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Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

ABSTRACT: Lung cancer remains the leading cause of cancer death in American men and women. Non–small-cell lung cancer (NSCLC) accounts for 85% of these cases. Although surgery is the best curative approach for resectable NSCLC, long-term survival for patients with operable disease remains poor. More than half of patients who initially present with stage I to IIIA disease experience relapse of metastatic disease. Postoperative adjuvant therapy has been evaluated in several randomized trials, and provides a survival benefit. It appears reasonable to look to induction chemotherapy, or preoperative chemotherapy, to provide a similar improvement in survival with early treatment of micrometastatic disease. Multiple trials of induction therapy have been carried out with encouraging results. The use of various induction regimens with chemotherapy alone or chemotherapy combined with radiotherapy for stage IIIA NSCLC is under investigation. Randomized trials are under way to better define the role of induction therapy in the multimodality treatment of NSCLC.

An estimated 173,000 men and
women in the United States
will develop lung cancer in
2004, of whom 160,000 will die.[1]
Non-small-cell lung cancer (NSCLC)
accounts for approximately 85% of
these cases. Despite advances in therapy
and attempts at prevention through
smoking cessation programs, limited
advertising, and restricted public
smoking, lung cancer continues to be
the leading cause of cancer death in
the United States.

Unfortunately, the majority of patients
with NSCLC will present with
advanced, incurable disease. At presentation,
approximately 30% of patients
will have stage I or II disease
that is potentially curable by surgery,
and an additional 25% to 30% of patients
will have locally advanced disease
(stage III) that is generally treated
with combined-modality therapy.[2]

Treatment BackgroundStandard Surgical Treatment
For patients with early-stage
NSCLC (clinical stage I/II), lobectomy
or pneumonectomy with mediastinal
sampling or lymphadenectomy
is the optimal treatment modality for
the potential cure of patients and may
result in a 5-year survival ranging from
67% in patients with pathologic T1,
N0 disease to 38% in patients with
pathologic T3, N0 disease.[3] Clinical
staging often understages NSCLC,
particularly if newer modalities such
as positron-emission tomography
(PET) scanning are not utilized. As a
result, patients with disease at a given
clinical stage fare much worse than
those at the corresponding pathologic
stages (Table 1).[2]

The majority of patients with stage III
NSCLC evaluated for resection have
a disease extent that precludes immediate
curative surgery. However, even
in patients who are immediately resectable,
those with pathologic T1-3,
N2 disease (stage IIIA) have a 5-year
survival of only 23%.[3] Moreover,
when bulky mediastinal involvement
is noted on chest radiography, 3-year
survival is dismal-less than 10%.[4]
Although in all of these patients disease
is confined to the chest at onset
and can be removed surgically, the
vast majority suffer from recurrent
NSCLC and ultimately die of metastatic
disease.

Adjuvant Approaches
In order to improve on the disappointing
results of surgery alone,
investigators have focused on chemotherapy
and radiotherapy in addition
to surgery. The majority of historical
clinical trials examining adjuvant (ie,
postoperative) therapy have not found
unequivocal, reproducible evidence of
efficacy for adjuvant chemotherapy.[
5-7] However, a meta-analysis of
14 trials including over 4,000 patients
and comparing postoperative chemotherapy
with no further therapy demonstrated
a survival advantage for
chemotherapy regimens containing
cisplatin.[8] More recently, a large
randomized study showed that cisplatin-
based adjuvant chemotherapy
improves survival by 4% at 5 years.[9]
More recently, two trials in early-stage
homogeneous populations demonstrated
significant survival benefits in
patients treated with platin-based adjuvant
chemotherapy. [10, 11]

Induction Therapy
Given this uncertainty, chemotherapy
prior to surgery, or induction ther-
apy,has been the subject of ongoing
investigations. Induction therapy has
been attractive to clinicians because
regression of the primary tumor to chemotherapy
serves as a surrogate marker
for the control of clinically undetectable
metastases. In fact, consistently
higher response rates and better tolerability
have been noted in locally advanced
disease than in metastatic
NSCLC.[12-14] Notably, a complete
pathologic response rate of 13% has
been reported in early clinical studies
of induction chemotherapy.[15]

Thus, chemotherapy given before
surgery has the potential to allow for
assessment of tumor response to chemotherapy,
to treat micrometastatic
disease early, to facilitate the complete
eradication of lesions, and to
provide better dose delivery with fewer
treatment interruptions. Additionally,
decreasing tumor size may
improve resectability and decrease the
morbidity of resection.

