Role of weekly paclitaxel in the treatment of advanced ovarian cancer

Role of weekly paclitaxel in the treatment of advanced ovarian cancer

Hilary Thomas a,�, Per Rosenberg b

a Department of Oncology, Postgraduate Medical School, University of Surrey, Stag Hill Campus, Guildford GU2 7XH, UKb Department of Gynecologic Oncology, University Hospital of Linkoping, S581 85 Linkoping, Sweden

Accepted 1 July 2002

Abstract

Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter

the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion

times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard

paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a

1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than

3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20�/65%. Combination therapy with

weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60�/88%. Triple-drug

combination therapy has produced response rates of 42�/67.5%. Such therapy has included weekly paclitaxel in combination with

carboplatin/cisplatin plus topotecan, and carboplatin plus doxorubicin. In an attempt to avoid problems with high corticosteroid

doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian

cancer.

# 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Advanced ovarian cancer; Carboplatin; Combination chemotherapy; Premedication; Weekly paclitaxel

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44

2. Single-agent weekly paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44

2.1. Intraperitoneal weekly paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45

3. Weekly paclitaxel in combination chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . S47

3.1. Paclitaxel plus carboplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S47

3.2. Other two-drug combinations with weekly paclitaxel . . . . . . . . . . . . . . . . . . . . . S47

3.3. Triple-drug combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48

4. Premedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

5. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

6. Authors’ commentaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

7. Summary of weekly paclitaxel in ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . S50

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50

Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S51

� Corresponding author. Tel.: �/44-1483-571122; fax: �/44-1483-406813

E-mail addresses: [email protected] (H. Thomas), [email protected] (P. Rosenberg).

Critical Reviews in Oncology/Hematology 44 (2002) S43�/S51

www.elsevier.com/locate/critrevonc

1040-8428/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.

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1. Introduction

Most patients with epithelial ovarian cancer have

advanced-stage disease when the diagnosis is estab-

lished. The survival rates of patients with advanced

ovarian cancer have steadily improved as a result of

both a more skilled surgical approach and the develop-

ment of more effective chemotherapy in first-line treat-

ment. Paclitaxel is an important agent in the

management of patients with advanced ovarian cancer.

Following cytoreductive surgery, the current optimal

chemotherapeutic approach consists of a platinum

compound together with paclitaxel [1�/3]. This recom-

mendation is supported by level 1 evidence from two

large randomized trials, the Gynecologic Oncology

Group (GOG) study and the Canadian�/European

Intergroup study that showed the paclitaxel/cisplatin

combination to be superior to the cyclophosphamide/

cisplatin combination in terms of survival [4�/6]. Long-

term follow-up data from the GOG study showed the

survival advantage was still maintained at 5 years in

patients who received the paclitaxel/cisplatin combina-

tion compared with those who received cyclophospha-

mide/cisplatin (27 vs 16%) [5].

However, neurotoxicity was a significant problem,

particularly in the Intergroup study [6], which used a

higher paclitaxel dose (175�/200 mg/m2 over 3 h) than

the GOG study (135 mg/m2 over 24 h) [4]. One of a

number of approaches to reduce toxicity has included

weekly administration of paclitaxel. The lower doses

and shorter infusion times used with weekly dosing

appear to minimize bone marrow suppression and othertoxicities associated with standard paclitaxel 3-weekly

administration. The dose-dense approach of weekly

paclitaxel may also achieve greater efficacy than stan-

dard doses every 3 weeks, through more sustained

exposure of dividing tumor cells to paclitaxel’s cytotoxic

and anti-angiogenic effects [7�/10].

Attempts to improve the outcome of chemotherapy in

women with advanced ovarian cancer have focused onattenuation of side-effects, improvements in responsive-

ness, progressive palliation of the disease and improve-

ments in quality of life.

2. Single-agent weekly paclitaxel

Several studies have used single-agent weekly pacli-

taxel in the treatment of advanced ovarian cancer (Table

1) [11�/22]. A number of studies have attempted to give

weekly paclitaxel in doses between 40 and 100 mg/m2.Activity has been seen in patients with ovarian cancer.

