Download A Prospective Nonrandomized Phase I/II Study of Carbon Ion

Original Article
A Prospective Nonrandomized Phase I/II Study of Carbon Ion
Radiotherapy in a Favorable Subset of Locally Advanced
Non–Small Cell Lung Cancer (NSCLC)
Wataru Takahashi, MD1,2; Mio Nakajima, MD, PhD1; Naoyoshi Yamamoto, MD, PhD1; Hideomi Yamashita, MD, PhD2;
Keiichi Nakagawa, MD, PhD2; Tadaaki Miyamoto, MD, PhD1; Hiroshi Tsuji, MD, PhD1; Tadashi Kamada, MD, PhD1;
and Takehiko Fujisawa, MD, PhD3
BACKGROUND: Although concurrent chemoradiotherapy (CCRT) has become the standard approach for unresectable locally
advanced non–small cell lung cancer (LA-NSCLC), most patients are not candidates for this treatment because of comorbidities. We
evaluated the safety and efficacy of carbon ion radiotherapy (CIRT) in LA-NSCLC patients. METHODS: Patients with stage IIA to IIIA
(UICC 7th edition) LA-NSCLC were enrolled in a sequential phase I/II trial. For a phase I dose escalation study, the total prescribed
dose was increased by 4 Gray equivalents (GyE) in 2 steps, from 68 to 72 GyE and then to 76 GyE, using 16 fractions over 4 weeks.
After determining the recommended dose, the phase II trial was started in an expanded cohort. RESULTS: Of the 36 patients treated
in phase I, 2 grade 3 adverse events (radiation pneumonitis and tracheoesophageal fistula) were observed in the 76 GyE group.
Accordingly, for phase II, the next consecutive 26 patients were treated with 72 GyE, with no grade 3 to 5 toxicities resulting. A total
of 62 eligible patients were recruited. The majority of patients (49 of 62) were N0 or N1 patients, and the rest (13 of 62) were singlestation N2 patients. The median follow-up period was 25.2 months. The 2-year local control rate (LCR) and overall survival (OS) for
the entire cohort were 93.1% and 51.9%, respectively. In particular, patients with cT3-4N0 had an excellent prognosis; the 2-year
OS and LCR were 69.3% and 100%, respectively. CONCLUSIONS: Short-course CIRT monotherapy shows promise as an effective
C 2015 American Cancer Society.
nonsurgical treatment for inoperable LA-NSCLC. Cancer 2015;121:1321-7. V
KEYWORDS: carbon ion Radiotherapy/TO, treatment effectiveness, non-small cell lung cancer, carbon ion radiotherapy/MT, clinical
trial, phase 1, clinical trial, phase 2.
INTRODUCTION
Worldwide, lung cancer is the most commonly diagnosed malignancy. Non–small cell lung cancer (NSCLC) accounts for
more than 85% of all lung cancers.1 Although surgical resection remains the mainstay of treatment for operable NSCLC,
most NSCLC patients present at an advanced stage. For unresectable locally advanced NSCLC (LA-NSCLC) patients,
concurrent chemoradiotherapy (CCRT) has become the standard of care based on several randomized trials and metaanalyses.2-6 Nevertheless, prognosis is still very poor. In addition, a significant proportion of these patients are not candidates for concurrent chemotherapy because of their advanced age and/or coexistent morbidities such as renal insufficiency.
For these high-risk patients, radiotherapy (RT) without chemotherapy remains the preferred approach, but LA-NSCLC
responds poorly to conventional photon irradiation.7
In 1994, we began research on carbon ion radiotherapy (CIRT) for NSCLC at the National Institute of Radiological
Sciences (NIRS). Early data for stage I NSCLC by Miyamoto et al8,9 showed that hypofractionated CIRT resulted in
excellent local control rates, comparable to those of surgery or stereotactic body radiotherapy, with markedly low toxicity.
Further, CIRT allowed the shortening of overall treatment time. Recently, a single fraction (fr) has been used for stage I
NSCLC.10 We initiated a phase I/II study in 2000 to investigate the feasibility and clinical outcomes of CIRT for LANSCLC, and report the results here.
