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Weekly docetaxel as a single agent and in combination with gemcitabine in elderly and poor performance status patients with advanced non-small cell lung cancer
Weekly Docetaxel as a Single Agent and in Combination With Gemcitabine in Elderly and Poor Performance Status Patients With Advanced Non-Small Cell Lung Cancer john Administering
docetaxel
D. Hainsworth,
weekly
at
a
dose minimizes myelosuppression and matologic toxicities. In a community-based trial
conducted
in 39 elderly
tus patients with weekly 36 mglm’
advanced docetaxel
of 20%.
The
Eastern status
response
was
2-year
survival
to
those
agents. associated
The
regimen with minimal
were
no cases
of
of grade
nia, toxicity-related related death.
ceived
weekly
citabine I5 every
800 28
first
patients
41
rate of 29%, stable disease. I5 dose
status a similar
elosuppression, ally well
enrolled
the tolerated.
and
evaluation is indicated.
of
Semin Oncol28 (suppf Saunders Company.
neutrope-
or treatmentwere also
plus
given analysis an
on
weekly
objective
docetaxel
because
having the day of my-
One
pa-
pulmonary infiltrates, possibly died of respiratory failure. Fur-
weekly
docetaxel-based
9):2 l-25.
Copyright
combina0 2001
by WB.
A
SUBSTANTIAL proportion of patients cell lung cancer with advanced non-small (NSCLC) are elderly and/or have poor performance status (I’S) at diagnosis. Many of these patients show poor tolerance of standard combination chemotherapy regimens. For these patients, weekly administration of active agents such as docetaxel, gemcitabine, and vinorelbine (alone or in combination) offers the possibility of maintaining activity while minimizing toxicity.‘-13 There have as yet been no large phase III trials of docetaxel delivered weekly in patients with advanced NSCLC. However, as data emerge it is becoming clear that this schedule of administration may offer distinct advantages, particularly in patients with poor I’S and in the elderly.l-s Seminars
in Oacdogy,
Vol 28. No 3. Suppl
Greco
In an initial phase I study, we showed that docetaxel could be delivered to a maximum tolerated dose of 42 mg/m’ weekly for 6 consecutive weeks, followed by 2 weeks of rest.1 Myelosuppression was relatively mild, and fatigue and asthenia proved to be the dose-limiting toxicities. With this regimen, it was possible to use a shortened period of steroid prophylaxis consisting of three doses of oral dexamethasone 8 mg orally every 12 hours starting 12 hours before docetaxel administration. The weekly docetaxel dose of 42 mg/m’ clearly had antitumor activity. For phase II trials, the slightly lower weekly dose of 36 mg/m2 docetaxel was selected as no serious adverse events were observed at this dose. WEEKLY DOCETAXEL NON-SMALL CELL
IN ADVANCED LUNG CANCER
response
regimen was generno hospitalizations
of myelosuppression.
Ill. and F. Anthony
gem-
days I, 8, and of data for the
45% of patients of patients missed
combination There were
bilateral and
single
2 patients. In a subgroup of patients re-
show
additional 26%
by complications
tient developed treatment-related,
febrile
at 30 mglm’
of gemcitabine
and are
active
admissions, toxicities
both drugs Preliminary
with an Although
an
results
other
4 leukopenia,
docetaxel mg/m’, days.