These have not shown cumulative myelosuppression and

grade 4 dose-limiting toxicity has only been seen at 100

mg/m2/week. An early phase I dose-ranging study

looked at weekly paclitaxel doses of 40�/90 mg/m2/

Table 1

Studies of single-agent weekly paclitaxel in patients with ovarian cancer [11�/22]

Study Dose

(mg/m2/week)

Prior

chemotherapy

N

(assessable for

response)

Overall

response

rate

Median survival

(months)

Median TTP

(months)

Loeffler et al. [11] 40�/90 100% 5 40% NA NA

Fennelly et al. [12] 40�/100 100% (2�/5

prior

regimens)

18 30% NA NA

Abu-Rustum et al. [13] 60�/100 over 1 h 100% 45 28.9% NA NA

Breier et al. [14] 80 over 1 h 100% 5 20% NA NA

Markman et al. [15] 60 i.p. 100% 80 (76) 24% (CR) NA 16.7

Benedetti-Panici et al. [16] 60 i.p. 100% 40 (38) 65% NA 5

Andersson et al. [17] 67 over 3 h No more

than one

platinum-

containing

regimen

208 35% 13.6 6.1

Markman et al. [18] 80 over 1 h 100%

(platinum

and

paclitaxel

refractory)

38 (22) 27.3% NA NA

Alvarez et al. [19] 80 100% 17 58.8% 12 NA

Kaern et al. [20] 80 over 1 h 100% 31 55% 9 4.9

Kaern et al. [21] 80 100% 36 47% 9.5 4.1

Thirapakawong et al. [22] 60 (N� 14) 100% 29 (27) 42.8% (60 mg) 11.8 (60 mg) 4.2 (60 mg)

80 (N� 15) 61.5% (80 mg) NA (80 mg) NA (80 mg)

TTP, time-to-progression; NA, not available.

H. Thomas, P. Rosenberg / Critical Reviews in Oncology/Hematology 44 (2002) S43�/S51S44

week for 6 weeks followed by a 3-week interval in 50

patients with pretreated solid tumors [11]. The study

included 5 patients with ovarian cancer. The overall

response rate was 40% in all 50 patients and also in the 5patients with ovarian cancer (2 partial responses (PRs)).

These authors recommended a starting dose for weekly

paclitaxel therapy of 80�/90 mg/m2/week.

Another dose-ranging phase I study of weekly pacli-

taxel in patients with advanced breast cancer (N�/ 17)

and ovarian cancer (N�/3) recommended a weekly dose

of 90 mg/m2/week [23]. The dose-limiting toxicity at 100

mg/m2/week was grade 4 neutropenia, which occurred in2 of 4 patients receiving this dose. Responses were

observed at all dose levels (70/80/90/100 mg/m2/week).

The authors concluded that weekly paclitaxel for 6

weeks could be safely administered as outpatient treat-

ment. The dose intensity achieved with the 90 mg/m2/

week 1-h infusion schedule was 85 mg/m2/week and

markedly higher than the 3-h 175 mg/m2 infusion every

3 weeks (57 mg/m2/week).A phase I and pharmacologic study of weekly

paclitaxel in patients with relapsed ovarian cancer

reported dose-intense paclitaxel delivery with a favor-

able toxicity profile [12]. They found dose-limiting

toxicity at a paclitaxel dose of 100 mg/m2/week in a

group of heavily pretreated patients. Escalating doses of

paclitaxel 40, 50, 60, 80 and 100 mg/m2/week were

administered to patients with recurrent ovarian cancerwho had all received prior paclitaxel and cisplatin

therapy. In 13 assessable patients, 4 PRs were observed.

