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Evolving Chemoradiation Treatment Strategies for Locally Advanced Non-Small-Cell Lung Cancer

Evolving Chemoradiation Treatment Strategies for Locally Advanced Non-Small-Cell Lung Cancer

ABSTRACT: Survival for patients with stage III non-small-cell lung cancer has gradually improved in recent years, with median survival times increasing from less than 10 months to more than 18 months. These increases are thought to result primarily from advances in chemoradiation. This article reviews major advances in the development of chemoradiation for patients with locally advanced nonSMQ-8211-SMQsmall-cell lung cancer. Results from cooperative group trials suggest that concurrent chemoradiation is superior to sequential therapy and may replace sequential therapy as the new standard of care in patients with good performance status. Technological advances such as 18F-fluorodeoxyglucose positron emission tomography (PET) staging can be used to improve patient selection and predict survival. Locoregional control may be improved by altering radiation fractionation or delivery (eg, hyperfractionation, highdose involved-volume radiotherapy, 3D conformal radiotherapy). Novel agents and regimens in combination with radiation are being investigated to further improve therapeutic outcomes.

Chemoradiation therapy for patients
with locally advanced
(stage IIIA/IIIB) non-smallcell
lung cancer has improved considerably
in recent years. Because of the
advanced tumor stage and/or
unresectability of these tumors, curative
surgery is not an option.[1] In such
cases, radiation therapy and chemotherapy
are the standard of care. A review
of efficacy data from national
cooperative group trials enrolling non-
small-cell lung cancer patients with
similar eligibility requirements shows
significant improvements in survival:
the overall median survival time for
non-small-cell lung cancer patients
was less than 10 months in trials starting
in 1984[2] compared to more than
18 months (and in one case, more than
24 months[4]) in trials initiated in the
1990s (Table 1).[2-5] Improvements
have also been observed in 3-year survival
rates. The reason for such improvements
cannot be explained by
stage migration alone. This review will
discuss the evolution of these changes,
and how chemoradiation has improved
and continues to improve patient outcomes
for those with non-small-cell
lung cancer.

The first large chemoradiation trial
to show a survival benefit was Cancer
and Leukemia Group B (CALGB)
8433.[2] This trial demonstrated a significant
survival advantage for patients
with unresectable stage III non-smallcell
lung cancer who received sequential
chemotherapy and radiation compared
with radiation alone. Patients
were randomly assigned to receive
induction chemotherapy (cisplatin/
vinblastine) before radiation therapy
(6,000 cGy in 30 fractions beginning
on day 50) or radiation therapy alone
(6,000 cGy beginning on day 1 for 6
to 7 weeks). Significant improvements
with the combined-modality regimen
prompted the study to close early after
enrolling only 155 patients. Radiographically,
the tumor response rate
was 56% for patients receiving the
combined modality compared with
43% for patients receiving radiation
therapy alone (P = .092). Median survival
times were 13.7 months for the
chemoradiation therapy group and 9.6
months for the radiation-only group
(P = .012); the 5-year survival rates
were 17% and 6%, respectively, indicating
2.8-fold increase.

Survival Benefit With
Concurrent Chemoradiation

The survival benefit of combined
chemotherapy and radiation therapy
for patients with advanced non-smallcell
lung cancer has been supported
by several additional phase III trials,[
2,5-8] including another large trial
(Radiation Therapy Oncology Group
[RTOG] 9410)[8] that evaluated the
efficacy of sequential vs concurrent
chemoradiation protocols. RTOG
9410 enrolled 611 patients over 4
years (1994 to 1998) with a minimum
follow-up of 4 years (Table 2).[8,9]
The study design compared the
CALGB sequential regimen of chemotherapy
(cisplatin/vinblastine) before
radiation therapy (60 Gy for 7 weeks
at day 50) with hyperfractionated radiation
(69.9 Gy twice daily for 6 weeks) or standard radiation therapy
(60 Gy daily for 7 weeks) administered
concurrently with chemotherapy.
The pilot data for the two concurrent
arms came from two RTOG phase II
trials. In the first trial, patients were
treated with vinblastine/cisplatin given
concurrently with hyperfractionated
radiation therapy, and the resulting
overall survival was 12.2 months.[10]
In the second RTOG trial, oral
etoposide and cisplatin were given
concurrently with hyperfractionated
radiation therapy, and the resulting
median survival was 20 months.[11]

