Stage 4 lung cancer

Study objectives: To determine the efficacy and toxicity of high-dose hypofractionated proton beam radiotherapy for patients with clinical stage I lung cancer.

Design: A prospective phase 2 clinical trial.

Setting: Loma Linda University Medical Center.

Patients: Subjects with clinical stage I non-small cell lung cancer who were medically inoperable or refused surgery.

Interventions: All patients were treated with proton beam radiotherapy. The target included the gross tumor volume as seen on CT scan, with additional margin to allow for respiratory motion. A multibeam treatment plan was generated. Delivered treatment was 51 cobalt Gray equivalent (CGE) in 10 fractions over 2 weeks to the initial 22 patients; the subsequent 46 patients received 60 CGE in 10 fractions over 2 weeks.

Results: Sixty-eight patients were analyzed for this report, with a median follow-up time of 30 months. No cases of symptomatic radiation pneumonitis or late esophageal or cardiac toxicity were seen. The 3-year local control and disease-specific survival rates were 74%, and 72%, respectively. There was significant improvement in local Ironer control in T1 vs T2 tumors (87% vs 49%), with a trend toward improved survival. Cox regression analysis revealed that patients with higher performance status, female gender, and smaller tumor sizes had significantly improved survival.

Conclusion: High-dose hypofractionated proton beam radiotherapy can be administered safely, with minimal toxicity, to patients with stage I lung cancer. Local tumor control appears to be improved when compared to historical results utilizing conventional radiotherapy, with a good expectation of disease-specific survival 3 years following treatment.

Key words: lung cancer, stage I; proton; treatment

Abbreviation: CGE cobalt Gray equivalent

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Lung cancer remains a major medical problem within the United States and around the world. It is the leading cause of cancer death in the United States, with an estimated 157,000 deaths per year. (1) The majority of newly diagnosed lung cancer eases are of the non-small cell histologies. Stage I disease is diagnosed when the primary tumor does not invade adjacent structures and there is no evidence of metastatic disease to the mediastinum or distant sites. Surgical resection with lobectomy or pneumonectomy is the standard approach in these patients, and has produced the best reported survival outcomes. Not all patients are suitable for surgical resection, however, because of comorbid conditions such as COPD and heart disease. These conditions are frequently seen in patients with lung cancer because of the strong correlation with cigarette smoking. Some patients will refuse surgical intervention even though they are eligible for it. The majority of these patients will be referred for consideration of radiotherapy with or without systemic chemotherapy. There are multiple reports of the use of conventional radiotherapy in patients with unresected stage I lung cancer, local failure rates in these series are in the 40 to 60% range, indicating that this form of treatment is inadequate for many patients (2,3) The most likely cause of excessive local recurrence would be poor targeting of the primary tumor volume and/or administration of an inadequate dose to the disease in a local area.

Proton beams have distinct physical advantages over conventional radiotherapy (x-rays) in the way the dose is deposited within the body. X-ray beams deposit the maximum dose within a few centimeters of the skin surface proximal to the intended target and continue to irradiate tissues beyond the region targeted for treatment. Tumors centrally located in the body typically receive 60 to 70% of the total dose administered with each individual x-ray beam. This is an inherent physical property of individual x-ray beams and cannot be altered despite sophisticated treatment delivery techniques such as intensity modulated radiation therapy. Proton beams, however, deliver approximately 50% of the dose proximal to the target, while 100% is delivered to the target region. The beam stops at the distal margin of the targeted region and all tissues beyond this area receive no dose. This stopping place can be made to occur at any depth within the patient and can be shaped to match the target area. Aerated lung tissue is less dense than other soft tissues of the body, and thus the stopping region of protons in pulmonary tissue is less precise than with other body treatments. Despite this difference, proton therapy has the potential to spare larger portions of lung tissue compared to x-rays. A review of the dosimetry of proton therapy in lung tissue with implications to treatment planning is provided by Moyers et al. (4) These physical properties allow proton beams to deliver maximal dosages of radiotherapy to targets within the body while minimizing the dose delivered to surrounding healthy tissues. (5,6) Proton beam radiotherapy has proven its efficacy in patients with tumors that require high doses of radiotherapy while simultaneously requiring limited doses to nearby critical structures, such as in the spine and the base of the skull. (7,8)

Patients with stage I medically inoperable nonsmall cell lung cancer present a significant challenge to the radiation oneologist. The tumor within the lung is known to require high doses of radiotherapy to provide a reasonable chance of tumor eradication. These tumors, however, are surrounded by normal lung parenchyma that requires maximal protection because the majority of these patients have compromised pulmonary and cardiac function. The excessive rate of local tumor recurrence following conventional radiotherapy indicates that improved treatment methods are needed for these patients. Proton beam radiotherapy can provide high-dose tumor radiation while simultaneously protecting nor real tissues. It is possible that delivering high-dose proton therapy to localized lung cancers may improve local tumor control while minimizing lung damage, which may lead to improved survival rates.

MATERIALS AND METHODS

A phase II protocol was developed in the Department of Radiation Medicine at Loma Linda University Medical Center. The protocol utilized proton beam radiotherapy for patients with early stage non-small cell lung cancer and received approval by the Institutional Review Board. Eligible patients were required to have a histologic diagnosis of non small ceil lung cancer with clinical stage I disease. Patients were either medically inoperable or refused surgical resection. All patients reviewed and signed a study-specific, Institutional Review Board approved informed consent document. The initial 68 patients enrolled in this tidal have been analyzed and have a minimum of 1 year of follow-up since completing treatment. Required pretreatment evaluations included a CT scan of the chest and upper abdomen and pulmonary function testing. The 46 later patients in this series also underwent a staging positron emission tomography scan.

Following entry, into the trial, patients underwent a treatment planning CT scan of the chest while lying in a custom-made, full-body immobilization device. Physiologic respiratory tumor motion was determined with fluoroscopy (motion target). The gross tumor volume was identified on the planning CT scan, with a margin added to account for respiratory motion. A three-dimensional treatment plan was then developed to deliver proton beam radiotherapy to the motion target while minimizing the dose delivered to the surrounding lung tissue. No treatment was given to the mediastinum. The initial 22 patients received a dose of 51 cobalt Gray equivalent (CGE) in 10 equally divided fractions over a 2 week course (CGE = dose in Gy x 1.1 relative biologic effectiveness). (9) An additional 46 patients were treated to a total dose of 60 CGE in 10 fractions over 2 weeks. A typical treatment plan utilized three to four beam angles centered on the motion target, with a minimum of two fields being treated each day. All patients were monitored weekly for acute toxicity during treatment.

Following completion of treatment, patients received clinical evaluation every 3 months for the first year, then every 6 months, and then annually after the fifth year after treatment. Chest CT scans were used to determine tumor status; these were done at 3-month intervals up to 1 year after treatment, then every 6 months, and then annually after the fifth year of follow-up. Pulmonary function testing was also done periodically after treatment.

RESULTS

The initial 68 patients treated on this trial were evaluated to form this report. All patients entered into the trial completed their prescribed treatments without interruptions, and all were available for follow-up. All patients analyzed had at least 12 months of follow-up 'after treatment. Table 1 summarizes the pretreatment characteristics.