- Email: [email protected]
Docetaxel (Taxotere) in the treatment of non-small cell lung cancer: An international update
Seminarsin
Oncology
Vol 28, No 1, Suppl 2
Docetaxel
(Taxotere) in the Treatment Lung Cancer: An International Mark
Based
on
the
(Taxotere; choice
for
lung
cancer
apy.
Trials
the
of two Antony,
are setting,
of
is refractory testing
trials,
role
of
the
drug
non-small
primary
and
docetaxel
is now
advanced to
the
as well
recent France)
treatment
that
induction tion
results
Aventis,
G. Kris
of cell
chemother-
docetaxel
as concomitantly
in the with
radia-
therapy.
Semin Saunders
Oncol
28 (suppl
2):/-3.
Copyright
0 ZOO/
by WB.
Company.
N 1999 lung cancer became the leading cause of cancer death worldwide. Cancers of the lung are the most preventable of all neoplasms. The consequences of changing patterns of cigarette use are not long in appearing. In the United States, women who started smoking within the past 30 years now comprise half of all new lung cancer cases. This development will soon be felt in other countries. Wherever in the world we practice, our duty as physicians is to use whatever influence we have to combat cigarette smoking. This meeting chronicled our attempts to deal with the reality of lung cancer. It also marked a happier milestone: in December 1999, docetaxel (Taxotere; Aventis, Antony, France) was approved for use in non-small cell lung cancer (NSCLC) in both the United States and the European Union. This is the culmination of clinical trial programs that started in the early 1990s (leading to approval in Japan, Canada, and Australia), and of the phase III program that began 4 years ago.l-7 Overall, the role of chemotherapy in the treatment of NSCLC has grown in recent years. Cytotoxic agents are currently used alone and in combination both first and second line for locally advanced and metastatic disease. They are increasingly incorporated into multimodality strategies for the management of earlier stage disease, either presurgically, postsurgically, or, in the case of in-
I
Seminars in Oncology, Vol 28, No I, Suppl 2 (February),
200 I: pp I-3
Christian
February 2001
of Non-Small Update
Cell
Manegold
operable tumors, concurrently or sequentially with radiotherapy. One of the main reasons for the increased use and acceptability of chemotherapy has been the development of new drugs with mechanisms of action that confer higher singlesagent activity and less toxicity. Taxanes that stabilize tubulin, such as docetaxel, are among the most promising of these novel drugs. Docetaxel in particular has gained the reputation of being one of the most effective agents in the treatment of NSCLC. Its development program has been comprehensive and embraces both advanced and early disease. The reports presented at this meeting began with the encouraging phase III results recently achieved with docetaxel.6-s It is appropriate to briefly review the phase II data that laid the foundations for the randomized trials. In previously untreated patients with advanced NSCLC, single-agent docetaxel at doses of 60, 75, or 100 mg/m’, administered once every 3 weeks has achieved objective response rates of approximately 30% (range, 19% to 63% in the 12 phase II trials).’ The median survival averaged approximately 9 months (range, 6 to 11 months), with 39% of patients alive at 1 year (range, 21% to 75%). The main side effect was neutropenia of short duration.
From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; and ThoraxKlinik, Heidelberg, Germany. Drs Kris and Manegold have received consulting fees, honoraria, and clinical trial support from Auentis, Inc. Address reprint requests to Mark G. K-is, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Aue, New York, NY 10021. Copyright 0 2001 by W.B. Saunders Company 0093.7754/01/X301-0201$35.00/O doi:I0.1053/sonc.2001.18387
2
DOCETAXEL
In the second-line setting, phase II trials at the 100 mg/m2 dose involved a total of 240 patients. Response rates of 8% to 21% were achieved.z-5 At a dose of 60 mg/m2 dose in 30 patients, a response rate of 21% was observed.9 From the phase II trials, median survival ranged from 5.7 to 9.4 months and l-year survival ranged from 25% to 41%.2-5s9 At the time the studies were conducted, there was no standard therapy for previously treated NSCLC patients. The phase II results achieved with docetaxel were sufficiently promising to justify two randomized phase III trials in the secondline setting. GAINS
IN SURVIVAL AND OF LIFE
QUALITY
