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`Paclitaxel and Recombinant Human Granulocyte
`Colony-Stimulating Factor as Initial Chemotherapy
`for Metastatic Breast Cancer
`
`By Bonnie S. Reichman, Andrew 0. Seidman, John P.A. Crown, Robert Heelan, Thomas B. Hakes, David E. Lebwohl,
`Theresa A. Gilewski, Antonella Surbone, Violante Currie, Clifford A. Hudis, T.J. Yao, Raymond Klecker,
`Carlos Jamis-Dow, Jerry Collins, Susan Quinlivan, Regina Berkery, Frieda Toomosi, Renzo Canetta,
`Jason Fisherman, Suson Arbuck, and Lorry Norton
`
`Purpose: A phase II study of Taxol (padltaxel; Bristol(cid:173)
`Myers Squibb Co, Princeton, NJ) os Initial chemotherapy
`for metastatic breast cancer was cond1Kted. Recombi(cid:173)
`nant human granulocyte colony-stimulating factor (rhG(cid:173)
`CSf) was used to ameliorate myelosuppresslon, the an(cid:173)
`ticipated dose-limiting toxicity.
`Patients and Methods : Twenty-eight patients w ith
`bidlmensionally measurable breast cancer who had not
`received prior chemotherapy for metastatic disease
`w ere tr.oted. Taxol was administered at 250 mg/m3 as
`a continuous 24-hour Intravenous (IV) Infusion every 21
`days. rhG-CSF was administered at 5 µg/ kg/ d subcu(cid:173)
`taneously on days 3 through 1 O.
`Results: Objective responses were observed In 16 of
`26 assessable patients (62%; 95% confidence Interval,
`41% to 80%). There were three (12%) complete re(cid:173)
`sponses (CRs) and 13 (50%) partial responses (PRs). Ten
`of 16 patients (63%) who had received prior adjuvant
`chemotherapy responded, which included one CR and
`four PRs among eight patients who had received prior
`doxorublcln-containlng therapy. Responses were ob(cid:173)
`served In all sites of metastatic d isease. The median time
`to first objective response was 5 weeks (range, 1 to 14).
`
`Administration of r+.G-CSF was associated with a short
`duration of neutropenla (median, 2 days with absolute
`neutrophll count < 500 cells/µL). Eight of 26 patients
`(31 % ) who received more than one course re<eived sub(cid:173)
`sequent therapy without dose reduction. One hundred
`seventy-eight cycles of treatment were administered,
`with a median of six cycles per patient (range, one ta
`19). Eight courses (4.5o/o) were associated with admis(cid:173)
`sions for neutropenlc fever. Twenty-two patients (79%)
`did not r6qulre admission for neuft'openlt f•ver. Treat(cid:173)
`ment was well tolerated. Adverse effecta Included gen(cid:173)
`erallJ:ed alopecla In all patients. Myalgias, arthralglas,
`and peripheral neuropathy were mild. No hypersensi(cid:173)
`tivity reactions and no cardiac toxicity were observed.
`Conclusion: Taxol Is highly active as Initial chemo·
`therapy for metastatic breast cancer. Administration of
`rhG-CSF red1Ked the Incidence, depth, and duration of
`neutropenia, compared with published prior ex perience.
`Further studies of Taxol In breast cancer, Including com(cid:173)
`binations with other active agents, are clearly war(cid:173)
`ranted.
`J Clin Oncol J J: J 943- J 95 J • © 1993 by American So(cid:173)
`ciety of Cllnlcol Oncology.
`
`T HE NOVEL DITERPENE Taxol (paclitaxel; Bristol(cid:173)
`
`Myers Squibb Co, Princeton, NJ), derived from the
`bark of the western yew, Taxus brevifolia, is one of the
`most exciting new anticancer drugs. 1
`2 Unlike other mi(cid:173)
`•
`crotubule toxins in clinical use, such as vincristine or col(cid:173)
`chicine, Taxol promotes the formation oftubulin dimers
`and stabilizes microtubules against depolymerization.H
`This results in growth inhibition and loss of cell viability.