Corresponding author: Mio Nakajima, MD, PhD, Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan; Fax: 81-43-284-0198; [email protected]
1
Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan; 2Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan; 3Chiba Foundation for Health Promotion and Disease Prevention, Chiba, Japan
This study was partially presented at ASTRO 2014, the 56th Annual Meeting of the American Society for Radiation Oncology.
We deeply appreciate Tsubasa Suzuki, MD, PhD, for his constant encouragement and continuing support with statistical analysis.
DOI: 10.1002/cncr.29195, Received: August 25, 2014; Revised: November 4, 2014; Accepted: November 14, 2014, Published online January 13, 2015 in Wiley
Online Library (wileyonlinelibrary.com)
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1321
Original Article
MATERIALS AND METHODS
TABLE 1. Patients and Treatment Characteristics
Eligibility Criteria
Characteristics
We enrolled patients with histologically or cytologically
confirmed LA-NSCLC stage IIA to IIIA (UICC 7th edition).11 Enrollment was based on the following inclusion
criteria: 1) patient age 20 years, 2) Eastern Cooperative
Oncology Group (ECOG) performance status of 0-2, 3)
N0, N1, or 1-station limited N2 lymph node metastasis,
4) inoperable for medical reasons or surgically unresectable, 5) no apparent signs of interstitial pneumonitis on
computed tomography, 6) no history of previous thoracic
radiotherapy, 7) no systemic therapy such as chemotherapy within 1 month of initiation of CIRT, and 8) an estimated life expectancy of greater than 6 months. Exclusion
criteria included tumors more than 7 cm, the presence of
satellite nodules within the same lobe, multiple primary
tumors, and malignant pleural effusion.
Initial workup included clinical and laboratory
examinations, contrast-enhanced CT of the chest,
contrast-enhanced magnetic resonance imaging (MRI) of
the brain, and [11C]-acetate or [18F]-fluorodeoxyglucose
positron emission tomography/computed tomography
(PET/CT) scan for detecting involved lymph nodes and
distant metastases. Bronchoscopy was also performed if
clinically feasible. Patient characteristics are summarized
in Table 1.
Study Design
This was a nonrandomized, open-label, single-center
study evaluating the efficacy and tolerability of CIRT
monotherapy. Written informed consent was obtained
from all patients before the initiation of therapy. This
study was approved by the institutional review board of
our institution (NIRS no. 9903).
Phase I was a dose escalation study. Prescribed doses
were expressed in photon equivalent doses (GyE), defined
as the physical dose (Gy) multiplied by the relative biologic effectiveness (RBE) of the carbon ions. A doselimiting toxicity (DLT) was defined as any grade 3 or
greater acute toxicity. When there was no acute DLT in at
least 5 patients for 6 months after the start of CIRT, the
dose per fraction was escalated from 68 GyE at 4.25 GyE
per fraction to 72 GyE at 4.5 GyE per fraction, and then
from 72 to 76 GyE at 4.75 GyE per fraction. If any
patient experienced DLT at a given level, then the previous level would be considered the maximally tolerated
dose (MTD). The clinical trial was conducted using 16 fr
over a 4-week regimen in 36 patients with LA-NSCLC.
The recommended dose was fixed at 72 GyE in 16 fr
because grade 3 radiation pneumonitis (RP) occurred in 1
1322
No. of patients (%)
Total
Age (y)
Median
Range
Sex (n)
Male
Female
Performance status
0
1
2
Histology (n)
Squamous cell carcinoma
Adenocarinoma
Large-cell carcinoma
Non–small cell lung caner, not otherwise specified
UICC stage (7th)/TN stage (n)
Stage IIA
T1aN1
T1bN1
T2aN1
Stage IIB
T2bN1
T3N0
Stage IIIA
T1aN2
T1bN2
T2aN2
T3N1
T3N2
T4N0
Prescribed dose
68 GyE
72 GyE
76 GyE
Systemic therapy
Neoadjuvant (not within 1 month of CIRT)
Salvage chemotherapy after recurrence/metastases
None
Follow-up (mo)
Median
Range
62 (100)
76
46-88
48 (77)
14 (23)
34 (55)
26 (42)
2 (3)
33
25
3
1
(53)
(40)
(5)
(2)
17 (27)
3 (5)
4 (6)
10 (16)
22 (35)
5 (8)
17 (27)
23 (37)
1 (2)
3 (5)
7 (11)
4 (6)
2 (3)
6 (10)
8 (13)
35 (56)
19 (31)
5 (8)
3 (5)
54 (87)
25.2
1.6 - 157.2
Abbreviations: UICC, International Union Against Cancer; CIRT. carbon ion
radiotherapy.
patient each in the 76 GyE subgroup. Then in May 2003
we initiated a nonrandomized phase II study to evaluate
efficacy and toxicity at the recommended dose beginning.