The studies of docetaxel versus best supportive care6 and of docetaxel versus vinorelbine or ifosfamide7 in previously treated NSCLC patients are presented in detail in the report by Shepherd et al (see pp 4-9). The essential finding of these trials is that docetaxel, particularly at the dose of 75 mg/m’, produces clinical benefits and improves both survival and quality of life when compared with control treatments. At the time the current American Society of Clinical Oncology’s treatment guidelines were drawn up, there were no randomized phase III data on which to make recommendations for the second-line treatment of NSCLC. This situation has now clearly changed, and our practice should change with it. For several years, the accepted first-line therapy for advanced NSCLC has been combination chemotherapy based on cisplatin. More recently, combinations involving gemcitabine or vinorelbine have been investigated, based on nonoverlapping toxicities and preclinical evidence of additive or synergistic interaction. Data from a range of studies that have docetaxel in such combinations were presented at this meeting. Early findings suggest that the combination of docetaxel with gemcitabine may be as effective as cisplatin-based chemotherapy in prolonging survival while having the advantage of lower toxicity. The challenge ahead is not just to equal the survival gains achieved with cisplatin combinations, but to better them. MULTIMODALITY
TREATMENT
In patients with locally advanced and inoperable NSCLC, attention has focused recently on the benefits of combining chemotherapy with radio-
FOR NSCLC
therapy. It has proven feasible to combine weekly docetaxel 20 mg/m2 with radiotherapy given at a dose of 2 Gy/d for 5 days every week.10 Given this finding, an ongoing international randomized phase II study is investigating the role of concomitant chemoradiotherapy with docetaxel versus radiotherapy alone in stage III A/B patients who have completed induction chemotherapy. Initial treatment is with docetaxel 85 mg/m2 on day 1 plus cisplatin 40 mg/m’ on days 1 and 2 every 3 weeks. Patients showing a response after two cycles are randomized to either docetaxel 20 mg/m2/wk for 6 weeks plus radiotherapy 2 Gy/d for 5 days per week for 6 weeks or radiotherapy alone. It is through the multimodality treatment of such patients that cures have been achieved with chemotherapy. The availability of new approaches raises the possibility that more patients can be cured. It is therefore a high priority to test the best of our new agents in this setting. In addition, presurgical chemotherapy involving docetaxel is being extensively investigated. A Finnish phase III study is comparing docetaxel plus surgery versus surgery alone, while three phase II trials are studying docetaxel given in combination with cisplatin or cisplatin plus gemcitabine. Preliminary data from one trial involving docetaxel plus cisplatin show promising response rates of 66%, with 12% complete responders and only 4% of patients experiencing progressive disease.” The latter part of the meeting included discussions on how the range of new agents can greatly increase the flexibility of treatment. It is now possible to find a drug or drug combination and an administration schedule matching the circumstances of the individual patient, including his or her susceptibility to various forms of toxicity. Weekly docetaxel schedules are especially welltolerated. MOLECULAR MARKERS CENTER STAGE
TAKE
Exciting developments in molecular biology have given us the ability to target therapies to particular tumor types or characteristics of individual tumors.12 For example, if tubulin mutations are present, tubulin-active drugs may not be the best choice. If the ~53 gene is nonfunctional, it makes more sense to use a treatment that induces apoptosis independently of ~53 pathways. Use of molecular markers is also poised to bring
KRIS AND
MANEGOLD
3
about a substantial refinement in our ability to stage disease and so focus treatment. Nowhere is this more critical than in the postsurgical setting in which some patients harbor deadly but undetectable micrometastases that remain after maximal induction and local treatment. Conversely, treatment could be withheld from those with no evidence of tumor cells in the marrow or circulating tumor DNA in peripheral blood. Such markers also promise to be an invaluable tool in measuring the burden of residual disease during therapy as a means to evaluate the effectiveness of interventions targeting micrometastases. The closing years of the 20th century were times of significant advances in the treatment of NSCLC. The new century holds great promise of further progress. Docetaxel has enriched the possibilities of effective therapy in the recent past and will continue to do so.
1. Rigas
JR:
Do newer
chemotherapeutic
agents
docetaxel
for advanced
or metastatic
platinum
refractory
improve
non-
12:335,
1993
(abstr
4. Gandara DR, Vokes tere) in platinum-treated
1116) E, Green non-small
M, et al: Docetaxel cell lung cancer:
(TaxoA con-
survival
16454a,
in a multicenter
1997
(abstr
trial.
