Hypofractionated Radiotherapy for Stage I Non-small Cell Lung Carcinoma in Patients Aged 75 Years and Older

doi:10.4236/jct.2011.22020

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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.

Email: [email protected], apsa[email protected], [email protected], [email protected], [email protected], [email protected],

[email protected], [email protected]

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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