1377
`
`Paclitaxel Administered by I -Hour
`Infusion
`Preliminary Results of a Phase 1/11 Trial Comparing
`Two Schedules
`lohn D. Hainsworth, M.D., and F. Anthony Greco, M.D.
`
`Background. Paclitaxel currently is administered by
`prolonged intravenous infusion because of the occur-
`rence of severe hypersensitivity reactions in patients in
`early clinical trials. However, intensive premedication
`probably is more important in eliminating allergic reac-
`tions than is the length of infusion. The authors evalu-
`ated the feasibility of two paclitaxel schedules using a 1-
`hour, outpatient infusion.
`Methods. Fifty-six patients with advanced, refrac-
`tory malignancies were randomized to receive one of two
`paclitaxel schedules: 135 mg/m2 administered as a single
`dose over 1 hour, or 135 mg/m" administered in divided
`daily doses for 3 days, each over 1 hour. All patients were
`premedicated with dexamethasone, diphenhydramine,
`and cimetidine.
`Results. No serious hypersensitivity reactions oc-
`curred with either schedule of paclitaxel. In addition,
`other adverse effects were usually mild and easily toler-
`ated. Other than alopecia, which occurred in all patients,
`myelosuppression was the most common severe toxicity.
`However, grade 3 leukopenia occurred in only 19% of
`treatment courses, and grade 4 leukopenia (nadir < 1000/
`NL) occurred in only 2%. Nine patients required hospital-
`ization for treatment of infection associated with neutro-
`penia. No significant differences in toxicity were ob-
`served when the two paclitaxel regimens were compared.
`Although it is too early to assess the results adequately,
`preliminary findings showed that thus far 11 of 56 pa-
`tients (20%) had a partial or complete response to ther-
`apy. Responses were observed in patients with breast,
`ovarian, and lung cancer.
`Conclusions. Paclitaxel can be safely administered in
`a 1-hour infusion in an outpatient setting, either as a sin-
`gle dose or in divided doses for three days. Severe hyper-
`
`From the Sarah Cannon (Minnie Pearl) Cancer Center, Nash-
`ville, Tennessee.
`Supported in part by a grant from Bristol-Myers.
`Address for reprints: John D. Hainsworth, M.D., Sarah Cannon
`Cancer Center, 250 25th Avenue North, Suite 412, Nashville, TN
`37203.
`Received March 17, 1994; revision received April 21, 1994; ac-
`ceptedApril21,1994.
`
`sensitivity reactions did not occur in 162 treatment
`courses, and neutropenia was mild in most patients. In-
`corporation of this dose and these schedules of paclitaxel
`into combination chemotherapy regimens should be fea-
`sible. An investigation of higher paclitaxel doses given in
`a 1-hour infusion is currently in progress. Cancer 1994;
`74~1377-82.
`
`Key words: paclitaxel, Phase I1 trial, 1-hour infusion
`schedules, hypersensitivity reactions.
`
`The clinical development of paclitaxel has been accom-
`panied by a great deal of anticipation and enthusiasm
`due to the novel mechanism of action of this drug and
`its wide range of antineoplastic activity. Paclitaxel is the
`first clinically available taxane, a group of compounds
`that cause cytotoxicity by stabilizing the microtubules
`and thereby inhibiting the dynamic reorganization of
`this network necessary for cell division.' Paclitaxel con-
`centrations as low as 0.05 pmol/l promote microtubule
`assembly in vitro;' serum levels greater than 10 times
`this high can be achieved in humans with clinically tol-
`erable doses.3r4 Despite relatively limited clinical trials,
`paclitaxel has demonstrated substantial activity in resis-
`tant ovarian cancer, breast cancer, and lung ~ a n c e r . ~ - ~
`Severe hypersensitivity reactions caused by pacli-
`taxel were observed early in its clinical development
`and led to discontinuation of early trials. Kris et al. re-
`ported severe reactions characterized by acute dyspnea,
`urticaria, and hypotension immediately after the initia-
`tion of paclitaxel infusion in 3 of 5 patients receiving
`total doses greater than 190 mg/m2.9 Similar observa-
`tions were made by Grem et al; two of their first nine
`patients experienced anaphylaxis." These patients
`were receiving paclitaxel over 1 hour on a daily sched-
`ule for 5 consecutive days, so that daily doses of pacli-
`taxel were low (5-15 mg/m'/day). In both reports, ana-
`phylaxis usually occurred with the first dose of pacli-
`taxel and began within minutes after the infusion was
`initiated. Anaphylaxis was thought to be due either to
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`1378 CANCER August 25,2994, Volume 74, No. 4
`
`the paclitaxel itself or to the cremophor vehicle in which
`paclitaxel is formulated; the rate of administration was
`also thought to be an important factor in producing hy-
`persensitivity reactions.