with
weekly docetaxel used was hematologic toxicity. There
hospital Nonhematologic
mild, even in performance sequent phase II trial,
cancer, rate
performance was 28%
These
II
sta-
in patients
15%. with
low
cell lung a response
Group survival
A. Burris
nonhephase
performance
26%
was
achieved
relatively reduces
non-small produced
rate
similar
ther tions
poor
Cooperative Oncology of 0 or I. Actual l-year
actuarial
caused
or
Howard
9 (June). 200 I : pp 2 I-25
Patients and Treat7nent In a Minnie Pearl Research Network phase II trial, patients aged 65 or over or who were medically compromised and had stage IV or IIIB NSCLC unsuitable for combined modality therapy were treated with 36 mg/m’ docetaxel for 6 consecutive weeks, followed by 2 weeks of rest.* The patients included in this multicenter, community-based study had a I’S of 0 to 2 and had not been previously treated with chemotherapy. Patients who had received radiotherapy were eligible if the disease site to be followed for response lay outside the irradiated area. The steroid prophylaxis schedule outlined previously was used and patients were I-e-evaluated after 8 weeks. Treatment was continued for a maximum of four S-week cycles. The median age of the 39 patients treated was 71 years (range, 55 to 83 years). Patients who were younger than 45 years had comorbid conditions making standard chemotherapy regimens inappropriate or were of poor PS. Seventeen patients were men and 22 were women. Two patients had an Eastern Cooperative Oncology Group PS ofO,21 had a PS of 1, and 16 had a status of 2. The lung cancer histologies of the group were
From The Sarah Cannon Cancer Center, Nash&, TN. Dr Hninsworrh has received honoraria and research grant support from Auentis Pharmaceuticals Inc and Eli Lily. Address reprint requeststoJohn D. Hainsworth, MD, The Sarah Cannon Cancer Center, 250 25th Awe Nor& Suite 412, Nash-
de, TN 37203. Copya+& 0 2001 by W.%. Saunders Company 0093-7754101/2803-0905$35.00/O dai:IO. 1053lsonc.2001.24604 21
22
JOHN
No. Patients Median
age (range)
71 years
(5=2
Men/Women ECOG
years)
status
0
Z Efficacy NowSmall
Overall
Response
Complete
response disease/minor
Stable Disease
16(41%)
Response Overall
I4 (36%)
Actual
Squamous
I3 (33%)
Acturial
large ECOG,
cell carcinoma Eastern
Cooperative
12(31%) Oncology
Group.
I (3%) 6(17%) response
I3 (36%)
progression
I6 (44%)
duration
2-12
Act&q
I -year
“lo
28%
2-year
15%
by Subgroup
Response
rate
Analysis
in performance
status 6t23 (26%)
0, I 2
l/16(6%)
I-year
survival
in performance
status 32%
0, 1 2
evenly divided between adenocarcinoma, and large cell carcinoma (Table 1).7-s
(x)
Survival
Adenocarcinoma carcinoma
response
Partial 2 (5%)
Histology
in
No. Patients
21 (54%) 2
of Single-Agent Weddy Docetaxel Cell Lung Cancer Patbats’
(%)
I7122
performance
Table
D. HAINSWORTH
24%
squamous carcinoma,
Response
Toxicity
Of the 39 patients, 33 (85%) completed at least 6 weeks (ie, one course) of treatment. Three patients failed to complete one cycle because of rapid tumor progression, two patients requested withdrawal, and one experienced a hypersensitivity reaction to the first dose of docetaxel. This patient was the only one to cease trial treatment because of toxicity. Overall, only 4% of scheduled doses were reduced or omitted. Thirty-six patients were evaluable for response (Table 2). Among this group of patients with relatively poor PS, there was one complete response. Six patients showed a partial response, producing an overall response rate of 20%. Thirteen patients (36%) showed disease stabilization at the time of first evaluation at 8 weeks, while 16 patients (44%) experienced disease progression. The duration of responses observed ranged from 2 to 12 months. Patients with PS 2 (response rate = 6%) were less likely to respond to therapy than those with a PS of 0 or 1, in whom the response rate was 26%. However, the l-year survival rates in good and poor PS patients (32% and 24%, respectively) were not significantly different.Ts Overall, the actual l-year survival in this relatively poor prognosis group was 28% and 2-year survival was 15%. These results must be considered relatively good.
Among the 39 patients treated with a total of 363 doses there were no cases of grade 4 leukopenia, thrombocytopenia, or anemia (Table 3). A total of 4% of doses were followed by grade 3 leukopenia. There were no cases of neutropenic fever, no hospitalizations for complications associated with this regimen, and no treatment-related deaths.
Grade Hematologic
314
No.
Patients
Toxicity
Leukopenia*
3 (8%) 0
Thrombocytopenia Anemia*
5 (13%) 0
Neutropenia/fever Treatment-related Nonhematological
death
0
Toxicity
Fatigue/asthenia
4(10%)
Nausealvomiting
4(10%)
Skin rash
I (3%)
Neuropathy Hypersensitivity
I (3%) reaction
Edema * No grade
I (3%) 0
4 toxicity
was observed.
