Download Non-small Cell Lung Cancer Adjuvant Chemotherapy for Early

Adjuvant Chemotherapy for Early-Stage
Non-small Cell Lung Cancer
Antonio L. Visbal, Natasha B. Leighl, Ronald Feld and Frances A.
Shepherd
Chest 2005;128;2933-2943
DOI 10.1378/chest.128.4.2933
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Adjuvant Chemotherapy for Early-Stage
Non-small Cell Lung Cancer*
Antonio L. Visbal, MD; Natasha B. Leighl; Ronald Feld, MD; and
Frances A. Shepherd, MD
Lung cancer is the leading cause of cancer-related mortality in the developed world. Non-small
cell lung cancer (NSCLC) represents 85% of cases of lung cancer, and patients have a poor 5-year
survival rate. Approximately one third of NSCLC patients present with early-stage disease that is
amenable to potentially curative resection and multimodality therapy. Several randomized trials
now have confirmed the survival benefit with adjuvant platinum-based chemotherapy, as seen in
the 1995 meta-analysis from the NSCLC Collaborative Group. The International Adjuvant Lung
Cancer Collaborative Group Trial demonstrated a 4.5% improvement in survival for patients with
stage I to III NSCLC. Studies from Japan have reported an improvement of 15.4% in the 5-year
survival rate among patients with T1N0 disease after they had received adjuvant therapy with a
combination of platinum and uracil-tegafur, and an improvement in the 5-year survival of 11%
rate favoring chemotherapy with uracil-tegafur in a subgroup analysis of patients with T2N0
disease. Two recently published metaanalyses have estimated a relative risk reduction in
mortality of 11 to 13% at 5 years. Significant improvement in the long-term survival rate has been
demonstrated for patients with stage IB and II disease by the Cancer and Leukemia Group B
9633 trial (4-year survival rate, 12%) and the The National Cancer Institute of Canada Clinical
Trials Group BR.10 trial (5-year survival rate, 15%; risk reduction for recurrence, 40%). Thus,
there is compelling evidence to now recommend adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC.
(CHEST 2005; 128:2933–2943)
Key words: drugs; lung cancer; thoracic surgery
Abbreviations: ALPI ⫽ Adjuvant Lung Project Italy; BLT ⫽ Big Lung Trial; CALGB ⫽ Cancer and Leukemia Group
B; CAP ⫽ cyclophosphamide, doxorubicin, and cisplatin; ECOG ⫽ Eastern Cooperative Oncology Group;
HR ⫽ hazard ratio; IALT ⫽ International Adjuvant Lung Cancer Collaborative Group Trial; LCSG ⫽ Lung Cancer
Study Group; NCIC-CTG ⫽ National Cancer Institute of Canada Clinical Trials Group; NSCLC ⫽ non-small cell lung
cancer; UFT ⫽ uracil-tegafur
cancer is the leading cause of cancer-related
L ung
mortality in the developed world. Of the 1.2 million
new cases of lung cancer that are diagnosed per year,
approximately 1 million individuals will die.1,2 Nonsmall cell lung cancer (NSCLC), the most common
subtype of lung cancer, represents 85% of cases and
has a poor 5-year survival rate. In a series3 of ⬎ 4,000
patients in whom NSCLC had been diagnosed over 5
consecutive years, the estimated survival rates at 1 and
5 years were 60% and 19%, respectively, in women,
and 51% and 15%, respectively, in men. Approximately
*From the Department of Medical Oncology, Princess Margaret
Hospital/University Health Network, University of Toronto, Toronto, ON, Canada.
Manuscript received February 14, 2005; revision accepted April
18, 2005.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Natasha B. Leighl, 5-222, 610 University
Ave, Toronto ON, M5G 2M9 Canada; e-mail: Natasha.Leighl@
uhn.on.ca
www.chestjournal.org
one third of NSCLC patients present with early-stage
disease that is amenable to potentially curative resection and multimodality therapy. However, even in early
stage I disease, 30% of patients relapse and die within
5 years,4 with systemic recurrence rates varying from 55
to 75%.5,6
The objective of this article was to provide a general
overview of the evolution of adjuvant therapy for
early-stage NSCLC, with special emphasis on recently
reported randomized trials that have demonstrated
improvements in survival and reductions in cancer
recurrence with the use of adjuvant therapy.7–10
Earlier Studies
In the 1980s and early 1990s, multiple studies of
adjuvant chemotherapy in patients who have undergone resection for NSCLC showed conflicting results. The Lung Cancer Study Group (LCSG) evaluated cyclophosphamide, doxorubicin, and cisplatin
CHEST / 128 / 4 / OCTOBER, 2005
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2933
(CAP) chemotherapy in four trials. As can be seen in
Table 1, two trials11,12 reported improvement in early
relapse rates, but no benefits in long-term survival.