At a median potential follow-up
time of 40 months, the RTOG 9410
trial demonstrated preliminary median
survival times of 14.6 months with sequential
therapy, 17.0 months with
concurrent therapy with daily radiation
therapy, and 15.2 months with hyperfractionated
concurrent therapy.[8]
Overall, significant improvements in
survival (P = .046) were observed with
concurrent chemotherapy and radiation
therapy (Figure 1). However, reversible
grade 3/4 nonhematologic
toxicities were substantially higher
with concurrent compared with sequential
therapies, especially for
esophagitis.[8] Interestingly, while
esophagitis was still considered to be
relatively low, the rate of pneumonitis
(regardless of when radiation therapy
was administered) was substantial and
may be an underappreciated toxicity
with such protocols. Indeed, most of
the late grade 5 toxicities in the study,
which occurred at a rate of only 2%,
were actually pneumonitis related.
With this in mind, a quality-adjusted
survival analysis that subtracts the time
spent with toxicity and/or relapse from
survival was performed to determine
if the improvement in survival outcome
data outweighed the increase in
reversible nonhematologic toxicities,
as seen with concurrent therapy.[12]

Treatments were compared over the
entire spectrum of toxicity and relapse
values for 593 evaluable patients. Despite
the increase in reversible
nonhematologic toxicities observed
with concurrent chemoradiation, the
overall mean toxicity was actually
highest in the sequential arm, where
treatment time was longest. Of the
concurrent therapies, concurrent
chemoradiation with once-daily radiation
therapy resulted in the optimal
quality-adjusted survival and supported
the use of concurrent
chemoradiation as a preferred treatment
for patients with advanced non-
small-cell lung cancer.

A second phase III study comparing
concurrent vs sequential therapy
has shown similar results.[13] In this
Japanese study, 320 patients with
unresectable stage III non-small-cell
lung cancer were randomized to receive
either concurrent radiation (28
Gy at 2 Gy per fraction, and 5 fractions
per week for a total of 14 fractions
beginning on day 2) with chemotherapy
(cisplatin at 80 mg/m2 on
days 1 and 29; vindesine at 3 mg/m2
on days 1, 8, 29, and 36; and mitomycin
(Mutamycin at 8 mg/m2 on days 1
and 29) or chemotherapy followed by
sequential radiation (56 Gy, or 2 Gy
per fraction, and 5 fractions per week
for a total of 28 fractions). Overall, the
response rate for the concurrent arm
was 84% compared with 66% for the
sequential arm, showing a significant
improvement in response with concurrent
therapies (P = .0002). The median
survival time was 16.5 months with
concurrent therapy vs 13.3 months
with sequential therapy (P = .03998;
Tables 2 and 3). While myelosuppression
was found to be significantly greater in patients receiving
concurrent chemoradiation therapy,
the increased response rate showed
concurrent therapy to provide a benefit
in long-term survival with acceptable
toxicity.

The Groupe Lyonnais d'Oncologie
Thoracique (GLOT) trial also evaluated
the survival effects of concurrent
chemoradiation therapy as compared
with sequential therapy in patients
with unresectable, locally advanced
stage III non-small-cell lung cancer.[
14] This study included 212 patients
randomized to receive cisplatin/
vinorelbine (Navelbine) followed by
thoracic radiation (66 Gy in 33 fractions
for 6.5 weeks), or concurrent radiation
therapy started on day 1 with
two concurrent cycles of cisplatin/
etoposide followed by cisplatin/
vinorelbine (Table 2). The total dose
of cisplatin was equivalent in both
groups. The preliminary report of this
study demonstrated a trend in favor of
concurrent therapy; however, these
differences were not statistically significant.

