A Phase I/II Trial of Stereotactic Body Radiation Therapy

Stage I Non-small Cell Lung Cancer Lung cancer is the most frequent cause of cancer death in
both men and women in North America, accounting for approximately 13% of all cancers
diagnosed and 28% of all cancer deaths. There will be an estimated 173,770 new lung cancer
cases in the United States in the year 2004 with an estimated 160,440 deaths due to lung
cancer.1 Seventy-five percent of patients with bronchogenic carcinoma will be diagnosed with
non-small cell lung cancer (NSCLC). The number of patients with early or localized disease
(currently an estimated 15-20% of NSCLC patients)2 is expected to rise over the next several
years due to widespread screening with CT scanning.

The treatment of choice for stage I (T1-T2N0) NSCLC is surgical resection which results in
5-year survival rates of approximately 60 to 70%.3-5 Occasionally, however, there are
patients with early-stage NSCLC that are unable to tolerate surgical resection or the
postoperative recovery period due to various comorbidities.

While conventionally fractionated radiation therapy has been utilized as nonsurgical therapy
for these medically inoperable patients, close observation with no specific cancer therapy
has also been advocated in highly selected cases. McGarry, et. al., reviewed outcomes in 75
patients who had received no specific cancer therapy for stage I NSCLC, and the cause of
death was progressive cancer in 53% of cases with a median survival time of 14.2 ± 2.4
months.6

Definitive conventionally fractionated RT for early-stage NSCLC is considered reasonable
non-surgical therapy but yields poor 5-year survival rates ranging from 10 to 30%.7-11
Several studies have suggested a dose-response relationship reporting a benefit to dose
escalation above the standard conventionally fractionated 4,500 to 6,600 cGy. This benefit
was evident in both survival and local control in these patients.10-14 Sibley, et. al.,
reviewed 156 medically inoperable patients with stage I NSCLC treated with primary RT at Duke
University between 1980 and 1995. They reported a 5-year, cause-specific survival rate of
32%. There was a trend toward improved survival in those patients achieving local control
which approached significance for higher RT doses (p = 0.07).13 At this institution, we have
published a series treating 56 patients with medically inoperable NSCLC with a median dose of
70 Gy using conformal radiotherapy techniques.15 Actuarial local control rates were 69% and
63% at two- and three years of follow up, respectively. These data serve as the estimate for
statistical power calculations for this trial.

Radiation fields have historically encompassed the primary tumor as well as the regional
lymphatics in the ipsilateral hilum and mediastinum. This elective treatment was based on the
identified risk of occult lymph node involvement ranging up to 20% in some surgical series.16
In recent years, elimination of elective nodal irradiation, which is potentially poorly
tolerated in this population,17 has been validated by several retrospective studies
permitting treatment of the primary tumor alone with limited fields.18-21 Slotman, et. al.,
in a study from the Netherlands, reported the use of limited "postage-stamp" fields to treat
early stage lung cancer patients using hypofractionated RT (i.e., 4,800 cGy in 400-cGy
fractions). Reported 3-year overall and disease-specific survival rates were 42% and 76%,
respectively.20

Most of the aforementioned retrospective studies utilized radiotherapy equipment from the era
of 1-D and 2-D treatment planning. Several limitations are evident from these older
techniques, including target visualization, selection of beam directions, and computational
algorithms describing deposited dose. Recent improvements in software, hardware, and computer
processing speed have revolutionized the delivery of radiation doses appropriate for tumor
cell killing.

In this new era of three-dimensional treatment planning, more precise delivery methods are
available allowing for dose escalation to the target volume without excessive dose being
deposited in normal tissues. The RTOG has completed an extensive dose escalation study of
conventionally fractionated three-dimensional conformal radiotherapy (3D-CRT) for NSCLC for
stages I, II, and III disease as long as all detectable tumor can be encompassed by the
radiation therapy fields including both primary tumor and regional lymph nodes.22 No
mechanism for minimizing lung and tumor movements was utilized. One hundred and seventy-nine
patients were treated with radiation doses escalated to as high as 90.3 Gy. Patients were
stratified within each dose level according to the percentage of the total lung volume that
received >20 Gy with the treatment plan (V20). For patients receiving radiation alone or
radiation following induction chemotherapy, data from RTOG 9311 established that the
radiation dose could be safely escalated using 3D-CRT techniques to 83.8 Gy for patients with
V20 values of <25% and to 77.4 Gy for patients with V20 values between 25% and 36%, using
fraction sizes of 2.15 Gy. Excess mortality was observed at 90.3 Gy with two dose-related
deaths. The incidence of grade 3 or higher acute toxicity is less than 10%; however, grade 3
or higher late toxicity was approximately 15%.