The LCSG 772 trial compared immunotherapy with
postoperative chemotherapy in patients with stage II
and III adenocarcinoma and large cell carcinoma
after complete surgical resection, and reported a
7-month improvement in both the median time to
recurrence and survival favoring chemotherapy.11
The LCSG 791 trial compared adjuvant chemotherapy and radiotherapy to adjuvant radiation therapy in
patients with residual tumor in the resection margin
or metastasis in the highest paratracheal lymph node
(station 2). Although there was an improvement of
14% in the survival rate at 1 year, the relapse and
death rates were similar at 2 years, with a median
survival time of 17 months for the entire group.12
The LCSG 801 trial randomized patients to CAP
chemotherapy or observation after surgery, and no
differences were seen. Only 53% of patients randomized to chemotherapy received all four courses, likely
because of toxicity.13 The LCSG 853 trial found
similar survival and time to progression when comparing CAP chemotherapy administered immediately after surgery vs that administered at the first
systemic recurrence. Immediate combination chemotherapy was associated with nonsignificant reductions of 12% and 18%, respectively, in the risk of
recurrence and death.14 A Finnish trial15 reported an
11% improvement in the 5-year survival rate after
adjuvant CAP chemotherapy in patients with T1–
3N0 NSCLC, which was statistically significant. A
63% rate of therapy-related grade 3 to 4 GI toxicity
prevented many patients from completing the
planned chemotherapy.
These disparate results prompted a metaanalysis
conducted by The Non-small Cell Lung Cancer
Collaborative Group.16 This included 9,387 completely resected NSCLC patients from 52 randomized trials performed between January 1, 1965,
and December 31, 1991. With 7,151 deaths for
analysis, the overall comparison of adjuvant chemotherapy vs no intervention after surgery demonstrated a 13% reduction in the risk of death, and
a 5% improvement in the 5-year survival rate
favoring adjuvant therapy. Adjuvant chemotherapy
with alkylating agents appeared to produce an
inferior survival rate and increased the risk of
death by 15% (hazard ratio [HR], 1.15; p ⫽ 0.005).
By contrast, adjuvant chemotherapy with platinum-based regimens improved the 5-year survival
rate by 5% and reduced the risk of death by 13%
(HR, 0.87; p ⫽ 0.08), which prompted ongoing
studies of platinum-based combination therapy.
Second-Generation and Third-Generation
Regimens
Improvements in supportive care have led to
better patient compliance in chemotherapy trials in
the advanced NSCLC setting. Response rates of 30%
and 1-year survival rates of 30 to 40% in stage IV
NSCLC trials using newer platinum-based combinations (including the taxanes, vinorelbine, gemcitabine, or docetaxel)17–20 encouraged further research
in adjuvant chemotherapy for earlier stages of disease.
Several trials have suggested a survival benefit
from adjuvant chemotherapy for completely resected early stage NSCLC. Table 2 describes details
of second-generation and third-generation regimen
trials, including patient distribution by stage, allocated arm, and outcomes. A randomized trial involving 66 patients with completely resected stage IB
disease reported an 18% improvement in the 5-year
survival rate after adjuvant chemotherapy with etoposide cisplatin, although the difference was not
significant due to the small sample size.21
Two large negative studies22,23 of adjuvant chemotherapy described an important lack of patient compliance to treatment. The Adjuvant Lung Project
Italy (ALPI) randomized 1,209 patients with radically resected stage I to IIIA disease to three cycles
of mitomycin, vindesine, and cisplatin every 3 weeks
or to observation. Stratification included tumor size,
lymph node involvement, center, and intended radiotherapy. There was no difference between the
arms in survival time or recurrence with a 64.5month median follow-up time. The main toxicity was
grade 3 neutropenia in 16% of the patients and grade
4 in 12% of patients. Only one third of patients
received all three cycles of chemotherapy; and radiotherapy was completed in only 65% of the 176
scheduled patients in the chemotherapy arm vs 82%
of the 152 scheduled patients in the control arm.22
The Big Lung Trial (BLT) randomized 381 patients
to three courses of cisplatin-based chemotherapy
(choosing from the following four combinations:
vinorelbine/cisplatin; cisplatin/vindesine; mitomycin/
ifosfamide/ cisplatin; or mitomycin/vinblastine/cisplatin) before or after surgery, or to observation.23
Approximately one third of patients had clinical stage
IIIA or greater disease, and the other two thirds of
patients had stage I-II disease. The patients in the
arms of the study were well-balanced for risk factors.