Resectable NSCLC

Patients with stage I/II NSCLC can
generally undergo immediate surgery
with curative intent. Although patients
with stage III disease have no evidence
of distant metastases and are
viewed as potentially curable, their
prognosis is generally poor, and the
overwhelming majority die of their
disease. Stage IIIA encompasses patients
for whom extended surgery can
remove all known sites of disease.
Patients with stage IIIB disease are
frequently considered unresectable,
because of contralateral mediastinal
lymph node involvement (N3) or extensive
tumor invasion (T4) that requires
specialized surgical techniques
to accomplish complete resections. A
carefully selected subset of patients
with T4 disease may be suitable for
surgical resection.

The basic division between stage IIIA
and IIIB NSCLC was established in
the 1980s.[3] However, in the 1997
revision of the International Staging
System, patients with T3, N0 disease
were reclassified as having stage IIB
because their survival was almost
identical to patients with T2, N1 tumors.
This grouping complicates interpretation
of stage III trials before
1997, because treatment groups with
T3, N0 patients have improved outcomes.
Futhermore, within stage IIIA
disease there is significant variability
that can have an impact on prognosis.
Larger tumors and multiple involved
lymph node stations result in worse
survival.[16-19]

Staging NSCLCComputed Tomography
Patients with potentially resectable
NSCLC, especially those with stage III
disease, benefit from rigorous staging
evaluation prior to therapy. Computed
tomography (CT) scanning is critical
in evaluating the location and
extent of the primary tumor. CT scans,
however, may under- or overestimate
mediastinal lymph node involvement.
Normal-sized lymph nodes (generally
considered to be < 1 cm in the short
axis) can contain tumor cells, and enlarged
lymph nodes do not always
contain metastatic tumor. Lymph node
metastases become more likely with
increasing nodal size.[20]

In one meta-analysis of 29 studies
involving 2,226 patients utilizing CT
scans for the detection of mediastinal
nodal metastases, the mean sensitivity
and specificity were 60% and 77%,
with a positive predictive value of
50% and a negative predictive value
of 85%. An enlarged mediastinal
lymph node detected by CT scanning,
therefore, only contains cancer 50%
of the time, and 15% of normal-sized
(< 1 cm) lymph nodes contain tumor
cells.[21]

Positron-Emission Tomography
PET with 18F-fluorodeoxyglucose
is a newer staging technique that uses
the relatively increased metabolic activity
of cancer cells to differentiate
them from normal cells. In the aforementioned
meta-analysis, data from
14 studies involving 514 patients were
examined, and the authors found that
the mean sensitivity and specificity
for PET were 79% and 91%, respectively,
with a positive predictive value
of 90% and a negative predictive
value of 93%.[21]

Pieterman et al reported their experience
in 102 patients with resectable
NSCLC with preoperative PET
scanning and found sensitivity and
specificity of 91% and 86%, respectively.[
22] However, in this group of
patients, the positive predictive value
of PET was 74%. Therefore, 26% of
patients with increased uptake on PET
have no evidence of nodal disease on
histopathology. Furthermore, even
lymph nodes that are positive by CT
and PET require histopathologic proof
of involvement. The negative predictive
value of both a negative PET and
CT scan of 97% was excellent in this
series, and many surgeons feel that
PET scans can reliably rule out N2
disease but that surgical staging is necessary
to confirm its presence.

Mediastinoscopy
In many centers, mediastinoscopy
is routinely performed to stage patients
with lung cancer who are
candidates for surgical resection. Mediastinoscopy
is used to detect N3
disease for which surgical therapy
would not be advised and to detect
N2 disease for which induction therapy
prior to definitive surgery would
be warranted. Because not all lymph
nodes can be sampled, cervical mediastinoscopy
provides sensitivity between
72% and 89%.[23-25] Cervical
mediastinoscopy allows access to the
right and left paratracheal lymph
nodes and subcarinal lymph nodes.
The aorticopulmonary window and
subaortic lymph nodes are not accessible
via cervical mediastinoscopy and
require anterior mediastinotomy.

