tamoxifen levels of less than
`
`70 ng/ml (known to be associated with response) was
`21-28 days. Tamoxifen was still detectable six weeks
`after treatment was stopped.
`
`Clinical Data
`
`Response Data
`
`Thirty—three patients were considered fully evaluable
`for response. Two patients did not have measurable
`disease and were thus not considered evaluable. One
`
`patient died after eight days on study, probably of a
`pulmonary embolism, and one patient had a flare re-
`action and refused further treatment after two weeks
`
`on study. These two patients were considered partially
`evaluable. The overall response rate for fully and
`
`TAMLEVEL
`
`ng/ml
`
`18
`16
`14
`12
`10
`8
`6
`4
`1234512
`20
`22
`24
`1-DAYS WEEKS
`TIME ON STUDY AFTER 1st DOSE
`
`FIG. 5. Blood tamoxifen levels in patients receiving 20 mg/m2
`twice daily for seven days and 20 mg/m2 single daily doses thereafter.
`
`|nnoPharma Exhibit 1084.0004
`
`
`
`CANCER August 15 1981
`
`Vol. 48
`
`880
`
`700?
`
`500)
`
`5001-
`
`TAMLEVELng/ml
`
`
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`TIME ow srum POST Ist DOSE
`
`borderline for one and unknown for two; levels varied
`from 26 to 88 pg/ml (normal premenopausal range,
`> 26 pg/ml). Response rates for postmenopausal
`women receiving 10 mg/m2 twice daily was 32%.
`Pretreatment estradiol levels were determined for 23
`
`of the response-evaluable patients receiving doses of
`10 mg/m2 twice daily. Five patients had estradiol
`levels of more than 26 pg/ml (premenopause range).
`Clinically, three ofthese patients were postmenopausal
`and two were premenopausal. No response was ob-
`served in the group of patients with estradiol levels
`of more than 26 pg/ml.
`Estrogen receptor determinations were performed
`for
`11 patients who were response evaluable. Six
`patients were estrogen-receptor positive.
`In this
`group, one patient had a partial response; one,
`im-
`provement; two, stable disease; and two, increasing
`disease. Seven additional patients did not have estro-
`gen receptor determinations but had had prior hormone
`response. In this group,
`two patients had complete
`responses; two, partial responses; two, stable disease;
`and one increasing disease. No response was observed
`for the five patients who were negative or borderline
`for estrogen receptor determination. Of 16 response-
`evaluable patients who neither had estrogen receptor
`determination nor a previous hormone trial,
`three
`responded.
`Of three patients who had previously undergone
`adrenalectomy,
`two had responded to the ablative
`procedure. All three responded to tamoxifen. Response
`may have resulted from competitive inhibition with
`estrogens at
`the receptor site, since maintenance
`hydrocortisone is partially converted to ll-8-OH-
`estradiol
`in oophoadrenalectomized individuals.“
`
`Toxici ty
`
`Of the 37 patients, 13 experienced toxic reactions
`(Table 1). The patient who exhibited probable paroxys-
`mal atrial tachycardia was receiving a loading dose
`of 80 mg/m2 twice daily. She had no later difficulties
`when the drug was withdrawn for two days and she was
`started on the 20 mg/m2 single daily dosage. One pa-
`tient had incapacitating headaches at 20 mg/m3 (40 mg)
`per day. She tolerated the drug well at 10 mg/m"-’ per
`day. Both patients with flare reactions had predomi-
`nant metastatic bone lesions. The flare consisted of a
`
`marked increase in bone pain in involved areas, seen
`within a few days of starting tamoxifen and lasting up
`to two weeks. One patient was positive for estrogen
`receptor and went on to achieve a partial response
`lasting 36 weeks. In the other patient, estrogen re-
`ceptor determination was not done and the patient re-
`fused further therapy after two weeks.
`
`|nnoPharma Exhibit 1084.0005
`
`FIG. 6. Blood tamoxifen levels in patients receiving 40 mg/m3
`twice daily for seven days and 20mg/mg single daily doses thereafter.
`
`partially evaluable patients was eight of 35 (23%). The
`median time to response was six weeks and the
`median duration of response was 36 weeks. Patients
`with stable disease had a median time of 24 weeks to
`
`disease progression. Of the 24 fully or partially evalu-
`able patients receiving 10 mg/m” twice daily seven
`(29%) responded. No response was seen for the nine
`fully evaluable loading dose patients; Of these, how-
`ever. 67% had bone metastases as their evaluable
`
`lesions which are traditionally difficult to evaluate. It
`is of note that four of the nine had improvement or
`prolonged stable disease lasting from 22 to 75+ weeks.
`Increasing disease was observed in the three pre-
`menopausal patients (two received doses of 10 mg/
`m2 twice daily and one,
`the 40 mg/m3 twice daily
`loading dose schedule.) Estrogen receptor status was
`
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`
`Fla. 7. Blood tamoxifen levels after discontinuation of tamoxifen
`past chronic dosing at 10 mg/m” twice daily in 17 patients.
