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* From the Department of Radiation Oncology (Drs. Timmerman and Papiez, and Ms. Likes and Ms. DesRosiers) and Division of Pulmonology (Dr. Williams), Indiana University School of Medicine, Indianapolis, IN; and the Department of Radiation Oncology (Dr. McGarry and Ms. Frost), Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN.
Correspondence to: Robert D. Timmerman, MD, Department of Radiation Oncology, Indiana University School of Medicine, 535 Barnhill Dr, RT041, Indianapolis, IN 46202; e-mail: rtimmerm{at}iupui.edu
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Abstract |
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Patients and methods: Eligible patients included those with clinically staged T1 or T2 (tumor size, 
7 cm) N0M0 biopsy confirmed NSCLC. All patients had comorbid medical problems that precluded thoracotomy. The median age was 75 years, and the median Karnofsky performance status was 80. ESR was administered in three separate fractions over 2 weeks. Three to five patients were treated within each dose cohort starting at 800 cGy per fraction (total, 2,400 cGy) followed by successive dose escalations of 200 cGy per fraction (total increase per cohort, 600 cGy). Waiting periods occurred between dose cohorts to observe toxicity. Patients with T1 vs T2 tumors underwent separate independent dose escalations.
Results: A total of 37 patients were enrolled since February 2000. One patient experienced grade 3 pneumonitis, and another patient had grade 3 hypoxia. For the entire population, there was no appreciable decline in cardiopulmonary function as measured by symptoms, physical examination, need for oxygen supplementation, pulmonary function testing, arterial blood gas determinations, or regular chest imaging. Both T-stage groups ultimately reached and tolerated 2,000 cGy per fraction for three fractions (total, 6,000 cGy). The maximum tolerated dose for this therapy in either T-stage group has yet to be reached. Tumors responded to treatment in 87% of patients (complete response, 27%). After a median follow-up period of 15.2 months, six patients experienced local failure, all of whom had received doses of < 1,800 cGy per fraction.
Conclusions: Very high radiation dose treatments were tolerated in this population of medically inoperable patients with stage I NSCLC using ESR techniques.
Key Words: lung neoplasms • non-small cell lung carcinoma • radioablation • radiotherapy • stereotactic
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Introduction |
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TOPAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients deemed medically inoperable have been treated with nonsurgical therapies, such as standard fractionated radiotherapy (RT), while many patients have been observed who received no tumor therapy. While some patients succumb to their comorbid illnesses, many of these patients will die of progressive lung carcinoma. McGarry et al4 reviewed outcomes in 75 patients at our institution who had received no specific cancer therapy for stage I NSCLC, and the cause of death was progressive cancer in 53% of cases.4
Primary RT for early-stage NSCLC is considered to be reasonable nonsurgical therapy for such patients, with reported 5-year survival rates ranging from 10 to 30%.5 6 7 8 9 The standard approach involves administering an approximate dose of 4,500 to 6,600 cGy in fractions of 180 to 200 cGy. Several studies8 9 10 11 12 have reported a benefit to dose escalation, suggesting a dose-response relationship in both survival and local control in these patients. A review of 156 medically inoperable patients with stage I NSCLC at Duke University between 1980 and 1995 demonstrated a 5-year, cause-specific survival rate of 32% with RT alone. Improved survival was significantly correlated with achieving local control and approached significance for higher RT doses (p = 0.07).11 Early-stage NSCLC is not inherently a systemic disease from diagnosis. It is possible that superior local control with improved RT techniques could translate to a survival benefit for medically inoperable patients with stage I NSCLC.