Combined Modalities
Appropriate staging procedures for
patients with resectable NSCLC,
therefore, include a CT scan not only
to assess the primary tumor and mediastinum
but also to evaluate for evidence
of metastatic disease within
the lung, liver, and adrenal glands.
All patients with mediastinal lymph
nodes that are greater than 1 cm by
CT imaging or are positive by PET
scan should have mediastinal disease
confirmed histopathologically. In patients
with normal mediastinal lymph
nodes by CT scan, a negative PET
scan may obviate the need for mediastinoscopy.
Mediastinoscopy, however,
may identify patients with
micrometastatic lymph node involvement
not apparent on imaging modalities
who may benefit from induction
therapy.

Detecting Brain Metastases
The incidence of brain metastases
in the initial staging of patients with
primary lung cancer has been reported
to between 12% and 18%.[26,27]
Asymptomatic brain metastases occur
more frequently in patients with
more advanced stages of disease, with
rates as high as 30% at 2 years in
stage II/III patients. Higher stage and
nonsquamous histology have been
identified as risk factors for brain metastases.[
28,29] In asymptomatic patients,
gadolinium-enhanced magnetic
resonance imaging (MRI) of the brain
is superior for the detection of occult
brain metastases.

A recent study randomized 332
patients with potentially operable
NSCLC, but without neurologic
symptoms, to brain CT or MRI in
order to detect occult brain metastasis
before lung surgery.[30] MRI showed
a trend toward a higher preoperative
detection rate than CT (P = .069),
with an overall detection rate of approximately
7% from pretreatment to
12 months after surgery. In patients
with stage I/II disease, the detection
rate was 4% (8 of 200), whereas for
individuals with stage III disease, the
rate was 11.4% (15 of 132).

Whether the improved detection
rate of brain metastases by MRI translates
into improved outcome remains
unknown. Brain imaging is currently
recommended as a part of the initial
evaluation for all patients with potentially
curable locally advanced
NSCLC. Finally, reevaluation of disease
after induction chemotherapy and
prior to thoracotomy is recommended
to exclude disease progression. The
ability of noninvasive tests to predict
pathologic response has thus far been
suboptimal.

Induction Chemotherapy TrialsInitial Observations
Several clinical trials have tested
combination chemotherapy prior to
surgery to improve the outcome of patients
with resectable NSCLC. Initial
studies using older chemotherapy regimens
suggested that preoperative chemotherapy
may be beneficial.[31,32]
Martini demonstrated that otherwise
resectable patients with ipsilateral mediastinal
lymphadenopathy as their
sole site of distant spread can have
3-year survivals of 43%, and 5-year
survivals of 24%, if both the primary
tumor and ipsilateral mediastinal
nodes were completely resected and
followed by mediastinal irradiation.[
33,34] These same studies revealed
that individuals with bulky
ipsilateral mediastinal lymphadenopathy
had only an 8% 3-year survival.

Based on these observations, a preoperative
combination chemotherapy
program with MVP (mitomycin [Mutamycin],
vinca alkaloids, and highdose
cisplatin [Platinol] at 120 mg/m2)
was developed at Memorial Sloan-
Kettering Cancer Center for use in
stage IIIA patients with clinical N2
disease.[15] In a group of 136 patients,
the objective major response
rate to MVP was 77%, with a 10%
complete response rate. Overall, 65%
of patients underwent complete resections;
14% had achieved a pathologic
complete response at surgery.

The median survival was 19 months
for all patients. The 3-year survival
for completely resected patients was
41%-a significant improvement over
the prior surgery-only experience,
where the 3-year survival for this
group was 8% (P = .001).[15] Particularly
noteworthy was that a pathologic
complete response was observed
in approximately 12% of advanced
NSCLC patients who received preoperative
MVP chemotherapy, with survival
estimates in this population of
54% at 5 years.[35]

The Cancer and Leukemia Group
B (CALBG) conducted a second similarly
designed trial. A total of 74 patients
with surgically staged IIIA (N2)
NSCLC were treated with two cycles
of preoperative cisplatin and vinblastine.[
36] Patients who underwent resection
were then treated with two
cycles of adjuvant cisplatin and vinblastine
followed by thoracic radiation.
Approximately 64% of patients
achieved a radiographic response or
stable disease, and 62% underwent a
complete resection. Operative mortality
was 3% (2 deaths). Median survival
was 15 months.