Stereotactic Body Radiation Therapy Stereotactic body radiation therapy (SBRT) is the
delivery of high precision, biologically potent doses of radiation to tumors of the chest,
abdomen, and pelvis. Implementing elements of 3D-CRT with stereotactic targeting, SBRT
permits delivery of 3-4 high dose fractions totaling 48-60 Gy with good local control and low
toxicity.

A phase I dose escalation trial has been completed at Indiana University for treatment of
medically inoperable patients with stage I NSCLC.26, 27 SBRT was administered with large
doses per fraction in an extracranial stereotactic body frame, which includes a system for
decreasing breathing motion. The starting dose was 8 Gy times 3 (24 Gy total), and fraction
dose was escalated by 2 Gy per fraction for each cohort. The target lesion was outlined by a
physician and designated as the gross tumor volume (GTV). An additional 0.5 cm in the axial
plane and 1.0 cm in the longitudinal plane was added to the GTV to constitute the PTV based
on validation measurements for this commercially available system.23, 28, 29 Typically, 7 to
10 non-coplanar beams were used to encompass the PTV. Dose was prescribed to the 80% isodose
line. However, higher isodoses occurred within the center of the target mimicking the
heterogeneous dose profile common to intracranial stereotactic radiosurgery. The treatment
isocenter was identified with 3-D coordinates defined stereotactically and localized on
verniers attached to the frame. No skin or bony landmarks were used to set the treatment
isocenter; however, orthogonal port films were used on a daily basis for isocenter
verification.30 Separate dose escalations were carried out independently for patients with T1
versus T2 small (≤ 5 cm) versus T2 large (5-7 cm) tumors at diagnosis.

According to the Indiana University protocol guidelines, dose-limiting toxicity (DLT) was any
grade 3 cardiac or pulmonary toxicity or any grade 4 toxicity attributed to the therapy.
Thirty-seven patients were treated using a standard dose escalation protocol with 3 patient
cohorts with minimum 1 month between dose levels to assess toxicity. Patients were
categorized into separate independent dose escalations according to tumor volume, T1 vs. T2
(≤ 5 cm) vs. T2 (> 5 to ≤ 7 cm). Grade 3 pneumonitis was seen at a dose of 14 x 3 = 42 Gy
total in one T2 patient with a 7-cm tumor and transient grade 3 hypoxia was seen at 16 x 3 =
48 Gy total in one patient. Additional patients were treated at each of these levels without
further toxicity observed. Twenty-one patients had mild to moderate fibrosis distal to the
treated lesion appear on chest x-ray after treatment. Nine of these patients had a decline of
an element of their pulmonary function tests (FEV1, FVC, DLCO, or PO2) by 10-20% of predicted
which returned back to baseline values with follow-up in all but two. The timing of onset of
this toxicity was generally acute to subacute (< 1 month in most cases). The maximum
tolerated dose (MTD) was not reached on this trial for patients with T1 tumors and smaller T2
tumors (≤ 5 cm). Dose-limiting pneumonitis or pericarditis occurred in 2/5 patients with
larger T2 tumors (>5 to ≤ 7 cm) at a dose of 24 x 3 = 72 Gy defining the MTD for this
subgroup at 22 x 3 = 66 Gy. Patients treated at a dose of 22 Gy per fraction times three
fractions had follow up of over 24 months without late toxicity for all T-stage tumor
categories. Treatment failure within the PTV has been observed in 8 of 26 patients treated at
doses of up to 20 x 3 = 60 Gy. However, all but one of these local failures occurred at doses
of 16 x 3 = 48 Gy or lower.31

The above data demonstrate that solitary lung lesions including early stage NSCLC are better
controlled with SBRT when compared to conventional radiation. In addition, reduced volume
treatments are attractive in these patients with medically inoperable stage I NSCLC who may
have an increased risk of radiation pneumonitis associated with conventional large volume
radiation fields. SBRT permits dose escalation by significantly reducing the high-dose
treatment volume.