`In the 1960s, bark extracts containing Taxol were found
`to be active against many murine cancers, including
`LI 210, P388, and P 1534 leukemias, Walker 256 carci(cid:173)
`nosarcoma, sarcoma 180, and Lewis lung carcinoma.7
`Taxol was isolated in 1971 . However, because of its limited
`supply and relative insolubility, and a preclinical testing
`profile that was not very different from other spindle poi(cid:173)
`sons, clinical trials with the drug were not initiated until
`the early 1980s. Phase I studies found that profound my(cid:173)
`elosuppression, specifically noncumulative reversible
`neutropenia, was dose-limiting. 8•12 Life-threatening type
`1 hypersensitivity reactions were also encountered. These
`may be at least partially the result of the infusion of a
`high concentration of Cremophor EL (BASF Aktienge-
`
`sellschaft), a mixture of polyoxyethylated castor oil and
`ethanol, used to solubilize the Taxol. In fact, similar hy(cid:173)
`persensitivity reactions have occurred when Cremophor
`EL was infused with drugs other than Taxol, such as di(cid:173)
`demnin B or teniposide. 1
`) Increasing the duration of the
`infusion to 24 hours and administering dexamethasone
`and H 1 and H2 receptor antagonists before Taxol suc(cid:173)
`cessfully reduces the incidence of hypersensitivity reac-
`
`From the Breast and Gynecological Ca11cer Medicine Service. Di(cid:173)
`vision of Solid Tumor Oncology, Depar1ment of Medicine, and De·
`partments of Medical Imagi11g and Epidemiology and Biostatistics.
`Memorial Sloan·Keuering Cancer Cemer, New York, NY: Food and
`Dmg Administration, Divisio11 of Clinical Phannacology, Rockville;
`National Cancer 1nsti111te, Division of Cancer Therapy, Cancer Ther(cid:173)
`apy Evaluation Program. Bethesda. MD; and Bristol-Myers Squibb,
`Pharmaceutical Research Institute, Wallingford, CT.
`Submitted November 24. 1992: accepted May 26. 1993.
`Supported in part by National Cancer Institute. Bethesda. MD.
`grants no. CA-09207-14 and 1-CM073/J.
`Address reprin.t requests to Bonnie S. Reichman, MD, Slrang-Cor(cid:173)
`nel/ Breast Center, 428 E 72 St. New York. NY 10021.
`© 1993 by American Society of Clinical Oncology.
`0732-183X/93/1110-0017$3.00/0
`
`Journal of Clinical Oncology, Vol 11, No 10 (October), 1993: pp 1943-1951
`
`1943
`
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`1944
`
`REICHMAN ET Al
`
`tions.6- 12 Phase I trials of this method of administration
`have concluded that phase II studies should use 135 to
`, depending on the degree of the patient's prior
`250 mg/m2
`exposure to cytotoxic therapy. In these phase I trials,
`significant anticancer activity was observed in ovarian
`carcinoma, non-small-cell lung carcinoma, and mela(cid:173)
`noma. 6-12
`Concerning breast cancer, Taxol is active against the
`implanted human MX-1 mammary tumor xenograft.7 In
`a recent phase II trial in metastatic breast cancer, the
`overall response rate was 56% (95% confidence interval,
`35% to 76%), including a 12% complete response (CR)
`rate.14 Hematopoietic growth factors were not used in this
`study, and myelosuppression was dose-limiting. For this
`reason, we performed the present trial in which recom(cid:173)
`binant human granulocyte colony-stimulating factor (rhG(cid:173)
`CSF) was administered to ameliorate neutropenia and its
`morbid consequences.
`
`PATIENTS AND METHODS
`
`Eligibility Criteria
`To be eligible for our trial, patients had to have histologically con(cid:173)
`firmed breast cancer with clinical evidence of biclimensionally mea(cid:173)
`surable metastatic clisease. Previous cytotoxic chemotherapy for stage
`IV clisease was not permitted. Patients may have received prior ra(cid:173)
`diation therapy if it was completed ~ 4 weeks before study entry and
`if the portals encompassed less than 30% of the marrow-bearing skel(cid:173)
`eton. Indicator lesion(s) could not have been irradiated previously.
