Lung cancer effects

Study objectives: We evaluated the effects on pulmonary function of irradiating lung cancer with protons alone or protons combined with photons.

Design: Prospective phase I/II study.

Setting: University medical center.

Patients and interventions: Ten patients with stage I-II non-small cell lung cancer (NSCLC) and FE[V.sub.1] [less than or equal to] 1.0 L were irradiated with protons to areas of gross disease only, using 51 cobalt gray equivalents (CGE) in 10 fractions (protocol 1). Fifteen patients with stage I-IIIA NSCLC and FE[V.sub.1] > 1.0 L received 45-Gy photon irradiation to the primary lung tumor and the mediastinum, plus a 28.8-CGE proton boost to the gross tumor volume (protocol 2).

Measurements: Pulmonary function was evaluated prior to treatment and 1 month, 3 months, and 6 to 12 months following irradiation.

Results: In patients receiving protocol 1, no significant changes in pulmonary function occurred. In patients receiving protocol 2, at 6 to 12 months, the diffusion capacity of the lung for carbon monoxide had declined from 61% of predicted to 45% of predicted (p < 0.05), total lung capacity had declined from 114% of predicted to 95% of predicted (p < 0.05), and residual volume had declined from 160% of predicted to 132% of predicted (p < 0.05). Airway resistance increased from 3.8 to 5.2 cm [H.sub.2]O/L/s (p < 0.05). No statistically significant changes occurred in vital capacity, FE[V.sub.1], or Pa[O.sub.2].

Conclusions: Our observations indicate that it is feasible to apply higher-than-conventional doses of radiation at a higher-than-conventional dose per fraction without excess pulmonary toxicity when conformal radiation techniques with protons are used. (CHEST 2001; 120:1803-1810)

Key words: irradiation; lung cancer treatment; non-small cell lung cancer; photon; proton; radiation

Abbreviations: ABG = arterial blood gas; CGE - cobalt gray equivalent; CHF = congestive hart failure; DLCO = diffusion capacity of the lung for carbon monoxide; IC - inspiratory capacity; KCO = Krogh factor; LLUMC = Loma Linda University Medical Center; MBC = maximum breathing capacity; NSCLC = non-small cell lung cancer; PFT = pulmonary function testing; Raw = airway resistance; RV = residual volume; TLC = total lung capacity

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Lung cancer is the leading cause of cancer death in the United States and remains a challenge to all clinicians who treat it. In 1996, the estimated occurrences of morbidity and mortality from lung cancer were 177,000 cases and 158,700 deaths, respectively. (1) Approximately 80% of patients had non-small cell lung carcinoma (NSCLC); approximately 20% had the small cell type. (2,3)

The standard treatment for patients with stage I, stage II, and selected stage IIIA NSCLC is surgical resection. (4-8) However, many patients with potentially resectable NSCLC are found to have inoperable conditions because of insufficient pulmonary reserve or other medical conditions. (9) One of the proposed therapies for this group of patients might be radiation.

Within the therapeutic range of doses usually administered for radiation therapy for unresectable lung cancer, virtually 100% of the lung parenchyma in the treatment field reacts to radiation. (10) Pathologic changes often supervene and are frequently clinically defined as early (acute radiation pneumonitis) or late (fibrosis). (8) During the acute phase, in many cases, demonstrable abnormalities on conventional radiographs (11) and physical findings on routine chest examinations (12) are absent. High-resolution CT of the chest (13) and pulmonary function testing (PFT) (14) are more sensitive procedures for determining the presence and extent of damage.

RADIATION THERAPY WITH PROTONS

One of the disadvantages of radiation therapy for NSCLC compared to surgical resection is reduced long-term survival, resulting from local failure. (5) Radiation Therapy Oncology Group studies (15) have indicated that higher doses of radiation, up to 60 Gy, are associated with increased survival. When doses have been increased to between 65 Gy and 70 Gy with conventional radiation, further survival benefits have not been demonstrated, presumably because significant morbidity supervenes after damage to surrounding tissues and offsets any possible benefit of increased local tumor control. (16) This limitation is especially true in patients with severe COPD, since there is no pulmonary reserve to compensate for any degree of radiation pneumonitis or fibrosis. Thus, a treatment designed to deliver higher doses of radiation to sites involved with tumor, while not delivering an excessive dose to surrounding normal tissues, may increase locoregional control and survival in patients not able to have surgical resection. (17)

Particle beam therapy with protons is one way of accomplishing this goal. (18) In conventional photon irradiation, the highest radiation dose is delivered directly on entry into the body. While the photon beam traverses the body, the tissue dose continually declines until the beam exits the body opposite to its entry site. In contrast, protons traveling in tissues follow a predetermined track, have minimal side scatter, and deliver most of their energy near the end of their track (Fig 1). (19) This property is obtained at any prescribed depth (20) and thus may be used to shape the dose distribution three dimensionally to fit virtually any tumor volume with very high precision.

[FIGURE 1 OMITTED]

Since to our knowledge proton beam radiation has never been clinically evaluated in the treatment of lung cancer, a prospective phase I/II study was initiated at Loma Linda University Medical Center (LLUMC), after approval by the institutional review board, to evaluate the pulmonary toxicity of the modality and to collect initial data on tumor response and survival. Reports on radiographic manifestations of pulmonary damage (21) and on survival (22) have been previously published. This article reports the results of phase I of the study: the effects observed from irradiation of lung cancer with protons alone (tumor alone) in patients with very poor pulmonary function, or protons combined with photons (tumor and mediastinum) in patients with acceptable pulmonary function, as reflected in pulmonary symptoms and function during the first 12 months following treatment.

MATERIALS AND METHODS

Patient Eligibility Requirements

Between August 1994 and January 1998, 37 patients with resectable but medically inoperable NSCLC were treated at LLUMC, either with proton radiation therapy alone when very poor pulmonary function was present (protocol 1), or with combined photon beam and proton beam therapy (protocol 2). To be included into the pulmonary function substudy, the patients must have agreed to have their PFT performed at the indicated intervals at Loma Linda University. This was believed to be necessary to ensure comparability of the pulmonary function data. Twenty-five patients fulfilled this criterion and were entered. There were 17 female and 8 male patients (mean age [range], 71.3 years [52 to 85 years]). All 25 patients had a history of heavy smoking, with a mean (range) of 75 pack-years (20 to 200 pack-years).

Patients were eligible for protocol 1 if they had tumor in stages T1N0M0 and had FE[V.sub.1] values [less than or equal to] 1.0 L, or any medical contraindications for lung resection. Patients with N1 status were considered eligible if the lymph node and the primary tumor could be included in one

radiation field. Ten persons met these criteria. Patients were eligible for protocol 2 if they had tumor in stage T1-3N0-2M0 and FE[V.sub.1] > 1.0 L prior to irradiation; 15 persons qualified for protocol 2 and were entered into the study.

Tissue diagnoses of NSCLC had to be established in all instances prior to radiation, and informed consent had to be signed. Further criteria for both protocols are as follows: age [greater than or equal to] 18 years, Karnofsky index > 60, medical contraindication or patient refusal to surgery, no prior radiation therapy to the chest, no chemotherapy within the past 6 months, no weight loss > 10% of body weight, and no other malignancies within the past 5 years.

Pretreatment Evaluation