Download The Role of Radiotherapy in Non-Small Cell Lung Cancer

The Role of Radiotherapy in
Non-Small Cell Lung Cancer*
William T. Sause, MD, FCCP
Most patients who receive a diagnosis of non-small
cell lung cancer (NSCLC) have advanced disease
and are not curable with surgery. Developments in
the technology of radiation therapy (RT) have
contributed to the broad utility of this treatment
modality in both a curative and palliative capacity.
Many patients at all stages, including those who
are medically inoperable, may benefit from RT.
Locally advanced NSCLC is treated commonly
with combined modality therapy. Novel RT administration schedules and chemotherapy regimens
for combined modality therapy are essential for
improving the management of NSCLC. Additional
benefits can be foreseen as new strategies for
patient selection emerge.
(CHEST 1999; 116:504S–508S)
Abbreviations: CALGB 5 Cancer and Leukemia Group B;
CMT 5 chemotherapy;
HFX 5 hyperfractionated;
KPS 5
Karnofsky performance status; NSCLC 5 non-small cell lung
cancer; RT 5 radiation therapy; RTOG 5 Radiation Therapy
Oncology Group
therapy (RT) is an effective method of local
R adiation
disease control for non-small cell lung cancer
(NSCLC) and can be used for definitive management in
selected patients. In patients with medically inoperable
disease, RT also is valuable for symptom palliation. In the
management of locally advanced (stage III) NSCLC, RT
as a single modality has been superseded by combined
chemotherapy (CMT) and RT as standard initial therapy.1
The optimal combination and sequence of these modalities are areas of current investigation.
RT in the Management of
Inoperable NSCLC
Both surgery and RT have been used as single
modalities in NSCLC to achieve local control of the
primary tumor and regional lymph nodes.1 In the only
randomized trial comparing surgery with radiation for
stage I and II NSCLC in 1963,2 the Medical Research
Council found that 1-year survival rates were 43% for
surgical patients and 64% for patients treated with RT;
however, as follow-up continued, results of surgical
resection clearly were better than those of RT, with
4-year survival rates of 23% vs 7%, respectively. In
patients who are medically unfit for surgery, RT may be
a reasonable alternative treatment, particularly in patients with small tumors.3– 8 In four studies involving
. 200 patients (most with T1–2 disease) who were
*From the LDS Hospital, Radiation Center, Salt Lake City, UT.
Correspondence to: William T. Sause, MD, FCCP, President,
Radiation Therapy, LDS Hospital, Radiation Center, 400 C St,
Salt Lake City, UT 84143; e-mail: [email protected]
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medically inoperable or refused surgical resection, RT
at doses of 50 to 60 Gy resulted in 5-year survival rates
of 16 to 32%.5– 8
Because many patients with medically inoperable
NSCLC are in need of immediate local palliation,9 the
relief of symptoms is an important treatment goal.1 The
palliative benefit of RT has been documented in a number
of randomized trials.10 –12 The symptoms palliated by RT
include hemoptysis, cough, shortness of breath, pain,
anxiety, fatigue, and sleeping difficulty.
RT in Locally Advanced,
Unresectable NSCLC
The treatment of regionally advanced NSCLC with RT
has been investigated in a large number of trials. Singlemodality external beam RT fails to eradicate disease in
most patients with locally advanced, unresectable
NSCLC.13 Therefore, therapeutic strategies that have
evolved over the past 2 decades reflect an increasingly
aggressive approach, incorporating combined modalities
or nonstandard approaches to RT scheduling.13,14 Technologic advances have influenced many aspects of RT for
NSCLC, from the development of computerized treatment planning and innovative methods of administration
to the integration of other treatment modalities with
RT.1,15 The optimization of RT administration has involved considerable manipulation of the dose, fractionation, and volume of radiation administered. Studies of the
Radiation Therapy Oncology Group (RTOG; eg, RTOG
73– 01) have demonstrated the need to deliver sufficiently
high doses of radiation to an adequate area to ensure
tumor regression with decreased recurrence and improved
survival.16
Prognostic Factors: Proper patient selection is critical to
maximize the benefits of treatment for NSCLC patients.