(%)
WEEKLY
DOCETAXEL
IN ADVANCED
NSCLC
23
Among the patients treated, grade 314 fatigue or asthenia (which may or may not have been treatment related) was experienced by 10% of patients (Table 3). A similar proportion suffered grade 3/4 nausea/vomiting, and there was a 3% rate of grade 3/4 skin rash, neuropathy, and hypersensitivity reaction. There were no cases of edema.7*8 Given these data showing the activity and tolerability of weekly docetaxel, it was appropriate to consider use of this schedule in combination with other active agents. WEEKLY
DOCETAXEL
AND
GEMCITABINE
A number of combination regimens based on weekly docetaxel have been investigated at our institution. The combination of docetaxel with gemcitabine has been studied in previously treated NSCLC patients, and the docetaxel/vinorelbine combination is being assessed both second-line in NSCLC and in metastatic breast cancer. However, this report confines itself to the presentation of preliminary results from a multicenter phase II community-based study of docetaxel plus gemcitabine first-line in a group of elderly patients with NSCLC. Gemcitabine has proven activity when used as a single agent in advanced NSCLC.10-13 It also has shown promise when used in combination with docetaxel in conventional docetaxel every--3 or 4-week schedules.l+Jz Therefore, an investigation of the combination using a weekly regimen was a logical development. Patients and Treatment Accrual to the trial was rapid, reflecting elderly, poor PS patients with advanced community.
Between
were entered patients.
into
The treatment minute intravenous mg/m2. The two of a 28-day methasone hours
August the study.
before
June
2000,66
the
administration
patients
on the first 41
given consisted of docetaxel30 mgjm’ infusion plus intravenous gemcitabine drugs were administered on days 1,8,
as a 30 800 and 15
was composed of dexafor 3 doses, starting 12
of docetaxel.
age of the 41 patients was 72 years (range, 58 to percent were men. Eastern Cooperative OnPS was 0 in lo%, 1 in 59%, and 2 in 31%.
Twenty-seven percent all pleural effusions)
of patienE had stage IIIB disease (almost and 73% had stage IV disease. Histology
was divided evenly between and large cell subtypes. Overall, 81% of patients the
and
are presented
cycle. Steroid prophylaxis 8 mg orally every 12 hours
The median 82). Sixty-eight cology Group
over
1999 Data
the large number of NSCLC seen in the
first two courses
squamous received of treatment.
cell, the
adenocarcinoma, full
On day
doses
intended
1, the planned
dose
was given
virtually
without
the planned docetaxel dose abine dose was administered. planned dose actually received for gemcitabine. predominantly
exception.
On
day
and 91% of the planned On day 15, the proportion was 76% for docetaxel
The reason for dose myelosuppression.
reduction
8, 93%
of
gemcitof the and 72%
or omission
was
Response and Toxicity One patient had a complete response and 10 had a partial response, giving an overall response rate of 29%. An additional 45% of patients had a period of stable disease while 26% progressed. No survival data are yet available because of short follow-up. The combination of weekly docetaxel and gemcitabine given on a 3 weeks on, 1 week off schedule was well tolerated. Grade 3/4 leukopenia was seen in 12% of patients and grade 3/4 thrombocytopenia also in 12%. Grade 3/4 anemia was recorded in 7% of patients. Granulocyte-colony stimulating factor or granulocyte macrophage-colony stimulating factor was used in 37% of patients to maintain cytotoxic dose, and 23% of patients received red blood cell transfusions. No patients were transfused with platelets. There were no cases of hospitalization for treatment-related toxicity and there were no cases of neutropenic fever. The one possibly treatment-related death occurred in a patient who did not have myelosuppression but who developed bilateral pneumonitis and respiratory failure. Pneumonitis has occasionally been reported as an adverse event associated with gemcitabine.23 Compared with the previous study of docetaxel alone, the 27% incidence of grade 314 fatigue/ asthenia seen in this combination trial was higher. The incidence of other grade 3/4 toxicities were: nausea/vomiting 12%; diarrhea 7%; myalgias 2% and peripheral neuropathy 2%. DISCUSSION Single-agent docetaxel can be administered weekly at a dose of 36 mg/m’ with minimal toxicity. Dose intensity and activity are preserved when compared with standard every-3-week schedules of docetaxel administration. This schedule is well tolerated and provides an advantageous treatment option for the large number of patients with advanced NSCLC who are elderly or of poor PS. Moreover, the regimen can feasibly be administered in the community setting. Several other single-agent weekly docetaxel trials have been
24