`As a result of these observations, two important
`modifications were made in subsequent clinical trials.
`First, premedication with corticosteroids, cimetidine,
`and diphenhydramine was initiated before treatment
`with paclitaxel. Second, the duration of paclitaxel infu-
`sion was lengthened, so that in most subsequent trials,
`paclitaxel was administered by continuous infusion
`over a 24-hour period. With these modifications, severe
`hypersensitivity reactions were largely abolished and
`have occurred in only 1-2% of patients in recently re-
`ported studies. 11*12
`Because two changes in the technique of paclitaxel
`administration were made simultaneously, it is unclear
`whether the premedication or the prolonged schedule
`of administration was responsible for decreasing hyper-
`sensitivity reactions. Nevertheless, the 24-hour contin-
`uous infusion was approved by the Federal Drug Ad-
`ministration for routine use. More recently, 3-hour con-
`tinuous infusions have also proven safe, and a recent
`randomized trial demonstrated significantly reduced
`myelosuppression with the shorter infusion schedule.12
`Because myelosuppression is less with a 3-hour infu-
`sion, it is possible that tumor cytotoxicity is also de-
`creased; however, response rates in relapsed ovarian
`cancer were not significantly different with 3-hour ver-
`sus 24-hour infusions.12 The administration of pacli-
`taxel by 3-hour infusion simplifies its use, because hos-
`pitalization can be avoided. However, a 3-hour infusion
`is still rather cumbersome for routine use in the outpa-
`tient setting.
`The current preliminary report principally de-
`scribes the toxicity results of a prospective, randomized
`study evaluating two different schedules of paclitaxel
`administered by a 1-hour infusion. We administered
`paclitaxel either by a 1-hour infusion on a single day
`or in 1-hour doses on three consecutive days. Giving
`paclitaxel by 1-hour infusion is easier and more eco-
`nomical than using longer infusions; either schedule
`can be easily administered in the outpatient setting.
`Toxicity of these two 1-hour paclitaxel regimens are re-
`ported in detail along with preliminary efficacy data.
`
`Patients and Methods
`
`Patients who had advanced cancer and were either re-
`sistant or refractory to standard therapy were eligible
`for the current study. Sensitive tumor types (e.g., breast
`cancer, ovarian cancer, limited stage small cell lung can-
`cer, non-Hodgkin's lymphoma) were eligible only if
`they had progressed after standard treatment. Other
`patients with primarily resistant tumor types (e.g., non-
`
`small cell lung cancer) were eligible for this treatment
`as first-line therapy. Although all types of malignancies
`were considered for this Phase 1/11 study, an attempt
`was made to enter patients with ovarian, breast, or lung
`cancer, because these tumor types had been previously
`demonstrated to be sensitive to paclitaxel. All patients
`had measurable or evaluable metastatic lesions. Eligi-
`bility requirements included the following: leukocyte
`count greater than or equal to 3000/~1; platelet count
`greater than or equal to 90,0OO/pl; Eastern Cooperative
`Oncology Group (ECOG) performance status of 0, 1, or
`2; and expected survival of at least 10 weeks. Patients
`were ineligible if they had a history of congestive heart
`failure, second- or third-degree heart block, or an acute
`myocardial infarction within 4 months before study en-
`try. Patients who had experienced previous allergic re-
`actions to any drugs mixed with cremophor solubilizer
`(e.g., radiocontrast material, vitamin K) were also ineli-
`gible. All patients gave written informed consent before
`study entry.