Two patients with disease progression receiving stan-

dard 3-week paclitaxel schedules demonstrated a re-

sponse with weekly paclitaxel treatment. The authors

concluded that weekly paclitaxel was well tolerated, did

not result in cumulative myelosuppression and had a

favorable toxicity profile.A phase I/II study evaluated the feasibility, toxicity

and efficacy of paclitaxel 80 mg/m2/week in 5 patients

with ovarian cancer and 18 patients with breast cancer

[14]. Patients were heavily pretreated, with a mean of

two prior chemotherapy regimens, and had failed prior

platinum and anthracycline regimen with disease pro-

gression. The response rate in patients with ovarian

cancer was 20% (1 complete response (CR)), with theother 4 patients having stable disease. In the whole study

of 23 patients, only one grade 3 toxicity was reported

(anemia).

A comparative study has evaluated paclitaxel admi-

nistered weekly or every 3 weeks at the same dose

intensity*/67 mg/m2/week over a 3-h infusion*/to

patients with ovarian cancer treated with prior platinum

therapy [17]. Patients had advanced disease and hadreceived treatment with no more than one platinum-

containing regimen. An intent-to-treat analysis included

208 patients, with 205 assessable for toxicity. Over a

median observation time of 27 months no difference in

median time to progression or overall median survival

between the weekly regimen and the 3-weekly regimen

was seen. More grade 3�/4 hematologic and non-

hematologic toxicity was seen with the 3-weekly thanwith the weekly regimen, leading to the conclusion that

the 3-weekly regimen is generally better tolerated.

A study performed by Kaern et al. treated 31 patients,

80% of whom had stage III�/IV disease with recurrent

ovarian cancer resistant to platinum, with weekly

paclitaxel 80 mg/m2/week in a 1-h infusion [19]. Patients

received a median of 14 (range 7�/22) courses and an

overall response rate of 55% (2 CRs, 15 PRs) wasachieved. No CRs were seen in patients with multiple

resistant (paclitaxel and platinum) disease, but 9 (45%)

of these patients had PRs and 4 (20%) had stable

disease. Median survival was 9 months and median

progression-free survival was 4.9 months. No treatment

was stopped due to toxicity.

Several other studies have looked at treatment with

paclitaxel 80 mg/m2/week by 1-h infusion. This has beenused in both platinum and paclitaxel refractory disease

and is summarized in Table 2 [18,19,21,22]. The

response rate varies with prior exposure to paclitaxel

or not as would be expected. Patients who have not

received prior platinum have a higher response rate and

response duration. Toxicity has been tolerable in all of

these studies.

2.1. Intraperitoneal weekly paclitaxel

Weekly paclitaxel therapy has also been given by

intraperitoneal (i.p.) administration to patients with

residual cancer following standard chemotherapy. A

phase I GOG pilot study gave weekly paclitaxel i.p. for

16 weeks starting at a dose of 20 mg/m2/week to 33 such

patients [24]. The investigators found i.p. paclitaxel to

be feasible and to have an acceptable toxicity profile,and recommended an i.p. paclitaxel dose of 60�/65 mg/

m2/week for phase II studies. In the phase II GOG

study, patients with small-volume (0.5 cm or less)

residual carcinomas of the ovary, fallopian tube or

peritoneum were treated with paclitaxel 60 mg/m2/week

i.p. for 16 weeks followed by surgical evaluation in

patients without evidence of disease progression [15]. Of

76 eligible patients recruited, 53 (70%) received all 16planned courses and only 14 (18%) received fewer than

11 courses. Fifty-seven patients (75%) had received prior

systemic paclitaxel therapy, and in all but 3 cases this

was in combination chemotherapy. Of 28 assessable

patients with microscopic disease at the start of therapy,

17 patients (61%) achieved a surgically defined CR,

whereas only 1 of 31 patients with macroscopic disease

achieved a CR. Overall, 18 of 76 (24%) eligible patientsachieved a CR. The median time-to-recurrence was 16.7

months and the estimated survival rate at 2 years was

58%. Treatment was well tolerated with only 1 (1.3%)