Elias and investigators at the Dana-
Farber Cancer Institute treated 34 patients
with pathologically confirmed
N2 disease, using infusional cisplatin,
fluorouracil (5-FU), and leucovorin
plus postoperative radiotherapy to 54-
60 Gy.[37] The radiographic response
rate to this regimen was 65%. Thoracotomy
was performed in 82% of patients.
No operative mortality was
noted, and 18% of patients achieved a
pathologic complete response. Median
survival was 18 months. The authors
noted that few local recurrences
occurred and that 15% of first relapses
were solely in the brain.

Randomized Studies
Following these initial observations
that suggested promising results with
induction therapy, a number of randomized
studies aimed at establishing
the role of induction therapy were
conducted.

  • Spanish Study-The first randomized
    trial that compared cisplatinbased
    chemotherapy plus surgery with
    surgery alone was conducted by Rosell
    et al in patients with stage IIIA disease.[
    38] Pathologic confirmation of
    N2 was not mandatory, and approximately
    27% of patients had clinical
    T3, N0/1 disease. Chemotherapy consisted
    of the MIP regimen (mitomycin,
    ifosfamide [Ifex], cisplatin) given
    at 3-week intervals before surgery for
    three cycles. All patients received
    mediastinal irradiation (50 Gy) after
    surgery. A total of 60 patients were
    randomized, 30 in each arm.

    After 2 years, the trial was prematurely
    terminated because of the
    significant benefits seen in the chemotherapy
    arm. No toxic deaths occurred
    during preoperative therapy.
    The partial response rate was 53%,
    with a 7% clinical complete response
    rate. Postoperative mortality was similar
    in both groups (two deaths each).
    Overall median survival was 26 months
    in the chemotherapy arm vs 8 months
    in the surgery arm (P < .001).

    Survival rates at 2 years were 27%
    and 0%. Survival in the control arm
    of surgery alone was much lower than
    expected from historic controls. An
    analysis performed 7 years later confirmed
    the survival advantage in favor
    of preoperative chemotherapy,
    with median survival of 22 months
    in the chemotherapy arm vs 10
    months in the surgery-alone arm
    (P = .005).[39] The survival rate at 5
    years was 17% and 0%, respectively.

  • M. D. Anderson Study-Roth and
    investigators at M. D. Anderson
    Cancer Center conducted another randomized
    study of preoperative chemotherapy
    in stage IIIA NSCLC.[40]
    Chemotherapy consisted of three cycles
    of cyclophosphamide (Cytoxan,
    Neosar), etoposide, and cisplatin. Patients
    who responded to preoperative
    chemotherapy were given an additional
    three cycles of adjuvant therapy
    after complete resection. Patients who
    were found to have unresectable disease
    with incomplete resection could
    undergo postoperative radiation
    therapy.

    A total of 28 patients were randomized
    to receive preoperative chemotherapy,
    and 32 were randomized
    to receive primary surgery. Almost
    one-quarter of patients had T3, N0/1
    disease. The overall response rate was
    35%, including one pathologic
    complete response. Disease progression
    developed in four patients during
    chemotherapy; however, the
    resectability rate and the rate of complete
    responses were the same in both
    arms.

    An interim analysis showed a statistically
    significant survival advantage
    for the preoperative chemotherapy arm
    (P < .008). The trial was therefore halted
    after 60 patients were enrolled. The
    estimated 2-year survival rate in the
    preoperative arm was 60% and in the
    surgery arm was 25%. An analysis
    4 years later revealed that median
    survival in the chemotherapy arm was
    21 months and in the surgery arm was
    14 months (P = .056).[41]