completed in the second-line treatment of patients with advanced NSCLC. Lilenbaum et al* evaluated weekly docetaxel (36 mgjm’) administered over 6 consecutive weeks, followed by 2 weeks rest, in 23 previously treated NSCLC patients. In the 22 eligible patients, there were no episodes of grade 3/4 anemia or thrombocytopenia, no grade 4 neutropenia, and only a 13% incidence of grade 3 neutropenia. Nonhematologic toxicities were mild. In 16 evaluable patients, the partial response rate was 12%, with stable disease in 25% after the first cycle. Serke et a15 treated 28 NSCLC patients with second-line weekly docetaxel (35 mgfm’) for 6 consecutive weeks, every 8 weeks. No grade 4 hematologic or nonhematologic toxicities were observed. The partial response rate was 14%, and an additional 36% of patients had minor response or stable disease. Garcia-Lopez et a124 administered 43 mgJm2 weekly docetaxel for 6 weeks, every 8 weeks, to 26 NSCLC patients who had progressed after prior platinum therapy. No grade 3/4 leukopenia was observed, and other toxicities were was uncommon. The response rate in 15 evaluable patients was 26.7% and 17.4% on an intent-to-treat analysis. Median survival was 12 months (range, 5 to 27 months) with a 46% l-year survival. When compared with previous reports of standard every-3-week docetaxel in refractory NSCLC, the efficacy observed with weekly administration is similar with substantially less toxicity. Full analysis of the study combining weekly docetaxel with weekly gemcitabine is awaited. However, the results to date show a response rate that is comparable with that achieved with combinations administered on conventional schedules. The toxicity seen with the combination is increased when compared with that observed with weekly docetaxel alone, but the regimen remains well tolerated even by patients with poor PS. The docetaxel/gemcitabine weekly combination also has been evaluated by Kouroussis et al*5 in a phase I trial. Docetaxel was administered at a starting dose of 30 ms/m2 and gemcitabine at a starting dose of 700 ms/m2. Doses were escalated to 40 mg/m2 and 800 mg/m2, respectively, with maximum tolerated dose level not yet reached. The study is ongoing. Other weekly docetaxel combinations have been explored. These include weekly docetaxel with cisplatin or carboplatin.26-28 Multimodality weekly docetaxel/platinum schedules with concur-
JOHN
D. HAINSWORTH
rent radiotherapy showed promising efficacy results and good feasibility.29-31 Phase II studies are planned with these schedules. Other active agents, such as irinotecan and vinorelbine, are also being assessed in combinations with weekly taxanes.32~33 Effective, well tolerated regimens containing weekly docetaxel have the potential for wide applicability in advanced lung, breast, and prostate cancer, as well as other common solid tumors. REFERENCES JB, et al: Phase
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1)
docetaxel
D. Hainsworth,
weekly
at
a
dose minimizes myelosuppression and matologic toxicities. In a community-based trial
conducted
in 39 elderly
tus patients with weekly 36 mglm’
advanced docetaxel
of 20%.
The
Eastern status
response
was
2-year
survival
to
those
agents. associated
The
regimen with minimal
were
no cases
of
of grade
nia, toxicity-related related death.
ceived
weekly
citabine I5 every
800 28
first
patients
41
rate of 29%, stable disease. I5 dose
status a similar
elosuppression, ally well
enrolled
the tolerated.
and
evaluation is indicated.
of
Semin Oncol28 (suppf Saunders Company.
neutrope-
or treatmentwere also
plus
given analysis an
on
weekly
objective
docetaxel
because
having the day of my-
One
pa-
pulmonary infiltrates, possibly died of respiratory failure. Fur-
weekly
docetaxel-based
9):2 l-25.
Copyright
combina0 2001
by WB.
A
SUBSTANTIAL proportion of patients cell lung cancer with advanced non-small (NSCLC) are elderly and/or have poor performance status (I’S) at diagnosis. Many of these patients show poor tolerance of standard combination chemotherapy regimens. For these patients, weekly administration of active agents such as docetaxel, gemcitabine, and vinorelbine (alone or in combination) offers the possibility of maintaining activity while minimizing toxicity.‘-13 There have as yet been no large phase III trials of docetaxel delivered weekly in patients with advanced NSCLC. However, as data emerge it is becoming clear that this schedule of administration may offer distinct advantages, particularly in patients with poor I’S and in the elderly.l-s Seminars
in Oacdogy,
Vol 28. No 3. Suppl
Greco
In an initial phase I study, we showed that docetaxel could be delivered to a maximum tolerated dose of 42 mg/m’ weekly for 6 consecutive weeks, followed by 2 weeks of rest.1 Myelosuppression was relatively mild, and fatigue and asthenia proved to be the dose-limiting toxicities. With this regimen, it was possible to use a shortened period of steroid prophylaxis consisting of three doses of oral dexamethasone 8 mg orally every 12 hours starting 12 hours before docetaxel administration. The weekly docetaxel dose of 42 mg/m’ clearly had antitumor activity. For phase II trials, the slightly lower weekly dose of 36 mg/m2 docetaxel was selected as no serious adverse events were observed at this dose. WEEKLY DOCETAXEL NON-SMALL CELL
IN ADVANCED LUNG CANCER
response
regimen was generno hospitalizations
of myelosuppression.
