Journal of Cancer Therapy, 2011, 2, 167-171
doi:10.4236/jct.2011.22020 Published Online June 2011 (http://www.SciRP.org/journal/jct)
167
Hypofractionated Radiotherapy for Stage I
Non-Small Cell Lung Carcinoma in Patients Aged
75 Years and Older
Ajay P. Sandhu1*, Karen Messer2, Mark M. Fuster3, Lyudmila Bazhenova4, Ehatsham Ahmad5, Minya
Pu6, Polly Nobiensky7, Stephen Seagren8
1UCSD Moores Cancer Center, Radiation Oncology Department, La Jolla, USA; 2UCSD Moores Cancer Center, Family & Preventa-
tive Medicine, La Jolla, USA; 3VA Medical Center San Diego Dept of Medicine, La Jolla, USA; 4UCSD Moores Cancer Center,
Medicine, La Jolla, USA; 5UCSD Moores Cancer Center, Radiation Oncology Department, La Jolla, USA; 6UCSD Moores Cancer
Center; 7UCSD Moores Cancer Center, Radiation Oncology Department, La Jolla, USA; 8UCSD Moores Cancer Center, Radiation
Oncology Department, La Jolla, USA.
[e-mail], [e-mail]
Received January 13th, 2011; revised April 10th, 2011; accepted April 19th, 2011.
ABSTRACT
Purpose: We report our single-institution experience using hypofractionated radiotherapy in a patient population 75
years and older diagnosed with stage IA or IB (T1/T2 N0) Non-Small Cell Lung Carcinoma. Materials and methods:
This is a single-institution, retrospective analysis examining disease free and overall survival and toxicity after hy-
pofractionated radiation therapy in a patient population 75 years and older diagnosed with stage IA or IB (T1/T2 N0)
NSCLC. Between 1991 and 2005, a total of 33 such patients were identified with a median age of 79 years. Patients
were treated with a median total dose of 7000 cGy using median daily dose fractions of 250 cGy. Analysis of competing
risks (local failure, distal failure or death as the first event) was performed and cumulative incidence functions (CIF)
were estimated. Results: The median length of follow-up was 19.8 months (range: 4.3 - 103.8 months). Of the 33 pa-
tients treated, 21 (63.6% of total) had no evidence of disease recurrence on follow-up imaging over the course of the
study. Of the 12 patients with disease recurrence, 6 (18.2% of total) had local failure as the first event and 6 (18.2% of
total) had distant metastasis as the first event. Analysis of competing risks showed that at 5 years, the probability of
local failure as the first detected event was 19.5% (95%CI: 7.6%, 35.6%); the probability of distal failure as the first
detected event was 21.5% (95%CI: 7.9%,39.4%); and the probability of death without recording a failure was 44.1%
(95%CI: 26.1%, 60.7%). There were no treatment related deaths reported. Conclusions: Elderly patients diagnosed
with stage I non-small cell lung cancer may safely be offered hypofractionated radiotherapy as an effective option with
curative intent.
Keywords: Non-small Cell Lung Cancer, Hypofractionated Radiotherapy, Stage I, Older Age
1. Introduction
With increased life expectancy, the incidence of lung
cancer continues to rise in the older population [1]. Even
though surgery is the treatment of choice for stage I
Non-small Cell Lung Carcinoma (NSCLC), this option is
limited in elderly patients due to concerns for post- op-
erative morbidity and mortality [2-4]. These patients of-
ten have a significant burden of co-morbidities, making
surgery an option only in few select patients [5]. In addi-
tion, long term smoking and consequent poor lung func-
tion from associated chronic obstructive lung disease
deems a significant proportion of these patients to be
non-surgical candidates. Non-intervention and observa-
tion as an approach is a poor choice even for elderly inop-
erable patients due to the significant short-term fatality rate
associated with even early-stage untreated NSCLC [6,7].
Radiotherapy is an attractive alternative to surgery in pa-
tients with stage I disease who are otherwise not optimal
candidates for surgery [8]. We report our single institu-
tional experience utilizing radiotherapy with a hypofrac-
tionated approach in patients 75 years of age or older.

