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* From the Departments of Radiation Medicine (Drs. Bush, J.D. Slater, Moyers, and J.M. Slater), Diagnostic Radiology (Dr. Dunbar), and Pulmonary Medicine (Dr. Cheek), Loma Linda University Medical Center, Loma Linda, CA; and Klinik für Pneumologie (Dr. Bonnet), Zentralkrankenhaus Bad Berka GmbH, Bad Berka, Germany.
Correspondence to: David A. Bush, MD, Department of Radiation Medicine, Loma Linda University Medical Center, 11234 Anderson St, P.O. Box 2000, Loma Linda, CA 92354; e-mail: dbush{at}dominion.llumc.edu
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Abstract |
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Design: Eligible patients had clinical stage I to IIIa non-small cell lung cancer and were not candidates for surgical resection for medical reasons or because of patient refusal. Patients with adequate cardiopulmonary function received 45 Gy to the mediastinum and gross tumor volume with photons with a concurrent proton boost to the gross tumor volume of an additional 28.8 cobalt gray equivalents (CGE). Total tumor dose was 73.8 CGE given over 5 weeks. Patients with poor cardiopulmonary function received proton-beam radiotherapy to the gross tumor volume only, with 51 CGE given in 10 fractions over a 2-week period.
Results: Thirty-seven patients were treated in the study from July 1994 to March 1998. Clinical staging of patients was as follows: stage I, 27 patients; stage II, 2 patients; and stage IIIa, 8 patients. Eighteen patients received a combination of protons and x rays, while 19 patients received proton-beam radiation only. Follow-up of evaluable patients ranged from 3 to 45 months, with a median of 14 months. Two patients in the proton and photon arm developed pneumonitis that resolved with oral steroids; otherwise, no significant toxicities were encountered. The actuarial disease-free survival at 2 years for the entire group was 63%; for stage I patients, disease-free survival at 2 years was 86%. Local disease control was 87%.
Conclusion: Preliminary results from this study indicate that proton-beam radiotherapy can be used safely in this group of patients. Disease-free survival and local control appear to be good and compare favorably with published reports utilizing conventional photon irradiation.
Key Words: inoperable • lung cancer • proton • radiotherapy
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Non-small cell lung cancer is commonly seen in patients who have extensive smoking histories. Because of this, many patients diagnosed with non-small cell lung cancer also have other smoking-related diseases, such as coronary artery disease, peripheral vascular disease, and COPD. Not infrequently, these diseases or other medical illnesses will render a patient medically inoperable, even though definitive resection might be indicated. The proportion of patients with early-stage lung cancer who are medically inoperable is unknown, but it is estimated to be 15 to 20%. Because the overall incidence of lung cancer is high, many patients find themselves in this unfortunate situation.
Conventional x-ray radiation therapy has been utilized for patients with early-stage but medically inoperable lung cancer. In general, local control and survival rates have been inferior to those produced with surgical resection.4 5 6 Some studies have found that delivering higher doses of radiation therapy may enhance survival.7 8 However, because many of these patients have severe underlying pulmonary disease, delivering high doses of thoracic irradiation often is not possible because it will worsen the pulmonary deficiencies that already exist.
Proton beams have a distinct physical advantage over conventional x-ray beams. X-ray beams (photons) can successfully treat malignant tumors if administered in sufficient doses, but in such cases they also deliver substantial doses of irradiation to normal tissues surrounding the tumor. Proton beams produce little side scatter and stop abruptly at any prescribed depth. The pattern of energy deposition is characterized by the Bragg peak, wherein the dose is minimal on entry and reaches a maximum at the stopping region, which is planned to occur in the target volume.9 Proton beams can be shaped to deliver homogeneous radiation doses to irregular three-dimensional volumes such as those required for lung tumors. These characteristics make it possible to reduce the dose delivered to normal tissue by a factor of one half to one fifth compared with conventional x-ray beams.10 Accordingly, proton radiation therapy should help minimize the extent and severity of pulmonary injury and so could benefit patients with localized lung cancer and severe underlying pulmonary disease, while simultaneously permitting an increased dose to the primary tumor. At Loma Linda University Medical Center, we use proton-beam radiotherapy to treat early-stage lung cancer patients who are medically inoperable or who refuse surgery; this paper reports our preliminary findings.
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Materials and Methods |
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Pretreatment Evaluation
Evaluation prior to study enrollment included a complete history
and physical examination, chest radiograph, contrast-enhanced thoracic
CT, pulmonary function testing, bronchoscopy, and routine blood work.
All diagnoses were established with biopsies obtained by means of
bronchoscopy or transthoracic needle biopsy. Brain and bone scans and
mediastinal node sampling generally were not performed unless there was
clinical suspicion of metastasis in these locations. All patients
reviewed and signed an Institutional Review Board–approved
study-specific consent form prior to enrollment.