`Before receiving treatment, all patients had the fol-
`lowing laboratory studies: complete blood count,
`differential platelet count, electrolytes, chemistry pro-
`file, prothrombin time, partial thromboplastin time,
`chest X-ray, and electrocardiogram. Additional radio-
`logic studies were performed as necessary for evalua-
`tion of tumor extent and to obtain tumor measurements.
`Patients were stratified according to performance
`status (ECOG 0 and 1 versus ECOG 2) and primary dis-
`ease site and were then randomized by a random card
`system to one of two schedules of paclitaxel. All pa-
`tients received paditaxel at a dose of 135 mg/m2; this
`was either administered as a single dose given over 1
`hour or given on 3 consecutive days for over 1 hour
`each day. Doses were repeated every 21 days. To ad-
`minister paclitaxel over 1 hour, the dose was mixed in
`250 ml normal saline and administered as a rapid intra-
`venous infusion.
`Before receiving paclitaxel, all patients were pre-
`medicated with 20 mg dexamethasone given orally 12
`hours and 4 hours before therapy. In addition, the fol-
`lowing drugs were administered intravenously 30 min-
`utes before paclitaxel infusion: dexamethasone, 20 mg;
`diphenhydramine, 50 mg; and cimetidine, 300 mg. In
`patients receiving the 3-day schedule, prernedications
`were administered on each day of treatment.
`All patients were treated as outpatients unless they
`were hospitalized for other reasons before paclitaxel
`therapy was initiated. During the entire infusion of
`paclitaxel, patients were monitored continuously by a
`nurse. Vital signs were recorded every 15 minutes. Pa-
`tients did not have continuous cardiac monitoring;
`however, any patient complaining of chest pain or other
`respiratory symptoms immediately had the paclitaxel
`infusion stopped and an electrocardiogram performed.
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`

`One-Hour Paclitaxel Infusion/Hainsworth and Greco
`
`If any symptoms of severe acute hypersensitivity reac-
`tions occurred, the paclitaxel infusion was to be discon-
`tinued and standard treatment for anaphylaxis insti-
`tuted immediately.
`After paclitaxel administration, patients had com-
`plete blood counts checked weekly. Patients were eval-
`uated for response to treatment after two courses of
`therapy. In addition to remeasurement of metastatic le-
`sions, patients had electrolytes, screening chemistries,
`and electrocardiograms repeated. Patients with prog-
`ressive disease were considered treatment failures and
`removed from the study. Those with stable dsease or
`objective tumor response were eligible to continue ther-
`apy until tumor progression occurred or for a maximum
`of 12 courses.
`No dose escalation was planned during this study.
`Patients experiencing severe hypersensitivity reactions
`with symptoms including dyspnea, wheezing, severe
`hypotension or hypertension, or generalized urticaria
`were removed from the study. Immediate treatment for
`severe hypersensitivity reactions was available and in-
`cluded administration of epinephrine, 0.35-0.5 ml sub-
`cutaneously; diphenhydramine, 50 mg intravenously;
`and normal saline, 250 ml/hour. Epinephrine could be
`repeated every 15 minutes until symptoms subsided;
`nebulized albuterol, 0.3 ml, was available if wheezing
`was a prominent symptom. Patients with mild symp-
`toms of hypersensitivity to paclitaxel were allowed to
`continue on study but were monitored closely during
`subsequent courses. At the initiation of the study, it was
`decided to terminate the study prematurely if 2 of the
`first 5 patients treated experienced severe (Grade 4) hy-
`persensitivity reactions or if 5 of the first 10 patients ex-
`perienced severe myelosuppression.
`Dose reductions for myelosuppression were based
`on the day 21 leukocyte count. If the leukocyte count
`was greater than 3500/p1, a full dose was administered.