No improvement in overall survival rate or diseasefree survival rate was seen. There were six treatmentrelated deaths, and 30% of patients experienced
toxicity grade 3 or greater (mainly hematologic toxicity). Only 64% of the 192 patients who were
allocated to chemotherapy received all three planned
2934
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CHEST / 128 / 4 / OCTOBER, 2005
2935
II/III§
IB/II
T1–3N0
Lad et al12/1988
Feld et al13/1993
Niiranen
et al15/1992
KPS ⬎ 60%
Age ⬍ 70 yr
Arrhythmias, stage,
weight loss of
⬎ 10%
Squamous cell
carcinoma,
microscopic vs
macroscopic,
KPS 50–70 vs
80–100
Squamous cell,
WBC
KPS 50–70 vs
80–100
Stratification
86
78
XRT 20 Gy ⫻ 2 or
CAP ⫻ 6 ⫹ XRT
Observation or
CAP ⫻ 6
56
54
141
142
70
71
BCG ⫹ levamisole or
CAP ⫻ 6
Observation or
CAP ⫻ 4
Patients,
No.
Randomization
GI, 63%
88%;
GI, 65%
Hematologic, 1
death from
toxicity
45%
96%,
Severe
hematologic,
14%
Severe GI, 27%
GI, 87%
Toxicity
0.31
0.48
0.13
0.10
0.83
0.46
0.70
0.47
Recurrence
Rate†
0.01
0.52
0.004
0.001
0.018
0.003
p
Value‡
1.2
HR
60%
58% (5 yr)
[p ⫽ 0.52]
8 mo
14 mo
(median)
Progression-Free
Survival
0.12
0.24
0.55
0.44
0.47
0.33
Death
Rate†
0.915
0.133
0.047
0.07
0.047
p
Value‡
0.53
(0.3–0.93)
0.98
HR
(95% CI)
56%
67% (5 yr)
[p ⫽ 0.05]
58%
58% (5 yr)
[p ⫽ 0.91]
13 mo
20 mo
(median)
Overall
Survival
*XRT ⫽ radiation therapy; BCG ⫽ bacillus Calmette-Guérin; KPS ⫽ Karnofsky Performance Standard; CAP ⫽ cyclosporin (400 mg/m2), adriamycin (40 mg/m2), cisplatin (40 mg/m2); CI ⫽ confidence
interval.
†Values are given as rate per person per year.
‡Log-rank Gehan, with significance at p ⫽ 0.05.
§Incomplete resection.
II/III
Disease
Stage
Holmes and
Gail11/1986
Study/Year
Table 1—Adjuvant Chemotherapy for Lung Cancer in Early Stages (Early Trials)*
2936
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Reviews
I, 39%; II, 32.5%;
IIA, 28.5%
I, 27%; II, 38%;
IIIA, 26%; IIIB
⫹ IV, 8%; ?, 1%
IA, 10%; IB, 26.6%;
IIA, 4.2%; IIB,
28.4%; IIIA,
29.4%; IIB, 1.4%
IB
IB, 42%; IIB, 55%
Metaanalysis
Metaanalysis
Scagliotti et al22/
2003
Waller et al‡23/2004
Arriagada et al8/
2004
Strauss et al9/2004
Winton et al10/2004
Hotta et al24/2004
Sedrakyan et al25/
2004
Plt-based
5,830
3,786
239
243
171
173
189
189
192
548
540
Observation ⫹/⫺ XRT (50 Gy) or
MVP ⫻ 3 ⫹/⫺ XRT
Observation or
cisplt ⫻ 3 ⫹ (vindesine;
mitomycin/ifosfamide;
mitomycin/vinblastine;
vinorelbine)
Observation or
cisplt ⫻ 3–4 (80–120 mg/m2) ⫹
(vindesine; vinblastine;
vinorelbine; etoposide)
Observation or
plt-carbo ⫻ 4 (paclitaxel, 225
mg/m2; carbo, AUC of 6)
Observation or
cisplt, 50 mg/m on day 1 ⫹ 8 ⫻
4 mo; vinorelbine,
25 mg/m2/wk ⫻
16 wk
Plt-based
33
33
242
246
Patients,
No.