`Patients could have received prior adjuvant chemotherapy if it was
`completed l year or longer before study entry. One hormonal agent
`as adjuvant treatment and/or one hormone therapy for metastatic
`disease were allowed, but hormone therapy must have been cliscon(cid:173)
`tinued at least 3 weeks before protocol entry. Blastic bone metastases,
`bone scan abnormalities alone, and pleural or peritoneal effusions
`were not considered measurable. Lytic bone metastases were ac(cid:173)
`ceptable as measurable indicator lesions if they were bidimensionally
`measurable on plain radiography, magnetic resonance imaging (MRI),
`or computed tomographic (CT) scan. Patients with stable brain me(cid:173)
`tastases were eligible if at least one other site of measurable disease
`existed. Patients with carcinomatous meningitis and/or symptomatic
`lymphangitic pulmonary metastases were ineligible. Other eligibility
`criteria included the following: total WBC count more than 3,000
`cells/µL, absolute granulocyte count ~ 1,500 cells/µL, hemoglobin
`~ 8 g/dL, platelet count 2: 100,000 cells/µL, serum creatinine s 1.4
`mg/dL, total bilirubin less than 1.5 mg/dL, serum calcium s 10.5
`mg/dL, Kamofsky perfonnance status ~ 60%, and an anticipated
`survival duration of~ 12 weeks. Patients must have recovered from
`prior surgery, being ~ 2 weeks from minor surgery and ~ 3 weeks
`from major surgery. Patients were ineligible if they had other prior
`malignancy (except for in situ cervical carcinoma and cured non(cid:173)
`melanoma skin cancer), other serious medical illnesses (including
`significant cardiac disease or arrhythmia), peripheral neuropathy, se(cid:173)
`vere infection, or malnutrition. Before study entry, all patients gave
`written informed consent indicating their awareness of the investi(cid:173)
`gational nature of this protocol.
`
`Treatment Plan
`Taxol was supplied by the National Cancer Institute as a concen(cid:173)
`trated sterile solution for i.ntravenous (IV) administration in a 5-mL
`vial containing 30 mg of Taxol in polyoxyethylated castor oil (Cre(cid:173)
`mophor EL) 50% and dehydrated alcohol, United States Pharma(cid:173)
`copeia, 50%. The drug was cliluted with either 5% dextrose injection
`or 0.9% sodium chloride injection. When tbe study was initiated,
`shelf-life stability studies had indicated that the solution was stable
`for at least 12 hours, so the total dose was divided into two consecutive
`12-hour infusions, each prepared immediately before administration. 7
`Subsequent studies demonstrated that the solution was stable for 24
`hours, so the total daily dose was prepared just before the start of
`therapy. 15 In-line filters, 0.2 µm, were used (IVEX-2, Abbott Labo(cid:173)
`ratories, North Chicago, IL). Only glass containers and polyethylene(cid:173)
`lined nitroglycerin tubing were used to avoid leaching of polyvinyl
`chloride from containers made of this material.
`Initial dosage ofTaxol was 250 mg/m1, administered as a contin(cid:173)
`uous IV infusion over 24 hours. Treatment was planned to be repeated
`every 21 days. Subsequent doses were modified on the basis of he(cid:173)
`matologic and nonhematologic toxicities (using National Cancer In(cid:173)
`stitute common toxicity criteria) listed in Table 1.16 The dose was
`reduced by one level to 200 mg/m1 if the granulocyte nadir was less
`than 250 cells/µL or ifthe platelet naclir was s 50,000 cells/µL, and
`by two levels to 180 mg/m2 if infection or bleeding occurred in as(cid:173)
`sociation with marrow suppression. Subsequent dose reductions fol(cid:173)
`lowed the same rules. In patients without dose-limiting toxicity, the
`dose was escalated by two levels to 300 mg/m1 if the granulocyte
`nadir was more than 2,000 cells/µL and the platelet nadir was more
`
`Tobie 1. Dose Modiffcotion Scheme
`
`level
`
`- 2
`- 1
`0
`I
`2
`
`o.rM'lition of Dose levels
`
`Oose (mg/m'l
`
`180
`200
`250
`275
`300
`
`Hemotolog~< T oxiclty
`
`Gronulocyle Nadir
`
`Platelet Nodlr
`
`Dow ModifkotH>n
`
`> 2,000
`> 1,000 but s 2,000
`
`;,_ 250 but s 1,000
`
`<250
`Infection or bleeding
`
`ond > 100,000
`and/or> 75,000 but
`s 100.000
`or > 50,0-00 but s
`75,000
`ors 50,0-00
`
`Increase 2 levels
`Increase I level
`
`No change
`
`Decrease I level
`Decrease 2 levels
`
`Not1hemotolo9ic T oxidty
`
`Grado
`
`0-1
`
`2
`3
`
`4
`
`Oose ModiAcotion
`
`Increase 1
`level
`No change
`Decrease 1
`level
`Decrease 2
`levels
`
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`PACLITAXEL AND rhG-CSF IN METASTATIC BREAST CANCER
`
`1945
`
`than 100,000 cells/µL, and by one level to 275 mg/m2 if the granu(cid:173)
`locyte nadir was more than 1,000 but less than 2000 ceUs/µL and/
`or the platelet nadir was more than 75,000 but less than 100,000
`cells/µL.