Hypofractionated Radiotherapy for Stage I Non-Small Cell Lung Carcinoma in Patients Aged 75 Years and Older
168
2. Materials and Methods
The current report is based on a retrospective analysis
examining the outcomes of radiation therapy in a patient
population 75 years and older diagnosed with stage IA or
IB (T1/T2 N0) NSCLC. The radiation treatment was de-
livered with a hypofractionated schedule (defined as dose
per fraction greater than 200 cGy). All patients were
treated at a single institution over the p eriod 1991 - 2005.
Patients selected for the analysis met the following inclu-
sion criteria: 1) Age of 75 and above; 2) completion of a
course of hypofractionated radiation treatment for NSCLC
stage IA or IB (T1 or T2 N0 M0); 3) deemed surgically
inoperable due to medical contraindications or surgical
refusal; and 4) no restrictions as to location of tumor
within the lungs.
2.1. Clinical Characteristics
From 1991 to 2005, a total of 33 patients meeting this
criterion were included, with 28 deemed to be surgically
inoperable and 5 that made the decision for treatment
with radiation despite surgical candidacy. The median
age of these patients was 79 years (range 75 - 86), and 29
of 33 patients were male (87.9%); most had stage IA (T1)
disease (22/33 or 66.7%; stage IB (T2), 11/33 or 33.3%).
Table 1 provides a summary of tumor characteristics.
Mean tumor size was 26.8 mm (range: 10 - 50 mm). All
patients were staged according to the American Joint
Commission on Cancer 2002 staging system. The initial
evaluation included complete history and physical ex-
amination, routine blood tests, pulmonary function tests,
chest X-ray, CT scans of chest and upper abdomen, and
18F-fluorodeoxyglucose positron emission tomography
(FDG-PET) (in recent years after this modality became
available). A tissue diagnosis through biopsy or needle
Table 1. Patient characteristics.
Median Age (range) 79 (75 - 86)
Gender
Male 29 (87.9%)
Female 4 (12.1%)
Tumor Stage
T1 22 (66.7%)
T2 11 (33.3%)
Mean Tumor Size, mm (range) 26.8 (10, 50)
Pathology
No Tissue Diagnosis 5 (15.2%)
Squamous 9 (27.3%)
Adeno 5 (15.2%)
NOS 14 (42.4%)
Dose Per Fraction (cGy)
220-249 5 (15.2%)
250-400 25 (75.7%)
401-666.7 3 (9.1%)
aspiration was obtained in 28 (84.8%) patients, and the
remaining 5 (15.2%) patients were treated with a pre-
sumptive clinical diagnos is based on imaging results and
consensus at the institutional Tumor Board.
2.2. Treatment Details
Radiation treatment details (total dose, dose per fraction,
frequency, time elapsed over treatment and use of 3-D
conformal mapping) were also obtained from medical
records. Patients received a median total dose of 7000
cGy using median daily dose fractions of 250 cGy. The
total radiation doses used and dose per fraction ranged
from 1980 - 7000 cGy and 220 - 666.7 cGy respectively.
All patients were treated using hypofractionated sched-
ules with daily dose fractions > 200 cGy, 33/33 (100%);
to be specific, 5 patients received daily dose fractions of
220 - 249 cGy, 25 patients received 250 - 400 cGy, and 3
patients received greater than 400 cGy. The most pre-
ferred schedule was 250 cGy per fraction to a total dose
of 6250 - 7000 cGy in 25 - 28 fractions (63.6%). The
majority of patients (84.8%) were treated with the dose
fractionation: 220 - 269 cGy in 25 - 30 fractions and total
dose ranging between 5000 - 7000 cGy. In a minority of
patients with tiny peripheral tumors, shorter fractionation
schedules such as 400 cGy in 10 fractions (3%), or 660 -
666.7 cGy in 3 fractions (6.1%), or 257 - 411 cGy in 15 -
17 fractions (6.1%) were employed. All patients were
treated in a supine position. The majority of patients (af-
ter 1995) underwent CT based planning. The gross tumor
volume (GTV) was contoured on the free breathing plan-
ning scans using lung windows. When PET scanning
became available, target information was optimized
through fusion with planning CT scans. The clinical tar-
get volume was determined by expanding GTV by 1 - 2
cm (more so in superior-inferior than lateral dimensions).