H. Thomas, P. Rosenberg / Critical Reviews in Oncology/Hematology 44 (2002) S43�/S51 S45

Table 2

Studies using single-agent paclitaxel 80 mg/m2/week [18,19,21,22]

Study N

(evaluable)

Patients CR (%) PR (%) ORR (%) Median survival (months) Toxicity

Markman et al. [18] 38 (22) Platinum and paclitaxel refractory �/ 6 (27%) 27% NA Acceptable

Alvarez et al. [19] 17 Recurrent disease (platinum-based initial treatment) 3 (17.6) 7 (41.2) 58.8% 12 Low-to-moderate

Kaern et al. [21] 36 Recurrent disease refractory to platinum and paclitaxel 1 16 47% 9.5 Mild

Thirapakawong et al. [22] 15 (13) Platinum-refractory epithelial ovarian cancer 3 (23.1) 5 (38.4) 61.5% NA Neutropenia 1.9% Peripheral

neurotoxicity 1.1%

Table 3

Studies of weekly paclitaxel in two-drug combination chemotherapy [31�/35]

Study Regimen Type of therapy N (assessable for response) Overall response rate

Katsumata et al. [31] P 80 mg/m2/week C AUC 2/week Salvage therapy 45 (33) 67%

Bolanos et al. [32] P 60 mg/m2/week C AUC 2/week First-line for late relapses 17 (15) 60%

Wu et al. [33] P 60 mg/m2/week C AUC 2/week First-line following surgery 14 71.4%

Kurihara et al. [34] P 80 mg/m2/week C AUC 1.5�/2/week Advanced gynecologic cancer 14 ovarian 3 uterine 64.7%

Salimichokami et al. [35] P 60 mg/m2/week Mitoxantrone 4 mg/m2/week Salvage therapy 28 85%

P, paclitaxel; C, carboplatin.

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grade 3 abdominal pain and 1 (1.3%) grade 3 neutro-

penia. Another study recruited patients with epithelial

ovarian cancer with small or microscopic residual

disease [16]. Patients had received treatment with atleast one previous platinum-based chemotherapy regi-

men and had residual disease or rising CA-125 levels.

Patients were treated with paclitaxel 60 mg/m2/week i.p.

for 16 weeks. Of 40 patients who entered the study, 38

were evaluable. Seventeen of 26 (65%) patients with

macroscopic disease and all patients with microscopic

disease or rising CA-125 showed a clinical response.

Among 29 responsive patients, 9 showed a recurrenceafter a median follow-up of 13 months. The median time

to recurrence was 5 months. The 1-year overall survival

rate was 79% and the 1-year recurrence-free survival rate

was 48%. Efficacy seemed to be related to the residual

tumor before i.p. therapy. No hematologic toxicities

were observed.

3. Weekly paclitaxel in combination chemotherapy

The recommended treatment strategy for patients

with advanced ovarian cancer is upfront radical cyto-

reductive surgery followed by combination chemother-

apy with a taxane and a platinum compound [25]. Inorder to increase efficacy further, three-drug regimens

have also been used. More than 80% of patients develop

recurrent disease after initial treatment and platinum-

free interval is the most important predictive variable of

response to second-line chemotherapy in patients with

recurrent ovarian cancer; the probability of response is

mainly related to platinum-free interval [26]. In addi-

tion, the activity of most agents is higher in platinum-sensitive disease.

3.1. Paclitaxel plus carboplatin

Although the GOG study showed that the combina-tion of paclitaxel and cisplatin was more effective than

cyclophosphamide/cisplatin regimens in women with

advanced ovarian cancer, because cisplatin is associated

with a high incidence of renal dysfunction and neuro-

toxic events [27,28] carboplatin has been used as a

substitute due to its lower non-hematologic toxicity and

similar efficacy to cisplatin [29]. In a phase I study of

paclitaxel and carboplatin [30], three patients were

assessable for response, including 1 PR, 1 with stable

disease and 1 with progressive disease. Several otherstudies have shown the combination of paclitaxel and

carboplatin given weekly to patients with advanced

ovarian cancer to be effective (Table 3) [31�/35].