Based on the preliminary results of
RTOG 9410 and the other supportive
phase III studies, concurrent chemoradiation
therapy appears to offer a
survival benefit over sequential
therapy. While sequential therapy has
been associated with lower toxicity, a
reduction in distant failures, and fewer
treatment interruptions, concurrent
therapy may offer several additional
advantages such as a synergism between
the two modalities and a reduction
in chest failures (ie, regional tumor
failures). It is likely that concurrent
therapy may replace sequential
therapy as the new standard, at least
in investigational therapy, and probably
in nonprotocol therapy for patients
with good performance status.
Significant benefits with concurrent
therapy have also been observed in
studies of other solid tumors, including
head and neck carcinomas (RTOG
9111 and RTOG 9003).[15,16] In
these solid tumors, the addition of chemotherapy
to radiation results in an
increase in cure rate by improving tumor
control in the region and eliminating
or delaying the emergence of
metastatic disease.

The efficacy and toxicity associated
with concurrent therapy are likely to
be optimized based on dose, schedule,
and type of chemotherapeutic agent.
Similarly, the quality and mode of radiation
delivery could be optimized by
taking advantage of technical improvements
in patient selection and
staging. Such improvements might
include imaging techniques, radiotherapy
sequencing and fractionation,
image guidance during radiation
therapy, brachytherapy (high radiation
doses provided directly to a tumor
through implantation of small radioactive
seeds), radiation intensity
modulation, and radiation dose
escalation.

Improving Tumor Definition

One of the more important factors
for improving patient survival may be
the use of techniques that aid in tumor
definition. Typically, tumors or target
lesions are defined using three-dimensional
(3D) treatment planning computed
tomography (CT) and diagnostic
CT scans. However, positron emission
tomography (PET) appears to be
an effective means of detecting and
staging mediastinal metastases in patients
with non-small-cell lung cancer
because of its higher sensitivity.[
17] PET scans are able to locate
target hot zones by excluding atelectasis
and uninvolved lymph node
stations, and thus may achieve greater
local control. Recent studies
have indicated that the use of
18F-fluorodeoxyglucose (FDG)-PET
staging can serve as a powerful tool to
improve patient selection[18] and effectively
predict patient survival.[19]
FDG-PET staging also appears to be
superior to CT for staging of non-
small-cell lung cancer.[20] In addition,
the residual metabolic rate of glucose
as measured by FDG-PET at the primary
lesion appears to be an effective
surrogate marker of tumor response to
induction therapy with combined
modality.[21]

Techniques such as CT and PET
scans may also improve treatment outcomes
for newer modalities such as
high-dose involved-volume radiotherapy,
which is currently under investigation.
Interestingly, a recent retrospective
analysis of clinical course
and tumor volume data from 135 patients
with non-small-cell lung cancer
revealed that long-term local control
and survival may depend on the
tumor volume and total dose of radiation.
The study found that while conventional
doses (≥ 70 Gy) may be effective
in local control of small tumors
(< 100 cm3, maximum diameter of 6
cm), these doses were unlikely to control
tumors ≥ 100 cm3 and supported
the use of dose escalation in patients
with non-small-cell lung cancer.[22]

Radiation Therapy Advances
That Impact Survival

Concurrent therapy studies clearly
demonstrate that the quality of radiation
therapy can impact tumor control
and survival. Nonetheless, the timing
of chemoradiation has yet to be optimized.
One study, the Locally Advanced
Multimodality Protocol
(LAMP) ACR 427, has been designed
to evaluate the long-term survival benefits
of induction chemotherapy prior
to or following concurrent chemoradiation
as compared with sequential
chemoradiation.[23]

The trial includes patients with a
good performance status and
unresectable stage III non-small-cell
lung cancer who are randomized to
one of three treatment arms: (1) two
cycles of paclitaxel at 200 mg/m2 with
carboplatin (Paraplatin) at an area under
the curve (AUC) of 6 followed by
daily radiation to 63.0 Gy; (2) weekly
paclitaxel at 45 mg/m2 with carboplatin
at an AUC of 2 concurrent with
daily radiation to 63.0 Gy; and (3)
radiation beginning on day 1 (to
63.0 Gy) with concurrent paclitaxel 45
mg/m2 and carboplatin at AUC 2 for 7
weeks, followed by two cycles of
paclitaxel at 200 mg/m2 and carboplatin
at AUC 6. All arms were to
be compared to a historical sequential
chemoradiation regimen (RTOG
8808), which observed a median survival
time of 13.7 months.

