Download Locally Advanced, Unresectable Non-Small Cell

Locally Advanced,
Unresectable Non-Small Cell
Lung Cancer*
New Treatment Strategies
David H. Johnson, MD
Approximately 40% of non-small cell lung cancer
(NSCLC) patients present with locally advanced,
unresectable lesions. Treatment with thoracic radiotherapy yields survivals averaging just 9 to 10 months,
and long-term survival at 5 years is poor. Recent
studies indicate that chemotherapy followed by thoracic radiotherapy improves 5-year survival by threeto fourfold. Nevertheless, most patients do ultimately
die of the underlying disease. New strategies designed
to enhance local tumor control— use of radiation-sensitizing drugs, three-dimensional treatment planning
techniques, or altered radiation fractionation schedules—may further improve survival outcome. In addition, newer cisplatin-based regimens containing either
paclitaxel or vinorelbine improve survival over that
achieved with older vinca alkaloid or podophyllotoxin
combination regimens. Accordingly, the newer drug
regimens combined with radiotherapy can be expected
to further improve survival in this subset of NSCLC
patients. Prospective studies are underway to test this
conjecture.
(CHEST 2000; 117:123S–126S)
Key words: distant metastases; fractionation; local control; radiation sensitization; radiotherapy; three-dimensional planning
Abbreviations: CHART ⫽ continuous hyperfractionated accelerated radiotherapy; NSCLC ⫽ non-small cell lung cancer
cell lung cancer (NSCLC) is a leading cause
N on-small
of cancer deaths worldwide. The high death rate is
1
due to the fact that NSCLC is usually in an advanced stage
not amenable to surgical resection when first diagnosed.
Although the outlook for NSCLC patients remains fairly
dismal, there is reason for guarded optimism, as modest
therapeutic advances have been realized in this disease
over the course of the past 2 decades. For example, in
stage IV disease, survival can be lengthened and symptom
palliation is possible with cisplatin-based chemotherapy.2,3
Similarly, survival for individuals with locally advanced,
stage III NSCLC has improved with combined-modality
therapy.4 – 6 Historically, patients with locally advanced
NSCLC were treated with thoracic radiotherapy alone.
However, because so many patients develop recurrent
disease outside the chest, chemotherapy was added to
standard thoracic radiotherapy in an attempt to diminish
this problem with a resultant fourfold increase in 2-year
survival rates.4 – 6 Despite these noteworthy advances, the
overwhelming majority of NSCLC patients continue to die
*From the Division of Medical Oncology, Vanderbilt Cancer
Center, Nashville, TN.
Correspondence to: David H. Johnson, MD, Division of Medical
Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 37232-5536
of their underlying malignancy, leaving considerable room
for further refinement in the management of this disease.
This review will focus on strategies aimed at improving
outcome in locally advanced NSCLC.
Current Management of Locally
Advanced, Unresectable NSCLC
Approximately 40% of patients with newly diagnosed
NSCLC first present with locally advanced disease, and
the majority are inoperable.1 Traditionally, these patients
were treated with radiotherapy alone, resulting in a median survival of approximately 9 to 10 months and a 5-year
survival rate of approximately 7%.7 These discouraging
results were largely due to the eventual development of
extrathoracic metastases. Several investigators have tried
combining local therapy (ie, radiotherapy) with systemic
therapy (ie, chemotherapy) in an attempt to overcome the
obstacle of systemic recurrence. Although the initial results with this approach were somewhat disappointing,8,9
possibly due to the modest activity of chemotherapy
regimens initially employed, there appeared to be a subset
of patients with locally advanced disease who derived a
modest survival benefit,4,10 particularly those with good
performance status and little or no weight loss. Most
thoracic oncologists now advocate the routine use of
chemotherapy plus radiotherapy in this group of patients
with locally advanced, unresectable NSCLC.
Improving Local Tumor Control
Although combined-modality treatment with chemotherapy and radiotherapy has improved survival in some
patients with stage III NSCLC, most still succumb to the
underlying disease.1 Tumor progression remains problematic, both locally within the chest and in extrathoracic sites.
We will first examine the problem of local tumor control.
It is commonly estimated that radiotherapy alone affords intrathoracic control in up to 50% of NSCLC cases,
provided a total dose ⱖ 60 Gy is employed.11 However,
such estimates are based on studies conducted ⬎ 20 years
ago, which are probably not very accurate. The signs and
symptoms associated with an extrathoracic lesion usually
so dominate the clinical picture that even if local progression is present, it is commonly overlooked. Indeed, a
patient who progresses outside of the chest rarely undergoes a thorough restaging. Consequently, the true incidence of local failure is almost certainly much higher than
is commonly believed. In those rare circumstances where
a careful reevaluation has been performed, the frequency
of local control is disappointingly low, even when total
radiotherapy doses are ⬎ 60 Gy.12 Fewer than 20% of
irradiated patients undergoing repeat bronchoscopy have
evidence of complete tumor control at the site of the
primary lesion.12,13
Does this lack of local control really matter given our
failure to adequately control systemic disease? The available data suggest improved local control is worthwhile.
