Editorial
Locally Advanced Non-Small Cell Lung Cancer: Whether Higher Dose of Radiation is a Winner?
Lucyna Kepka*
Department of Radiotherapy, Military Institute of Medicine, Poland
*Corresponding author: Lucyna Kepka, Department of Radiotherapy, Military Institute of Medicine, Poland
Published: 11 Sep, 2017
Cite this article as: Kepka L. Locally Advanced Non-Small
Cell Lung Cancer: Whether Higher
Dose of Radiation is a Winner?. Clin
Oncol. 2017; 2: 1345.
Editorial
Radiotherapy is a mainstay of treatment of locally advanced Non-Small Cell Lung Cancer
(NSCLC). Despite that there is a relative paucity of prospective trials directed on the radiotherapy
use in this indication in comparison with prospective studies related to the use of chemotherapy.
In this context, a recently published randomized study by [1]. is certainly to be welcomed. This
randomized phase II trial (NARLAL: Navelbine and Radiotherapy in Locally Advanced Lung
cancer) compared two commonly used radiation dose schedules 60 Gy in 30 fractions (60 Gy/30F)
and 66 Gy in 33 fractions (66 Gy/33F) based on a “pick the winner” design. Radiotherapy was given
concomitantly with a convenient oral formulation of Vinorelbine administered 50 mg three times
weekly. Radio-chemotherapy was preceded by two cycles of full-dose induction chemotherapy
Carboplatin and oral Vinorelbine. After demonstration that plan of 66 Gy/33F (with 3-dimensional
conformal technique or IMRT at the discretion of treating institution) may fulfill predefined dose
constraints criteria patients were randomized to 60 Gy or 66 Gy. All patients had FDG-PET CT
performed as a part of initial work-up and at nine months of follow-up as part of the protocol.
The primary end-point of this study was Local Progression Free Interval (LPFI). Local failure was
defined as a progression within radiation field. Overall Survival (OS) was a secondary endpoint. Of
121 patients included, three were not able to receive 66 Gy/33F, because of dose constraints, one had
distant metastases at the inclusion, thus finally 117 stage IIB and III NSCLC cases were considered
eligible and were subject to the analysis. The LPFI at 9 months was 54% and 59% for 60 Gy/30Fand
66 Gy/33F arms, respectively (p = 0.55). The median OS was also not different for compared groups,
23.3 months for 60 Gy/30F and 23.7 months for 66 Gy/33F. Toxicity in this trial, partially earlier
published in detail [2], was mild and not statistically different in compared schedules. Based on the
complex “pick the winner” study design, the 66 Gy/33F was chosen as a winning arm for further
phase III studies that will test further dose escalation given as a simultaneous boost to the areas of
high FDG uptake within tumor and pathological lymph nodes with a standard arm of 66 Gy/33F
concurrently with doublet platinum based chemotherapy [3].
Although this trial as acknowledged also by the authors was not ideal because of debatable
treatment schedule (the use of radio sensitizing monotherapy instead of doublet platinum based
chemotherapy for fit patients and the use of induction chemotherapy) which reflected more local
habits than evidence based recommendations [4], we may still learn a lot from this trial because of
the high quality of prospectively gathered data.