`
`
`
`No. 4
`
`TAMOXIFEN PHARMACOLOGY IN BREAST CANCER
`
`Fabian er al.
`
`881
`
`Discussion
`
`TABLE 1. Toxicity in 37 Patients Receiving Tamoxifen
`
`The median peak time of 6 hours and half life of
`9-12 hours achieved in the single—dose studies are in
`agreement with results reported by Fromsonf’ Inter-
`estingly, a low peak value of 14 ng/ml was observed
`after the initial dose of 10 mg/m"’ as compared with a
`mean value of 144 ng/ml at four weeks after chronic
`dosing. At the dosage of 10 mg/m2 twice daily, steady-
`state values were not obtained for 16 weeks (mean
`value, 262). The lowest steady—state Value in a re-
`sponder was 150 ng/ml. The median time to response
`was six weeks which is in close agreement with the 5.3
`weeks
`reported by Tormey.” The mean blood
`tamoxifen value at six to eight weeks was 180 ng/ml.
`The lowest value in a responder was 70 ng/ml. After
`loading doses of 20 mg/m2 twice daily, steady—state
`values were reached in three of four patients within a
`week. With loading doses of 40 mg/m2 twice daily,
`all four patients achieved steady state within a week
`and all were well within the known therapeutic range
`(>150 ng/ml) by 72 hours. The large variations in
`individual patient sampling are not a result of inter-
`assay variation but may be a result of variation in
`drug absorption and metabolism as influenced by other
`medications and hepatic and renal function. Studies
`regarding these possibilities are underway. Con-
`clusions cannot be reached regarding the efficiency of
`the loading dose schedule at
`this point. However,
`theoretically, it would appear advantageous to use a
`loading dose of 20-40 mg/m2 twice daily for one week
`as steady—state levels and those known to be associated
`with response are reached much earlier than with the
`conventional dosage schedule of 10-20 mg/m2 twice
`daily. Further
`studies
`regarding this point are
`underway.
`It would appear feasible to give tamoxifen on a once
`daily basis since values obtained at 3 hours post dose
`(206 ng/ml) were not different from values obtained at
`12 hours post dose (182 ng/ml) in the patients receiving
`10 mg/m2 twice daily. In patients receiving a single
`daily dose of 20 mg/m2, median values at 3 hours post
`dose were higher (376 ng/ml) than those at 24 hours
`(262 ng/ml) but the 24-hour value was well above the
`therapeutic levels and was higher than the 12-hour
`value for the patients receiving 10 mg/m2 twice daily.
`The excretion of tamoxifen after chronic dosing was
`prolonged. Median half-life was seven days (range,
`three to 21 days. Blood tamoxifen levels known to be
`associated with response (270 ng/ml) were still present
`21 days after drug discontinuation. Tamoxifen was
`still detectable in the blood six weeks after treatment
`
`was discontinued although levels after 28 days or more
`are generally less than 25 ng. From this data, it would
`
`Toxic effect
`
`Headache
`
`Hot flashes
`
`Nausea
`
`Flare
`
`Paroxysmal atrial
`tachycardia
`
`Number of
`patients
`
`Dose
`
`3
`
`7
`
`2
`
`2
`
`1
`
`1-20 mg’m’ twice daily
`loading dose
`1-20 mgjmz single dose
`1- 10 mg]m2 twice daily
`
`1-20 mg]m2 twice daily
`loading dose
`[-40 mg/m2 twice daily
`loading dose
`2-20 mg/m2 single dose
`3- 10 mg’m* twice daily
`
`1-20 mgfmz twice daily
`loading dose
`1-10 mg/m” twice daily
`
`1-20 mg/m2 twice daily
`loading dose
`1-10 mg/m” twice daily
`
`80 mg/m2 twice daily
`loading dose
`
`to delay sampling for cytoplasmic
`appear prudent
`estrogen receptor for four weeks after discontinuation
`of tamoxifen.
`
`REFERENCES
`
`1. Barret A. In Proceedings of a Symposium on the Hormonal
`Control of Breast Cancer, Alderly Park, September l975:40.
`2. Carter AC, Sedransk, Kelley RM, er al. Diethylstilbestrol:
`recommended dosages for different categories of breast cancer pa-
`tients: Report of the Cooperative Breast Cancer Group. JAMA
`1977; 237:2079—2085.
`
`' 3. Cole MP, Jones CTA, Todd IDH. A new anti-oestrogenic agent
`in late breast cancer, an early clinical appraisal. Br J Cancer 1971;
`25:270-273.
`‘
`4. Cooperative Breast Cancer Group. Testosterone propionate in
`breast cancer. JAMA 1964; 188:1069—1072.