Historically, RT fields for early-stage NSCLC encompassed the primary tumor and regional lymphatics in the ipsilateral hilum and mediastinum. This "prophylactic" treatment was based on the identified risk of occult nodal involvement from surgical series ranging up to 20%, and surgical data indicating better control with more extensive resections.13 However, large RT fields are potentially poorly tolerated in this population of patients with limited pulmonary reserves.14 More recent retrospective experiences15 16 17 18 have demonstrated similar survival results with fields limited to the primary tumor or gross disease alone, compared to fields including prophylactic treatment to lymph node chains. In a report from the Netherlands,17 limited "postage-stamp" fields were treated using hypofractionated RT (ie, 4,800 cGy in 400-cGy fractions) with reported 3-year overall and disease-specific survival rates of 42% and 76%, respectively.
Extracranial stereotactic radioablation (ESR), which utilizes elements of three-dimensional conformal therapy in addition to stereotactic targeting, incorporates a variety of systems for decreasing the effects of lung and other organ movement that would otherwise translate into target motion. These systems allow the dramatic reduction of treatment volumes facilitating hypofractionation with markedly increased daily doses and significantly reduced overall treatment times. ESR has been used clinically to treat metastatic tumors in the liver, lung, and retroperitoneum with local tumor progression rates 10 to 20%.19 20 21 22 23 24 25 26
The aforementioned data would imply that stage I NSCLC could be better controlled with higher biologically damaging doses of RT, perhaps resulting in improved survival. In addition, the patient population with medically inoperable stage I NSCLC may be significantly harmed by large-volume RT, which is a good rationale for a prudent reduction in treatment volume. ESR is a technique intended to allow dose escalation through significant reduction in high-dose treatment volume. Therefore, we set out to formally test this emerging technology in a prospective fashion first by conducting a phase I study to characterize toxicity, while moving toward a biologically more potent dose of ESR in this patient population.
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Patients and Methods |
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7 cm. A histologic confirmation of cancer, by either biopsy or cytology, was required. The following primary cancer types were eligible: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, bronchioloalveolar cell carcinoma, or NSCLC (not otherwise specified).
All patients were required to be considered medically inoperable. As such, it was required that the primary tumor be deemed technically resectable by an experienced thoracic cancer clinician with a reasonable possibility of obtaining a gross total resection with negative margins (defined as a potentially curative resection [PCR]). However, for study entrance the patient should have underlying physiologic medical problems that would prohibit a PCR due to a low probability of tolerating general anesthesia, the operation, the postoperative recovery period, or the removal of the adjacent functioning lung. Our institution’s "cutoff" guidelines regarding the feasibility of surgical resection of NSCLC were used for the trial and included the following: baseline FEV1, < 40% predicted; likely postoperative FEV1, < 30% predicted; severely reduced diffusion capacity, < 40% predicted; baseline hypoxemia (ie, 70 mm Hg [a relative contraindication]) and/or hypercapnia (ie, > 50 mm Hg), and exercise oxygen consumption, < 50% predicted. Patients who refused a PCR due to preference, ideology, emotional or psychological issues, mental illness, or inability to give consent for the PCR, and who had no specific accepted medical contraindications for the PCR, were not eligible.
A history of previous lung RT or mediastinal RT excluded patients from the trial. It was required that there be no plans for further concomitant or adjuvant antineoplastic therapy (including chemotherapy or fractionated RT) while on the protocol except at disease progression. Patients with active systemic, pulmonary, or pericardial infection were not eligible. Pregnant or lactating women were not eligible. Patients were required to be at least 18 years old and have a Karnofsky performance status of 
60 in order to be enrolled into the trial.
Pretreatment Assessment and Follow-up Studies
The following evaluations were performed prior to treatment, at 4 to 6 weeks post treatment, and every 3 months thereafter: (1) physical examination; (2) weight and performance status assessment; (3) pulmonary function testing, including measurement of arterial blood gases, spirometry, volumes, and diffusing capacity of the lung for carbon monoxide (DLCO); and (4) either chest radiograph (CXR) or CT scan of the chest and upper abdomen. Although not specifically required by the protocol, all but the first four patients enrolled underwent a fluorodeoxyglucose positron emission tomography (PET) scan prior to treatment as part of staging. The tumor response for follow-up evaluation was defined as being complete if all abnormalities that were anatomically related to the tumor disappeared after treatment, and partial if the maximum dimension of these abnormalities decrease by 50%. Local tumor recurrence was defined as progressive CT scan soft-tissue abnormalities between successive CT scans that corresponded to avid areas on the PET scan. Biopsies were not required to confirm the recurrence of disease. The timing of recurrence was scored at the time that progressive CT scan abnormalities were first noted. Metastatic recurrence was defined as including both regional nodal recurrence (ie, outside of the planning target volume [PTV]) and disseminated systemic metastases.