In phase II, 26 patients received a total dose of 72 GyE.
The most commonly used schedule was a fractionation
regimen of 72 GyE in 16 fr for the treatment of 35 of 62
total lesions.
Radiotherapy Technique
Using 250 or 290 MeV carbon ion beams generated by
the Heavy Ion Medical Accelerator in Chiba (HIMAC)
synchrotron, external carbon ion beam radiotherapy was
delivered with respiratory gating.12 Using an individually
tailored immobilization device (Moldcare; Alcare, Tokyo,
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CIRT for Locally Advanced NSCLC/Takahashi et al
Japan; and Shelfitter; Kuraray, Osaka, Japan), all patients
were fixed in the supine or prone position (depending on
tumor location) with the hands above the head, without
abdominal compression. Planning CT images in the expiratory phase were acquired at a 2.5- or 5.0-mm slice
thickness. The respiratory phase was monitored using a respiratory sensing system consisting of a position sensor
and an infrared-emitting light marker (Toyonaka Kenkyujo, Osaka, Japan). Using the HIPLAN software program (NIRS, Chiba, Japan), 3-dimensional treatment
planning was performed using a parallel broad beam algorithm for dose calculation.13
The primary tumor and involved lymph nodes were
contoured as gross tumor volume. Clinical target volume
(CTV) included the primary tumor with 10-mm margins
in all directions, as well as involved and uninvolved regional lymph nodes. For prophylactic nodal irradiation,
the regional lymph nodes included the ipsilateral hilar and
mediastinal lymph nodes. In phase I, the prescribed dose
(68, 72, or 76 GyE) was administered to the primary tumor, and a reduced dose was delivered to the CTV up to a
total dose of 57 GyE at the discretion of the treating physician. For N0 cases, prophylactic irradiation of the regional lymph nodes was omitted. Planning target volume
(PTV) was defined as the CTV plus a 5-mm margin to
account for setup error. Routinely, position verification
was performed using an in-house computer-aided online
positioning system (CXDI-50C; Canon, Tokyo, Japan).
The PTV was enclosed conformally at the minimum by the 95% isodose line with the prescribed dose.
The planned doses were delivered over a course of 16
daily fr administered 4 days per week (Tuesday through
Friday). To reduce skin and lung doses, all CIRT plans
utilized 3-4 coplanar and oblique beam fields from the
ipsilateral side of the tumor. Figure 1 shows typical contours and isodose curves for an N1 case. Dose constraints were maintained as follows: spinal cord, 30
GyE; esophagus, 50 GyE; and mainstem bronchus, 60
GyE. To avoid severe toxicity, these dose constraints
were strictly adhered to even if the target coverage
would be compromised.
Follow-up
After the end of radiotherapy, regular follow-up examinations were performed every 3 months for the first 2 years
and every 6 months thereafter. Each follow-up included at
least a physical evaluation, chest CT, brain MRI, and laboratory tests. Additional imaging investigations such as
bone scan and PET/CT were ordered if there was clinical
suspicion of recurrence.
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Figure 1. Carbon ion dose distribution in a typical patient
with locally advanced non–small cell lung cancer. The yellow
and red lines indicate clinical target volume and 95% isodose
of the prescribed dose, respectively.
Acute toxicities were scored using National Cancer
Institute Common Terminology Criteria for Adverse
Events, version 3.0, for the first 90 days after the start of
CIRT. Thereafter, until the end of follow-up, late toxicities were graded according to the Radiation Therapy Oncology Group (RTOG)/European Organization for
Research and Treatment radiation morbidity score.14
End Points and Statistical Analysis
The study was designed as a phase I/II trial of CIRT in
our institution. The aims of the phase I study were to
determine the DLT of CIRT monotherapy, to define the
recommended dose for a phase II trial, and to obtain preliminary efficacy data for unresectable LA-NSCLC
patients.