XRT (50 Gy) or
Concurrent XRT (50 Gy) ⫹
EP ⫻ 4
Observation or
EP ⫻ 6
Randomization
48
61
(p ⫽ 0.012)
935
932
51
53 (2 yr)
关p ⫽ 0.81兴
30
59
(p ⫽ 0.02)
5-yr
Rate,† %
46.7
None
reached
(p ⫽ 0.0004)
34.3
39.4
(p ⫽ 0.003)
28.9
36.5
(p ⫽ 0.128)
24.7
27
30.4
26.1
(p ⫽ 0.88)
Median
Time, mo
0.61
0.69 (0.48–0.98)
0.97 (0.74–1.26)
0.89 (0.76–1.03)
HR
(95% CI)
59
71
(p ⫽ 0.028) 关4 yr兴
54
69
(p ⫽ 0.002)
0.83 (0.74–0.94)
60
74
(2 yr)
关p ⫽ 0.90兴
39
33
(p ⫽ 0.56)
45
63
(p ⫽ 0.04)
5-yr
Rate,† %
73
94
(p ⫽ 0.012)
40
44
(p ⫽ ⬍ 0.03)
48
55.2
(p ⫽ 0.589)
32.6
33.9
39
38
Median
Time, mo
Overall Survival
0.89 (0.81–0.79)
关p ⫽ 0.012兴
0.89 (0.82–0.96)
关p ⫽ 0.003兴
0.7 (0.46–080)
0.62 (0.41–0.95)
0.86 (0.76–0.98)
1.02 (0.77–1.26)
0.96 (0.81–1.13)
0.58 (0.34–0.99)
0.93 (0.74–1.18)
HR
(95% CI)
*AUC ⫽ area under the curve; plt ⫽ platinum; carbo ⫽ carboplatin; cisplt ⫽ cisplatin; EP ⫽ etoposide (120 mg/m2 ⫻ 3), cisplatin (100 mg/m2); MVP ⫽ mitomycin (8 mg/m2), cisplatin (100 mg/m2),
vindesin (3 mg/m2 ⫻ 2); ⫹/⫺ ⫽ with or without. See Table 1 for other abbreviations not used in the text.
†Log rank for comparison of proportion and median with significance at p ⫽ 0.05.
‡Information is for clinical stage.
IB
II, 42%; IIIA, 58%
Disease Stage
Mineo et al21/2001
Liu et al39‡/1997
Study/Year
Progression-Free Survival
Table 2—Adjuvant Chemotherapy in Patients With Completely Resected Early-Stage NSCLC (Second-Generation and Third-Generation Trials)*
cycles, and just two thirds of them did so without
modification or delays; 7% of patients received two
cycles, 14% of patients received one cycle, and 13%
received no chemotherapy.
The International Adjuvant Lung Cancer Collaborative Group Trial (IALT)8 is the largest study of
adjuvant chemotherapy that has been conducted to
date. With a planned accrual of 3,300 patients, it was
designed to have the statistical power to confirm a
5% absolute survival benefit for chemotherapy at 5
years (from 50 to 55%).8 Patients were randomly
assigned after surgery to receive either three to four
cycles of cisplatin-based chemotherapy or to observation. Each center determined its policy for postoperative chemotherapy and radiotherapy before
randomization. Due to slow accrual, the study closed
after the enrollment of 1,867 patients. At least 74%
of the patients received 240 mg/m2 of cisplatin; and
in more than half of patients, this regimen was
combined with etoposide (56.5%) or vinorelbine
(26.8%). Seven patients (0.8%) died of chemotherapy-induced toxic effects. With a median follow-up
period of 56 months, there was a statistically significant improvement in overall survival with an absolute difference of 4.1% at 5 years favoring adjuvant
chemotherapy. Several explanations have been proposed for the varying results of these trials. One is
that a larger proportion of patients in the IALT8
received a higher dose of cisplatin, while in the BLT
and ALPI studies few patients completed the
planned courses of chemotherapy. Two recent metaanalyses including trials published since 1995 have
reported a consistent relative risk reduction for
mortality at 5 years of 11% after postoperative
platinum-based chemotherapy.24,25
based chemotherapy followed by 1 year of UFT
therapy compared to observation after surgery, with
a 5.1% improvement in the 5-year overall survival
rate and a 4.3% improvement in the disease-free
survival rate. A subgroup analysis28 of 116 T1N0
patients demonstrated a 15.4% improvement in the
5-year survival rate favoring chemotherapy over observation (p ⫽ 0.03). A study limited to completely
resected stage I and II NSCLC patients that was
conducted by the North-east Japan Study Group for
Lung Cancer Surgery29 described a nonsignificant
4% improvement in the survival rate after 2 years of
oral adjuvant UFT therapy compared to observation.
A larger study of patients with stage I adenocarcinoma comparing UFT therapy for 2 years vs observation by the Japan Lung Cancer Research Group in
Post Surgical Adjuvant Chemotherapy found a significant 11% improvement in the 5-year survival
rate favoring UFT therapy in a subgroup analysis
of patients with pathologic state T2N0 disease
(p ⫽ 0.04). Despite minimal toxicity, the treatment
compliance dropped from 80% at 6 months to 61%
at 24 months.7 Two recent metaanalyses24,25 have
confirmed a survival benefit favoring postoperative
UFT therapy, with a 17% risk reduction for mortality
at 5 years. While one study30 has suggested that the
pharmacokinetics of tegafur are similar in Japanese
and Western patients, there may be differences in
5-fluorouracil exposure based on differences in body
size between different populations. Thus, it would be
helpful to confirm the adjuvant benefits of tegafur in
other populations before it is introduced in adjuvant
regimens elsewhere.