`When appropriate, re-treatment was to be held beyond day 22
`until hematologic recovery to a granulocyte count 2: 1,500 cells/µL
`and platelets more than 100,000 cells/µL, and until gastrointestinal
`and/or infectious complications resolved. We planned to take patients
`off study if they did not rcoover sufficiently to receive treatment within
`35 days from their prior dosage. Subcutaneous ports were implanted
`in patients with poor peripheral venous access before beginning ther(cid:173)
`apy. All patients received the following regimen to prevent hyper(cid:173)
`sensitivity reactions: dexamethasone 20 mg orally at 14 and 7 hours
`before each Taxol treatment, and diphenhydramine hydrochloride
`50 mg, and cimetidine 300 mg IV at I hour before Taxol. During
`the first 30 minutes ofTaxol infusion, a physician or a chemotherapy
`nurse remained at the bedside. Blood pressure was monitored every
`15 minutes during the first hour of the infusion.
`rhG-CSF (Neupogen, Amgen, Thousand Oaks, CA) at 5 ,..gfkg/d
`was specified to be administered subcutaneously on days 3 through
`10 of each course (a total of 8 days) or until the absolute neutrophil
`count recovered to 2: 2000 cells/ µL for 3 consecutive days, even if
`antibiotic treatment for febrile neutropcnia was required. Treatment
`with rhG-CSF was discontinued if the absolute neutrophil count ex(cid:173)
`ceeded 10,000 cells/µL. rhG-CSF was discontinued for at least 48
`hours before institution of the next cycle ofTaxol.
`
`Duration of Therapy
`After the initial dose of Taxol, we planned to administer at least
`one additional treatment unless there was disease progression or if
`intolerable (grade 3 to 4) toxicity, excluding neutropenia, precluded
`further treatment. Due to the limited supply of Taxol, we planned
`to administer only two courses beyond the best observed response,
`or to stop treatment when a maximum of 10 cycles were given, unless
`the tumor was still regressing at 10 cycles.
`
`Pretreatment EvaluaJion
`A complete history and physical examination were performed be(cid:173)
`fore the first cycle of therapy. Laboratory studies included a complete
`blood cell (CBC) count with differential and platelet count, biochem(cid:173)
`ical screening profile, serum creatinine, carcinoembryonic antigen
`(CEA) and CA 15-3 determinations, serum human chorionic gonad(cid:173)
`otropin-beta (if indicated to rule out pregnancy), ECG, and postero(cid:173)
`anterior (PA) and lateral chest x-rays. CT scan, MRI, and ultrasound
`were performed as needed to evaluate bidimensionally measurable
`disease. Bone scans were to be performed if clinically warranted.
`
`Eva/UaJion During Treatment
`During treatment, CBC with differential and platelet counts were
`performed three times per week (each Monday, Wednesday, and
`Friday) to measure the duration and depth of neutropenia, and to
`monitor the effect of rhG-CSF. Before each treatment course, a phys(cid:173)
`ical examination and a detailed history documenting disease symp(cid:173)
`toms and the side effects of t.reatmenl was obtained. In addition,
`biochemical screening profile, scrum creatinine, CEA, CA 15-3, ECG,
`and PA and lateral chest x-rays were performed every 3 weeks just
`before each treatment course. Tumor measurements were required
`at each cycle if these could be obtained by physical examination or
`chest x-ray. Otherwise, the measurements were to be obtained every
`
`6 weeks (every two cycles) by CT, MRI. ultrasound, or plain x-ray
`(guided, if necessary, by bone scan}. Patients with cutaneous lesions
`were to have serial photographic documentation whenever possible.