For a combined phase I/II cohort, the primary end
point was local control rate (LCR). Local control was
defined as the absence of primary tumor recurrence in the
PTV, along with either the absence of abnormal maximum standardized uptake values (SUVmax) 5 on PET/
1323
Original Article
Figure 2. Chart of the sequential phase I/II trial.
CT or a negative biopsy. Secondary end points included
progression-free survival (absence of disease progression at
any site or death from any cause), cause-specific survival,
overall survival (OS), disease-free survival, and toxicity.
Sample size was determined using a 1-stage design with
binominal probability. Assuming an expected LCR of
85% and a lower limit of interest of 65%, the 2-sided a
was .05 and the power was .80. As the estimated number
of patients accrued was 37, we assumed an inevaluability
rate of 10% and planned an accrual of 40 LA-NSCLC
patients in total. Patient characteristics and toxicity are
summarized using a standard descriptive analysis.
From the beginning of treatment, Kaplan-Meier
survival analysis was performed to generate survival curves
for the defined survival outcomes. Survival between
groups was compared with the Wilcoxon test. For multiple comparisons, the Steel-Dwass test was used. A P < .05
was considered statistically significant. All statistical analyses were performed using JMP version 9.0 (SAS Institute
Inc., Cary NC).
Figure 3. Overall survival (OS), local control rate (LCR),
disease-free survival (DFS), and cause-specific survival (CSS)
rates in 62 patients with locally advanced non–small cell lung
cancer. The 2-year OS, LCR, DFS, and CSS were 51.9%, 93.1%,
35.7%, and 71.7%, respectively.
2013 were enrolled (Fig. 2), and their prospectively collected data were reviewed. The clinical characteristics of
these patients are summarized in Table 1. Age ranged
from 46 to 88 years, with a median of 76 years, and 55
were older than 65 years at the time of therapy. ECOG
performance status (PS) of these patients was relatively robust; 34 were PS0 (55%), 26 were PS1 (42%), and 2 were
PS2 (3%). The most common histological type was squamous cell carcinoma (53%), followed by adenocarcinoma
(40%) and large cell carcinoma (5%). Seventeen patients
were stage IIA, 22 were stage IIB, and 23 were stage IIIA.
Thirty-five patients were treated with 72 GyE (including
all patients in phase II), 8 patients received 68 GyE, and
19 received 76 GyE. Five patients had received chemotherapy before CIRT, and 3 received chemotherapy as salvage systemic therapy after CIRT.
Survival and Local Control
RESULTS
Phase I Results
The phase I component consisted of 36 patients (Fig. 2).
The most common side effects of CIRT were mild dermatitis, esophagitis, and RP. In the 76 GyE group, there was
1 RP as DLT and 1 case of tracheoesophageal fistula as
late toxicity. There were no grade 4 toxicities. MTD was
therefore determined to be 72 GyE.
Patient Characteristics
For the present combined phase I/II study, 62 patients
(48 men and 14 women) consecutively treated with CIRT
alone with curative intent from May 2000 to February
1324
Median follow-up was 25.2 months (range, 1.6-157.2
months), and no patient was lost to follow-up. Overall 1and 2-year survival rates were 77.2% (95% CI, 66.7%87.7%) and 51.9% (95% CI, 39.2%-64.5%), respectively
(Fig. 3), with a median overall survival time of 24.1
months. Twenty-two of 62 patients (35.4%) showed a
long-term survival of longer than 3 years. At this writing,
48 of 62 patients have died and 10 patients are disease
free. Of the 48 deaths, 21 patients died from LA-NSCLC,
and 27 died from conditions other than lung cancer, such
as bacterial pneumonia or cardiovascular events. We
observed 3 local recurrences. The resulting 1- and 2-year
LCRs were 96.0% (95% CI, 90.5%-100.0%) and 93.1%
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CIRT for Locally Advanced NSCLC/Takahashi et al
TABLE 2. Frequency of Grade 2 or Greater Acute and Late Toxicity in Overall Patients
Total dose (GyE) in 16 Fractions
Acute: NCI-CTC criteria
Radiation pneumonitis
Grade 2
Grade 3
Radiation dermatitis
Grade 2
Grade 3
Late: RTOG/EORTC criteria
Lung
Grade 2
Grade 3
Esophagus
Grade 2
Grade 3
Skin
Grade 2
Grade 3
68.0 GyE (n 5 8)
72.0 GyE (n 5 35)
76.0 GyE (n 5 19)
Total (n 5 62)
0
0
0
0
1
1
1
1
0
0
1
0
4
0
5
0
0
0
2
0
1
0
3
0
0
0
0
0
0
1
0
1
0
0
1
0
0
0
1
0
Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; NCI-CTC, National Cancer Institute Common Toxicity Criteria; RTOG,
Radiation Therapy Oncology Group.