Studies of Adjuvant Tegafur in NSCLC
Current Trials of Early-Stage NSCLC
(IB and II) Disease
Uracil-tegafur (UFT) is an oral prodrug of fluorouracil that was administered in daily doses for up to 2
years, thereby offering a theoretical advantage of
prolonged exposure to fluorouracil resembling a
continuous infusion.26 Table 3 describes details of
adjuvant tegafur trials in patients with NSCLC,
including patient distribution by stage, allocated
regimens, and outcomes. A three-arm study in patients with resected stage I-IIIA NSCLC conducted
by the West Japan Study Group for Lung Cancer
Surgery described a significant 14% improvement in
5-year survival with adjuvant UFT therapy over 2
years and an 11% improvement with combined
platinum-based chemotherapy and UFT over 1 year,
compared to observation.27 The same group described a trend toward better survival rates in patients with stage I and II NSCLC after platinum-
The Cancer and Leukemia Group B (CALGB)
conducted a trial to evaluate adjuvant chemotherapy
in completely resected stage IB NSCLC.9 Three
hundred forty-four patients with stage T2N0 disease,
with negative lymph nodes proven by mediastinoscopy or thoracotomy, were randomized within 4 to 8
weeks after undergoing complete surgical resection
to observation or to four cycles of therapy with
paclitaxel (200 mg/m2) and carboplatin (area under
the curve, 6) administered on day 1 every 3 weeks.
The groups were well-balanced for known prognostic
factors, including age, gender, race, ethnicity, histology, tumor differentiation, and resection type. The
regimen was well-tolerated with no treatment-related deaths. The most commonly reported toxicity
was grade 3 or 4 neutropenia in 36% of patients. The
overall survival time was significantly longer in the
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IA, 49.5%;
IB, 34.5%;
IIA, 8%; IIB, 8%
IA, 56%; IB, 31%;
IIA, 6%; IIB, 7%
IA, 73%; IB, 27%
Metaanalysis
Metaanalysis
Wada et al28/1999
Endo et al29/2003
Hotta et al24/2004
Sedrakyan et al25/2004
Observation,
UFT ⫻ 1 yr (400 mg/d), or
PV ⫻ 3 ⫹ UFT ⫻ 1 yr
(cisplt, 50 mg/m2; vindesine,
2–3 mg/m2, ⫹ UFT, 400 mg/
d ⫻ 1 yr)
Observation or
PVM ⫻ 2 ⫹ UFT ⫻ 1 yr
(cisplt, 80 mg/m2 on days 1–2;
vindesine, 2–3 mg/m2 on days
1–8; mitomicin, 8 mg/m2 on
day 1; UFT, 400 mg/d ⫻ 1 yr)
Observation or
UFT ⫻ 2 yr (400 mg/d)
Observation or
UFT ⫻ 2 yr (250 mg/m2/d)
UFT vs observation
UFT vs observation
Randomization
*See Table 1 for other abbreviations not used in the text.
†Significance at p ⫽ 0.05 (log rank for comparison of proportion).
Kato et al7/2004
I, 68%; II 26%;
IIIA 18%;
IIIB 2%
Stage
Wada et al /1996
27
Study/Year
110
109
488
491
1,751
1,370
116
109
100
108
115
Patients,
No.
71
78
51
53 (2 yr)
69.8
74.1
5-yr
Rate, %
0.81
0.24
0.46
p Value†
0.97 (0.74–1.26)
1.37 (0.81–2.31)
HR (95% CI)
Progression-Free Survival
75
79
85
88
71.1
76.8
49
64.1
60.65
Survival
Rate, %
0.015
0.006
0.04
0.701
0.39
All groups, 0.053
Observation vs
UFT, 0.022
Observation vs
CVUFT, 0.083
p Value†
5-yr Survival
Table 3—Adjuvant Chemotherapy Including UFT Treatment in Patients With Completely Resected Early-Stage NSCLC*
0.8 (0.68–0.95)
0.83 (073–0.95)
0.71 (0.52–0.98)
1.34 (0.65–196)
0.55 (0.36–0.86)
关p ⫽ 0.009兴
0.64 (0.42–0.97)
关p ⫽ 0.037兴
HR (95% CI)
chemotherapy arm (p ⫽ 0.028) with a 12% improvement in 4-year survival at a median follow-up time of
34 months.
The National Cancer Institute of Canada Clinical
Trials Group (NCIC-CTG) conducted a study to
evaluate adjuvant chemotherapy in completely resected stage IB NSCLC (T2N0) and stage II
NSCLC (excluding T3N0 patients). Four hundred
eighty-two patients were randomized to observation
or to four cycles of therapy with vinorelbine (25
mg/m2 weekly for 16 weeks) and cisplatin (50 mg/m2
on days 1 and 8 every 4 weeks). The patients were
stratified by nodal status (ie, N0 vs N1) and ras
mutation status (ie, present vs absent vs unknown).