Study Design
The study had two treatment arms. Patients were assigned to one
of them according to pulmonary reserve and cardiac function (Table 1
). Because mediastinal radiation was judged to be contraindicated in
patients who had severely limited pulmonary reserve and/or severe
cardiac dysfunction (congestive heart failure), patients in the first
arm of the study were given proton-beam radiation therapy that covered
only the gross tumor volume as identified on the planning CT scan. No
attempt was made to cover areas without radiographic evidence of
disease, such as the hilum or mediastinum. These patients received 10
daily fractions of 5.1 cobalt gray equivalents (CGE)11
for
a total of 51 CGE. A typical dose distribution for these patients is
shown in Figure 1
.
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Technique of Proton Irradiation
Preparation for proton radiation therapy began with construction
of a custom-made full-body mold, which was used to ensure reproducible
patient immobilization. A CT scan of the chest was then obtained with
the patient in the mold (treatment position), and a computerized,
three-dimensional treatment plan was developed. From this plan, a wax
bolus and lead apertures were fabricated to shape the proton beam both
to match the target volume in all three dimensions and to adjust the
beam for tissue inhomogeneity. An additional margin was added around
the tumor volume to account for tumor motion during normal respiration.
Tumor motion was measured for each patient using fluoroscopy under
normal respiratory conditions. A dose-volume histogram (DVH) analysis
was performed for each patient to quantify the radiation dose received
by normal tissues. In general, one to three individual proton-beam
portals were used to treat a given patient. Proton treatments typically
were delivered through lateral or oblique fields. Figure 1
shows a
typical dose distribution achieved with a three-field proton beam
arrangement. The colored contours demonstrate how the dose delivered
conform to the targeted tumor in three dimensions.
Follow-up
After completion of treatment, all patients were followed
regularly in the radiation medicine clinic and/or in concert with the
patient’s primary physician. Follow-up examinations at 1, 3, 6, 9, and
12 months after treatment included chest radiograph, chest CT scan, and
pulmonary function testing. After the first year, radiographic imaging
was performed twice a year. Routine blood work was also obtained
periodically. A radiographic metastatic evaluation was only done if
there was clinical suspicion of progressive disease.
Several treatment outcome measures were identified prior to instituting this study. Radiotherapy toxicity was monitored and documented during treatment and at each follow-up visit. Follow-up chest CTs were analyzed for tumor response and pulmonary injury by a panel of physicians including a diagnostic radiologist, radiation oncologist, and pulmonologist. Overall survival and disease-free survival were calculated from the data obtained. In the disease-free survival analysis, if a patient died without clinical or radiographic evidence of disease progression, the event was censored from the analysis at the time of death. Local control was defined as lack of tumor growth within the radiation field. Regional tumor control was defined as disease control within the thorax. Metastatic disease was defined as tumor progression outside of the thorax or the contralateral lung.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 cm in short-axis diameter were considered
negative. One patient underwent surgical node sampling prior to
treatment. Pretreatment characteristics of all patients are shown in
Table 2 . The majority of patients had underlying COPD; the average
FEV1 for all patients was 1.3 L (53% of the
predicted value), although the average FEV1 was
1.1 L (47% predicted) in stage I patients.
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Actuarial overall survival was calculated utilizing the Kaplan-Meier technique (Table 3 ). Actuarial overall survival at 2 years for the entire group was 31%. For the clinical stage I patients, the actuarial 2-year overall survival rate was 39%. The 2-year survival rate for stage IIIa patients was 13%. The disease-free survival rate at 2 years was 63% for the entire group; it was 86% for stage I patients and 19% for stage IIIa patients. Local tumor control at the primary site was 87% at 2 years. Figures 2 , 3 show CT images of two selected cases.
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Discussion |
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A difficult clinical situation arises when a patient with an early-stage lung tumor is medically unfit for an operation. The most common conditions that render patients medically inoperable are advanced COPD, cardiovascular disease, and poor overall medical condition. Many of these patients are referred for definitive radiotherapy because it is believed that such treatment will cause less severe morbidity and mortality than surgery.
Several reports describe results of treating early-stage lung cancer patients with conventional photon irradiation. In general, survival of patients so treated appears to be inferior to that produced with surgical resection. Published reports of overall and disease-specific survival for clinical stage I patients at 2 years ranges from 32 to 43% and 31 to 54%, respectively.4 5 6 7 8 These studies have reported high local failure rates, ranging from 42 to 55%. Table 5 summarizes recently published results of conventional radiotherapy on early-stage lung cancer.
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The delivery of doses of radiotherapy capable of eradicating tumors has long been a problem in radiation therapy because of the increased risk of normal tissue damage and complications associated with conventional x-ray beam irradiation of significant volumes of normal tissue surrounding the tumor volume. Certainly, in patients with medically inoperable, localized lung cancer, delivering radiation doses to normal lung tissue is undesirable because of the frequency of underlying emphysema. These patients have minimal reserve to tolerate aggressive thoracic radiotherapy if a significant portion of the lung parenchyma is within the radiation field.