Immobilization, Targeting, and Dosimetry
All patients were immobilized in a stereotactic body frame (Elekta Oncology; Norcross, GA) that employs a rigid frame and vacuum pillow to make a large contact surface area on three sides of the patient. The immobilization system includes an abdominal compression device that limits the ability of the patient’s diaphragm to move caudally, thereby limiting the respiratory motion of the target. Patients are repositioned in this system using two tattoo marks on the sternum and bilateral tibial tattoo marks that are all referenced to the frame. The accuracy and reproducibility of this specific frame system and other similar frames has been described in previous reports.27
28
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The patients underwent contrast-enhanced, treatment-planning CT scans in the stereotactic frame with inhibition of respiratory motion using abdominal compression. Three-dimensional reconstructions of patient outlines and anatomy for treatment planning were drawn from the CT scan images, which were obtained every 2 to 5 mm. All image sets included the stereotactic fiducial markers for stereotactic targeting and isocenter localization. The gross tumor volume (GTV) was identified on each axial CT scan slice using pulmonary windowing. Only solid tumor and ground glass density were targeted. Atelectasis was not targeted. The clinical target volume was identical to the GTV as no prophylactic treatment was allowed. Although PET scanning was performed as part of staging for nearly all of the patients, the PET scan images were not used in the design of the GTV or clinical target volume. The PTV, which includes setup uncertainty, was designed from the GTV by enlarging the volume 0.5 cm in the axial plane and 1.0 cm in the cranial-caudal plane in all directions. These margins have been documented in previously published methods articles27 28 29 30 to account for the setup uncertainties for this specific immobilization system. The geometric center of mass of the PTV was used to locate the isocenter of the treatment. Stereotactic cartesian coordinates of the isocenter were measured from the fiducial markers on the frame. These isocenter coordinates that were identified on the frame were used to set up the patient for each subsequent treatment.
Treatment planning was conducted (RenderPlan 3-D planning system; Elekta Oncology), and a total of seven noncoplanar, nonopposing beams were used to deliver a dose to the PTV for each patient. The beam apertures were drawn to just encompass the PTV defined above (ie, no margin). Forward-planning intensity modulation was used to create parabolic dose profiles across each beam in an effort to deliver higher central tumor dose in regions of hypoxia with steeper falloff gradients to normal tissue.28 33 Beam intensities were manipulated to deliver roughly equal absolute dose to the isocenter from each beam. In all cases, 95% of the PTV was covered by the 80% prescription isodose volume. Hot spots (ie, > 80% isodose) occurred solely within the GTV. Beam angles were directed to ensure that no point along the spinal cord received > 600 cGy in a single treatment. The intensity modulation was achieved by milling beam attenuation compensators for each field. Carefully cut and verified focus blocks for each field were created to custom shape the fields at treatment.
Dose-Limiting Toxicity
The primary end point of the phase I study was to determine the toxicity profile in the context of dose escalation of the experimental therapy for the study patient population. From the onset, the protocol defined a maximum tolerated dose (MTD) based on specific dose-limiting toxicity (DLT) criteria, beyond which the dose escalation would not be allowed. The protocol aimed to escalate the dose to a substantial dose (limited by the MTD) thought to be biologically potent enough to significantly disrupt tumor clonogenicity. The protocol allowed dose escalation to end if the investigators became uncomfortable with further dose escalation (ie, at very high doses) within the study design of the protocol. Toxicity was graded using the National Cancer Institute common toxicity criteria.34
DLT was considered to be any grade 3 pulmonary, esophageal, cardiac, or pericardial toxicity, or any grade 4 toxicity that was ascribed to the protocol treatment.