Preliminary analysis of phase II
data showed that the most promising
therapy was chemoradiation followed
by chemotherapy (arm 3), and the least
promising was chemotherapy followed
by chemoradiation (arm
2).[23,24] Patient accrual in arm 2 was
terminated after evaluating data for the
first 80 patients enrolled because early
survival analysis did not demonstrate
a survival benefit as compared with
the historical sequential chemoradiation
data.

After a median follow-up time of
26 months, median survival time was
16.1 months for arm 3, 12.5 months
for arm 1, and 11.0 months for arm 2,
suggesting adjuvant chemotherapy
following chemoradiation to be the
arm most worthy of further study.[24]
Thus, although the optimal radiation
dose and fields remain unknown in the
setting of chemotherapy, combinedmodality
chemoradiation protocols
continue to demonstrate improvements
in patient survival.

Other attempts to enhance patient
survival include strategies to improve
locoregional control of radiation by
increasing radiation dose intensity
through the administration of multiple
and/or altered radiation fractions each
day. Methods of altering radiation
dose intensity include altering fractionation
(eg, hyperfractionated accelerated
radiotherapy) or increasing lo-
cal control in the initially involved area
by delivery of high-dose radiation
(high-dose involved-volume radiotherapy
and 3D conformal radiotherapy
[CRT]).

The effects of accelerated
hyperfractionation radiation therapy in
non-small-cell lung cancer have recently
been evaluated in several trials.[
10,25-28] The Continuous
Hyperfractionated Accelerated Radiotherapy
(CHART) trial compared
hyperfractionated radiation (36 fractions
of 1.5 Gy/fraction given as 3 fractions
per day for 12 days, for a total
dose of 54 Gy) with standard radiotherapy
(60 Gy over 6 weeks).[25] The
hyperfractionated dose was found to
significantly improve 2-year survival
by 9% compared to standard radiotherapy,
and improved survival was
directly linked to a decrease in local
tumor progression. A follow-up quality-
of-life and toxicity analysis showed
that the hyperfractionated dose did not
increase short- or long-term morbidity
as compared with the standard
therapy.[26] The Hyperfractionated
Accelerated Radiation Therapy
(HART) trial, sponsored by the Eastern
Cooperative Oncology Group
(ECOG 4593), evaluated 1.5- to 1.8-
Gy fractions given three times daily
for 16 days (total dose of 57.6 Gy).[27]
The median survival for patients enrolled
on this trial was 13 months, with
a 1-year survival rate of 57%

A dose-escalation study by
Saunders and colleagues of continuous
hyperfractionated accelerated
radiotherapy weekend-less
(CHARTWEL) combined with
neoadjuvant chemotherapy also
showed a survival benefit for the combination
compared to radiation therapy
alone.[28] Locoregional control at 2
years was 37% for patients receiving
CHARTWEL at 54 Gy, 55% for those
receiving CHARTWEL at 60 Gy,
and 72% for patients receiving
CHARTWEL at 60 Gy with
neoadjuvant chemotherapy. Unfortunately,
there remains a development
of recurrence in 80% of patients
treated with such therapies, and 60%
will develop distant metastases. Interestingly,
hyperfractionated radiation
studies performed in the United States
with concurrent chemotherapy have
not shown any apparent benefit.

Because of the high rate of distant
metastases and local recurrence, intensified
radiotherapy techniques are now
being integrated with 3D-CRT techniques,
a technique based on virtual
simulation that reconstructs the tumor
and surrounding organs in 3D and creates
custom-shaped radiation fields
around the tumor site in order to avoid
excessive exposure to nontarget tissues.
Three-dimensional CRT is a
high-precision technique based on the
3D volumetric definition of the tumor
and the anatomy of critical organs.
After obtaining a series of images of
the transverse section of the treated
region, a digital reconstruction of these
volumes is produced. A simulation
program is then used to determine the
optimal orientation of the irradiation
beam and the number of fields, which
allows the calculation of the dose to
be conducted on the whole treated
volume and not just the surface (as is
done for conventional radiotherapy).[
29] By applying an intensity
modulation technique to 3D-CRT, the
dose distribution can be changed dynamically,
permitting an irregular dose
distribution that conforms exactly to
the volume of the target.