Charged-particle beams such as proton beams have physical properties that allow tumor irradiation with maximal sparing of normal tissue. These properties are superior to what can be accomplished with conventional x-ray beams.13 14 15 Accordingly, we employed proton-beam radiotherapy to deliver high-dose tumor irradiation while simultaneously reducing the amount of normal lung irradiation, in the hope of improving local disease control and, possibly, disease-free survival. We also utilized an accelerated treatment schedule that delivered high-dose radiotherapy within a reduced overall treatment time (2 to 5 weeks) compared with a standard fractionated course of treatment (7 to 8 weeks). Protracted fractionation schedules are commonly used in radiation therapy to reduce late toxicity to normal tissue.16 17 It has been found, however, that tumor clonogens can proliferate during protracted radiation courses, increasing the likelihood of local tumor regrowth following treatment.18 19 A recent randomized trial has demonstrated improved tumor control and survival with use of an accelerated treatment schedule in locally advanced lung cancer.20
The present study utilized two treatment arms with patients being assigned to one of the arms depending on the presence and/or severity of comorbid conditions such as COPD and cardiac insufficiency. Thus, patients were assigned, not randomized, to a treatment arm, and no direct comparison between the two treatment arms has been made. Although the radiation dose delivered in the treatment arms appear to be different (51 CGE vs 73.8 CGE), the biologically effective dose is similar. When large daily radiation doses are given as in arm 1 of our study (ie, 5.1 CGE), the biologically equivalent dose is greater then the physical dose actually given. Methods for determining biologically equivalent doses of various fractionation schemes are given elsewhere.21 Although the radiation doses in the two arms were designed to be similar, the volume of radiated tissue did differ: coverage of the mediastinum and ipsilateral hilum was omitted in patients with severe cardiopulmonary disease because of toxicity concerns. The volume of lung receiving radiation with each technique is shown in Figure 4 , illustrating the essential difference between the two treatment volumes in the two study arms.
Overall survival at 2 years in our study was 31% for the entire group and 39% for clinical stage I patients. These survival rates are low, but most deaths occurred in patients who had no evidence of recurrent cancer. The low survival rates, then, are probably related to the age and poor pulmonary function of our patients. Several reports document poor survival in this group of patients even without a diagnosis of lung cancer13 14 15 16 ; these studies have shown that the most important prognostic factors for COPD patients are age and FEV1. Thus, disease-free survival is likely a more accurate reflection of the efficacy of proton-beam therapy in this group of patients. For the entire group, the disease-free survival rate at 2 years was 63%; for stage I patients, it was 86%. Local control, as assessed by frequent chest CT scans, was 87%. Although these numbers are preliminary, they do appear to compare favorably with results of conventional radiotherapy techniques (Table 5) .
Pulmonary toxicity was also monitored closely in this study. Patients underwent frequent clinical assessment in the radiation oncology and pulmonary clinics. We identified only two cases of clinical pneumonitis, and both resolved following a short course of oral steroids. We also monitored patients for subclinical lung injury radiographically by utilizing high-resolution chest CT scanning. We observed a lesser degree and frequency of pulmonary damage in patients treated in the protons-only arm than in patients receiving the combination of proton and photon irradiation.12 It is likely that the differences in pulmonary injury we observed in the two groups of patients result from the smaller volume of lung that was irradiated in patients who received protons only, as DVHs suggest (Fig 4) . Overall, the low incidence of significant toxicity suggests that dose escalation is possible, especially in patients treated with local field proton-beam radiotherapy only.
Our study suggests that high-dose proton radiotherapy can be administered safely to patients with poor underlying pulmonary function when conformal techniques are used. We believe our study has demonstrated encouraging results in local tumor control and disease-free survival that compare favorably with previously reported data using conventional radiotherapy techniques. Accordingly, we intend to continue to use proton-beam therapy in this group of patients and plan to escalate the proton dose delivered. We also intend to extend this treatment option to patients who have locally advanced lung cancers.
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Acknowledgements |
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Footnotes |
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Supported in part by grants from The Hearst Foundation.
Received for publication January 13, 1999. Accepted for publication June 9, 1999.
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This article has been cited by other articles:
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R. B. Bonnet, D. Bush, G. A. Cheek, J. D. Slater, D. Panossian, C. Franke, and J. M. Slater Effects of Proton and Combined Proton/Photon Beam Radiation on Pulmonary Function in Patients With Resectable but Medically Inoperable Non-small Cell Lung Cancer Chest, December 1, 2001; 120(6): 1803 - 1810. [Abstract] [Full Text] [PDF]
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