When tumors were visible, respiratory motion of the tu-
mor was gauged fluoroscopically for individualized
planning margins. There was no attempt to electively
treat hilar or mediastinal nodal regions and therefore
such regions were not included in the clinical target
volume. A single treatment plan was approved to cover
the target to prescribed dose and minimizing the dose to
normal tissues. The spinal cord was almost always ex-
cluded from the radiation portal with few exceptions
when dose was kept below 45 Gy depending on dose
fractionation employed. Patients were treated with linear
accelerator beam energies of 6 - 18 MV.
2.3. Statistical Analysis
Analysis of competing risks (local failure, distal failure
or death as the first event) was performed and cumulative
incidence functions (CIF) were estimated. Point esti-
mates of CIFs and their variances at 5 years were calcu-

Hypofractionated Radiotherapy for Stage I Non-Small Cell Lung Carcinoma in Patients Aged 75 Years and Older 169
lated. Gray’s tests were used to assess the association
between CIFs and a covariate [9]. Brookmeyer and
Crowley’s 95% confidence intervals were calculated for
median survival times [10]. Kaplan-Meier curves were
plotted for the two survival outcomes of local failure-free
survival and overall surv iv al (LFFS and OS). Association
between a categorical factor and a survival outcome was
assessed using log rank tests. All analyses used the statis-
tical package R version 2.5.1, 2007 (www.r-project.org).
The details of evaluation and analysis of outcomes in-
cluding local control, survival and toxicity have been
outlined in detail in our previous publications [11,12].
3. Results
Between 1991 and 2005, 33 patients with inoperable
Stage I NSCLC completed a full treatment schedule of
hypofractionated radiotherapy with no deaths due to
treatment. The median follow-up duration from date of
diagnosis to the date of last outcome/follow-up or date of
death for this analysis was 19.8 months (range: 4.3 -
103.8 months).
3.1. Local Control and Survival
Of the 33 patients treated, 21 (63.6%) had no evidence of
disease recurrence on follow-up imaging over the course
of the study with 6 of the 21 (18.2% of the 33 total) be-
ing event-free and 15 of the 21 (45.5% of the 33 total)
succumbing to death without evidence of disease recur-
rence. Of the 12 patients with disease recurrence over the
course of the study, 6 (18.2% of the total) had local fail-
ure as the first event and 6 (18.2% of the total) had dis-
tant metastasis as the first event. Analysis of competing
risks (Figure 1) showed that at 5 years, the probability o f
local failure as the first detected event was 19.5%
(95%CI: 7.6%, 35.6%); the probability of distal failure as
the first detected event was 21.5% (95%CI: 7.9%, 39.4%);
and the probability of death without recording a failure
was 44.1% (95%CI: 26. 1%, 60.7%). The event rates and
median surviv al times are listed in Table 2.
Median local failure free survival (LFFS) was 21.2
months (95% CI: 13.8 - 31.1 months) (Table 2); and
median overall survival (OS, graphed in Figure 2) was
21.3 months (95% CI: 14.4 - 40.7 months). There was
not a statistically significant difference in LFFS between
the 5 subjects with no tissue diagnosis versus the rest of
the subjects (median LFFS time was 21.3 vs. 14.7
months, p = 0.44).
3.2. Toxicity
Radiation related toxicity was limited to grade 2 or less
and none had grade 3 or higher toxicity. There were no
treatment related deaths reported.
Figure 1. Cumulative incidence functions for competing
risk of local failure, distal failure, and death as first ob-
served event. Patients were aged 75 years and older and
diagnosed with stage IA or IB (T1/T2 N0) Non-Small Cell
Lung Carcinoma between 1993 and 2001, and treated using
hypofractionated radiotherapy at UCSD (n = 33).
Table 2. Event rates, cumulative incidence functions (CIFs)
and median survival times.
Number of Events (Estimated Event Rate), CIF (95%CI) by 60
Months
Local Failure First 6/33 (18.2%), 19.5% (7.6%, 35.6%)
Distal Failure First 6/33 (18.2%), 21.5% (7.9%, 3 9.4%)
Death with No Failure 14/33 (42.4%) , 44.1% (26.1%, 60.7%)
Any Event (Death or Failure)26/33 (78.8%), 85.1% (61.7%, 94.8%)
Median Survival in Months (95% CI)
Overall Survival 21.3 (14.4 - 40.7)
Local-Failure-Free Survival 21.2 (13.8 - 3 1 .1)
Figure 2. Kaplan-Meier curve showing overall survival.
Median overall survival was 21.3 months (95% CI: 14.40 -
40.7 months).