Belderbos and colleagues are conducting
a phase I/II dose-escalation
trial using 3D-CRT to evaluate the
maximum tolerated dose in patients
with stage I-IIIB non-small-cell lung
cancer.[30] Patients who had previously
received elective nodal irradiation
or who had received chemotherapy
6 weeks prior to the study were
excluded. Fifty-five patients were divided
into five risk groups (defined
according to mean lung dose), and
each group was treated 5 days a week
with 2.25 Gy per fraction for 6 weeks.
When fewer than 30 fractions were
prescribed, two fractions were administered
per day. Within each group, the
dose was escalated with three fractions
per step (6.75 Gy).

An interim analysis revealed that 17
patients received a dose of 74.3 Gy and
23 received a dose of 81.0 Gy. Radiation
pneumonitis occurred in seven
patients (grade 4, n = 1), while esophageal
toxicity was mild. Fifty patients
were evaluable for response at 3
months: 6 patients experienced a com-
plete response, 38 had a partial response,
5 patients had stable disease,
and 1 patient experienced progressive
disease. To date, the radiation dose has
been safely escalated to 87.8 Gy, and
the maximum tolerated dose has not
yet been reached. Phase II/III studies
of 3D-CRT are currently ongoing.

Xu et al recently conducted an efficacy
study of 3D-CRT vs conventional
radiotherapy in 135 non-smallcell
lung cancer patients.[31] The 62
patients enrolled on the 3D-CRT arm
received 48 to 64 Gy in 6 to 8 fractions
over 2 to 3 weeks (6-8 Gy per
fraction). The remaining 73 patients
received conventional radiotherapy at
a total dose of 60 to 70 Gy in 30 to 35
fractions over 6 to 7 weeks. After 3
months, 45% of patients receiving
conventional radiotherapy experienced
a complete remission of lesions
compared with 77.8% of patients on
the 3D-CRT arm. The 1- and 2-year
survival rates significantly favored the
3D-CRT treatment (42.5% vs 77.8%
and 30.1% vs. 48.6%, respectively).
There were no significant differences
in the incidence of radiation-induced
lung and esophageal injuries, suggesting
that the survival benefit of 3D-CRT
may be a preferred treatment protocol
for patients with non-small-cell
lung cancer.

Singh et al recently performed a retrospective
review of 207 patients
treated with 3D-CRT.[32] Patients received
either sequential chemotherapy,
concurrent chemotherapy, or radiation
alone with a median prescription dose
of 70 Gy delivered in once-daily 2-Gy
fractions. Of the 207 patients enrolled,
16 (8%) developed acute or late grade
3-5 esophageal toxicity, and 1 patient
died due to grade 5 esophageal toxicity.
Concurrent chemotherapy was significantly
associated with a risk of
grade 3-5 esophageal toxicity. However,
no such toxicities were observed
when the maximal point dose to the
esophagus was less than 58 Gy
(P = .0001). The number of patients
who developed grade 3-5 esophageal
toxicity in the absence of chemotherapy
was too small to statistically
evaluate for a relationship between
maximal dose and esophagitis. The
authors concluded that there may be a
maximal radiation point dose thresh
old of 58 Gy for the esophagus in patients
with non-small-cell lung cancer
receiving concurrent chemotherapy
with 3D-CRT.

These results are similar to a study
performed at the Memorial Sloan-
Kettering Cancer Center, which observed
a survival advantage with the
use of induction chemotherapy prior
to 3D-CRT compared to 3D-CRT
alone.[33] Of the 152 patients enrolled,
70 received radiation alone
(median dose: 70.2 Gy) and 82 received
chemotherapy (generally a
platinum-based regimen) prior to radiation
(mean dose: 64.8 Gy). The
median survival time for patients receiving
radiation alone was 11.7
months compared with 18.1 months
for those receiving combined-modality
therapy. A reduction in grade 3 or
higher nonhematologic toxicities was
also noted in the combined-treatment
group (16% vs 20%), suggesting that
chemotherapy provides additional
benefit to those receiving radiation
therapy alone.

Currently, standard-dose extendedvolume
radiotherapy is the radiotherapy
of choice in many RTOG trials
and has become the standard in
many clinics across the United States.
With proper patient selection and
within settings of cooperative groups
such as the RTOG, radiation doses of
90 to 100 cGy have been administered
to selected patients with smaller volumes
employing involved-volume
radiotherapy.[34]

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