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Excessive Toxicity When Treating Central Tumors in a Phase II Study of Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Lung Cancer

Robert Timmerman, Ronald McGarry, Constantin Yiannoutsos, Lech Papiez, Kathy Tudor, Jill DeLuca, Marvene Ewing, Ramzi Abdulrahman, Colleen DesRosiers, Mark Williams, James Fletcher

From the Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX; and the Department of Radiation Oncology, Department of Medicine (Biostatistics), Division of Pulmonology, and Department of Radiology (Nuclear Medicine), Indiana University School of Medicine, Indianapolis, IN

Address reprint requests to Robert Timmerman, MD, Department of Radiation Oncology, The University of Texas Southwestern Medical Center, 5801 Forest Park Rd, Dallas, TX 75390-9183; email: robert.timmerman{at}utsouthwestern.edu

	ABSTRACT

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PURPOSE: Surgical resection is standard therapy in stage I non–small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population.

PATIENTS AND METHODS: Eligible patients included clinically staged T1 or T2 ( 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks.

RESULTS: All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have died as a result of cancer (n = 5), treatment (n = 6), or comorbid illnesses (n = 17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in a total of 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors.

CONCLUSION: High rates of local control are achieved with this SBRT regimen in medically inoperable patients with stage I NSCLC. Both local recurrence and toxicity occur late after this treatment. This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.

	INTRODUCTION

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Surgical resection of stage I (T1-2, N0) non–small-cell lung cancer (NSCLC) results in 5-year survival rates of approximately 60% to 70%^1-3 and remains the treatment of choice for this population. Unfortunately, some patients with early-stage NSCLC are unable to tolerate the rigors of surgery or the postoperative recovery period due to lack of adequate respiratory reserve, cardiac dysfunction, diabetes mellitus, vascular disease, general frailty, or other comorbidities. More limited resections can be offered (segmentectomies, wedge resections, and so on), but these are associated with poorer outcome in prospective trials.⁴ Primary radiation therapy (RT) for early-stage NSCLC is considered reasonable nonsurgical therapy for such patients, with reported 5-year survival rates ranging from 10% to 30%.^5-12 The standard approach involves administering approximately 45 to 66 Gy total in 1.8- to 2.0-Gy fractions. However, local control with this approach has been poor, with 55% to 70% of patients experiencing local relapse.^5-12

Stereotactic body radiation therapy (SBRT) uses elements of three-dimensional conformal therapy in addition to stereotactic targeting while incorporating a variety of systems for decreasing the effects of lung and other organ movement that would otherwise translate into target motion.^13-17 This approach allows dramatic reduction of treatment volumes, facilitating hypofractionation with markedly increased daily doses and significantly reduced overall treatment time. SBRT has been used clinically to treat metastatic and primary tumors in the liver, lung, and retroperitoneum with impressive local tumor progression rates but limited follow-up.^18-33

Previously, we reported the results of a formal phase I dose escalation toxicity trial using SBRT in patients with medically inoperable early-stage lung cancer.^34,35 We showed that when using a convenient three-fraction regimen of SBRT, the peripheral tumor dose could be escalated to 60 Gy total for T1 tumors and 66 Gy total for T2 tumors (< 7 cm) without exceeding the maximum-tolerated dose.

Building on our experience, this phase II trial was designed to treat a larger population of uniformly selected patients using the biologically potent doses shown to be reasonably safe in our phase I trial. The goal of this phase II trial was to confirm the phase I toxicity predictions and ascertain a preliminary view of efficacy to determine whether the new therapy is worthy of additional investigation for treating patients with medically inoperable early-stage NSCLC.

	PATIENTS AND METHODS

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Eligibility
Before enrollment of any patients, the protocol and consent form were reviewed and approved by the Indiana University (Indianapolis, IN) and Richard L. Roudebush Veterans Administration Medical Center (Indianapolis, IN) institutional review boards. All patients were required to undergo appropriate staging studies identifying them as American Joint Committee on Cancer stage I (T1 or T2 7 cm, N0, M0) NSCLC. Histologic confirmation of cancer was required by either biopsy or cytology. The following primary cancer types were eligible: squamous cell carcinoma, adenocarcinoma, large-cell carcinoma, bronchioloalveolar cell carcinoma, or NSCLC (not otherwise specified). There was no restriction for enrollment relating to the location of the lesion.

