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A Phase I/II Trial of Stereotactic Body Radiation Therapy (SBRT) Dose Escalation in the Treatment of Patients With Inoperable Stage I/II Non-Small Cell Lung Cancer Arising Within the Zone of the Proximal Bronchial Tree

Phase 1/Phase 2
18 Years
Open (Enrolling)
Inoperable Stage I/II Non-small Cell Lung Cancer

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Trial Information

A Phase I/II Trial of Stereotactic Body Radiation Therapy (SBRT) Dose Escalation in the Treatment of Patients With Inoperable Stage I/II Non-Small Cell Lung Cancer Arising Within the Zone of the Proximal Bronchial Tree

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

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%,

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).

Inclusion Criteria


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

- 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.


- 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.-

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I Portion Only: Determine the maximum tolerated dose

Outcome Time Frame:

Completion of phase I enrollment

Safety Issue:


Principal Investigator

Jeffrey D Bradley, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Washington University School of Medicine


United States: Institutional Review Board

Study ID:

06-0691 / 201012832



Start Date:

September 2006

Completion Date:

August 2019

Related Keywords:

  • Inoperable Stage I/II Non-small Cell Lung Cancer
  • SBRT
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



Washington University School St. Louis, Missouri  63110