`
`Criteria for Response
`CR was defined as the disappea ranee of all clinical evidence of
`active tumor, with complete reossification of bone lesions and absence
`or disease-related symptoms for a minimum of 4 weeks. Partial re(cid:173)
`sponse (PR) was defined as a :.:. 50% reduction in the sum of the
`products of the biperpendicular diameters of all measurable lesions,
`without the appearance of new lesions for at least 4 weeks. When
`there were multiple sites of metastases, the largest masses (up to five)
`were considered as the index lesions. Minor response (MR) was de(cid:173)
`fined as a decrease of less than 50% but more than 25% in tumor
`size for at least 4 weeks. Stable disease (SD) was defined as no change
`in tumor size or a less than 25% increase for at least 4 weeks. Pro(cid:173)
`gressive disease (PD) was defined as the unequivocal appearance of
`any new lesions or an increase of~ 25% in the sum of the perpen(cid:173)
`dicular diameters of any measured lesion or in the estimated size of
`a nonmeasurable lesion. MR, SD, and PD were considered to be
`treatment failures.
`
`Pharmacokinetic Studies
`During the initial treatment cycle, three venous samples were col(cid:173)
`lected from each patient: one before Taxol and two during the last
`2 hours of the infusion (between hours 22 and 23) with at least 30
`minutes separating these final two samples. At each sampling, 7 to
`10 mL of blood was collected in a heparinized tube. This was cen(cid:173)
`trifuged to separate the plasma, which was then transferred to a conical
`1 S-mL polypropylene screw-top tube and stored at - 20°C. An aliquot
`of the infusate from each patient was also stored at -20°C.
`Taxol levels in plasma samples were measured by a reverse-phase
`high-performance high-performance liquid chromatography (HPLC)
`method described by Jamis-Dow et al.11 Briefly, cepbalomannine
`was added as an internal standard to 0.5 mL of plasma standard or
`sample. Each sample or standard was extracted on a C11 solid-phase
`extraction column. The extracts were dried under vacuum, recon(cid:173)
`stituted in mobile phase, and resolved by HPLC. Samples were chro(cid:173)
`matographed isocratically, with 45% acetonitrile in water at a flow
`rate of I mL/min. Separation was accomplished on an octadecylsilane
`(ODS) Hypersyl C18, 5 µmol/L, 100 X 4.6-mm column (Hewlett(cid:173)
`Packard Co, Palo Alto, CA) with a C11 prccolumn insert (Millipore
`Corp, Milford, MA). Taxol and ccphalomannine were quantitated
`at 230 nm with peak confirmation by diode-array detection.
`
`StaJisticaJ Methods
`The two-stage phase ll design reported by Geban11 was applied
`for this study. Therapeutic responses were seen in the first 14 patients,
`so accrual was extended to estimate the response rate better. Duration
`of response and survival determinations were measured from the
`date of initiation ofTaxol.
`
`RESULTS
`
`Patients
`Between April 8 and October 24, 1991, 28 patients
`were accrued to this study (Table 2). The median age
`was 52 years (range, 30 to 67) and the median Karnofsky
`performance status was good at 90% (range, 70% to
`
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`
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`
`Tobie 2. Patient Characteristics
`
`Chorocteri$1i(
`
`No. entered
`No. assessable
`Age, years
`Median
`Range
`Karnofsky performance status (%)
`Median
`Range
`Menopausal status
`Pre-
`Post-
`Sites of metastatic disease
`Bone
`lung
`liver
`lymph nodes
`Soft tiuue
`No. of metastatic disease sites
`l
`2
`;,:. 3
`Prior theropy
`No prior adjuvant chemotherapy
`Prior odjuvont chemotherapy
`CMF
`CMFVP
`CAF
`CAMF
`CAMFV
`Prior hormonal therapy
`Adjuvont only
`Metastatic only
`Both
`Time from prior adjvvant therapy
`to study entry, months
`Medi on
`Ronge
`
`No.
`
`28
`26
`
`52
`30-67
`
`90
`70- 100
`
`9
`19
`
`17
`10
`11
`16
`14
`
`5
`12
`11
`
`ll
`17
`8
`l
`6
`
`l
`II
`s
`2
`4
`
`20
`12- 47
`
`32
`68
`
`54
`36
`39
`57
`4Q
`
`18
`43
`39
`
`39
`61
`
`39
`
`Abbreviotions, C, cyclophosphomide; M, methotrexote; F, ffuorouracil;
`V, vincristine; P, prednisone; A, doxorubicin.
