A Phase I/II Study of Hypofractionated Proton Therapy for Stage II-III Non-Small Cell Lung Cancer

Conventional fractionated photon-based radiotherapy to 60-63 Gy at 1.8-2 Gy/fraction with
concurrent chemotherapy remains the standard treatment practice in patients with stage III
non-small cell lung carcinoma (NSCLC) with local control rates of approximately 50% and a
median overall survival of just 18 months.Unfortunately, even the standard treatment has
significant toxicity with approximately 40% of patients developing grade 3 or higher acute
toxicities in the RTOG 9410 study.1 These outcomes are poor and more effective treatment
regimens are needed.

Higher doses of radiation have been hypothesized to improve local control in patients with
stage III NSCLC. This is expected to translate into better overall survival.Given the
significant improvements in outcome in patients receiving hypofractionation for stage I
NSCLC, perhaps similar gains could be achieved if hypofractionated radiotherapy could be
safely delivered to stage II-III NSCLC with concurrent chemotherapy. Hypofractionated
radiotherapy may offer improvement in local control compared with conventional fractionation
that may translate into improved overall survival. Furthermore, hypofractionation will
shorten the time interval during which patients are receiving less aggressive chemotherapy.
Proton therapy is a highly conformal radiotherapy technique that takes advantage of the
proton's characteristic Bragg Peak, resulting in significant reductions in the exit dose of
the treatment beam. Thus, proton therapy can substantially reduce the dose to critical
structures even compared with IMRT.

This study will investigate the safety and efficacy of delivering hypofractionated proton
therapy with concurrent chemotherapy in patients with stage II-III NSCLC

Inclusion Criteria:

- Pathologically confirmed invasive non-small cell lung cancer within 12 weeks prior to
study registration. OR Pathologically confirmed invasive non-small cell lung cancer
within 6 months prior to study registration if the patient received induction
chemotherapy.

- AJCC (American Joint Committee on Cancer) 7th Ed. clinical stage II-III.

- ECOG Performance status 0-1 within 8 weeks prior to study registration.

- Patient must give study-specific informed consent on an IRB-approved consent prior to
any research-related procedures or study treatment.

- Patient must be at least 18 years old at the time of consent.

- Patient must complete all required tests in section 4.

- Lab results per the following within 4 weeks prior to study registration:

- Absolute neutrophil count (ANC) >1,800 cells/mm3.

- Platelets > = 100,000 cells/mm3.

- Hemoglobin > =10 g/dl. The use of transfusion or other intervention to achieve
Hgb ≥10.0 g/dl is acceptable.

- AST/SGOT and ALT/SGPT < 2.5 x the institutional upper limit of normal (IULN).

- Post exploratory thoracotomy must be done > 3 weeks prior to study registration or
patient did not have post exploratory thoracotomy.

- PFT (pulmonary function test) with a FEV1 > 0.75 liters/second within 16 weeks prior
to study registration.

- Patients must be evaluated by a thoracic surgeon, pulmonologist or medical oncologist
and deemed medically or surgically unacceptable for resection.

Exclusion Criteria:

- Evidence of distant metastasis (M1) involvement.

- Prior radiotherapy to thoracic area.

- Unintentional weight loss >10% within 4 weeks prior to study registration.

- Pregnant and/or breast-feeding women, or patients (men and women) of child-producing
potential not willing to use medically acceptable forms of contraception while on
study treatment and for at least 12 months after study treatment. Pregnancy testing is
not necessary for women who have had a hysterectomy or have not had a menstrual period
for at least 24 consecutive months.