The RTOG observed in early analyses that patients with
minimal weight loss (, 5%) and good Karnofsky performance status (KPS; $ 90%) demonstrated prolonged survival.17 In a more recent recursive partitioning analysis,
data were examined from four RTOG trials (RTOG 83–11,
83–21, 84 – 03, and 84 – 07) including 1,592 patients.18
Among the factors suggested to be of prognostic importance based on univariate analysis were KPS, # 70% vs 80
to 100%; pleural effusion; weight loss, # 5% vs 5%; age,
$ 60 years vs , 60 years; tumor stage, T1/T2 vs T3/T4;
and nodal stage, N 2 vs N 1. Analyses such as this
ultimately may permit discrimination between the efficacy
of therapy and the natural history of disease in subsets of
patients, thereby improving study design and patient
selection.1,18
Altered Fractionation: In hyperfractionated (HFX) RT,
1.1 to 1.2 Gy are typically administered bid instead of the
usual once-daily dose of 1.8 to 2.0 Gy.15 Although this
approach may intensify adverse effects on oral and esophageal mucosa, it also may permit an overall dose increase
with less effect on late-reacting normal tissues.15,19 Following a pilot study suggesting that doses of up to 69.6 Gy
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Table 1—Improved Survival With Chemoradiation in Unresectable NSCLC*
RTOG Trial
RT Type
CMT Sequencing
Median Survival, mo
2-yr Survival Rate, %
88-08
88-0813
88-04, 92-0428,29
90-15, 91-06, 92-0428,30,31
Std RT
Std RT
Std RT
HFX RT
None
Induction
Induction/Concurrent
Concurrent
11.4
13.8
13.9 to 15.5
12.2 to 18.9
19
32
NR
28 to 36
13
*Std RT 5 external beam radiotherapy; NR 5 not reported.
could be administered in 1.2-Gy fractions bid,20 a significant (p 5 0.02) dose-survival relationship was observed in
an RTOG trial (RTOG 83–11) of patients with favorable
prognostic factors who received a total dose of 69.6 Gy
compared to those who received lower doses (60 Gy or
64.8 Gy).21
In another trial, 509 patients from 11 centers in the
United Kingdom were randomized to treatment with
either 17 Gy in 2 fractions 1 week apart or 39 Gy in 13
fractions 5 days per week.22 Survival was lengthened in
patients receiving more fractions, although palliation of
symptoms was not as rapid. The median survival in
patients receiving 2 fractions of RT was 7 months,
compared to 9 months in patients receiving 13 fractions.
Survival rates at 1 year and 2 years were 31% and 9%,
respectively, in the 2-fraction group, compared to 36%
and 12%, respectively, in the 13-fraction group.
A condensed regimen, continuous HFX-accelerated
radiotherapy, has been used to shorten the treatment
period from 42 to 12 days by administering RT on
consecutive days through weekends. A trial evaluated a
total of 36 1.5-Gy fractions administered tid for a total
dose of 5,400 Gy.23 This regime has been tested in a
phase III trial, and superiority over standard RT has
been confirmed,23,24 with a 9% improvement in survival
at 2 years.
Combined CMT and RT: Several phase III trials and
a meta-analysis demonstrated the superiority of combined modality treatment of locally advanced, unresect-
able NSCLC over RT alone.25–27 In a meta-analysis
including data from 2,589 patients with locally advanced, unresectable NSCLC, the addition of CMT
to RT extended median survival from 10.3 to 12.0
months.27 However, increased biological activity and
altering the natural history of disease are accompanied
by increased toxicity. Future work should include optimization of delivery of CMT/RT and careful quantitation of the benefit of this type of treatment, which may
be modest.
The experience of the RTOG includes trials using no
CMT or induction CMT (RTOG 88 – 08); induction and
concurrent CMT/RT (RTOG 88 – 04, 92– 04); and concurrent CMT/RT alone (RTOG 90 –15, 91– 06, and 92– 04).
When patients with favorable performance status were
considered, this progression in design, together with altered RT fractionation, resulted in substantial gains in
survival (Table 1).
Sequential CMT/RT: When RT follows induction CMT,
increased drug delivery is possible with less overall toxicity, and the effects of CMT may permit delivery of RT to
a reduced tumor volume. However, toxicity may prevent
administration of RT, cell resistance can decrease the
efficacy of RT, and the overall duration of treatment may
be lengthy. Several trials demonstrated benefits for treatment with induction CMT followed by RT (Table 2). The
Cancer and Leukemia Group B (CALGB)25 and Intergroup studies enrolled only those patients with low weight
loss, favorable KPS, and, in the CALGB trial, no palpable
Table 2—Trials of Induction CMT Followed by RT*
Trial
CMT
Supportive of combined therapy
CALGB25
VP
French26
VCPC
USA Intergroup13,32
VP
Unsupportive of combined therapy
SWOG†
FOMI/CAP
FLCSG33
CAP
NCCTG34
MACC
2-Year Survival Rate, %
Median Survival, mo
Local Failure Rate, %
RT Dose,
Gy
CMT and RT
RT Alone
CMT and RT
RT Alone
CMT and RT
RT Alone
60
65
60 to 69.6
26
21
NR
13
14
NR
13.7
12
13.8
9.6
10
11.4
NR
83
NR
NR
85
NR
50
55.0, split
course
60
NR
19
NR
17
9.1
10.2
9.2
10.9
NR
43
NR
60
21
16
10.4
10.3
50‡
47
*VP 5 vinblastine and cisplatin; VCPC 5 vindesine, lomustine, cisplatin, and cyclophosphamide; SWOG 5 Southwest Oncology Group;
FOMI/CAP 5 fluorouracil, vincristine, mitomycin, cyclophosphamide, doxorubicin, and cisplatin; CAP 5 cyclophosphamide, doxorubicin, and
cisplatin; FLCSG 5 Finnish Lung Cancer Study Group; MACC 5 methotrexate; NCCTG 5 North Central Cancer Study Group; see Table 1
for other abbreviation.