The RTOG opened in May 2004 a phase II trial of SBRT in the treatment of medically inoperable
patients with stage I/II non-small cell lung cancer in an effort to determine if SBRT could
achieve acceptable local control as seen in retrospective series.24, 26, 32-38 A secondary
objective is to determine if this technique achieves acceptable treatment-related toxicity.
In this trial, patients with T1, T2 (≤ 5 cm), or T3 (≤ 5 cm), N0, M0 medically inoperable
non-small cell lung cancer are treated with SBRT to a total of 60 Gy in 3 fractions of 20 Gy
each over 1.5 to 2 weeks. This protocol excludes patients with T3 tumors involving the
central chest and structures of the mediastinum as well as patients with any T-stage tumor
within or touching the zone of the proximal bronchial tree. This region is defined as a
volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main
bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus,
lingular bronchus, and right and left lower lobe bronchi).

ELIGIBILITY:

Inclusion Criteria

- Histologically confirmed non-small cell cancer by biopsy or cytology. Squamous cell
carcinoma, adenocarcinoma, large cell carcinoma, bronchioalveolar carcinoma, or
non-small cell carcinoma (not otherwise specified) are allowed.

- Staging studies must identify patient as AJCC Stage I or II based on only 1 of
following combinations of TNM staging:

- T1, N0, M0

- T2 (<=7cm), N0, M0

- T3 (<=7cm), N0, M0

- Primary tumor must be arising in one of the following central chest locations:

- Within or touching the zone of the proximal bronchial tree (a volume 2cm in all
directions around the proximal bronchial tree [carina, R & L main bronchi, R & L
upper lobe bronchi, intermedius bronchus, R middle lobe bronchus, lingular
bronchus, R & L lower lobe bronchi])

- Adjacent to (within 5 mm) or invading the mediastinal pleura

- Adjacent to (within 5 mm) or invading the parietal pericardium

- To differentiate T3 lesions involving the mediastinal pleura from T4 lesions involving
major vessels or organs, a chest MRI will be obtained. If any uncertainty remains, the
patient will have four-dimensional CT scans (4DCT) in an effort to determine the
degree of tumor motion. A freely mobile tumor during ventilation will be judged to be
T3 disease.

- Patients with hilar or mediastinal lymph nodes <=1cm and no abnormal hilar or
mediastinal uptake on PET will be considered N0. Patients with >1cm hilar or
mediastinal lymph nodes on CT or abnormal PET (including suspicious but non-diagnostic
uptake) may be eligible if directed tissue biopsy of all abnormally identified areas
are negative for cancer.

- Primary tumor must be technically resectable by an experienced thoracic cancer
clinician, with a reasonable possibility of obtaining a gross total resection with
negative margins (potentially curative resection, PCR). However, patients must have
underlying physiological medical problems prohibiting PCR (i.e., problems with general
anesthesia, the operation, the post-op recovery period, or removal of adjacent
functioning lung) or refuse surgery. Deeming a patient medically inoperable based on
pulmonary function for surgical resection may include any of the following: baseline
FEV1 <40% predicted; post-operative predicted FEV1 <30% predicted; severely reduced
diffusion capacity; baseline hypoxemia and/or hypercapnia; exercise oxygen consumption
<50% predicted; severe pulmonary hypertension; diabetes with severe end organ damage;
severe cerebral, cardiac, or peripheral vascular disease; or severe chronic heart
disease. Any one of these problems will qualify a patient for this trial.

- Age >=18.

- Zubrod performance status 0-2.

- Women of childbearing potential must use effective contraception.

- No direct evidence of regional or distant metastases after appropriate staging
studies. No synchronous primary or prior malignancy in past 2 years except
non-melanoma skin cancer or in situ cancer.

- No previous lung or mediastinal radiation therapy.

- No plans for concomitant antineoplastic therapy (including standard fractionated RT,
chemo, biologic, vaccine therapy, or surgery) while on this protocol except at disease
progression.

- No active systemic, pulmonary, or pericardial infection.

- No pregnant or lactating women.

- PRESTUDY REQUIREMENTS:

- History and Physical Examination, Weight, Zubrod performance status (within 4
weeks pre-study entry)

- Evaluation by thoracic cancer clinician (within 8 weeks pre-study entry)

- Pregnancy test, if applicable (serum or urine, within 72 hours prior to treatment
start.)

- CT (preferably with contrast unless medically contraindicated; both lungs,
mediastinum, liver, adrenals)

- PET (using FDG with visualization of primary tumor and draining lymph node basins
in hilar and mediastinal regions)

- Brain MRI or head CT with contrast

- PFTs - include routine spirometry, lung volumes, diffusion capacity

- Signed informed consent.

Exclusion Criteria:

There is no exclusion criteria associated with this protocol. Please see the above
inclusion criteria.-