A number of regimens combining weekly paclitaxel

with carboplatin have been used as first-line treatment

in ovarian cancer. Carboplatin has been given weekly at

an AUC of 2 with dose escalation in some studies. The

treatment appears to be well tolerated with a lowincidence of non-hematologic toxicity (Table 4) [36].

A preliminary report of a phase II study of weekly

paclitaxel 60 mg/m2 plus carboplatin AUC 2/week as

first-line chemotherapy in late relapses of epithelial

ovarian cancer has shown promising results [32] (Table

3). The median time-to-progression was 18 weeks and

median survival was 44.9 weeks. Grade 3�/4 toxicities

were: hemoglobin 17%; leukocytes 17%; platelets 18%;and alopecia 29%.

A comparative study conducted by Wu et al. [33]

compared weekly and monthly regimens of paclitaxel

plus carboplatin (Table 5). No significant differences in

non-hematologic toxicity were seen. Treatment delays

were more common with monthly treatment and gen-

erally the weekly regimen was better tolerated. It was

also more cost effective as a result of lower unantici-pated hospitalization and supplemental support with

G-CSF.

3.2. Other two-drug combinations with weekly paclitaxel

Weekly paclitaxel has been given together with weekly

mitoxantrone as salvage therapy for recurrent ovarian

cancer [35]. The study recruited 28 patients with

recurrent epithelial ovarian cancer who had received

paclitaxel in first-line therapy. Salvage therapy consistedof mitoxantrone 4 mg/m2 i.v. followed by paclitaxel 60

mg/m2 i.v. both repeated weekly for 3 weeks every 4

weeks. Patients were treated for 6 cycles and an overall

response rate of 85% was observed, with 10 CRs and 14

PRs. Mean progression-free survival was 15 months and

mean overall survival had not been reached at the time

Table 4

Toxicities reported in a study of weekly paclitaxel plus carboplatin as first-line treatment in 19 patients with advanced ovarian cancer [36]

Paclitaxel dose

(mg/m2/week)

Carboplatin dose Dose-limiting toxicity Overall grade 3�/4 toxicity in all courses

(N� 19)

100 AUC 2/week None Thrombocytopenia 2%

Leukopenia 8%

Anemia 1%

100 AUC 3/week (N�8) 2 thrombocytopenia

1 neutropenic fever


of publication. Grade 3�/4 leukopenia occurred in 60%

of patients and was the dose-limiting toxicity.Weekly paclitaxel plus etoposide has been studied in a

phase II trial in patients with relapsed ovarian cancer

[37]. Paclitaxel 60 or 70 mg/m2/week and etoposide 100

mg/m2/week were given for 12 weeks to 35 patients with

recurrent ovarian cancer within 1 year of receiving at

least one platinum-based chemotherapy with or without

taxanes. Women relapsing beyond 1 year of therapy also

received carboplatin AUC 4 every 3 weeks. Table 6shows the results obtained. With paclitaxel 70 mg/m2/

week, an overall response rate of 46% was achieved,

with 3 patients (20%) with stable disease and 2 patients

(13%) with disease progression. At this paclitaxel dose,

grade 3 neutropenia occurred in 1 of 15 (7%) patients

and gastrointestinal toxicity occurred in 3 (20%) pa-

tients. No patients required treatment cessation due to

toxicity. Although weekly paclitaxel plus etoposide wasthird- or fourth-line therapy in many of these patients,

this drug regimen showed good activity and manageable

toxicity.

3.3. Triple-drug combination therapy

Weekly paclitaxel and platinum analogs have been

combined with other drugs including doxorubicin and

topotecan [38�/40]. These are largely phase I studies and

it is difficult to make any valuable conclusions abouttheir role in the future management of patients in the

absence of more phase III data.