(95% CI, 85.4%-100.0%), respectively (Fig. 3). The median survival rate of the 3 patients who received salvage
chemotherapy was 16.4 months (range, 7.2-21.9
months).
Toxicity
In our series, CIRT was completed in all patients without
interruption. Table 2 summarizes the acute and late toxicities in all patients. Transient mild dermatitis (grade 1-2)
and a nagging feeling in the esophagus with swallowing
(grade 1) occurred in most patients. Four patients (6.5%)
and 1 patient (1.6%) experienced grade 2 and grade 3 RP,
respectively. The patient with grade 3 RP required steroids and oxygen and then had remission of oxygen desaturation. Except for the 1 patient experiencing a grade 3
tracheoesophageal fistula (TEF) as late toxicity, there were
no other instances of grade 3 or greater gastrointestinal
adverse events. In N1/N2 patients, the median CTV dose
for involved/uninvolved lymph node metastases was 49.5
GyE (range, 36.0-57.0 GyE). The patient with TEF had
undergone CIRT, consisting of 76 GyE in 16 fr, and he
developed thoracic pain 10 months after irradiation. A
CT scan and emergency endoscopic examination revealed
TEF and he underwent endoscopic stenting. Eventually,
he died from bacterial pneumonitis 20 months after the
stenting.
As mentioned above, both grade 3 RPs occurred in
the 76 GyE/16 fr subgroup in phase I, leading to the decision to set the dose at 72 GyE/16 fr for the LA-NSCLC
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TABLE 3. Pattern of First Recurrence Sites in 62
Patients
Pattern
Local failure (1)
Local only
1 Distant metastases
1 Lymph nodea 1 dstant metastases
Local failure (-)
Lymph node
Distant metastases
Lymph nodeb 1 distant metastases
n (%)
0 (0)
2 (3.2)
1 (1.6)
2 (3.2)
18 (29.0)
5 (8.1)
a
Lymph node metastases within irradiated regions.
All 5 patients presented with lymph node metastases out of the radiation
field.
b
patients in phase II. No cases of grade 4 or 5 acute or late
toxicity have been recorded at this writing.
Patterns of Failure
Patterns of disease progression are shown in Table 3. The
most frequent pattern of failure was distant metastases
(DM) alone (18 patients), followed by regional lymph
node metastases (LNM) and DM combined (5 patients).
Three patients developed local recurrence with some
LNM or DM. First site of failure did not differ by dose.
Clinical Outcomes According to N Stage
We also analyzed differences in OS and disease-free survival according to N stage stratification. As expected, the
patients with N2 had worse prognoses than those without
lymph node metastasis (P 5 .03 in the Wilcoxon test,
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Figure 4. Outcomes for patients with cT3N0M0 and
cT4N0M0 locally advanced non–small cell lung cancer (CSS,
cause-specific survival; LCR, local control rate; OS, overall
survival).
which compared N0, N1, and N2 in total versus no significant difference on multiple comparison using the
Steel-Dwass test, which compared N0 vs N1, N0 vs N2,
and N1 vs N2). Other factors, including sex, history of
prior chemotherapy, and tumor size, were not significantly associated with survival. In contrast, patients with
cT3-4N0 had an excellent LCR, with more than half
achieving long-term survival; the 2-year OS and LCR
were 69.3% and 100%, respectively (Fig. 4). As monotherapy, these results might be a result of the high RBE of
carbon ion beams.