Ill. and F. Anthony
gem-
days I, 8, and of data for the
45% of patients of patients missed
combination There were
bilateral and
single
2 patients. In a subgroup of patients re-
show
additional 26%
by complications
tient developed treatment-related,
febrile
at 30 mglm’
of gemcitabine
and are
active
admissions, toxicities
both drugs Preliminary
with an Although
an
results
other
4 leukopenia,
docetaxel mg/m’, days.
with
weekly docetaxel used was hematologic toxicity. There
hospital Nonhematologic
mild, even in performance sequent phase II trial,
cancer, rate
performance was 28%
These
II
sta-
in patients
15%. with
low
cell lung a response
Group survival
A. Burris
nonhephase
performance
26%
was
achieved
relatively reduces
non-small produced
rate
similar
ther tions
poor
Cooperative Oncology of 0 or I. Actual l-year
actuarial
caused
or
Howard
9 (June). 200 I : pp 2 I-25
Patients and Treat7nent In a Minnie Pearl Research Network phase II trial, patients aged 65 or over or who were medically compromised and had stage IV or IIIB NSCLC unsuitable for combined modality therapy were treated with 36 mg/m’ docetaxel for 6 consecutive weeks, followed by 2 weeks of rest.* The patients included in this multicenter, community-based study had a I’S of 0 to 2 and had not been previously treated with chemotherapy. Patients who had received radiotherapy were eligible if the disease site to be followed for response lay outside the irradiated area. The steroid prophylaxis schedule outlined previously was used and patients were I-e-evaluated after 8 weeks. Treatment was continued for a maximum of four S-week cycles. The median age of the 39 patients treated was 71 years (range, 55 to 83 years). Patients who were younger than 45 years had comorbid conditions making standard chemotherapy regimens inappropriate or were of poor PS. Seventeen patients were men and 22 were women. Two patients had an Eastern Cooperative Oncology Group PS ofO,21 had a PS of 1, and 16 had a status of 2. The lung cancer histologies of the group were
From The Sarah Cannon Cancer Center, Nash&, TN. Dr Hninsworrh has received honoraria and research grant support from Auentis Pharmaceuticals Inc and Eli Lily. Address reprint requeststoJohn D. Hainsworth, MD, The Sarah Cannon Cancer Center, 250 25th Awe Nor& Suite 412, Nash-
de, TN 37203. Copya+& 0 2001 by W.%. Saunders Company 0093-7754101/2803-0905$35.00/O dai:IO. 1053lsonc.2001.24604 21
22
JOHN
No. Patients Median
age (range)
71 years
(5=2
Men/Women ECOG
years)
status
0
Z Efficacy NowSmall
Overall
Response
Complete
response disease/minor
Stable Disease
16(41%)
Response Overall
I4 (36%)
Actual
Squamous
I3 (33%)
Acturial
large ECOG,
cell carcinoma Eastern
Cooperative
12(31%) Oncology
Group.