†Unpublished data.
‡First site of progression.
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Table 3—Trials of Concurent CMT/RT With Platinum-Containing CMT Regimens*
Trial
Supportive of combined therapy
EORTC37
Jeremic et al38
Unsupportive of combined therapy
GOCCNE39
Treatment Regimen
Patients, No.
Response Rate, %
1-yr Survival Rate, %
Cisplatin 30 mg/m2/wk plus 55 Gy RT
or
Cisplatin 6 mg/m2/d plus 55 Gy RT
or
55 Gy RT
CBDCA 50 mg/d plus VP-16 50 mg/d
plus 69.6 Gy HFX RT
or
69.6 Gy HFX RT
98
60
44
102
66
54
108
65
57
92
46
74
66
85
68
85
51
NR†
88
59
NR‡
Cisplatin 6 mg/m2/d plus 45 Gy RT
or
45 Gy RT
*EORTC 5 European Organization for Research in the Treatment of Cancer; CBDCA 5 carboplatin; VP-16 5 etoposide; GOCCNE 5 NorthEastern Italian Oncology Group; see Table 1 for other abbreviation.
†Median survival 5 10.0 mo.
‡Median survival 5 10.3 mo.
supraclavicular lymph nodes.13 Improved survival was
observed in both of these trials, with median survival times
of 13.7 months and 9.6 months reported by the CALGB
for patients receiving CMT/RT or RT alone, respectively,
and 13.8 months and 11.4 months reported by the RTOG
for these patient groups, respectively.13
Concurrent CMT/RT: Concurrent CMT/RT presents
an opportunity to benefit from synergy between modalities
and a method for the potential control of micrometastatic
disease.35 Concurrent treatments may be shorter in duration, but toxicity is enhanced and possible reductions in
dose intensity may be necessary.35 Recent studies evaluating platinum-containing CMT demonstrated improved
survival rates in patients with advanced NSCLC (Table
3).36 In a study conducted by the European Organization
for Research and Treatment of Cancer, patients were
randomized to treatment with RT, 10 fractions of 3 Gy,
alone or in combination with weekly cisplatin, 30 mg/m2,
or daily cisplatin, 6 mg/m2. Survival rates were significantly
improved in the daily cisplatin/RT group compared to the
group treated with RT alone (p 5 0.009), whereas survival
rates with weekly cisplatin/RT were not significantly different from RT alone (p 5 0.36).37 Patients who received
cisplatin experienced significantly longer times to local
disease recurrence (p 5 0.015), particularly with daily
cisplatin (p 5 0.003). Carboplatin in combination with RT
also shows considerable promise for the treatment of
locally advanced NSCLC and may have a role in combination CMT administered concurrently with RT.
Concurrent and sequential regimens are being compared in current trials. In a phase III study, 320 patients
with stage IIIA and IIIB NSCLC were randomized to
treatment with cisplatin, 80 mg/m2, and mitomycin, 8
mg/m2, on days 1 and 29 plus vindesine, 3 mg/m2, on days
1, 8, 29, and 36 (MVP) and 56 Gy of concurrent or
sequential RT.40 Preliminary analysis demonstrated signif506S
icantly better response and survival (p # 0.05) with concurrent treatment. Hybrid combined modality strategies,
which maximize the advantages and minimize the disadvantages of sequential and concurrent CMT/RT, may be
among the most promising approaches yet to treatment of
unresectable stage IIIA and IIIB NSCLC and should
continue to be an area of development.15
Conclusion
Most patients have metastatic NSCLC at the time of
diagnosis; only approximately one third of patients with
NSCLC are treated surgically, due to nodal status or other
factors.1 RT is an effective method of local disease control
and is valuable for symptom palliation. In patients with
locally advanced NSCLC, the combination of RT and
CMT improves survival compared with RT alone. However, the optimal method and sequence of RT administration with other treatment modalities has not yet been
determined. Methodologic refinements in RT administration and improved identification of prognostic factors and
patient selection are likely to contribute to better responses with RT.
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