  • NCI Study-A third randomized
    trial in histologically confirmed N2
    NSCLC was conducted by Pass et al
    at the National Cancer Institute
    (NCI).[42] Chemotherapy consisted
    of cisplatin and etoposide. At interim
    analysis, 27 patients had been randomized.
    The response rate was 61%.
    Preliminary results suggested a trend
    toward increased survival for the preoperative
    chemotherapy arm (median
    survival = 29 vs 16 months, P = .095).
  • Japanese Study-A fourth randomized
    study, conducted in Japan,
    compared induction chemotherapy
    with cisplatin and vindesine (Eldisine)
    vs surgery alone in patients with
    stage IIIA (N2) NSCLC. After 62 patients
    were enrolled, this study was
    terminated due to slow accrual. There
    were no statistically significant differences
    in survival in this trial (median
    overall survival was 17 months
    for patients receiving induction and
    16 months for patients undergoing surgery
    alone).[43]

Early-Stage Disease
Taken together, the four small, randomized
studies described above demonstrated
a potential benefit with the
addition of induction chemotherapy in
stage IIIA NSCLC. Studies have since
been designed to evaluate the role of
induction chemotherapy before surgery
in even earlier-stage NSCLC.

  • French Study-The French Cooperative
    Oncology Group conducted
    a large randomized study in stage I
    (except T1, N0), II, and IIIA resectable
    NSCLC.[44,45] The 355 eligible
    patients were randomized to induction
    therapy with two cycles of mitomycin,
    ifosfamide, and cisplatin or to
    primary surgery. Patients who responded
    to chemotherapy received an
    additional two cycles postoperatively.
    In both arms, patients with pT3 or
    pN2 disease or incomplete surgery
    received radiotherapy after either surgery
    or completion of chemotherapy.
    This regimen yielded a response rate
    of 64% with a pathologic complete
    response rate of 11%.

    The complete resection rate was
    similar between the two arms: 92%
    with induction vs 86% with surgery
    alone. A 10-month improvement in
    median survival in the chemotherapy
    arm was documented (26 vs 36
    months), although this was not statistically
    significant (P = .11). Operative
    mortality was similar in both arms, but
    there was a trend toward increased postoperative
    mortality (7% vs 4.5%) and
    increased postoperative complications
    in the chemotherapy arm. Although a
    statistically significant improvement in
    survival could not be demonstrated,
    subset analysis showed that patients
    with stage N0/1 disease derived a survival
    benefit from induction chemotherapy
    (hazard ratio = 0.68, 95% CI =
    0.49-0.96, P = .027). This survival benefit
    was not observed in patients with
    N2 disease (hazard ratio = 1.04, 95%
    CI = 0.68-1.60, P = 0.85).

    The study by Depierre et al is the
    largest trial of induction chemotherapy
    conducted to date. However, it remains
    nonconclusive as it included a
    heterogeneous group of patients with
    various stages of disease and its implications
    for the treatment of patients
    with stage IIIA NSCLC are only based
    upon subset analysis.

  • US Studies-The role of induction
    chemotherapy for early-stage
    NSCLC has also been under investigation
    in the United States. Pisters et
    al reported promising results from the
    multicenter phase II study, the Bimodality
    Lung Oncology Team (BLOT)
    trial.[46] Patients with stage IB-IIIA
    (T3, N1, M0) NSCLC received induction
    therapy with two cycles of
    carboplatin (Paraplatin) and paclitaxel
    followed by three additional cycles
    postoperatively. Evaluable patients
    included 94 evaluated for survival and
    toxicity and 90 for response. The response
    rate was 56%, the pathologic
    complete response rate was 6%, and
    3% of patients had disease progression
    during induction. The 1-year survival
    rate was 85%.

    Results from a second group of
    patients who received three rather than
    two cycles of induction chemotherapy
    with carboplatin and paclitaxel have
    also been reported.[47] In a total of 124
    patients, the response rate was 51%
    and 3-year survival was 61%, which
    was superior to historical controls. The
    surgical mortality rate was only 1%.

    The North Central Cancer Treatment
    Group (NCCTG) conducted a
    similar phase II study with induction
    carboplatin and paclitaxel in patients
    with stage T1-3, N0/1, M0 disease.[48]
    Of 52 patients, 3 died postoperatively.
    The 2-year survival rate was 73%.

    An ongoing phase III randomized
    study (S9900) is randomizing patients
    to three cycles of induction carboplatin
    and paclitaxel followed by two
    additional cycles of postoperative carboplatin
    and paclitaxel or surgery
    alone. Over 325 patients have thus far
    been entered into this trial, which has
    an accrual goal of 600.

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