`
`100%). However, 82% of patients had two or more sites
`of metastatic disease, and I 1 (39%) had at least three
`sites of metastatic disease. Seventeen patients (61 %) had
`received prior ad ju vant chemotherapy, with a . median
`time interval from completion of adjuvant chemotherapy
`to study entry of 20 months (range, 12 to 47). Eight pa(cid:173)
`tients had received doxorubicin-containing adjuvant
`chemotherapy, and nine had received cyclophospha(cid:173)
`mide, methotrexate, and fluorouracil (CMF) variants.
`Two patients had received vincristine as part of the ad(cid:173)
`juvant chemotherapy regimen. Eleven patients (39%) had
`received hormonal therapy: five in the adjuvant setting,
`two for treatment of metastatic disease, and four for
`both.
`
`REICHMAN ET Al
`
`Therapeutic Responses
`Twenty-six of 28 patients entered were assessable for
`response. The other two patients were not assessable for
`response, but were evaluated for toxicity. One patient had
`received her first cycle of treatment when it became nec(cid:173)
`essary to administer radiation therapy for a cervical spine
`fracture, which became apparent only after a motor vehicle
`accident. The other patient had received two prior hor(cid:173)
`mone regimens as treatment for stage IV breast cancer,
`but this information was withheld at the time of study
`entry. This latter patient had stable disease after four cycles
`of treatment with Taxol.
`Objective responses were observed in 16 of 26 fully
`assessable patients (62%; 95% confidence interval, 41 % to
`80%) (Table 3). Three CRs ( 12%; 95% confidence interval,
`2% to 30%) were seen: one patient had complete resolution
`of supraclavicular lymphadenopatby and pleural effusion,
`another had disappearance of supraclavicular and cervical
`lymphadenopathy by physical examination and CT scan,
`and the third had disappearance of supraclavicular
`lymphadenopathy and histologically confirmed resolution
`of diffuse involvement of the skin of the anterior and pos(cid:173)
`terior chest wall. She had received adjuvant radiation to
`the anterior chest wall, as well as adjuvant doxorubicin(cid:173)
`containing chemotherapy. There were 13 PRs (50%; 95%
`confidence interval, 30% to 70%), which were observed
`in all sites of metastatic disease.
`Hormone receptor status did not appear to influence
`response. Although menopausal status per se did not in(cid:173)
`fluence the probability of response, responses were seen
`more frequently in women younger than 50 years of age
`(J 1 of 14 [79%) v five of 12 [42%), P = .105, two-sided
`Fisher's exact test). The median age of patients with re(cid:173)
`sponding tumors was 45.5 years (range, 30 to 67), as com(cid:173)
`pared with 55 years (range, 37 to 64) for patients whose
`tumors did not respond.
`Prior adjuvant treatment did not appear to influence
`response to Taxol (Table 4). Six PRs occurred in the 10
`patients who did not receive prior adjuvant chemotherapy.
`Ten of 16 patients (63%) who had received prior adjuvant
`
`Tobie 3. Therapeutic Response•
`
`Response
`
`CR
`PR
`CR + PR
`MR
`so
`PD
`
`No.of
`Potients
`
`3
`13
`16
`4
`0
`6
`
`Percent
`
`12
`50
`62
`
`95% Confl<lence
`Interval
`
`2-30
`30-70
`41 -80
`
`Note. N = 26 patients ossessoble for response .
`
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
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`PACLITAXEL AND rhG-CSF IN METASTATIC BREAST CANCER
`
`1947
`
`Table 4. Response by Prior Therapy (N • 26)
`
`Adjuvont Chemolh0topy
`(n • 16)
`
`Prk>r Regimen
`{no. of potients)
`
`2 CMF (n ; 7)
`1 CAF (n ; 8)
`2 CMF (n = 7)
`1 CMFVP (n • 11
`4 CAF (n = 8)
`1 CMF (n s 7)
`I CAF (n p 8)
`
`2 CMF (n • 71
`2 CAF (n ; 2)
`
`Response
`roloxol
`
`No.of
`Patients
`
`CR
`
`PR
`
`MR
`
`so
`PD
`
`3
`
`7
`
`2
`
`0
`4
`
`Overall Response Rote
`No.
`10/ 16
`63
`%
`
`No Adjuvont
`Chemother opy
`(n • 10)
`
`0
`
`6
`
`2
`
`0
`2
`
`6110
`60
`
`Abbreviations: C, cyclophosphamide; M, methotrexote; f , lluorourocll:
`V, vincris.tine; P. prednisone; A, doxorubicin.