`Criteria for dose reductions were as follows: leukocyte
`count 2500-3500/pl, 75% dose administered; leuko-
`cyte count less than 2500/p1, treatment delayed 1 week
`and then a 75% dose administered. Dose reductions
`based on platelet counts were as follows: platelets less
`than 75,OOO/pl, treatment withheld 1 week and then
`a 75% dose administered; platelets 75,000-125,0OO/pl,
`75% dose given; platelets greater than 125,00O/pl, full
`dose given. With the exception of alopecia and myal-
`gias, patients experiencing other Grade 3 or 4 toxicities
`(as determined using ECOG toxicity criteria), received a
`75% dose of paclitaxel on subsequent cycles. This dose
`was administered on day 21 if the treatment-related
`toxicity had already resolved and was delayed 1 week if
`symptoms persisted on day 21.
`Although determination of antitumor activity was
`not the primary objective of this study, all patients were
`evaluated for treatment response after completion of
`
`Table 1. Patient Characteristics [n = 56)
`Characteristic
`Median age (range)
`Sex (male/female)
`ECOG performance status
`0
`1
`2
`Cancer type
`Breast
`Lung, non-small cell
`Ovarian
`Lung, small cell
`Colorectal
`Non-€Iodgkin lymphoma
`Prostate
`Sarcoma
`Hypopharynx
`Adenocortical
`Parotid (adentxystic)
`Pancreas (neuroendocrine)
`No. of previous chemotherapy regimens
`0
`1
`L
`> 2
`
`1379
`
`No. (%)
`57 (30-73)
`20/36
`
`8
`39
`9
`
`17
`16
`9
`5
`2
`1
`1
`1
`1
`1
`1
`1
`
`7
`18
`15
`16
`
`two courses of therapy. All patients were assigned re-
`sponse categories using standard definitions. Complete
`response required the complete resolution of all objec-
`tive evidence of tumor for at least 3 months. Partial re-
`sponse occurred when measurable lesions decreased by
`50% or more in the product of perpendicular diameters
`for at least 1 month and no new lesions appeared. Min-
`imal response occurred when the objective decrease in
`size was less than 50% but greater than 25% in the
`products of perpendicular diameters for at least 1
`month with no new lesions. Stable disease occurred
`when measurable lesions changed by less than 25% in
`the products of perpendicular diameters and no new le-
`sions appeared during treatment. Progressive disease
`occurred when measurable lesions increased by more
`than 25% during treatment.
`In consenting patients, blood and urine samples
`were obtained for pharmacokinetic studies. Results of
`pharmacokinetic analyses will be reported at a later
`time. The toxicities encountered with the two taxol
`schedules were compared using the standard chi-
`square test applied at a significance level of P = 0.05.
`Patient characteristics are outlined in Table 1. Be-
`tween March 1993 and August 1993, 56 patients en-
`tered the study. The median age was 57 years (range,
`30-73 years). Most patients (69%) had an ECOG per-
`formance status of 1. Eighty-four percent of patients
`had either breast, lung, or ovarian cancer. Eighty-seven
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`1380 CANCER August 25,1994, Volume 74, No. 4
`
`percent of patients had received previous chemother-
`apy; 55% had received two or more previous regimens.
`Twenty-eight patients received the 1-day paclitaxel
`schedule and 28 received the 3-day schedule.
`
`Results
`
`The 56 patients in the current study have received 162
`courses of paclitaxel. Ninety courses were administered
`by the 1-day schedule, whereas 72 courses were admin-
`istered by the 3-day schedule. Twenty-nine patients
`have been removed from the study, whereas 27 are con-
`tinuing to receive paclitaxel. The number of courses re-
`ceived ranged from one to eight; 29 patients have re-
`ceived more than two courses, and 11 of these patients
`remain on study. Four patients were removed from
`study after receiving only one course of paclitaxel; all of
`these patients were withdrawn prematurely because of
`rapidly progressive tumor. All 56 patients were evalu-
`able for toxicity.