I (3%) 6(17%) response
I3 (36%)
progression
I6 (44%)
duration
2-12
Act&q
I -year
“lo
28%
2-year
15%
by Subgroup
Response
rate
Analysis
in performance
status 6t23 (26%)
0, I 2
l/16(6%)
I-year
survival
in performance
status 32%
0, 1 2
evenly divided between adenocarcinoma, and large cell carcinoma (Table 1).7-s
(x)
Survival
Adenocarcinoma carcinoma
response
Partial 2 (5%)
Histology
in
No. Patients
21 (54%) 2
of Single-Agent Weddy Docetaxel Cell Lung Cancer Patbats’
(%)
I7122
performance
Table
D. HAINSWORTH
24%
squamous carcinoma,
Response
Toxicity
Of the 39 patients, 33 (85%) completed at least 6 weeks (ie, one course) of treatment. Three patients failed to complete one cycle because of rapid tumor progression, two patients requested withdrawal, and one experienced a hypersensitivity reaction to the first dose of docetaxel. This patient was the only one to cease trial treatment because of toxicity. Overall, only 4% of scheduled doses were reduced or omitted. Thirty-six patients were evaluable for response (Table 2). Among this group of patients with relatively poor PS, there was one complete response. Six patients showed a partial response, producing an overall response rate of 20%. Thirteen patients (36%) showed disease stabilization at the time of first evaluation at 8 weeks, while 16 patients (44%) experienced disease progression. The duration of responses observed ranged from 2 to 12 months. Patients with PS 2 (response rate = 6%) were less likely to respond to therapy than those with a PS of 0 or 1, in whom the response rate was 26%. However, the l-year survival rates in good and poor PS patients (32% and 24%, respectively) were not significantly different.Ts Overall, the actual l-year survival in this relatively poor prognosis group was 28% and 2-year survival was 15%. These results must be considered relatively good.
Among the 39 patients treated with a total of 363 doses there were no cases of grade 4 leukopenia, thrombocytopenia, or anemia (Table 3). A total of 4% of doses were followed by grade 3 leukopenia. There were no cases of neutropenic fever, no hospitalizations for complications associated with this regimen, and no treatment-related deaths.
Grade Hematologic
314
No.
Patients
Toxicity
Leukopenia*
3 (8%) 0
Thrombocytopenia Anemia*
5 (13%) 0
Neutropenia/fever Treatment-related Nonhematological
death
0
Toxicity
Fatigue/asthenia
4(10%)
Nausealvomiting
4(10%)
Skin rash
I (3%)
Neuropathy Hypersensitivity
I (3%) reaction
Edema * No grade
I (3%) 0
4 toxicity
was observed.
(%)
WEEKLY
DOCETAXEL
IN ADVANCED
NSCLC
23
Among the patients treated, grade 314 fatigue or asthenia (which may or may not have been treatment related) was experienced by 10% of patients (Table 3). A similar proportion suffered grade 3/4 nausea/vomiting, and there was a 3% rate of grade 3/4 skin rash, neuropathy, and hypersensitivity reaction. There were no cases of edema.7*8 Given these data showing the activity and tolerability of weekly docetaxel, it was appropriate to consider use of this schedule in combination with other active agents. WEEKLY
DOCETAXEL
AND
GEMCITABINE
A number of combination regimens based on weekly docetaxel have been investigated at our institution. The combination of docetaxel with gemcitabine has been studied in previously treated NSCLC patients, and the docetaxel/vinorelbine combination is being assessed both second-line in NSCLC and in metastatic breast cancer. However, this report confines itself to the presentation of preliminary results from a multicenter phase II community-based study of docetaxel plus gemcitabine first-line in a group of elderly patients with NSCLC. Gemcitabine has proven activity when used as a single agent in advanced NSCLC.10-13 It also has shown promise when used in combination with docetaxel in conventional docetaxel every--3 or 4-week schedules.l+Jz Therefore, an investigation of the combination using a weekly regimen was a logical development. Patients and Treatment Accrual to the trial was rapid, reflecting elderly, poor PS patients with advanced community.
Between
were entered patients.
into
The treatment minute intravenous mg/m2. The two of a 28-day methasone hours
August the study.
before
June
2000,66
the
administration
patients
on the first 41
given consisted of docetaxel30 mgjm’ infusion plus intravenous gemcitabine drugs were administered on days 1,8,
as a 30 800 and 15
was composed of dexafor 3 doses, starting 12
of docetaxel.
age of the 41 patients was 72 years (range, 58 to percent were men. Eastern Cooperative OnPS was 0 in lo%, 1 in 59%, and 2 in 31%.
Twenty-seven percent all pleural effusions)
of patienE had stage IIIB disease (almost and 73% had stage IV disease. Histology
was divided evenly between and large cell subtypes. Overall, 81% of patients the
and
are presented
cycle. Steroid prophylaxis 8 mg orally every 12 hours
The median 82). Sixty-eight cology Group
over
1999 Data
the large number of NSCLC seen in the
first two courses
squamous received of treatment.
cell, the
adenocarcinoma, full
On day
doses
intended
1, the planned
dose
was given
virtually
without
the planned docetaxel dose abine dose was administered. planned dose actually received for gemcitabine. predominantly
exception.