Hypofractionated Radiotherapy for Stage I Non-Small Cell Lung Carcinoma in Patients Aged 75 Years and Older
170
4. Discussion
Stereotactic Body Radiation Therapy (SBRT) is currently
regarded as the standard treatment for inoperable early
stage NSCLC. Prior to implementation of SBRT at our
institution, we used conventional techniques to treat
stage I NSCLC patients using hypo fractionation sched-
ule. Due to limited data on outcomes of older patients
treated with radiotherapy. We report our experience us-
ing hypofractionated radiotherapy in patients 75 years of
age and older with conformal techniques. We have pre-
viously reported our comprehensive experience using
conformal radiation planning for stage I lung cancer in-
cluding hypofractionated radiotherapy [11,12]. This re-
port is based on a subgroup of patients 75 years and older
treated with a hypofractionated approach. This is an im-
portant issue, as there is wide variation in treat ment deci-
sion making for this age group with early stage lung
cancer. The intervention can vary from radical surgery to
no treatment, and there is a paucity of data on outcomes
of treatment for elderly patients. This considerable varia-
tion in managing elderly patients with lung cancer may
be due to multiple reasons, including not only age-related
characteristics but also concern among physicians for
toxicity and ensuing impact on quality of life for elderly
patients undergoing therapeutic interventions. However,
some of these concerns may be unfounded due to the
lack of good data on outcomes in this age group. The
elderly are of ten und err epr esen ted in clin ical trials testing
new and aggressive treatment approaches. There is a
trend toward under treatment and underutilization of ra-
diotherapy among older patients, and several authors
have reported that this may have a negative impact on
both the quality and quantity of life, even in elderly pa-
tients undergoi ng conservative ma nagement [6,7,13,14] .
A significant proportion of patients in their mid 70s
and 80s are not suitable for surgery due to medical
co-morbidities, age related frailty, and patient pr eference.
Even patients with potential for resection may opt out of
aggressive surgical management due to concerns for
morbidity and mortality associated with these procedures.
For these patients, radiotherapy remains a viable alterna-
tive with good outcomes and minimal toxicity. Our re-
sults employing hypofractionated radiotherapy in this age
group show impressive local control, with a large pro-
portion being cancer free (or at least without radio-
graphic evidence of progression) at the time of last fol-
low-up or death. Bonfili et al. [8] recently reported simi-
lar results using hypofractionated radical radiotherapy in
elderly patients with stage I-II non-small cell lung carci-
noma. The incidence of both local an d distant failure was
higher compared to our study possibly due to larger tu-
mor size and inclusion of patients with stage II and N1
disease. In addition, treatment using hypofractionated
radiotherapy did not negatively impact quality of life due
to minimal associated toxicity as reported by us and other
investigators. Even though an earlier study [15] had
shown a higher rate of pn eumonitis in p atients > 70 years
(which was dose dependent) we used a hypofractionated
schedule up to 70 Gy with minimal toxicity. This could
be attributed not only to modern conformal planning
techniques but also to use of involved fields and no at-
tempt to electively treat nodes. Importantly, in spite of
tight margins employed, loco-regional failure was low,
and estimated to be under 20% at 5 years.
Some older patients may have a younger biological
age; however results are almost always reported based on
the chronological age. Therefore treatment decision
based on chronological age may hypothetically exclude
patients from clinical trials and other appropriate inter-
ventions which could effectively prolong their life ex-
pectancy and maintain desired quality of life. Selection
of patients for conservative treatment based purely on
age alone should be discouraged. Our study has limita-
tions in terms of small sample size, single institution ex-
perience, and its retrospective nature, thereby limiting the
strength of our conclusions and recommendations. Nev-
ertheless, our findings point to the importance of recog-
nizing the safety and potential efficacy of hypofraction-
ated radiation therapy as a modality with curative intent
for early-stage NSCLC in this population.
There is an urgent need to design clinical trials spe-
cifically for the growing elderly population, especially
with a significant and growing degree of lung cancer
burden forcing us to seriously focus on outcome and
quality of life measures [16]. Optimal treatment recom-
mendations and guidelines in the near-future could be
based on evidence from growing prospective and ran-
domized studies, which are currently arbitrary and vague.
We also need to develop geriatric oncology services that
focus on formulating clinical and research protocols for
the elderly cancer population.
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