`
`5. Council on Drugs, Subcommittee on Breast and Genital
`Cancer, Committee on Research AMA. Androgens and estrogens
`in the treatment of dissemminated mammary carcinoma—retro~
`spective study of 944 patients. JAMA 1960; 172: 1271- 1283.
`. 6. Fracchia AA, Randall HT, Farrow JH. The results ofadrenalec-
`tomy in advanced breast cancer
`in 500 consecutive patients.
`Surg Gynecol Obstet 1967: 125:747—756.
`7. Fracchia AA, De Palo AJ, Huvos AG, et al. Castration for
`primary inoperable or recurrent breast carcinoma. Surg. Gynecol
`Obster 1969; l28:1226—1234.
`8. Fracchia AA, Miller, TR, Greenberg, EJ, et al. Hypo-
`physectomy as compared to adrenalectomy for advanced breast
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`9. Fromson JM, Pearson S, Bramah SM. The metabolism of
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`1973'. 32711-714.
`
`(lCl Ltd, Macclesfield and
`10. Fromson JM, Sharp DS,
`University Hospital, South Manchester, England). The selective
`uptake of tamoxifen by human uterine tissue. J Obstet Gyrieml
`Br Commonw 1974;81:321-323.
`11. Goldenberg IS, Waters M, Ravdin RS, er al. Androgenic
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`1267-1268.
`12. Hueson JC. Current overview of EORTC clinical trials with
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`
`|nnoPharma Exhibit 1084.0006
`
`
`
`882
`
`CANCER August 15 1981
`
`Vol. 48
`
`13. Hoogstraten BH, Irwin L, Ahmar D, er ul. Breast Cancer:
`Suggested Protocol Guidelines for Combination Chemotherapy
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`(NIH) 77-1192.
`14. Kennedy BI, Tibitts DM, Nathanson IT, at al, Hyper-
`calcemia, a complication of hormone therapy of advanced breast
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`15. Kennedy BJ. Systemic effects of androgenic and estrogenic
`hormones in advanced breast cancer J Am Geriatric Soc 1965:
`13:230-235.
`16. Lerner HI, Bank PR, lsreal L, Leung BS. Phase II study of
`tamoxifen; Report of 74 patients with stage IV breast cancer.
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`17. MacDonald I. Endocrine ablation in disseminated mammary
`carcinoma. Surg Gynecol Obstct 1962: 1l5:2l5—222.
`18. Manni A. Trujillo J, Marshall JS, Pearson OH. Antiestrogen-
`induced remissions in Stage IV breast cancer. C(m('m‘ Treat Rep
`1976: 60:1445—l450.
`19. Mendenhall DW, Kobayashi H, Shin FML, 81 a1. Clinical
`analysis of tamoxifen, and anti-neoplastic agent,
`in plasma. Clin
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`20. Morgan LR, Schein PS, Woolley PV, et al. Therapeutic use
`of tamoxifen in advanced breast cancer: Correlation with biochemi-
`cal parameters. Cancer Treat Rep 1976; 60:1437— 1443.
`21. Moseson DL, Sasaki, GH, Kraybill WG, er al. The use of anti-
`estrogens tamoxifen and nafoxidine in the treatment of human breast
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`4l:797—800.
`
`22. Pearson OH, Ray BS. I-lypophysectomy in the treatment of
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`23. Schmidt MS, Nemoto T, Dao T, Bross ID. Prognostic factors
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`breast. Cancer 1971; 27:] 106-1111.
`24. Silverstein ME, Buron RL, Jr, Yonemoto RH, Riihemaki DU,
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`25. Stonesifer GL, Lowe RH, Cameron JH, Ganis FM. Con-
`version ofhydrocortisone to estrogen in carcinoma ofthe breast after
`oophorectomy and adrenalectomy. Ann Surg 1973', l78:563—564.
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`28. Veronesi U, Pizzocaro G, Rossi A, er al. Oophorectomy for
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`
`29. Ward HWC, Arthur K, Banks AI, et al. Anti—oestrogen
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`30. Willis K, London DR, Bluff WR. Investigations of hormone
`changes in breast cancer patients before and after
`treatment
`with novaladex.
`In Proceedings on Hormonal Control of Breast
`Cancer. Alderly Park, September 24, 1975:59—63_
`
`Wilmot Cancer Research Fellowships
`
`The University of Rochester School of Medicine is offering training in cancer research to
`individuals with an MD degree and at least one year of postdoctoral experience. Research Fellows
`can train for up to three years in any discipline relevant to the cause, diagnosis, treatment or preven-
`tion of cancer.
`
`Stipends range from $22,000 to $25,000, depending on the number of years since the MD degree was
`achieved. There is also an annual allowance of $4000 for other research costs.
`
`Direct inquiries to:
`
`Wilmot Cancer Research Fellowship Program
`Box 706
`
`University of Rochester School of Medicine & Dentistry
`601 Elmwood Avenue
`Rochester, NY 14642
`
`|nnoPharma Exhibit 1084.000?
`
`