On
day
and 91% of the planned On day 15, the proportion was 76% for docetaxel
The reason for dose myelosuppression.
reduction
8, 93%
of
gemcitof the and 72%
or omission
was
Response and Toxicity One patient had a complete response and 10 had a partial response, giving an overall response rate of 29%. An additional 45% of patients had a period of stable disease while 26% progressed. No survival data are yet available because of short follow-up. The combination of weekly docetaxel and gemcitabine given on a 3 weeks on, 1 week off schedule was well tolerated. Grade 3/4 leukopenia was seen in 12% of patients and grade 3/4 thrombocytopenia also in 12%. Grade 3/4 anemia was recorded in 7% of patients. Granulocyte-colony stimulating factor or granulocyte macrophage-colony stimulating factor was used in 37% of patients to maintain cytotoxic dose, and 23% of patients received red blood cell transfusions. No patients were transfused with platelets. There were no cases of hospitalization for treatment-related toxicity and there were no cases of neutropenic fever. The one possibly treatment-related death occurred in a patient who did not have myelosuppression but who developed bilateral pneumonitis and respiratory failure. Pneumonitis has occasionally been reported as an adverse event associated with gemcitabine.23 Compared with the previous study of docetaxel alone, the 27% incidence of grade 314 fatigue/ asthenia seen in this combination trial was higher. The incidence of other grade 3/4 toxicities were: nausea/vomiting 12%; diarrhea 7%; myalgias 2% and peripheral neuropathy 2%. DISCUSSION Single-agent docetaxel can be administered weekly at a dose of 36 mg/m’ with minimal toxicity. Dose intensity and activity are preserved when compared with standard every-3-week schedules of docetaxel administration. This schedule is well tolerated and provides an advantageous treatment option for the large number of patients with advanced NSCLC who are elderly or of poor PS. Moreover, the regimen can feasibly be administered in the community setting. Several other single-agent weekly docetaxel trials have been
24
completed in the second-line treatment of patients with advanced NSCLC. Lilenbaum et al* evaluated weekly docetaxel (36 mgjm’) administered over 6 consecutive weeks, followed by 2 weeks rest, in 23 previously treated NSCLC patients. In the 22 eligible patients, there were no episodes of grade 3/4 anemia or thrombocytopenia, no grade 4 neutropenia, and only a 13% incidence of grade 3 neutropenia. Nonhematologic toxicities were mild. In 16 evaluable patients, the partial response rate was 12%, with stable disease in 25% after the first cycle. Serke et a15 treated 28 NSCLC patients with second-line weekly docetaxel (35 mgfm’) for 6 consecutive weeks, every 8 weeks. No grade 4 hematologic or nonhematologic toxicities were observed. The partial response rate was 14%, and an additional 36% of patients had minor response or stable disease. Garcia-Lopez et a124 administered 43 mgJm2 weekly docetaxel for 6 weeks, every 8 weeks, to 26 NSCLC patients who had progressed after prior platinum therapy. No grade 3/4 leukopenia was observed, and other toxicities were was uncommon. The response rate in 15 evaluable patients was 26.7% and 17.4% on an intent-to-treat analysis. Median survival was 12 months (range, 5 to 27 months) with a 46% l-year survival. When compared with previous reports of standard every-3-week docetaxel in refractory NSCLC, the efficacy observed with weekly administration is similar with substantially less toxicity. Full analysis of the study combining weekly docetaxel with weekly gemcitabine is awaited. However, the results to date show a response rate that is comparable with that achieved with combinations administered on conventional schedules. The toxicity seen with the combination is increased when compared with that observed with weekly docetaxel alone, but the regimen remains well tolerated even by patients with poor PS. The docetaxel/gemcitabine weekly combination also has been evaluated by Kouroussis et al*5 in a phase I trial. Docetaxel was administered at a starting dose of 30 ms/m2 and gemcitabine at a starting dose of 700 ms/m2. Doses were escalated to 40 mg/m2 and 800 mg/m2, respectively, with maximum tolerated dose level not yet reached. The study is ongoing. Other weekly docetaxel combinations have been explored. These include weekly docetaxel with cisplatin or carboplatin.26-28 Multimodality weekly docetaxel/platinum schedules with concur-
JOHN
D. HAINSWORTH
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