`
`chemotherapy responded to Taxol. These included one
`CR and four PRs in patients who had previously received
`doxorubicin-containing adjuvant chemotherapy, and two
`CRs and three PRs in patients who had received adjuvant
`CMF, one of whom bad also received prior vincristine.
`Responses to Taxol were seen in six of 10 patients who
`had received prior hormone treatment: three of five who
`bad received adjuvant hormone treatment, and three of
`five who had received such treatment for advanced disease.
`The median time to first objective response (which is
`defined as the occurrence of a PR, even in patients even(cid:173)
`tually achieving a CR) was short at a median of 5 weeks
`(range, I to 14 ). Two of three patients whose tumors re(cid:173)
`sponded completely achieved their best response at 6
`weeks and 12 weeks. The third patient's skin disease, which
`had achieved a PR at 6 weeks, continued to resolve slowly
`and a pathologic CR was documented at 57 weeks. It is
`of note that this patient's dermal metastases were partially
`in a site of prior radiation therapy. Her supraclavicular
`lymphadenopathy had resolved completely by 3 weeks.
`Excluding this patient, the median time to best response
`was 6 weeks, with a range of I to 14 weeks.
`Due to the limited supply ofTaxol, it was necessary to
`remove patients from study when they had received two
`treatment cycles beyond their best response. Subsequent
`therapy was unspecified by the protocol, so response du(cid:173)
`ration and survival cannot be assessed.
`
`Toxicity
`ln general, treatment was well tolerated. The predom(cid:173)
`inant toxicity was hematologic, with a deep but brief
`
`granulocyte nadir. The first two patients who received
`treatment did not receive rhG-CSF with any of their treat(cid:173)
`ment cycles. Both patients had significant WBC nadirs
`(0.1 and 0.2 cells/µL), which lasted 7 and 8 days. One was
`hospitalized for 4 days for treatment offebrile neutropenia
`without a documented source. Both patients received ad(cid:173)
`ditional treatment at 200 mg/m2 without growth factor
`support: one received three cycles and the other seven
`cycles with no further significant toxicity.
`Because of these two cases and the depth and duration
`of neutropenia reported by investigators from the M.D.
`Anderson Hospital, all subsequent patients received rhG(cid:173)
`CSF. 14 One hundred seventy-eight cycles of treatment were
`administered, with a median of six cycles per patient
`(range, one to 19) (Table 5). Only one patient received
`one cycle at the escalated dose of 300 mg/m2
`; this was
`well tolerated, but treatment was discontinued because of
`PD. Dose reductions were necessary in the second cycle
`for 12 of26 patients. Subsequently, dose reductions were
`necessary for four patients in cycle no. 3, for three patients
`in cycle no. 4, for one patient in cycle no. 6, and for one
`patient in cycle no. I 0. Five patients had treatment re(cid:173)
`duced by two dose levels, but one of these patients had
`subsequent dose reescalation to 200 mg/m2
`, which was
`well tolerated. One patient had three sequential dose re(cid:173)
`ductions, with a final dose level of 160 mg/m2• This patient
`had a CR. Neutropenia was the reason for dose reduction
`in all but one patient, who received modified doses because
`of nausea and emesis. Of 178 cycles administered, there
`we.re eight admissions (4%) for treatment of febrile neu(cid:173)
`tropenia, involving six of 28 patients (21 % ). One patient
`was hospitalized for three episodes of neutropenic fever,
`
`Table 5. Extent of Administered Therapy
`
`No. of
`cycles
`
`28
`26
`25
`23
`17
`17
`11
`9
`6
`5
`3
`I
`178
`
`Cycle
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12- 19
`T otol cycle•
`No.
`%
`
`Dose (mg/m'l
`
`160
`
`180
`
`200
`
`250
`
`275
`
`300
`
`28
`13
`10
`8
`6
`6
`3
`
`11
`13
`11
`8
`8
`5
`5
`3
`2
`
`1
`2
`4i
`3
`3
`3
`3
`3
`2
`1
`8
`
`2
`
`33
`18.5
`
`67
`38
`
`75
`42
`
`0
`0
`
`1
`.5
`
`NOTE. Toto! of 178 patient cycle ..
`
`Downloaded from ascopubs.org by INFOTRIEVE on March 2, 2018 from 216.033.062.017
`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`
`
`6 of 10
`
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`
`

`

`1948
`
`only one of which was associated with a source (positive
`cultures of blood and urine). Treatment was never delayed
`for slow hematologic recovery. The two treatment delays
`observed were because of a mediport catheter infection
`and for a pericardia! effusion that required surgery.