DISCUSSION
In this single-institution phase I/II trial of the clinical efficacy and toxicity of CIRT in patients with LA-NSCLC,
we found that CIRT using 16 fr was associated with manageable toxicity and encouraging local control rates in
patients with inoperable LA-NSCLC who were not candidates for concurrent chemotherapy. Two-year local control and overall survival rates in the 62 patients were
93.1% and 51.9%, respectively.
The management of patients with LA-NSCLC
remains one of the most challenging issues in oncology,
especially in patients with medical contraindications to
surgery. Although CCRT is the standard approach for the
treatment of patients with good performance status, no
standard approach exists for high-risk patients who are
not candidates for standard combined modality therapy.
Our CIRT approach seemed to yield better survival results
while causing less toxicity than photon monotherapy. To
our knowledge, this study is the first assessment of CIRT
for LA-NSCLC.
1326
The phase I dose escalation trial established the
MTD of 72 GyE/16 fr (4.5 GyE per fr) using 3dimensional conformal carbon ion radiation therapy with
respiratory gating. The phase II trial used this recommended dose prescription for all patients. Combining the
results of phase I and phase II, we found 1- and 2-year
overall survival rates in all 62 patients receiving 68-76
GyE in 16 fr of 77.2% (95% CI, 66.7%-87.7%) and
51.9% (95% CI, 39.2%-64.5%), respectively. As
expected, the most frequent pattern of failure was DM.
Although concurrent use of chemotherapy with CIRT
could be a beneficial intervention for patient without
complications, further study may be needed to assess its
feasibility.
Many studies have addressed treatment outcome
with CCRT in LA-NSCLC patients. In the RTOG 0117
trial, Bradley et al15 reported a median OS of 21.6
months, with an incidence of grade 3 RP of 21.8%.
According to a single-center phase II trial, Oshiro et al
reported that chemoproton therapy for stage III NSCLC
achieved favorable survival (mean, 26.7 months) with tolerable toxicities.16 Several groups have also reported RT
monotherapy for LA-NSCLC. In the JCOG0301 phase
III trial, Atagi et al reported a median OS of 16.9 months
for elderly LA-NSCLC patients receiving photon RT
alone.17 According to a retrospective review by Nakayama
et al, high-dose photon monotherapy (66-84 Gy) for stage
III NSCLC achieved a 3-year OS of 31.0% (95% CI,
18.9-43.1%).18 Although the current favorable outcomes
of CIRT might result from differences in excluding over
2-station N2 metastases, our strategy could provide comparable results with photon or proton monotherapy.
For the most part, the treatment-related toxicities
observed in this study were mild. No patients receiving
the recommended 72 GyE/16 fr experienced a severe
adverse event. For lung, except for the grade 3 RP events
occurring in the 76 GyE/16 fr subgroup in phase I, no
grade 3 pulmonary toxicity was observed in any patient.
Although sample size was relatively small, this finding is
similar to those of previous CIRT studies of stage I
NSCLC.8,9 As for the esophagus, despite inclusion of the
mediastinal region, only 1 grade 3 event occurred in 1
patient. This might be a result of strict dose constraint
(esophagus Dmax <50 GyE was achieved in all patients).
As mentioned above, of the 49 deaths, 27 died from
conditions other than LA-NSCLC. Causes of death
included bacteria pneumonitis (including aspiration
pneumonitis; n 5 17), acute exacerbation of chronic obstructive pulmonary disease (n 5 4), stroke (n 5 2), other
cancer (n 5 2), ruptured aortic aneurysm (n 5 1), and
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CIRT for Locally Advanced NSCLC/Takahashi et al
myocardial infarction (n 5 1). Frequent occurrence of serious bacteria pneumonitis might be a result of the relatively older inoperable population of this trial.
As a new management option for LA-NSCLC, especially in patients who are not candidates for concurrent
chemotherapy, a standard CIRT regimen of 72 GyE in 16
fr, the dose delivered to the majority of our cohort, has the
potential to improve survival.
Study Limitations
The follow-up period in this study was relatively short.
Assessing the robustness of the promising disease control
and low toxicity observed to date requires additional longterm follow-up. In addition, the single-site nature of the
current study suggests a need to expand the CIRT methodology employed here to different patient populations in
different institutions. In the meantime we are encouraged
by the relatively low toxicity and excellent disease control
with CIRT.