`
`Toxicity
`
`No serious hypersensitivity reactions were encountered
`with either paclitaxel schedule. Allergic symptoms were
`
`Table 2. Nonhematologic Toxicity
`3-Day
`1-Day
`Grade
`(ECOG scale) Total schedule schedule
`
`Adverse effect
`
`I lypersensitivity
`reactions
`Urticaria
`
`WheeAng/dyspnea
`Flushing
`Pruritus
`Alopecia
`Myalgias
`
`Fatigue/weakness
`
`Nausea
`
`Emesis
`
`Mucositis
`
`Diarrhea
`
`Light-headedness
`Headache
`PeriDheral neurouathv
`Values are no. uf patients.
`
`1
`2
`1
`1
`1
`4
`1
`2
`3
`1
`2
`3
`1
`2
`3
`1
`2
`1
`2
`1
`2
`1
`1
`1
`
`1
`1
`1
`2
`1
`56
`9
`14
`9
`5
`16
`5
`9
`6
`2
`4
`2
`7
`3
`2
`3
`2
`2
`1
`
`0
`0
`1
`1
`1
`28
`7
`7
`4
`2
`10
`3
`4
`4
`1
`3
`0
`2
`3
`1
`3
`1
`0
`1
`
`1
`1
`0
`1
`0
`28
`2
`7
`5
`3
`6
`2
`5
`2
`1
`1
`2
`5
`0
`1
`0
`1
`2
`0
`
`Table 3. Myelosuppression
`
`Nadir
`
`1-Day
`Total (I) schedule
`
`3-Day
`schedule
`
`Leukeopenia
`(leukocyte)
`
`3000 3900
`2000-2900
`iuoo-i900
`< 1000
`
`Thrornbocyiopenia
`(platelet)
`
`75,000-99,000
`50,000-74,000
`25,000-49,000
`< 25,000
`Values are no of episodes
`
`17(10%)
`32 (20%)
`30 (18%)
`4 (2%)
`
`3 (2%)
`6 (4%)
`6 (4%)
`2 (1%)
`
`7
`19
`12
`3
`
`3
`5
`5
`2
`
`10
`13
`18
`1
`
`0
`1
`1
`0
`
`seen in 6 of 162 courses; 5 of these were ECOG Grade 1
`reactions and one was a grade 2 reaction, as shown in
`Table 2. Four episodes occurred with the 3-day sched-
`ule and two occurred with the 1-day schedule. All hy-
`persensitivity reactions occurred on the first day of
`treatment.
`Myelosuppression was common but was mild or
`moderate in most patients (Table 3). Nadir leukocyte
`counts of 1000-2000/~1 occurred during 30 courses
`(1 8%), whereas Grade 4 toxicity (leukocyte count <
`lOOO/pl) occurred in only 4 instances (2%). Nine hos-
`pitalizations in eight patients were required for treat-
`ment of infections associated with neutropenia. In five
`instances, blood cultures were positive. Two patients
`had localized infections (one patient had pneumonia
`and the other had Groshong catheter infection). All pa-
`tients received intravenous antibiotics and recovered
`from these episodes. All episodes of Grade 4 neutro-
`penia and all hospitalizations for neutropenia and fever
`occurred in patients who had received two or more pre-
`vious chemotherapy regimens.
`Duration of Grade 3 and 4 neutropenic episodes
`was generally brief, and treatment delays were neces-
`sary in only two treatment courses. Three patients re-
`quired dose reductions to 75% of the starting dose after
`Grade 3 or 4 neutropenia. Cytokines were used only in
`patients hospitalized with neutropenia and fever. The
`two schedules of paclitaxel were not significantly
`different with regard to the incidence of severe neutro-
`penia.
`Thrombocytopenia was infrequent, and Grade 3 or
`4 thrombocytopenia occurred in only 8 of 162 courses
`(5%). No patients had hemorrhagic probIems related to
`thrombocytopenia.
`Toxicities other than myelosuppression are out-
`lined in Table 2. Total alopecia occurred in all patients.