Frasci et al. gave cisplatin 40 mg/m2, paclitaxel 85 mg/

m2 and escalating topotecan doses (from 0.75 mg/m2)

weekly to 15 patients with ovarian and 18 patients with

small cell lung cancer (SCLC) [38]. Responses were seen

in 5 of 12 patients (42%) and 7 of 15 patients (47%) in

patients with ovarian cancer and SCLC, respectively.

Topotecan doses of at least 2 mg/m2 were administered

weekly with cisplatin and paclitaxel and the study is

continuing with topotecan doses of 2.25 mg/m2/week.

Weekly paclitaxel and carboplatin followed by topo-

tecan has been used as first-line therapy for patients with

advanced epithelial ovarian cancer suboptimally de-

bulked [40]. Paclitaxel 60 mg/m2 plus carboplatin

AUC 2 were given weekly, with 6 doses in each course,

for 2 courses followed by a 14-day rest period, followed

by 4 courses of topotecan 1.5 mg/m2/day for 5 days

every 3 weeks. Prophylactic G-CSF was allowed after an

episode of grade 3�/4 neutropenia and the topotecan

dose was reduced with other grade 3�/4 toxicities.

Patients with progressive disease during paclitaxel/

carboplatin therapy were changed to topotecan. Of 37

patients who completed treatment with paclitaxel plus

carboplatin followed by topotecan, response rates were

78.3% (32.4% CR, 45.9% PR) after paclitaxel plus

carboplatin and 67.5% (40.5% CR, 27% PR) after

treatment with the 3 drugs. During paclitaxel plus

carboplatin therapy, grade 3�/4 toxicities were anemia

3%, neutropenia 27%, alopecia 28% and nephrotoxicity

3%. During topotecan therapy, grade 3�/4 toxicities were

anemia 10%, neutropenia 44%, thrombocytopenia 10%

and alopecia 75%. Thus, these preliminary results show

weekly paclitaxel plus carboplatin followed by topote-

can to be very active and well tolerated.

A phase I study has looked at escalating doses of

weekly paclitaxel 60/75/90 mg/m2 together with carbo-

platin AUC 6 plus doxorubicin 50 mg/m2 given 4-weekly

in 12 patients with gynecological malignancy believed to

be of ovarian origin [39]. Of 8 patients evaluable for

Table 5

Response rates and hematologic toxicity in a comparative study of weekly vs monthly paclitaxel plus carboplatin [33]

Paclitaxel�carboplatin regimens Overall response rate Hematologic toxicity

Anemia

Egrade 2

Granulocytopenia

grade 3�/4

Thrombocytopenia

Egrade 2

60 mg/m2/week�AUC 2/ week

(N� 15)

71.4% 7.1% 7.1% 0

175 mg/m2/month�AUC 6/month

(N� 14)

66.7% 18.6% 32.3% 15.7%

Table 6

Results obtained with weekly paclitaxel plus etoposide in patients with recurrent ovarian cancer [37]

Paclitaxel 60 mg/m2/week�etoposide

100 mg/m2/week (N�13)

Paclitaxel 70 mg/m2/week�etoposide

100 mg/m2/week (N�15) (4 also�carboplatin)

CA-125 response 54% (7/13) 60% (9/15)

Objective response 15% (2 PRs) 46% (2 CRs, 5 PRs)

Median time-to-progression 8 months 8 months


response, 4 patients had a PR (50%), 3 had stable disease

and 1 had disease progression. The dose-limiting toxicity

was grade 3�/4 neutropenia myelosuppression with

paclitaxel 90 mg/m2/week. The authors concluded thatthis regimen was manageable with paclitaxel 75 mg/m2/

week.

4. Premedication

As described by Urien et al. [41], the approved

premedication for the 3-weekly regimen consists of

dexamethasone 20 mg, 12 and 6 h before paclitaxeladministration, diphenhydramine (or its equivalent) 50

mg i.v. 30�/60 min before paclitaxel, and cimetidine 300

mg or ranitidine 50 mg i.v. 30�/60 min before paclitaxel.