Strategies employed in recent years to further improve
local tumor control include the use of radiation-sensitizing
drugs, altered radiotherapy fractionation schedules, and
the use of three-dimensional treatment planning techCHEST / 117 / 4 / APRIL, 2000 SUPPLEMENT
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123S
Table 1—Concomitant Cisplatin Plus Radiotherapy in
Locally Advanced NSCLC*
Survival, %
Radiotherapy
Alone
Variables
Duration
1-Yr
2-Yr
3-Yr
Progression
Local
Distant
Radiotherapy
and Weekly
Cisplatin
Table 3—CHART vs Conventional TRT in the
Treatment of Unresectable NSCLC*
Variables
Radiotherapy and
Daily Cisplatin
Patients, No.
Median survival,
mo
2-yr survival, %
CHART
Standard TRT
338
⬃ 15
225
⬃ 12
33
19
46
13
2
54
26
16
44
19
13
*Adapted from Saunders et al.34 TRT ⫽ thoracic radiation therapy.
54
46
44
36
41
48.5
several studies suggest hyperfractionated irradiation yields
a survival benefit comparable to that achieved with combined-modality therapy (Table 2).29,31,32 These tantalizing
data lend strong support to the notion that improving local
tumor control is a worthwhile goal, even in the absence of
improved control of extrathoracic disease.
In further support of this position are the results of a
recently completed British trial in which continuous hyperfractionated accelerated radiotherapy (CHART) was
compared with standard daily radiotherapy (total dose, 60
Gy in 30 fractions) for the treatment of patients with
unresectable NSCLC.33,34 CHART consisted of thricedaily 1.5-Gy fractions of irradiation given for 12 consecutive days to a total dose of 54 Gy (36 fractions). Median
and long-term survival favored the CHART-treated group
(Table 3), as did local control group rates. If these results
are validated in confirmatory trials, the impact on the
practice of NSCLC treatment could be profound.
*Adapted from Schaake-Koning et al.18
niques. Several antineoplastic agents including cisplatin,
topoisomerase-inhibiting agents, paclitaxel, and gemcitabine all have radiation-sensitizing potential.14 –17 This approach was tested in a European randomized trial showing
that concomitant cisplatin and irradiation improved survival compared with radiotherapy alone.18 The survival
benefit was clearly attributable to improved local tumor
control because the rate of distant failure was not affected
(Table 1). Although this approach warrants additional
study, it is worth noting that the simultaneous use of
radiation and drugs can be a double-edged sword. Administering chemotherapy and radiotherapy concomitantly
may increase host toxicities, necessitating dose reductions
in one or both treatment modalities. Esophagitis and
pulmonary toxicities are particularly worrisome in this
regard.19 –21
There appears to be a linear correlation between radiotherapy dose and local control of NSCLC.7,22 Accordingly,
one theoretically could improve control at the primary
tumor merely by increasing the dose of radiotherapy.
However, it is difficult to increase the radiation dose ⬎ 60
Gy, due to toxicities engendered in normal tissues. Threedimensional treatment planning may permit use of increasing total radiation doses without causing excessive
host toxicity.23 Preliminary studies indicate radiotherapy
doses can be escalated to as high as 85 to 90 Gy without
causing major damage to normal tissues with this technique.24 –27
Yet another means of increasing radiotherapy dose
while minimizing normal tissue toxicity is the use of
multiple daily radiation fractions.28 Pilot studies indicate
this approach also is feasible.29,30 In fact, the results of
Improved Control of Systemic Disease
Several meta-analyses clearly showed that cisplatinbased chemotherapy can improve survival in patients with
NSCLC.2,35,36 The modest survival advantage benefits
primarily those patients treated with cisplatin-based combination regimens, although there is a trend toward
improved survival with regimens containing vinca alkaloids
or etoposide.2 Within the past few years, several new drugs
have shown excellent activity against NSCLC, including
the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and irinotecan.37 Importantly, some of these
agents possess unique mechanisms of action and, with rare
exception, appear to be less toxic than many of the older
agents used in the management of NSCLC.
In recently completed randomized studies, the combinations of cisplatin plus paclitaxel or cisplatin plus vinorelbine
yielded modest survival advantages over older cisplatin-based
combination regimens.38,39 Given these observations, it is
Table 2—Radiotherapy Plus Chemotherapy and Hyperfractionated Radiotherapy in Locally Advanced NSCLC*
Author
Dillman et al
Sause et al5
4
Cox et al29
Jeremic et al32
Radiotherapy, Gy
Chemotherapy
Median Survival, Mo
2-Yr Survival, %
4-Yr Survival, %
60
60
69.6 (bid)
69.6 (bid)
69.6 (bid)
CDDP ⫹ Vbl
CDDP ⫹ Vbl
–
–
–
13.7
13.6
12.3
13.0
14.0
26
31
24
29
26
19
11
9
9
9
*CDDP ⫽ cisplatin; Vbl ⫽ vinblastine.
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Multimodality Approach to Lung Cancer
reasonable to anticipate these newer regimens will provide
similar (or greater) survival benefit in locally advanced
NSCLC. Already there is considerable preliminary data to
suggest this is likely to be true, and randomized trials are
in progress. Furthermore, combining chemotherapy with
newer techniques of thoracic radiotherapy may well provide additional survival benefit as suggested by the results
of several pilot studies 19 and at least one recently reported
randomized trial.40
Summary
In summary, better local control, as well as greater
control of extrathoracic micrometastases, should result in
improved survival among patients with locally advanced
NSCLC. The methods of improving local control are quite
varied, and each merits continued investigation. Potentially, these techniques will lead to further improvement in
the survival of NSCLC patients with locally advanced
disease.
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Multimodality Approach to Lung Cancer