`Myalgias and fatigue occurred 57% and 46% of pa-
`tients, respectively. However, these side effects were
`usually mild; only nine patients (1 6%) had Grade 3 my-
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`One-Hour Paclitaxel Infusion/Hainsworth and Greco
`
`algias and five patients (9%) had Grade 3 fatigue. Be-
`cause all patients in the current study had advanced
`cancer, it is probable that fatigue was multifactorial in
`some instances. Gastrointestinal symptoms were un-
`common, and only one patient experienced severe
`(Grade 3) nausea. Only one patient experienced mild
`(Grade 1) peripheral neuropathy.
`
`Responses
`
`Although the assessment of toxicity was the primary
`objective of this study, all patients were also evaluated
`for tumor response. Forty-eight of 56 patients were
`evaluable for response; the remaining 8 patients are
`considered treatment failures because they declined
`rapidly as a result of their cancer and did not receive
`two full courses of therapy.
`Eleven of 56 patients (20%) had major responses to
`paclitaxel (two complete responses, nine partial re-
`sponses). Seven responding patients received the 1 -day
`schedule, and four patients (including both patients
`with complete response) received the 3-day schedule.
`Responses were distributed by tumor type as follows:
`breast cancer, 6 of 17 (35%); ovarian cancer, 3 of 9
`(33%); and non-small cell lung cancer, 2 of 16 (13%).
`Twenty-seven additional patients had either stable dis-
`ease or minimal response after two courses of therapy,
`and many of these are still receiving therapy. The pa-
`tients with stable disease or minimal response will be
`reevaluated for response status after four courses are
`administered. The final response rate and the duration
`of response is unknown, because a sizable number of
`patients are continuing therapy.
`
`Discussion
`
`Paclitaxel has demonstrated a wide range of antineo-
`plastic activity; however, its role in the treatment of can-
`cer has not yet been defined. To date, most studies have
`evaluated paclitaxel as a single agent in patients with
`advanced, refractory neoplasms. Although activity has
`been observed, it is unlikely that the use of paclitaxel in
`this way will have any major effect on overall treatment
`results. As with other active antineoplastic agents,
`paclitaxel is most likely to have an effect when used in
`combination with other drugs at a time when patients
`still have sensitive tumors. However, the dose and
`schedule of paclitaxel used in reported Phase I1 studies,
`particularly in breast cancer, make successful combina-
`tion with other agents problematic due to toxicity.
`Therefore, the optimal dose and schedule of paclitaxel
`administration remain undefined, as well as its use in
`combination regimens.
`In the current preliminary report, we present new
`data concerning the schedule of paclitaxel administra-
`
`1381
`
`tion. The 1-hour schedules we have investigated have
`several potential advantages. First, recent data have
`shown that the same dose of paclitaxel is less myelo-
`suppressive when given over 3 hours versus 24 hours.'*
`A 1-hour infusion may further lessen toxicity. Second,
`reduction of myelosuppression (and perhaps other
`paclitaxel-related adverse effects) may allow escalation
`of dose and/or successful combination with other my-
`elosuppressive agents. Finally, a short infusion would
`allow paclitaxel to be easily administered to outpatients,
`thereby creating an easier treatment for patients as well
`as reducing the cost of therapy.
`The major adverse effect of paclitaxel that led to the
`adoption of a 24-hour continuous infusion schedule
`was the occurrence of severe hypersensitivity reactions.
`In the current study, we unequivocally demonstrated
`that paclitaxel can be safely administered by a 1-hour
`infusion when adequate prernedications are given. We
`encountered no severe hypersensitivity reactions in 162
`courses; only six patients had mild allergic reactions. Se-
`vere hypersensitivity reactions to paclitaxel are there-
`fore prevented by the premedication schedule, and
`with adequate premedication the length of infusion ap-
`pears unrelated to hypersensitivity reactions.