When paclitaxel is given on a weekly basis, however,

various premedication regimens have been used, many

of which have used lower doses of dexamethasone to

avoid problems with the corticosteroid intake.

In one study of 50 patients with various pretreatedsolid tumors, patients were given dexamethasone 16 mg

i.v., ondansetron 8 mg i.v. cimetidine 200 mg i.v. and

clemastine 2 mg i.v. administered as 15-min infusions

immediately before paclitaxel [11]. No hypersensitivity

reactions were reported in this study.

Breier et al. used a premedication regimen of dex-

amethasone 8 mg, diphenhydramine 30 mg and raniti-

dine 50 mg as outpatient therapy just before treatmentwith paclitaxel 80 mg/m2/week to 18 patients with breast

cancer and 5 patients with ovarian cancer [14]. The

authors did not report any hypersensitivity reactions.

In the treatment of ovarian cancer, Klaasen et al. used

a premedication regimen of dexamethasone 8 mg oral 12

and 6 h before each paclitaxel infusion and cimetidine

400 mg i.v. and clemastine 2 mg i.v. 30 min before each

paclitaxel treatment to 17 patients with advanced breastcancer and 3 patients with ovarian cancer [23]. Neither

mild nor severe hypersensitivity reactions occurred and

no major corticosteroid side-effects were observed.

Thirapakawong et al. used a premedication regimen

of dexamethasone 10 mg i.v., cimetidine 400 mg orally

and metoclopramide 10 mg i.v. 30 min before paclitaxel

administration to 29 patients with ovarian cancer [22].

No hypersensitivity reactions were observed with thispremedication regimen.

Andersson et al. compared paclitaxel given weekly to

paclitaxel given every 3 weeks and also assessed the

safety of steroids administered intravenously in preme-

dication [17]. They reported no difference in the number

of severe hypersensitivity reactions between patients

receiving oral or parenteral steroids.

Quock et al. used a premedication regimen ofdexamethasone 10 mg i.v., diphenhydramine 25 mg i.v.

and cimetidine 300 mg i.v. for the first weekly dose of

paclitaxel [42]. If no hypersensitivity reactions occurred,

no premedication was given for subsequent paclitaxel

doses. The investigators applied this strategy to 14

patients who received 56 1-h infusions of weekly

paclitaxel 90 mg/m2/week without premedications andexperienced no hypersensitivity reactions.

5. Future directions

The combination of paclitaxel/carboplatin is currently

the preferred regimen for the treatment of ovarian

cancer. Studies of combinations of paclitaxel/carbopla-

tin plus oral etoposide, gemcitabine or epirubicin are inprogress. Other studies in progress include those of high-

dose chemotherapy regimens of paclitaxel/carboplatin in

untreated patients with optimal stage II ovarian cancer.

A randomized multicenter study of monoclonal anti-

body radioimmune-therapy is currently ongoing. Pa-

tients with advanced ovarian cancer with complete

clinical, chemical, radiologic and laparoscopic remission

are randomized to receive one i.p. Yttrium-HMFG1antibody infusion or no further treatment.

A randomized Nordic Society of Gynecologic Oncol-

ogy (NSGO) study of chemotherapy vs hormonal

treatment in patients with ovarian cancer resistant or

refractory to platinum and taxane therapy has recently

started recruiting. Patients are randomized to receive

tamoxifen or chemotherapy with weekly paclitaxel 80

mg/m2 or doxorubicin 40 mg/m2. It is planned to include250 patients.

There is now a wealth of studies involving weekly

paclitaxel using different regimens. Weekly paclitaxel

appears to be well tolerated and has manageable toxicity

with less toxicity than 3-weekly or monthly regimens.

6. Authors’ commentaries

Sadly the majority of patients with advanced ovarian

cancer will ultimately have disease relapse. For this

group of patients, quality of life is important. For this

reason weekly paclitaxel provides a well tolerated regi-

men with activity comparable to other newer agents and

limited toxicity. It should be considered both as therapy

for relapsed disease, for both taxane-naıve patients andthose with prior exposure, and*/where appropriate*/as

maintenance therapy in patients for whom the quality of

life it offers appears greater than most alternatives.

