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Adjuvant Chemotherapy for Resected Non–Small-Cell Lung Cancer

Adjuvant Chemotherapy for Resected Non–Small-Cell Lung Cancer

ABSTRACT: Because of the high rate of distant disease recurrence, the 5-year survival of patients who have undergone complete surgical resection of localized non–small-cell lung cancer (NSCLC) is approximately 50%. Initial results from early studies of adjuvant postoperative chemotherapy reported an adverse effect of alkylating agent and older chemotherapy regimens on survival. Cisplatin-based combinations were the first to show a survival advantage. A 1995 meta-analysis of these studies suggested a 13% reduction in the hazard ratio for death (HR = 0.87), leading to a 5% survival benefit at 5 years. Still, these trials involved limited numbers of patients (N = 1,394), and the results failed to reach statistical significance (P = .08). Of the five largest subsequent randomized trials of platinum-based adjuvant therapy, three showed a significant survival advantage. Although it is impossible to determine the reasons for the differing outcomes of these studies, several key features distinguish them, and the data suggest that medically fit patients with resected stage IB or II NSCLC should be offered chemotherapy with a platinum/ new drug combination.

Surgery is potentially curative
and represents the most appropriate
treatment modality for
medically fit patients who present with
localized non-small-cell lung cancer
(NSCLC; stage I, II, and IIIA without
N2 involvement). Despite complete
surgical resection, however, recurrence
rates remain unsatisfactorily
high. The majority of patients who
relapse do so with distant metastatic
disease, highlighting the need for effective
systemic adjuvant therapy.
Until recently, convincing evidence
for the benefit of postoperative adjuvant
chemotherapy has been lacking.
However, recent studies have demonstrated
the value of modern platinumbased
chemotherapy and also of
uracil/tegafur (UFT) in defined populations
of patients with resected
NSCLC.

The overall 5-year survival of patients
following resection of NSCLC
is only about 50%. The major determinant
for survival is the stage of the
tumor, reflecting the importance of
tumor size and particularly lymph
node involvement. In American Joint
Committee on Cancer (AJCC) pathologic
stage I cancer survival is approximately
64.6%, while in stage II
disease survival falls to 41.2%.[1] Survival
is highest in pathologic stage IA
disease (pIA), with 5-year survival rates
of 69% to 83% depending on the surgical
series. In contrast, the 5-year survival
for pIIIA is only about 23%.[2]

Other factors that influence survival
include histologic subtype (improved
survival in squamous cell
carcinoma vs adenocarcinoma), involvement
of multiple lymph nodes,
involvement of multiple levels of N2
disease, and the presence of extranodal
extension. Molecular markers
such as Ras, p53, and EGFR, although
thought to be important, have not consistently
been shown to be of prognostic
significance.

Rationale for Adjuvant Therapy

The majority of deaths occur as a
result of recurrent disease. Analysis
of the pattern of failure in patients
who relapse following primary resection
of NSCLC reveals that local recurrence
occurring in isolation
accounts for only about one-quarter
of relapses (Table 1).[3-10] Distant
recurrence alone or in combination with local recurrence occurs considerably
more frequently. The brain is
the most frequent site of recurrent
metastatic disease, followed by bone
and the contralateral lung. These data
draw attention to the importance of
unrecognized micrometastatic disease
present at the time of operation. It is
of concern that sensitive immunohistochemical
techniques (using antibody
to cytokeratin 18) have demonstrated
the presence of micrometastatic disease
in the bone marrow of as many as
28% to 60% of patients undergoing
surgical resection thought not to have
evidence of extrathoracic disease after
conventional staging.[11-13]

The rationale for adjuvant systemic
therapy is that postoperative chemotherapy
can eliminate residual sites
of micrometastatic disease following
surgical resection of the primary tumor
and prevent the subsequent emergence
of incurable clinical disease. It
is based on the observation in experimental
models that there is an inverse
relationship between tumor burden and
potential curability by drugs.[14,15]
This may be mediated by factors such
as the increased proportion of actively
dividing cells in micrometastatic
deposits, reduced opportunities for the
emergence of drug resistance, and
improved access of drug to tumor
cells. Support for this concept is provided
by the demonstrated effectiveness
of adjuvant chemotherapy in
breast cancer, colorectal cancer, and
a growing list of other tumor types
including early-stage ovarian cancer
and soft-tissue sarcomas of the extremities.