Dosage and Dose Escalation
The starting dose for the trial was 800 cGy, prescribed to the 80% isodose volume per fraction for a total of three fractions (total dose, 2,400 cGy). According to protocol guidelines, the fractions were to be separated by a minimum of 2 days and a maximum of 8 days, but no more than two fractions per week.
Subsequent cohorts of patients on the trial received an additional 200 cGy per treatment (total, 600 cGy per increment) at each dose-escalation step. A minimum of three patients was accrued for each specified dose level. If two or more of the patients experienced DLT, as defined above, the MTD would be considered to have been exceeded. If DLT was experienced in one of the three patients, an additional two patients would be accrued at that dose level. If no additional DLT was noted in the additional two patients within a minimum observation period (ie, four of five patients free of severe toxicity), dose escalation to the next dose level would proceed. Otherwise, if one or more of the additional two patients experienced DLT, the MTD would be considered to have been exceeded.
The minimum observation period for toxicity was incorporated into the trial. If the first patient enrolled at a given dose level did not experience DLT, the second patient was required to have completed a minimum of 4 weeks of follow-up observation without DLT prior to the enrollment of the third patient. The third patient was required to have completed a minimum of 2 weeks of follow-up observation without experiencing DLT before the next cohort was initiated. Starting at 1,400 cGy per fraction, the study was revised, creating two separate dose escalation groups based on tumor size (ie, 3 cm vs > 3 cm [or stage T1 vs stage T2]). Each of the groups underwent an independent dose escalation according to the guidelines stated above with the same waiting periods.
Statistical Analysis
Follow-up was determined from the date of the last stereotactic treatment, not from the date of diagnosis, to determine the median follow-up and Kaplan-Meier time-to-event estimates35
of survival data. Paired data sets from pulmonary function tests prior to and after the treatment were compared using a paired two-tailed t test. Statistical significance was defined as a p value of < 0.05.
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Results |
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Cardiopulmonary Toxicity
Cardiac toxicity, which manifested as an asymptomatic pericardial effusion seen on a CT scan, occurred in one patient. Symptoms of radiation pneumonitis that were followed up prospectively included fatigue, fever, shortness of breath, nonproductive cough, and pulmonary infiltrates seen on a CXR. Fatigue was reported in every patient, and fever was reported in none. Six patients reported worsening shortness of breath and nonproductive cough, and were treated with steroids, inhalers, cough medicines, and oxygen therapy. One patient had worsening pulmonary infiltration seen on CXRs or CT scans. Worsening fibrotic changes appeared on CXRs or CT scans in 25 patients. These fibrotic changes were generally limited to a small fraction of total lung volume, extending peripherally starting at the location of the treated tumor.
Pulmonary function testing at baseline prior to treatment is shown for the population in Table 2 . After treatment, a total of 10 patients had a decline of at least 10% predicted in at least one measured value of pulmonary function (ie, FEV1, FVC, DLCO, or PO2), usually within 6 weeks of treatment. The conditions of the majority of these patients subsequently improved, with seven of them returning to their pretreatment baseline levels. Figure 1 shows the percentage change in pulmonary function test results at various intervals after follow-up for the entire cohort. A percentage change of zero indicates no change from baseline, a positive value indicates an improvement, and a negative value indicates a decline. Figure 1 reveals that DLCO and PO2 demonstrate a declining trend immediately after treatment but return to baseline by 3 to 6 months after treatment. None of the changes in pulmonary function were statistically significant for the population.