The arms of the study were well-balanced for important prognostic factors. Toxicity included grade 4
neutropenia, with febrile neutropenia in 7% of patients receiving vinorelbine at 30 mg/m2, which
prompted a dose reduction to 25 mg/m2 shortly after
the study started. Two patients died of drug-related
toxicity (febrile neutropenia, one patient; pulmonary
fibrosis, one patient). In the long-term follow-up, the
most common cause of death was NSCLC (including
one patient with a second primary NSCLC). There
was significant improvement in median survival time
for patients in the adjuvant chemotherapy arm from
73 to 94 months (p ⫽ 0.011). There was also a 15%
improvement in 5-year survival favoring adjuvant
chemotherapy (HR, 0.7; p ⫽ 0.012).10 The results of
the CALBG 9633 trial,9 the NCIC-CTG BR10 trial,10 and the recently published metaanalyses24,25
suggest that adjuvant chemotherapy improves survival time and the period free of disease in patients
with early-stage NSCLC, and appears greater than
the benefit of adjuvant therapy in cancer of other
organs, such as the colon,31 ovary,32 and breast,33 as
demonstrated in Table 4.
Closing Remarks
Recent data strongly support the use of adjuvant
therapy in patients with early-stage completely resected NSCLC. Table 5 describes the evolving beneficial trend in favor of platinum-based adjuvant
chemotherapy since the metaanalysis published in
1995.16 The IALT8 demonstrated a 4.5% improvement in survival time for patients with stage I to III
NSCLC. Two metaanalyses24,25 demonstrated an
estimated 11 to 13% relative risk reduction in mortality at 5 years. Significant improvement in longterm survival has been demonstrated for patients
with stage IB and II disease by the CALGB 9633
trial (improvement at 4 years, 12%)9 and the NCICCTG JBR10 trial (improvement at 5 years, 15% [with
a 40% risk reduction for recurrence]).10 Thus, the
www.chestjournal.org
evidence compels us to propose a paradigm shift in
favor of recommending adjuvant chemotherapy for
fit patients with NSCLC lung cancer in early stages
IB and higher.
Systemic therapy for lung cancer has long been an
area of therapeutic nihilism. The toxicity of the
treatment was high, and the potential benefits were
considered to be minimal. In the last decade, clinicians have increased the proportion of lung cancer
patients to whom they offer systemic therapy. Novel
combinations of third-generation agents have demonstrated better efficacy with response rates of
ⱖ 30%, better tolerability, and, now, evidence to
support second-line and even third-line systemic
treatment (ie, docetaxel or pemetrexed, then erlotinib) to prolong survival and to improve symptoms
and quality of life in patients with advanced NSCLC.
Prior studies, including the IALT,8 included older
chemotherapy combinations, with potentially higher
toxicity, less patient compliance, and lesser efficacy
than presently used novel combinations. For example, regimens containing alkylating agents were associated with decreased survival time when administered in the adjuvant setting. Thus, while the
IALT8 confirms the modest benefits seen in the
metaanalysis of adjuvant chemotherapy and is statistically significant, most patients received an older
combination regimen (ie, etoposide and cisplatin).
The results of the NCIC-CTG BR10 trial10 and
CALBG 9633 trial9 are important as they are the first
trials of third-generation platinum-based combination therapies to be reported, and both demonstrate
a significant survival benefit when these newer
agents, which are accepted as standard regimens
around the world in patients with advanced disease,
are administered in the adjuvant setting.
There are still areas for further research. The role
of adjuvant chemotherapy for the treatment of stage
IA NSCLC or for other stages of disease has not
been established. Adjuvant studies7,29 including only
UFT have had negative results. Chemotherapy with
platinum and UFT resulted in a 5-year survival rate
improvement of 15.4% in a subgroup of 116 patients
with T1N0 disease.28 The IALT8 demonstrated a
trend for better survival after platinum-based adjuvant chemotherapy in 183 patients with T1N0M0
disease.8 Thus, further studies are needed to clarify
the best approach for adjuvant therapy in patients
with stage IA NSCLC. A phase III chemoprevention
trial of selenium supplementation in patients with
resected stage IA and IB NSCLC (Eastern Cooperative Oncology Group [ECOG] study E5597) is
underway and may provide valuable information in
the near future.