Proc Am
1632)
5. Robinet G, Kleisbauer JP, Thomas I’, et al: Phase II study of docetaxel (Taxotere) in first- and second-line NSCLC. Proc Am
Sot Clin Oncol 16:480, 1997 (abstr 1726) 6. Shepherd F, Gralla R, Ramlau R, et al: Randomized study of Taxotere (TAX) versus best supportive care (BSC) in nonsmall cell lung cancer (NSCLC) with platinum based chemotherapy. (suppl 4) (abstr 979) 7. Fossella F, Devore
patients previously treated Em J Cancer 35:247, 1999
R, Kerr
RN,
et al: Randomized
phase
III study of Taxotere (T) (100 mg/m’ and 75 mg/m’) versus vinorelbine (V) or ifosfamide (I) in non small cell lung cancer (NSCLC)
patients,
chemotherapy. 1859)
Proc
previously Am
treated
Sot Clin
with
Oncol
a platinum-based
17:483a,
1998 (abstr
8. Roszkowski K: Taxotere (Txt) versus best supportive (BSC) in chemotherapy naive patients with unresectable
care non-
small cell lung cancer (NSCLC): Final results of the phase study. Eur J Cancer 35:246, 1999 (suppl 4) (abstr 976) low
9. Nakamura Y, Kunitoh dose docetaxel (DCT)
advanced non-small Clin Oncol 18:518a,
11. Betticher of
small cell lung cancer. J Clin Oncol 1:645-651, 1995 3. Burris H, Eckardt J, Fields S, et al: Phase II trials of Taxotere with non-small cell lung cancer. Proc Am Sot Clin Oncol
of prolonged Oncol
Clin
10. Mauer of docetaxel J Clin Oncol
REFERENCES survival in NSCLC! Semin Oncol 25:5-9, 1998 (suppl 8) 2. Fossella FV, Lee JS, Shin DM, et al: Phase II study
firmation Sot
adjuvant cisplatin
H, Aono H, et al: Phase II trial of 60 mg/m’ in platinum-pretreated
cell lung cancer (NSCLC). 1999 (abstr 1997)
AM, Masters GA, with concomitant 16:159-164, 1998 DC,
III
Sot
Haraf DJ, et al: Phase I study thoracic radiation therapy.
Hsu Schmitz
chemotherapy with (CIS) in patients
Proc Am
SF, Gauthier
Y, et al: Neo-
docetaxel (DOC, Taxotere) (pts) with non-small cell
cancer (NSCLC), stage IIIA, N2 toxicities. Proc Am Sot Clin Oncol
and lung
is highly active with few 18:473a, 1999 (abstr 1824)
12. Gumerlock P: Molecular-clinical correlative studies in non-small cell lung carcinoma, in American Society of Clinical Oncology 1999 Educational cott, 1999, pp 374-381
Book.
Baltimore,
MD,
Lippin-
Oncology
Vol 28, No 1, Suppl 2
Docetaxel
(Taxotere) in the Treatment Lung Cancer: An International Mark
Based
on
the
(Taxotere; choice
for
lung
cancer
apy.
Trials
the
of two Antony,
are setting,
of
is refractory testing
trials,
role
of
the
drug
non-small
primary
and
docetaxel
is now
advanced to
the
as well
recent France)
treatment
that
induction tion
results
Aventis,
G. Kris
of cell
chemother-
docetaxel
as concomitantly
in the with
radia-
therapy.
Semin Saunders
Oncol
28 (suppl
2):/-3.
Copyright
0 ZOO/
by WB.
Company.
N 1999 lung cancer became the leading cause of cancer death worldwide. Cancers of the lung are the most preventable of all neoplasms. The consequences of changing patterns of cigarette use are not long in appearing. In the United States, women who started smoking within the past 30 years now comprise half of all new lung cancer cases. This development will soon be felt in other countries. Wherever in the world we practice, our duty as physicians is to use whatever influence we have to combat cigarette smoking. This meeting chronicled our attempts to deal with the reality of lung cancer. It also marked a happier milestone: in December 1999, docetaxel (Taxotere; Aventis, Antony, France) was approved for use in non-small cell lung cancer (NSCLC) in both the United States and the European Union. This is the culmination of clinical trial programs that started in the early 1990s (leading to approval in Japan, Canada, and Australia), and of the phase III program that began 4 years ago.l-7 Overall, the role of chemotherapy in the treatment of NSCLC has grown in recent years. Cytotoxic agents are currently used alone and in combination both first and second line for locally advanced and metastatic disease. They are increasingly incorporated into multimodality strategies for the management of earlier stage disease, either presurgically, postsurgically, or, in the case of in-
I
Seminars in Oncology, Vol 28, No I, Suppl 2 (February),
200 I: pp I-3
Christian
February 2001
of Non-Small Update
Cell
Manegold
operable tumors, concurrently or sequentially with radiotherapy. One of the main reasons for the increased use and acceptability of chemotherapy has been the development of new drugs with mechanisms of action that confer higher singlesagent activity and less toxicity. Taxanes that stabilize tubulin, such as docetaxel, are among the most promising of these novel drugs. Docetaxel in particular has gained the reputation of being one of the most effective agents in the treatment of NSCLC. Its development program has been comprehensive and embraces both advanced and early disease. The reports presented at this meeting began with the encouraging phase III results recently achieved with docetaxel.6-s It is appropriate to briefly review the phase II data that laid the foundations for the randomized trials. In previously untreated patients with advanced NSCLC, single-agent docetaxel at doses of 60, 75, or 100 mg/m’, administered once every 3 weeks has achieved objective response rates of approximately 30% (range, 19% to 63% in the 12 phase II trials).’ The median survival averaged approximately 9 months (range, 6 to 11 months), with 39% of patients alive at 1 year (range, 21% to 75%). The main side effect was neutropenia of short duration.