As for the exceptionally high LCR in this study, we
should give careful consideration to the possibility of overestimation of LCR. In patients with early lymph node/distant metastases after CIRT, precise evaluation of primary
tumor recurrence tended to be inadequate because further
tests like PET or biopsy for primary lesions were not
needed to make salvage treatment decisions. In addition,
radiation-induced changes are common after CIRT, and
the discrimination between just fibrosis and recurrence is
relatively difficult without PET or biopsy.
Conclusions
We conducted a single-institution phase I/II trial to determine the clinical efficacy and toxicity of CIRT in patients
with LA-NSCLC. For inoperable LA-NSCLC patients
who were not candidates for concurrent chemotherapy,
CIRT using 16 fr was associated with manageable toxicity
and encouraging local control rates. We suggest that the
best candidates for CIRT are cT3-4N0M0 patients who
are not candidates for concurrent chemotherapy.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
REFERENCES
1. Gompelmann D, Eberhardt R, Herth FJ. Advanced malignant lung
disease: what the specialist can offer. Respiration. 2011;82:111-123.
Cancer
April 15, 2015
2. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of
concurrent versus sequential thoracic radiation therapy in combination with mitomycin, vindesine, and cisplatin in unresectable
Stage III non-small cell lung cancer. J Clin Oncol. 1999;17:26922699.
3. Sause WT, Kolesar P, Taylor S, et al. Final results of a phase III
trial in regionally advanced unresectable non-small cell lung cancer.
Chest. 2000;117:358-364.
4. Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial
of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer: Groupe
Lyon-Saint Etienne d’Oncologie Thoracique—Groupe Francais de
Pneumo-CanceÇrologie NPC 95-01study. J Clin Oncol. 2005;23:
5910-5917.
5. Auperin A, Le Pechoux C, Pignon JP, et al. Concomitant
radio-chemotherapy based on platin compounds in patients with
locally advanced non-small cell lung cancer (NSCLC): a metaanalysis of individual data from 1764 patients. Ann Oncol. 2006;17:
473-483.
6. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent
chemoradiation for stage III non-small cell lung cancer: randomized
phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:14521460.
7. Roswit B, Patno ME, Rapp R, et al. The survival of patients with
inoperable lung cancer: a large-scale randomized study of radiation
therapy versus placebo. Radiology. 1968;90:688-697.
8. Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer. Radiother Oncol.
2003;66:127-140.
9. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for
stage I non-small cell lung cancer using a regimen of four fractions
during 1 week. Thorac Oncol. 2007;2:916-926.
10. Takahashi W, Nakajima M, Yamamoto N, et al. Carbon ion radiotherapy in a hypofractionation regimen for stage I non-small-cell
lung cancer. J Radiat Res. 2014;55(Suppl 1):i26-i27.
11. Sobin LH, Gospodarowicz MK, Wittekind C. International Union
Against Cancer (UICC). TNM Classification of Malignant Tumours,
7th ed. New York: Wiley; 2010.
12. Minohara S, Kanai T, Endo M, Noda K, Kanazawa M. Respiratory
gated irradiation system for heavy-ion radiotherapy. Int J Radiat
Oncol Biol Phys. 2000;47:1097-1103.
13. Kanai T, Endo M, Minohara S, et al. Biophysical characteristics of
HIMAC clinical irradiation system for heavy-ion radiation therapy.
Int J Radiat Oncol Biol Phys. 1999;44:201-210.
14. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for
Research and Treatment of Cancer (EORTC). Int J Radiat Oncol
Biol Phys. 1995;31:1341-1346.
15. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase
II component of a phase I/II dose intensification study using threedimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG
0117. J Clin Oncol. 2010;28:2475-2480.
16. Oshiro Y, Okumura T, Kurishima K, et al. High-dose concurrent
chemo-proton therapy for stage III NSCLC: preliminary results of a
phase II study. J Radiat Res. 2014;55:959-965.
17. Atagi S, Kawahara M, Yokoyama A, et al. Thoracic radiotherapy
with or without daily low-dose carboplatin in elderly patients with
non-small-cell lung cancer: a randomised, controlled, phase 3 trial
by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol.
2012;13:671-678.
18. Nakayama H, Satoh H, Kurishima K, et al. High-dose conformal
radiotherapy for patients with stage III non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2010;78:645-650.
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