In NSCLC, early trials of postoperative
adjuvant chemotherapy revealed
a detrimental effect of
alkylating agent and older chemotherapy
regimens on survival.[16] Subsequent
studies performed with
cisplatin-based combinations were the
first to suggest a survival advantage.
The magnitude of the survival benefit
in these early studies, when seen, was
small and often counterbalanced by
the toxicities of the agents used.
However, recent studies using more
effective and less toxic modern platinum-
based combinations have provided
convincing evidence for the value
of adjuvant chemotherapy for
NSCLC. These studies and those evaluating
a parallel strategy of postoperative
adjuvant therapy with UFT
treatment are discussed below.

Platinum-Based Adjuvant
Chemotherapy

Trials of adjuvant cisplatin-based
chemotherapy for completely resected
NSCLC commenced in the 1970s.
Several of these early trials evaluated
cisplatin in combination with cyclophosphamide
and doxorubicin, a
combination widely used in patients
with advanced disease at that time.
These included the Lung Cancer Study
Group (LCSG) trial 772[17] in which
141 patients with resected stage II or III NSCLC were randomized to CAP
chemotherapy (six cycles of monthly
cyclophosphamide at 400 mg/m2, doxorubicin
[Adriamycin] at 40 mg/m2,
and cisplatin [Platinol] at 40 mg/m2 )
or intrapleural BCG (TheraCys, TICE
BCG) and 6 months of oral levamisole
(Ergamisol). Although the recurrence
rate was significantly reduced
in patients receiving CAP, the improvement
in median survival failed
to reach statistical significance.

Another LCSG study (LCSG 791)
randomized 172 patients to postoperative
CAP plus thoracic radiotherapy
or to thoracic radiotherapy alone.[18]
Again improvements were observed
in median survival which did not reach
statistical significance (20 vs 13
months, P = .113). A third LCSG
study (LCSG 801) randomized 269
patients with resected T1, N1 or T2,
N0 NSCLC to four cycles of CAP
chemotherapy or no treatment.[19] No
difference in time to recurrence or
median survival was found with CAP
chemotherapy.

A small Finnish study[20] found a
beneficial effect on 5- and 10-year
survival of six cycles of postoperative
CAP chemotherapy compared
with no treatment in 110 patients.
However, after adjustment for an imbalance
in randomization (more patients
underwent pneumonectomies in
the observation arm and thus had potentially
less favorable disease), the
results lost significance. Other randomized
trials evaluated postoperative
cisplatin and vindesine (alone[21]
or followed by UFT[22]) or cisplatin
in combination with doxorubicin followed
by UFT.[23] Many of these
studies suffered from difficulties in
accruing patients, heterogeneity in
patient populations, and difficulties
in delivering full doses of chemotherapy.
All failed to demonstrate an unequivocal
survival advantage for
adjuvant platinum-containing chemotherapy.

Meta-analysis
Recognition of the difficulties in
detecting small but potentially real
survival benefits in individual trials
with limited sample size led to a metaanalysis
using updated individual patient
data conducted by the Non-Small Cell Lung Cancer Collaborative
Group reported in 1995.[16] The
meta-analysis incorporated data from
52 randomized trials encompassing
9,387 patients. Included were eight
trials (1,394 patients, 614 deaths) that
evaluated the role of cisplatin-based
combination chemotherapy following
surgery. These trials used cisplatin in
a range of doses (50 to 240 mg/m2 total dose) and in various combinations
with doxorubicin, cyclophosphamide,
and vindesine. A 13 % reduction
in the risk of death was observed in
favor of chemotherapy plus surgery
compared with surgery alone, which
translated to an absolute benefit from
chemotherapy of 5% at 5 years (Figure
1).[8] However, the result fell short
of statistical significance with 95%
confidence intervals (CIs) ranging
from a detriment of 1% to a benefit of 10% for adjuvant chemotherapy (hazard
ratio [HR] = 0.87; P = .08). This
contrasted with the clear benefit of
chemotherapy for patients with advanced
disease where a 27% reduction
in the risk of death was
demonstrated (HR = 0.73; P < .0001).

ALPI and IALT Trials
In spite of the lack of statistical
significance, the suggestion of activity
of adjuvant cisplatin-based chemotherapy
evident in meta-analysis encouraged
the initiation of a large number
of randomized studies of
postoperative adjuvant chemotherapy,
many of which have been recently
reported (Table 2).[24-31] The two
largest studies and arguably the only
studies sufficiently powered to detect
an improvement in survival of the size
suggested by the meta-analysis were
the Adjuvant Lung Project Italy
(ALPI) and the International Adjuvant Lung Trial (IALT) study. These
two randomized trials provided apparently
contradictory results.