`The degree of myelotoxicity associated with the first
`cycle of treatment (including the two patients who did
`not receive rhG-CSF) is listed in Table 6. More than half
`of our patients had neutrophil nadirs less than 500 cells/
`µL, and 25% bad WBC counts less than 1,000 cells/µL.
`Severe thrombocytopenia was seen in only one patient.
`With rhG-CSF, granulocyte nadirs occurred approxi(cid:173)
`mately 1 week after Taxol. The two patients who did not
`receive rhG-CSF experienced leukocyte nadirs at day 14
`and day 15. One of these patients had relatively prolonged
`myelosuppression of 8 days' duration. In the 16 patients
`who had grade 4 neutropenia, the median time to recovery
`to more than 500 granulocytes/µL was 3.5 days (range, 1
`to 8). Median nadir counts associated with subsequent
`treatment cycles are listed in Table 7.
`In the first cycle, only one patient required transfusions
`of platelets and packed RBCs. This patient required hos(cid:173)
`pitalization for neutropenic fever associated with oral and
`rectal bleeding, hematuria, mucositis, and disseminated
`intravascular coaguJopathy. In this case, extensive hepatic
`metastases were present at study entry, with more than
`50% liver involvement on CT scan, a bilirubin level of
`1.2 mg/dL, AST level of309 mg/dL, lactate dehydrogenase
`level of 429 mg/dL, and an alkaline phosphatase level of
`789 mg/dL. This patient had rapid progression of hepatic
`metastases after the first cycle of treatment.
`Generalized alopecia was universal and always occurred
`within the first three cycles of treatment. Mild peripheral
`sensory neuropathy ( < grade 2+) was seen in 79% of pa(cid:173)
`tients. No patient had disabling sensory or motor neu(cid:173)
`ropathy. Mild to moderate myalgias and arthralgias (grade
`I to 2+) were observed in all patients and were exacerbated
`during rhG-CSF administration. These symptoms were
`relieved with nonnarcotic analgesics in all but four pa(cid:173)
`tients. Nausea and vomiting, diarrhea, and mucositis were
`mild when reported. Only one patient (the patient with
`extensive liver metastases) required hospitalization for se(cid:173)
`vere mucositis and dehydration, but this was associated
`with concomitant pancytopenia and fever. Another pa(cid:173)
`tient was hospitalized for grade 3 nausea and vomiting,
`but this patient did not experience notable myelosup(cid:173)
`pression. She had progressive respiratory insufficiency and
`on further evaluation was found to have an enlarging
`pericardia! effusion. Drainage of the malignant effusion
`and placement of a subxiphoid pericardia! window re(cid:173)
`sulted in symptomatic improvement. She received two
`
`REICHMAN ET Al
`
`Table 6. Cycle No. 1 Myel otoxicity: CTEP Toxicity
`
`mG-CSF
`
`No rhG·CSF
`
`No.
`
`26
`
`5
`3
`5
`8
`5
`
`8
`
`l
`2
`14
`
`20
`5
`
`11
`6
`8
`
`No. of potients
`Toxicity (grodel
`WBC count
`0
`l
`2
`3
`4
`ANC
`0
`1
`2
`3
`4
`Plotelets
`0
`1
`2
`3
`4
`HGB
`0
`1
`2
`3
`4
`
`%
`
`19
`12
`19
`31
`19
`
`31
`4
`4
`8
`54
`
`77
`19
`
`4
`
`42
`23
`31
`
`4
`
`No.
`
`2
`
`%
`
`2
`
`100
`
`2
`
`2
`
`100
`
`100
`
`2
`
`100
`
`Abbreviations, CTEP, Cancer T reotment Evoluotion Progrom; ANC, ob·
`solute neutrophil count; HGB, hemoglobin.
`
`additional cycles at 200 mg/m2 without significant toxicity.
`She died of PD 26 days after treatment was discontinued.
`No significant hypersensitivity reactions were observed.
`No cardiac toxicity was encountered. No significant
`changes in vital signs during the infusion were observed
`either during the first hour, when they were monitored
`every 15 minutes, or subsequently, when they were mea(cid:173)
`sured at 8-hour intervals. Mild facial flushing was com(cid:173)
`mon, but this may have been due to the premedication
`wi