During the last few years, patients with recurrences of

ovarian cancer are, with increasing frequency, treated

with weekly paclitaxel, even outside protocols. This is

probably due to its favorable side-effect profile and high

response rate, even among heavily pretreated patients.In Linkoping, 44 patients with relapse after primary

taxane/platinum-containing chemotherapy have been

subjected to such treatment over the last 2 years. In


most cases, weekly paclitaxel therapy was third- or

fourth-line, but had an overall response rate of 38%. In

Linkoping, nail problems are the most significant side-

effect, but are seldom seen until after 3�/4 months ofweekly treatment without interruptions.

7. Summary of weekly paclitaxel in ovarian cancer

Response rates ranging from 20 to 65% have been

reported with single-agent weekly paclitaxel. Combina-

tion chemotherapy has mainly included carboplatin,

either given on a weekly basis or 3-weekly. Response

rates in studies of weekly paclitaxel plus carboplatin

have ranged from 60 to 88%. Other drugs used withweekly paclitaxel in two-drug combination therapy

include doxorubicin, cisplatin, etoposide and mitoxan-

trone. Response rates with such combinations were 19,

67, 54�/60 and 85%, respectively. Triple-drug combina-

tions with weekly paclitaxel have included cisplatin plus

topotecan, carboplatin plus topotecan, and carboplatin

plus doxorubicin. Response rates with these regimens

were 42, 67.5 and 50, respectively. Weekly paclitaxel isgenerally well tolerated in the treatment of advanced

ovarian cancer. Neutropenia is the most common dose-

limiting toxicity and this can be reduced with the use of

G-CSF. In general, weekly paclitaxel seems to be better

tolerated than the 3-weekly regimen. Regarding the

premedication regimen for paclitaxel given weekly to

patients with ovarian cancer, several studies used the

conventional regimen including a 20-mg dexamethasonedose given 6 and 12 h before paclitaxel. However,

several studies have used a reduced dexamethasone

dose administered intravenously 30 min before pacli-

taxel administration without hypersensitivity reactions.

Dexamethasone doses of 16, 10 and 8 mg have been used

successfully and oral and intravenous administrations

have been shown to be equally effective.

Weekly paclitaxel has been shown to be feasible,effective and to have manageable toxicity in patients

with advanced ovarian cancer, both as single-agent

therapy and in combination therapy.

This review highlights the pressing need for weekly

paclitaxel’s further investigation in the setting of main-

tenance therapy as well as larger comparative studies in

relapsed disease.

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Biographies

Hilary Thomas was appointed to the Chair of

Oncology at the University of Surrey and The Royal

Surrey County Hospital in September 1998. Her main

clinical interest is gynecologic cancer and clinical trials.

She is a member of the NCRI gynae cancer group. She

has a Ph.D. in the cytokine biology of breast cancer and

has established a small research group active in the areas

of monoclonal antibodies and drug resistance. Professor

Thomas has been an elected medical member of the

General Medical Council since 1994 and since that time

has been a member of the Standards Committee,

chairing the working group for the guidance on Con-

fidentiality. In the past year she has been a member of

the revalidation steering group and was a member of the

Governance Working Group that undertook a review of

the current structure of the Council. She was appointed

Macmillan Network Lead Clinician for the Surrey West

Sussex and Hampshire Network in October 2001.

Per Rosenberg was appointed Head of the Depart-

ment of Gynecologic Oncology at the University

Hospital in Linkoping in July 1996. He undertook

medical studies at the Karolinska Institute in Stockholm

and obtained his MD in 1980. In 1985 he specialized in

obstetrics and gynecology and in 1987 specialized in

gynecologic oncology. In 1992 he obtained a PhD from

the Medical Faculty of the University of Linkoping. He

has published widely in the field of gynecologic oncol-

ogy.


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Role of weekly paclitaxel in the treatment of advanced ovarian cancer