  • ALPI Trial-The ALPI study randomized
    1,209 patients with resected
    stage I (42%), II (31%), or IIIA (27%)
    NSCLC to receive chemotherapy with
    three postoperative cycles of the triplet
    combination MVP (mitomycin at 8
    mg/m2on day 1, vindesine at 3 mg/m2
    on days 1 and 8, and cisplatin at 100
    mg/m2 on day 1 every 3 weeks) or no
    chemotherapy. Postoperative radiotherapy
    was permitted at the discretion
    of the participating centers and
    was given to about 65% of patients in
    the MVP arm and 82% of the patients
    in the control arm. Results were reported
    on 1,088 patients (13 patients
    were ineligible, and 108 patients from
    one center were excluded because of
    concerns about data integrity). After
    median follow-up of 64.5 months no
    significant difference in overall survival
    was observed (HR = 0.96, 95%
    CI = 0.81-1.13; P = .589). Progression-
    free survival favored chemotherapy,
    but was not statistically
    significant (HR = 0.89, 95% CI =
    0.76-1.03; P = .128). Only 69% received
    the planned three cycles of
    MVP chemotherapy.
  • IALT Trial-The IALT was a
    large international study that evaluated
    the effect of adjuvant chemotherapy
    with cisplatin plus a vinca alkaloid
    or etoposide compared with no adjuvant
    therapy in patients with resected
    NSCLC. A total of 1,867 patients with
    completely resected stage I-III
    NSCLC were recruited by 148 centers
    in 33 countries. The study utilized
    an open choice design to
    facilitate accrual. Each participating
    center could determine the pathologic
    stages of disease to include, the dose
    of cisplatin given per cycle, the drug
    that was combined with cisplatin, and
    the postoperative radiotherapy policy.
    The chemotherapy options included
    3 or 4 cycles of cisplatin (with
    doses ranging from 80 to 120 mg/m2)
    in combination with etoposide
    (49.3%), vinorelbine (26.8%), vinblastine
    (11.0%), or vindesine (5.8%).
    A total of 73.8% of patients received
    at least 240 mg/m2 of cisplatin. In the chemotherapy group 7.8% did not receive
    any chemotherapy. Seven patients
    (0.8%) died from chemotherapy
    related toxicity. Postoperative radiotherapy
    was given to slightly more
    patients in the control group (27.7%)
    than in the chemotherapy group
    (22.9%).

    In contrast to the ALPI study, after
    a median follow-up of 56 months in
    the IALT study both overall and disease-
    free survival were found to be
    significantly improved in the group
    receiving chemotherapy. An absolute
    improvement in 2-year survival of
    3.6% (70.3% vs 66.7%) and 5-year
    survival of 4.1% (44.5% vs 40.4%)
    was seen in the chemotherapy group
    (HR = 0.86, 95% CI = 0.76-0.98;
    P < .003). Disease-free survival was
    also improved in the chemotherapy
    arm (P < .003) with an absolute difference
    in deaths or recurrence of
    5.1% at 5 years. Subset analyses
    showed the greatest improvement in
    overall survival in patients with resected
    stage III disease.

  • Discrepancies Between ALPI and
    IALT Trials
    -There are several possible
    explanations for the discrepancy
    between the positive IALT study and
    the negative ALPI trial. A mitomycincontaining
    triplet combination (MVP)
    was used in the ALPI trial, while in
    the IALT trial several cisplatin-based
    doublet combinations were used. Recent
    randomized studies have shown
    that two-drug regimens are less toxic
    and possibly more efficacious than
    three-drug regimens such as
    MVP.[32-35] The negative impact of
    toxic chemotherapy is likely to be of
    particular importance in the population
    of NSCLC patients who frequently
    suffer from multiple comorbidities
    and is likely to negate any beneficial
    effect on survival. Consistent with this
    is the excess of early deaths (< 12
    months from randomization) seen in
    the chemotherapy arm of the ALPI
    study (90 patients in the MVP arm
    and 69 patients in the control arm).

    Furthermore, improved delivery of
    chemotherapy was possible in IALT
    (74%) compared with the ALPI study
    (69%), although a subset analysis from
    ALPI did not suggest that this was
    sufficient to explain the negative result
    of the study.

    A further contributory factor is
    likely to be the use of postoperative
    thoracic radiotherapy (PORT). A recent
    update of the PORT meta-analysis[
    36] based on the results of 10
    randomized controlled trials and 2,232
    individuals continued to show, as did
    the 1998 meta-analysis,[37] that there
    was a detrimental effect of surgery
    followed by postoperative radiotherapy,
    with an 18% increased relative
    risk of death (HR = 1.18; P = .02).
    Postoperative radiotherapy, which is
    likely to contribute additive toxicity
    to adjuvant chemotherapy, was used
    in more patients in the ALPI study
    than in the IALT study.

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