First of all, there is the issue of the use of 60 Gy/30F in comparison with 66 Gy/33F. Doseresponse
curve in radiotherapy for lung cancer has a sigmoidal shape what means that the probability
of local control increases with the increase of radiation dose [5]. However, higher dose may cause
additional toxicity which compromises benefit of dose escalation. Recently, it was demonstrated in
the randomized study that dose escalation in conventionally fractionated radiotherapy concomitant
with chemotherapy from standard dose of 60 Gy in 30 fractions to 74 Gy in 37 fractions was
detrimental for OS; median OS in the standard dose group was 28.7 months and 20.3 months in the
escalated dose group, p = 0.004 [6]. There are several probable reasons of the decreased survival with
dose escalation above 70 Gy; underreported toxicity, lower local control due to inadequate target
coverage in high-dose arm or prolongation of treatment time with higher total dose. However, in the
lower range of doses, higher dose revealed to be beneficial. RTOG 73-01 phase III trial randomized
patients with NSCLC to 40, 50, or 60 Gy in 2 Gy fractions. Local control improved with higher dose
and three-year local control rates were 52%, 62%, 73% for 40, 50, and 60 Gy groups, respectively, p =
0.02 [7]. Thus a dose of 60 Gy in 30 fractions became a recommended dose for radical radiotherapy
for NSCLC. In the RTOG 73-01 trial, no dose in homogeneity correction was used what means
in practice that in the thoracic region the actual target absorbed dose exceeded the prescribed
dose by up to 15 percent [8]. For this reason, with introduction of
dose in homogeneity corrections algorithms for treatment planning
that made dose calculation more accurate, the dose schedules of 66
Gy/33F became also a standard dose for radical radiotherapy in many
countries. The standard dose arm in CHARTWEL trial may serve as
an example of the successful use of the 66 Gy/33F schedule [9]. On
the other hand, many radiotherapy trials for NSCLC with concurrent
chemotherapy were still using 60 Gy/30F as a standard arm [10]. Such
a radiation schedule of 60 Gy/30F was also used in the phase I study
that established a dose level for oral Vinorelbine used in the NARLAL
trial [11]. In this context [10]. Concept of conducting a study with a
goal of selecting a radiation dose schedule of 60 Gy/30F or 66 Gy/33F
as a standard dose for further testing of dose escalation was justified.
Only 3 out of 121 patients with locally advanced NSCLC were not
able to get 66 Gy/33F due to dose constraints. Authors consequently
realized their project and showed that indeed 66 Gy/33F given for
NSCLC does not result in higher toxicity. Local control and OS
were similar. Even, as for many practitioners that are commonly
using 66 Gy/33F such a trial may seem odd in this regard, for many
others that are still giving 60 Gy/30F the results of this trial may
be convincing and lead to the change of their practice. Once more
this was shown that increasing a radiation dose within a commonly
accepted in radiation oncology range as in this case from 60 to 66
Gy is safe. However, a question remains what about a further dose
escalation and does it matter to develop this concept in the light of
recently demonstrated in RTOG 0617 trial a detrimental effect of
conventionally fractionated dose of 74 Gy [5]. Alternative ways of
dose escalation may be warranted, as a planned NARLAL2 dose per
fraction escalation study, in which investigators from the presented
NARLAL trial will compare 66 Gy/33F with dose heterogeneously
escalated to the FDG-PET avid volumes, with mean doses up to 95
Gy/33 fractions and 74 Gy/33 fractions to the escalated volumes in
the tumor and malignant lymph nodes, respectively [11]. Such an
approach has for a rationale a concept that shortening of treatment
time may be beneficial and hypo fractionation using modern
treatment technologies is safe. This may be supported by the recently
published long-term results of the Raditux trial on 102 patients, in
which the exceptionally long median OS of 31.5 months was obtained
in hypo fractionated accelerated radiotherapy schedule (66 Gy in
24 fractions). Five-year OS rate was 37% in this trial [12]. Secondly,
the study by Hansen et al. [1] brings robust data on the outcome
of contemporarily treated locally advanced NSCLC patients with
standard dose conventionally fractionated radiotherapy. Despite a
suboptimal chemotherapy regimen used in this study, median OS was
23.5 months, higher than in older completed about 10-20 years ago
radiotherapy trials, in which OS after radical radiotherapy or radiochemotherapy
trials was almost always lower than 20 months [10].
Recently, this is always higher than 20 months, and often approaching
30 months. In a standard dose arm 60 Gy/30F in the RTOG 0617 trial
that used concomitant full dose chemotherapy a median OS was 28.7
months [6]; in SOCCAR trial with either sequential or concurrent
chemotherapy and accelerated hypo fractionated radiotherapy 55 Gy
in 20 fractions OS was 27.4 months [13]; in INDAR trial of radiochemotherapy
using individualized accelerated (partially hyper
fractionated) radiotherapy to median dose of 65 Gy, stage IIIA patients
had median OS of 26 months [14]. This indicates the progress of the
last decade made in radiotherapy techniques, advances in diagnostics
and supportive care.
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