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DLT and MTD
DLT as defined by the study criteria was observed in two patients on the trial. For stage T1 tumors, a single patient treated at levels of 1,600 cGy per fraction experienced grade 3 hypoxemia. The patient was treated as an outpatient with oxygen and bronchodilator therapy for 2 weeks and made a full recovery to his baseline status. For stage T2 tumors, a single patient treated at 1,400 cGy per fraction experienced symptomatic radiation pneumonitis requiring hospitalization. He was treated with oxygen, bronchodilators, IV steroids, and, subsequently, oral steroids with significant improvement in his pulmonary status. Figure 2
shows the pattern of pneumonitis on CT for this patient. Additional patients were enrolled and treated for each of these levels without experiencing DLT. Doses escalated to very high levels, beyond any previously published experience. The investigators elected to suspend the trial in its current form after the dose level of 2,000 cGy per fraction. As such, while the trial escalated the dose to a high biological potency as intended, the MTD of either T-stage cohort in the trial was never reached.
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Response
The tumors of nearly all patients responded to therapy. The extent of tumor response was difficult to measure in many cases due to the appearance of postradiation fibrotic changes (described earlier). In cases in which postradiation fibrotic changes could not be distinguished from residual tumor, it was assumed that the response was incomplete. With this caveat, the partial and complete response rates were 60% and 27%, respectively. The percentage of complete responses for patients receiving doses of < 1,600 cGy per fraction was not appreciably different from those who received doses of 1,600 cGy per fraction. Figure 3
shows an example of a favorable response.
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1,800 cGy per fraction times three fractions. Seven patients died of what the investigators determined to be comorbid medical problems without cancer recurrence. Of these seven patients, five died of noncardiopulmonary dysfunction (ie, broken hip, prostate cancer, renal failure due to outlet obstruction, renal failure due to hepatorenal syndrome, and pancreatic cancer). The other two died of cardiopulmonary problems that were thought by the investigators to be unrelated to the therapy (ie, lower extremity deep venous thrombosis with pulmonary embolism and progressive idiopathic pulmonary fibrosis diagnosed prior to the protocol treatment). No autopsy was performed to verify the actual cause of death in any patient. The Kaplan-Meier disease-free survival rate and the overall survival rate at the median time of follow-up (15.2 months) were 50% and 64%, respectively. |
Discussion |
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Models predicting radiation-induced pulmonary toxicity have used conventional lung fields treated with standard fractionated radiation as their input data37 38 and, typically, have described pulmonary toxicity in relation to the volume of lung receiving or exceeding a specified dose. Prescription dose volumes in conventional fractionated RT are generally much larger than those for the ESR techniques described in this article. The geometric dose distribution for conventional RT is more polygonal, as opposed to spherical or stellate for ESR. Furthermore, the biological effect on both normal tissue and tumor tissue after treatment with very large doses per fraction would be expected to be much different than that observed with standard fractionated radiation. Dose-conversion models, such as the linear quadratic model proposed by Douglas and Fowler,39 may be applicable to the lower dose ranges used in this study, but will likely overpredict the potency of the therapy at high doses per fraction. In addition, these models do not directly account for an anatomic location of injury as it relates to overall organ dysfunction.
Radiation pneumonitis is typically a subacute (weeks to months from therapy) inflammation of the end bronchioles and alveoli. While grade 3 or higher radiation pneumonitis was predicted to be the most likely DLT in this patient population treated with ESR, only one patient in the trial experienced such severe pneumonitis. A few other patients had grade 2 pneumonitis, but overall the incidence of any pneumonitis was unexpectedly low. The patients who experienced pneumonitis with ESR presented relatively "early" after radiation (ie, as soon as 3 weeks and always within 6 weeks). The pattern of the infiltrates did not assume the regular polygonal distribution seen in conventionally fractionated radiation corresponding to the field edges, but rather to a stellate distribution around the tumor target corresponding to the dose falloff. Prompt management with steroid therapy and supportive care appears to reverse the condition, not unlike the situation with fractionated radiation.