It is not clear whether preoperative induction
chemotherapy could confer benefits to adjuvant
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Reviews
Lung (344)
Lung (7,200)
Lung (5,716)
Colon (3,238)
Ovary (925)
Breast (11,000)
Strauss et al9/2004
Sedrakyan et al25/2004
Hotta et al24/2004
Comets et al30/2004
Gray et al31/2003
Pisters et al34/1992
Carbo,
placlitaxel
Plt-based ⫾ UFT
Plt-based ⫾ UFT
5FU/FA ⫾
levamisole
Plt
Polychemotherapy
Cisplt- vinorelbine
Chemotherapy
0.64 (0.50- 0.82)
76 vs 65
59 vs 50
IA-IC ⬎ 90%
0.69 (0.48–0.98)
0.6
Risk of
Recurrence‡
0.82 (0.70–0.97)
46.7
Median
Time,
mo
I-III
I-III
Dukes B, 91%
IB, 45%; IIA,15%;
IIB, 40%
IB
Stage
*5FU ⫽ 5-fluorouracil. See Tables 1 and 2 for abbreviations not used in the text.
†Values in parentheses are the No. of patients.
‡Values are given as HR (95% CI).
Lung (482)
Organ†
Winton et al /2004
10
Study/Year
5-yr
RecurrenceFree Rate, %
Recurrence
0.001
0.02
0.03
0.0003
p
Value
82 vs 74
71 vs 67.5
71 vs 59
(4 yr)
69 vs 54
5-yr
Survival
Rate, %
94 vs 73
Median
Time,
mo
Adjuvant Therapy vs Observation After Surgery
0.67 (0.50–0.90)
0.87 (0.81–0.93)
0.87 (0.80–0.94)
0.88 (0.75–1.05)
0.62 (0.41–0.95)
0.7 (0.46–0.80)
Risk of Death‡
Survival
Table 4 —Comparison of Benefit From Adjuvant Chemotherapy for Patients With Early-Stage Cancers of Various Types*
0.008
⬍ 0.0001
0.001
0.15
0.028
0.012
p Value
Table 5—Adjuvant Chemotherapy in Patients With
Early-Stage NSCLC*
Study/Year
19
Dancey et al /1995
Liu et al39/2000
Scagliotti et al22/2003
Waller et al23/2004
Arriagada8/2004
Sedrakyan et al25/2004
Hotta et al24/2004
Strauss et al9/2004
Winton et al10/2004
Patients, No.
HR
95% CI
1,394
488
1,209
381
1,867
7,200
5,716
330
482
0.87
0.93
0.96
1.02
0.86
0.87
0.87
0.62
0.7
(0.74–1.02)
(0.74–1.18)
(0.81–1.13)
(0.77–1.26)
(0.76–0.98)
(0.80–0.94)
(0.80–0.94)
(0.41–0.95)
(0.46–0.80)
*See Table 1 for abbreviation not used in the text.
chemotherapy in early stage NSCLC. Induction
chemotherapy has proven to be safe and feasible,
with no increase in surgical complications.34 Despite
the possible advantages of induction chemotherapy
(such as potentially better patient compliance and
treatment delivery, early control of micrometastasis,
and reduction in tumor size prior to surgery allowing
complete resections to be performed more frequently), a phase III trial by the French Thoracic
Cooperative Group reported no overall benefit in
patients with early-stage NSCLC.35 There was a
nonsignificant improvement of 8.6% in survival rate
at 4 years, and of 11% in disease-free survival at 3
years, favoring neoadjuvant therapy over surgery
alone.35 A randomized phase III trial comparing
neoadjuvant paclitaxel/carboplatin chemotherapy to
surgery alone in patients with clinical stage IB and II
and T3N1 NSCLC (Southwest Oncology Group
9900 trial) was closed in view of the significant
benefits seen in the NCIC-CTG JBR10 trial.10 Open
trials are evaluating the potential role of neoadjuvant
therapy in patients with early-stage NSCLC. The
NATCH in Spain allocates patients to three arms (ie,
three courses of neoadjuvant paclitaxel plus carboplatin followed by surgery, vs surgery followed by
three courses of adjuvant paclitaxel plus carboplatin,
vs surgery alone). The CLINCH is a second Spanish
trial comparing three courses of neoadjuvant paclitaxel plus carboplatin plus gemcitabine vs surgery
alone. The CHEST trial in Italy compares three
courses of neoadjuvant gemcitabine plus cisplatin vs
surgery alone. The LU22 trial in the United Kingdom compares three courses of platinum-based neoadjuvant chemotherapy vs surgery alone (Table 6).