From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; and ThoraxKlinik, Heidelberg, Germany. Drs Kris and Manegold have received consulting fees, honoraria, and clinical trial support from Auentis, Inc. Address reprint requests to Mark G. K-is, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Aue, New York, NY 10021. Copyright 0 2001 by W.B. Saunders Company 0093.7754/01/X301-0201$35.00/O doi:I0.1053/sonc.2001.18387
2
DOCETAXEL
In the second-line setting, phase II trials at the 100 mg/m2 dose involved a total of 240 patients. Response rates of 8% to 21% were achieved.z-5 At a dose of 60 mg/m2 dose in 30 patients, a response rate of 21% was observed.9 From the phase II trials, median survival ranged from 5.7 to 9.4 months and l-year survival ranged from 25% to 41%.2-5s9 At the time the studies were conducted, there was no standard therapy for previously treated NSCLC patients. The phase II results achieved with docetaxel were sufficiently promising to justify two randomized phase III trials in the secondline setting. GAINS
IN SURVIVAL AND OF LIFE
QUALITY
The studies of docetaxel versus best supportive care6 and of docetaxel versus vinorelbine or ifosfamide7 in previously treated NSCLC patients are presented in detail in the report by Shepherd et al (see pp 4-9). The essential finding of these trials is that docetaxel, particularly at the dose of 75 mg/m’, produces clinical benefits and improves both survival and quality of life when compared with control treatments. At the time the current American Society of Clinical Oncology’s treatment guidelines were drawn up, there were no randomized phase III data on which to make recommendations for the second-line treatment of NSCLC. This situation has now clearly changed, and our practice should change with it. For several years, the accepted first-line therapy for advanced NSCLC has been combination chemotherapy based on cisplatin. More recently, combinations involving gemcitabine or vinorelbine have been investigated, based on nonoverlapping toxicities and preclinical evidence of additive or synergistic interaction. Data from a range of studies that have docetaxel in such combinations were presented at this meeting. Early findings suggest that the combination of docetaxel with gemcitabine may be as effective as cisplatin-based chemotherapy in prolonging survival while having the advantage of lower toxicity. The challenge ahead is not just to equal the survival gains achieved with cisplatin combinations, but to better them. MULTIMODALITY
TREATMENT
In patients with locally advanced and inoperable NSCLC, attention has focused recently on the benefits of combining chemotherapy with radio-
FOR NSCLC
therapy. It has proven feasible to combine weekly docetaxel 20 mg/m2 with radiotherapy given at a dose of 2 Gy/d for 5 days every week.10 Given this finding, an ongoing international randomized phase II study is investigating the role of concomitant chemoradiotherapy with docetaxel versus radiotherapy alone in stage III A/B patients who have completed induction chemotherapy. Initial treatment is with docetaxel 85 mg/m2 on day 1 plus cisplatin 40 mg/m’ on days 1 and 2 every 3 weeks. Patients showing a response after two cycles are randomized to either docetaxel 20 mg/m2/wk for 6 weeks plus radiotherapy 2 Gy/d for 5 days per week for 6 weeks or radiotherapy alone. It is through the multimodality treatment of such patients that cures have been achieved with chemotherapy. The availability of new approaches raises the possibility that more patients can be cured. It is therefore a high priority to test the best of our new agents in this setting. In addition, presurgical chemotherapy involving docetaxel is being extensively investigated. A Finnish phase III study is comparing docetaxel plus surgery versus surgery alone, while three phase II trials are studying docetaxel given in combination with cisplatin or cisplatin plus gemcitabine. Preliminary data from one trial involving docetaxel plus cisplatin show promising response rates of 66%, with 12% complete responders and only 4% of patients experiencing progressive disease.” The latter part of the meeting included discussions on how the range of new agents can greatly increase the flexibility of treatment. It is now possible to find a drug or drug combination and an administration schedule matching the circumstances of the individual patient, including his or her susceptibility to various forms of toxicity. Weekly docetaxel schedules are especially welltolerated. MOLECULAR MARKERS CENTER STAGE
TAKE
Exciting developments in molecular biology have given us the ability to target therapies to particular tumor types or characteristics of individual tumors.12 For example, if tubulin mutations are present, tubulin-active drugs may not be the best choice. If the ~53 gene is nonfunctional, it makes more sense to use a treatment that induces apoptosis independently of ~53 pathways. Use of molecular markers is also poised to bring
KRIS AND
MANEGOLD
3
about a substantial refinement in our ability to stage disease and so focus treatment. Nowhere is this more critical than in the postsurgical setting in which some patients harbor deadly but undetectable micrometastases that remain after maximal induction and local treatment. Conversely, treatment could be withheld from those with no evidence of tumor cells in the marrow or circulating tumor DNA in peripheral blood. Such markers also promise to be an invaluable tool in measuring the burden of residual disease during therapy as a means to evaluate the effectiveness of interventions targeting micrometastases. The closing years of the 20th century were times of significant advances in the treatment of NSCLC. The new century holds great promise of further progress. Docetaxel has enriched the possibilities of effective therapy in the recent past and will continue to do so.