While radiation pneumonitis appeared less frequently in this trial than might have been predicted, radiation damage to the lung was still apparent. Repeat imaging studies (ie, CT scans and CXRs) in the majority of patients revealed new fibrotic changes posttherapy. These changes typically assumed a wedge or triangular shape, with the apex occurring at the site of the treated tumor and extending laterally toward the chest wall. In all likelihood, these imaging changes correspond to the collapse of the lung distal to the airway passages near the treated tumor. These airway passages (bronchioles) would likely be severely damaged by the ESR treatment with sloughing of epithelium, stenosis, and blocking of the downstream airway. Perhaps the resulting loss of functioning pulmonary tissue explains the measured decline in pulmonary function test results (particularly DLCO and PO2) for some of the treated patients. However, for our patients with mostly peripheral lesions, the loss of lung did not correspond to significant respiratory compromise. According to the radiobiological models describing injury to various architectural arrangements of normal tissues described by Wolbarst et al40 and Yeas and Kalend,41 however, the same treatment given to central lesions near serially functioning major bronchi could result in significant respiratory toxicity.
With a median follow-up duration of only 15.2 months, late radiation toxicity cannot be fully assessed at this point in this trial. Late radiation toxicity after conventionally fractionated RT for lung cancer includes pulmonary fibrosis, bronchial and esophageal stenosis, and pericardial thickening. All of these conditions may have a significant detrimental impact on cardiopulmonary reserve. These aspects are of particular concern in our study population of patients who were deemed medically inoperable due to preexisting health problems that were mostly associated with tobacco-related diseases. Prior to treatment, about half of the patients enrolled into this trial continued to smoke. Although not carefully scrutinized by obtaining serum nicotine levels, only four or five of the patients continued to smoke cigarettes after receiving treatment. We attribute this partly to a rigorous smoking-cessation program that was combined with ongoing counseling. Whether the relatively low rate of acute and subacute toxicity that was observed may have been facilitated with a higher than average rate of smoking cessation is unclear, but it does appear that an opportunity to convince patients to quit smoking exists in association with this treatment and that it should be actively pursued.
Intuitively, both toxicity and local failure after a given dose of radiation would be expected to be greater for treating larger T2 tumors compared to T1 tumors. In our study, T1 and T2 tumors were treated within separate dose-escalation groups. We did not observe any obvious differences in toxicity or local failure between the T-stage groups. However, our study was neither designed nor powered to detect such differences. While it is likely that larger tumors will both be more difficult to control and that patients with such tumors will be at higher risk for treatment-related toxicity, further study will be required to quantify any difference.
In this prospective trial, ESR techniques have been shown to allow the delivery of very high, biologically potent doses of radiation to small, medium, and even some large NSCLC primary tumor targets in frail patients. The occurrence of acute and subacute toxicity has been limited and manageable. Further follow-up from this trial and others will be required to assess for late toxicity, such as symptomatic pulmonary fibrosis, and for survival characteristics. These ESR treatments require careful patient selection, reliable immobilization, efforts to reduce the effect of internal organ motion, rigorous treatment planning, and carefully conducted treatment sessions under the direct supervision of a physician. Whether these treatments can be performed on a wide scale with acceptable quality assurance remains to be seen. Using this phase I study as the basis for dose selection, the Radiation Therapy Oncology Group is currently considering moving forward with a limited institution phase II study of ESR in the same patient population. In the meantime, our group at Indiana University is treating patients with T1 tumors in a phase II study using the highest dose achieved in this phase I study. Since local control is lower for T2 tumors compared to T1 tumors for fractionated radiation, and since the MTD was not reached in this trial, we are continuing with a modified phase I study for patients with T2 tumors using radiation doses of 2,200 cGy per fraction times three fractions.
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Acknowledgements |
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Footnotes |
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The Elekta Oncology Corporation, Norcross, GA, loaned a Stereotactic Body Frame for carrying out treatments done as part of this protocol at our Veterans Affairs hospital.
Received for publication September 20, 2002. Accepted for publication March 26, 2003.
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