There are no data to support concurrent or sequential adjuvant radiation therapy in patients with
completely resected early-stage NSCLC. In the
IALT,8 572 patients received thoracic radiotherapy
(chemotherapy arm, 284 patients [compliance rate,
70.4%]; control arm, 288 patients [compliance rate,
Table 6 —Unreported NSCLC Chemotherapy Trials*
Trials
Country
Therapy or Stage
Regimens
LU22
CHEST
United Kingdom
Italy
Neoadjuvant therapy vs surgery
Neoadjuvant therapy vs surgery
Survival
Survival
CLINCH
Spain
Neoadjuvant therapy vs surgery
NATCH
Spain
Neoadjuvant vs adjuvant
therapy vs surgery
ANITA-1 (840)
International
I-IIIA (except T1N0M0)
ANITA-2 (slow accrual)
International
I-IIIA (except T1N0M0)
Marseille (21/150)
France
NCIC-CTG BR19
Trial
Canada
IA-IIIA; Standardized resection
Lymph node dissection
Bronchoangioplasty to avoid
pneumonectomy
Bronchial stump coverage
after right pneumonectomy
Completely resected IB-IIIA;
stratify by stage, histology,
chemotherapy, radiation,
gender
Completely resected IB-IIIA
Plt-based ⫻ 3 vs surgery only
Gemcitabine ⫹ cisplt ⫻ 3 vs
surgery only
(Paclitaxel ⫹ carbo ⫹
gemcitabine) ⫻ 3 ⫹ surgery
vs surgery only
(Paclitaxel ⫹ carbo) ⫻ 3 ⫹
surgery vs surgery ⫹
(paclitaxel ⫹ carbo) ⫻ 3 vs
surgery only
Observation vs cisplt ⫻ 4 wk ⫹
vinorelbine ⫻ 16 wk
Observation vs vinorelbine ⫻
16 wk
(Gemcitabine ⫹ cisplt) ⫻ 3 vs
(docetaxel ⫹ cisplt) ⫻ 3
Observation vs gefitinib, 250
mg/d per 2 yr
Survival
Observation vs erlotinib, 150
mg/d per 2 yr
Survival
Roche
Primary End Point
Survival
Survival
Survival (closed in
December 2000)
Survival (closed early)
Quality of life (opened
in September 2004)
*See Tables 1 and 2 for abbreviations not used in the text.
www.chestjournal.org
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2941
84.2%]), and established no interaction between
treatment effect and patients’ characteristics or
the treatment options on overall or disease-free
survival, and no significant interaction between
the effect of chemotherapy and postoperative
radiotherapy.8 Radiation therapy provides local
control when the mediastinum is involved by nodal
disease.36 The results of adjuvant radiation therapy
trials diverge from the encouraging trend of adjuvant chemotherapy, as the Post Operative Radiation Therapy metaanalysis37 yielded no survival
benefit, adjuvant radiation therapy appeared to be
detrimental in patients with stage I/II, N0-N1
disease, and no adverse effect in patients with
stage III disease were described. The ECOG 3590
trial38 (with pN2 disease in at least 53% of patients) found no reduction of intrathoracic recurrence within the radiation field, and no survival
advantage in patients with completely resected
stage II and IIIA NSCLC who had been treated
with concurrent radiation therapy and adjuvant
therapy with cisplatin-etoposide, as the regimen
appeared more toxic than radiation therapy alone.
Unreported and open trials such as ANITA-I trial
(observation vs vinorelbine plus cisplatin), the
ANITA-II trial (vinorelbine vs observation), and
the Marseille trial (cisplatin combined with either
gemcitabine or docetaxel) may yield important
information regarding varied therapy combinations and quality of life (Table 6).
Future trials may include molecularly targeted
agents, for example, as maintenance after adjuvant
chemotherapy, particularly if they demonstrate
activity in patients with advanced NSCLC. The
use of orally administered drugs with potentially
lower toxicity is an attractive option. This is particularly true from the patients perspective, in
which patients have shown appreciation for oral
medications as long as drug efficacy is not sacrificed.39 For example, the NCIC-CTG BR 19 study
is assessing the value of adjuvant gefitinib in
patients with completely resected stage IB, II, or
IIIA NSCLC. Patients are randomized to receive
gefitinib, 250 mg/d for 2 years, or placebo after
undergoing resection. Studies of epidermal growth
factor receptor protein expression, gene copy
number, and mutation status will be integral
to this trial. In a similar phase III trial sponsored
by Roche/Genetech, patients with completely resected stage IB to IIIA NSCLC will be randomized to receive erlotinib, 150 mg/d for 2 years,
or to observation alone. Studies of vascular endothelial growth factor inhibitor are also being
considered.
Conclusion
The results of a number of trials make a compelling case in favor of adjuvant chemotherapy in the
treatment of patients with early-stage NSCLC as the
new standard of treatment for patients with good
performance status. In the future, molecularly targeted therapy may also be part of the protocols
for adjuvant therapy in patients with early-stage
NSCLC.
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2943
Adjuvant Chemotherapy for Early-Stage Non-small Cell Lung Cancer
Antonio L. Visbal, Natasha B. Leighl, Ronald Feld and Frances A. Shepherd
Chest 2005;128;2933-2943
DOI 10.1378/chest.128.4.2933
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