1. Rigas
JR:
Do newer
chemotherapeutic
agents
docetaxel
for advanced
or metastatic
platinum
refractory
improve
non-
12:335,
1993
(abstr
4. Gandara DR, Vokes tere) in platinum-treated
1116) E, Green non-small
M, et al: Docetaxel cell lung cancer:
(TaxoA con-
survival
16454a,
in a multicenter
1997
(abstr
trial.
Proc Am
1632)
5. Robinet G, Kleisbauer JP, Thomas I’, et al: Phase II study of docetaxel (Taxotere) in first- and second-line NSCLC. Proc Am
Sot Clin Oncol 16:480, 1997 (abstr 1726) 6. Shepherd F, Gralla R, Ramlau R, et al: Randomized study of Taxotere (TAX) versus best supportive care (BSC) in nonsmall cell lung cancer (NSCLC) with platinum based chemotherapy. (suppl 4) (abstr 979) 7. Fossella F, Devore
patients previously treated Em J Cancer 35:247, 1999
R, Kerr
RN,
et al: Randomized
phase
III study of Taxotere (T) (100 mg/m’ and 75 mg/m’) versus vinorelbine (V) or ifosfamide (I) in non small cell lung cancer (NSCLC)
patients,
chemotherapy. 1859)
Proc
previously Am
treated
Sot Clin
with
Oncol
a platinum-based
17:483a,
1998 (abstr
8. Roszkowski K: Taxotere (Txt) versus best supportive (BSC) in chemotherapy naive patients with unresectable
care non-
small cell lung cancer (NSCLC): Final results of the phase study. Eur J Cancer 35:246, 1999 (suppl 4) (abstr 976) low
9. Nakamura Y, Kunitoh dose docetaxel (DCT)
advanced non-small Clin Oncol 18:518a,
11. Betticher of
small cell lung cancer. J Clin Oncol 1:645-651, 1995 3. Burris H, Eckardt J, Fields S, et al: Phase II trials of Taxotere with non-small cell lung cancer. Proc Am Sot Clin Oncol
of prolonged Oncol
Clin
10. Mauer of docetaxel J Clin Oncol
REFERENCES survival in NSCLC! Semin Oncol 25:5-9, 1998 (suppl 8) 2. Fossella FV, Lee JS, Shin DM, et al: Phase II study
firmation Sot
adjuvant cisplatin
H, Aono H, et al: Phase II trial of 60 mg/m’ in platinum-pretreated
cell lung cancer (NSCLC). 1999 (abstr 1997)
AM, Masters GA, with concomitant 16:159-164, 1998 DC,
III
Sot
Haraf DJ, et al: Phase I study thoracic radiation therapy.
Hsu Schmitz
chemotherapy with (CIS) in patients
Proc Am
SF, Gauthier
Y, et al: Neo-
docetaxel (DOC, Taxotere) (pts) with non-small cell
cancer (NSCLC), stage IIIA, N2 toxicities. Proc Am Sot Clin Oncol
and lung
is highly active with few 18:473a, 1999 (abstr 1824)
12. Gumerlock P: Molecular-clinical correlative studies in non-small cell lung carcinoma, in American Society of Clinical Oncology 1999 Educational cott, 1999, pp 374-381
Book.
Baltimore,
MD,
Lippin-