`Both of the paclitaxel schedules reported in the cur-
`rent study were well tolerated with respect to myelo-
`suppression. Despite the fact that many of these
`patients were heavily pretreated, Grade 3 or 4 myelo-
`suppression was uncommon, and only nine hospitaliza-
`tions resulted from infections associated with neutro-
`penia (5% of total courses). The duration of neutropenia
`was short, even though cytokines were not used, and
`treatment at 21-day intervals was easily tolerated. Al-
`though these data do not allow definitive comparison
`with paclitaxel infusions of other durations, the myelo-
`suppression produced by our 1-hour schedules seems
`similar to that reported for 3-hour paclitaxel infusions
`and less than that reported for 24-hour infusions. The
`3-day schedule is particularly interesting in this respect,
`because toxicity was not increased despite the probable
`increased chronicity of exposure to paclitaxel with this
`schedule.
`Except for alopecia, which was severe in all pa-
`tients, other adverse effects were uncommon with these
`two schedules of paclitaxel administration. Both regi-
`mens were easily tolerated, and no statistical differences
`between these regimens w-ith respect to any adverse
`effect were documented.
`Although assessment of treatment toxicity was the
`major goal of this trial, tumor response was also evalu-
`ated. The response data are preliminary, because many
`patients are currently receiving treatment, and a final
`report concerning treatment efficacy will await longer
`follow-up. However, we have already observed objec-
`tive responses in patients with refractory ovarian can-
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`1382 CANCER August 15,1994, Volume 74, No. 4
`
`cer, breast cancer, and non-small cell lung cancer. The
`overall response rate in these 56 patients is 20%; when
`only patients with ovarian, breast, and lung cancers are
`considered, the response rate is 23%. With further fol-
`low-up, it is possible that some of the patients with min-
`imal response or stable disease after two courses may
`achieve partial or complete responses. These response
`rates are similar to those reported by others using pacli-
`taxel as a single agent in patients with refractory tu-
`
`m o r ~ . ~ , ~ , ~ ~ Responses were observed with the 1- and 3-
`day schedules. One theoretical concern about a short
`infusion schedule of paclitaxel is that the antineoplastic
`efficacy as well as the toxicity may be decreased. Our 3-
`day schedule was designed because of this consider-
`ation. Paclitaxel has been administered by infusions
`ranging from 1 to 96 hours, and responses have been
`reported with all schedule^.'^-'^ No clinical data is avail-
`able to suggest that the efficacy of paclitaxel changes
`with the duration of infusion; in fact, the only random-
`ized trial reported has demonstrated similar response
`rates in refractory ovarian cancer with a 3- versus a 24-
`hour paclitaxel infusion.”
`In summary, we have demonstrated that paclitaxel
`at a dose of 135 mg/m2 can be safely administered by a
`1-hour infusion in the outpatient setting. Serious hy-
`persensitivity reactions did not occur in 56 patients re-
`ceiving a total of 162 courses. Either a 1-day schedule
`or a 3-day divided dose schedule is easily tolerated, and
`the incidence of adverse effects is similar when the reg-
`imens are compared. Pharmacokinetic comparisons of
`the two schedules will be of interest. Antitumor efficacy
`was seen with both regimens. The mild to moderate
`myelosuppression produced in most patients suggests
`that this dose and schedule would be well tolerated
`when used as part of a combination chemotherapy reg-
`imen.
`Decreasing the length of infusion from 3 hours to 1
`hour greatly facilitates the use of paclitaxel in the office
`setting. This advantage will be even more evident in the
`future, because paclitaxel will be frequently used with
`other agents (e.g., asplatin) that are time-consuming to
`administer in the outpatient setting.
`We are continuing to study paclitaxel given by 1-
`hour infusion. As a continuation of the current study,
`we are administering paclitaxel200 mg/m’ by either a
`1 -day or 3-day short infusion schedule, again without
`cytokines. With additional patients, an adequate com-
`parison of the efficacy of these two schedules may be
`possible. In addition, we have incorporated the 1-hour
`135 mg/m2 paclitaxel dose into combination regimens
`
`for breast cancer, small cell lung cancer, and locally ad-
`vanced non-small cell lung cancer and are evaluating
`these regimens in a Phase I1 setting. We believe that the
`use of paclitaxel in a 1-hour infusion will eventually
`provide opportunities for the optimal use of this agent
`as well as allow for less toxic, less expensive treatment
`for patients.
`
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