All patients were required to be considered medically inoperable. Our institution's cutoff guidelines regarding feasibility of surgical resection of NSCLC were used for the trial and included the following: baseline forced expiratory volume at 1 second (FEV₁) less than 40% predicted, likely postoperative FEV₁ less than 30% predicted, severely reduced diffusion capacity less than 40% predicted, baseline hypoxemia ( 70 mmHg) and/or hypercapnia (> 50 mmHg) and exercise oxygen consumption less than 50% predicted. A history of previous lung or mediastinal RT excluded patients from the trial. No planned additional concomitant or adjuvant antineoplastic therapy (including chemotherapy or fractionated RT) was allowed while patients received the protocol except at disease progression. Patients were required to be at least 18 years old and have a Karnofsky performance status of 60 to qualify for trial enrollment.

Pretreatment Assessment and Follow-Up Studies
The following evaluations were performed before treatment, at 4 to 6 weeks post-treatment, and every 3 months thereafter: physical examination; weight and performance status assessment; pulmonary function testing including arterial blood gases, spirometry, volumes, and diffusing capacity; and either chest x-ray or computed tomography (CT) of the chest and upper abdomen. All enrolled patients had a fluorodeoxyglucose positron emission tomography (PET) scan done before treatment as part of staging. Tumor response for follow-up evaluation was defined as complete if the tumor disappeared after treatment, and as partial if the maximum dimension of these abnormalities decreases by 50% or more. Local tumor recurrence was defined as progressive CT soft tissue abnormalities between successive CT scans that corresponded to avid areas on PET (standard uptake values similar to pretreatment levels) or post-treatment biopsy showing carcinoma. Timing of recurrence was scored at the time progressive CT abnormalities were first noted. Disseminated recurrence was defined to include both regional nodal recurrence (outside of the planning treatment volume [PTV] defined in Immobilization, Targeting, and Dosimetry) and disseminated systemic metastases.

Immobilization, Targeting, and Dosimetry
Our techniques for immobilization and planning have been described in previous reports.^17,34,35 All patients were immobilized in the Stereotactic Body Frame (Elekta Oncology, Norcross, GA), which uses a rigid frame and vacuum pillow making a large surface area contact on three sides of the patient. The immobilization system includes an abdominal compression device that limits the ability of the patient's diaphragm from moving caudally, thereby limiting respiratory motion of the target.

The patients underwent contrast-enhanced treatment planning CT scans in the stereotactic frame. The gross tumor volume (GTV) was identified on each axial CT slice using pulmonary windowing. Only solid tumor and ground glass density were targeted. The clinical target volume was identical to the GTV. Although PET scanning was performed as part of staging, the PET scan images were not used for targeting. The PTV, which includes setup uncertainty and residual target motion, 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. An isocenter was placed at the geometric center of mass of the PTV. Stereotactic Cartesian coordinates of the isocenter were measured from the fiducials on the frame. These isocenter coordinates identified on the frame were used to set up the patient for each subsequent treatment.

Treatment planning was conducted on the RenderPlan 3-D (Elekta Oncology) planning system. A total of 10 to 12 noncoplanar, nonopposing beams were used to deliver the dose to the PTV for each patient. The beam apertures were drawn to encompass just the PTV defined (no margin). Beam weights were manipulated to deliver roughly equal absolute dose to isocenter from each beam. Lung or bone tissue density corrections were not used for planning. The treatment dose was prescribed to the margin of the PTV, which corresponded to the 80% of isocenter dose volume. In all cases, 95% of the PTV was covered by this 80% prescription isodose volume. Beam angles were directed to ensure that no point along the spinal cord received more than 6 Gy in a single treatment.

Toxicity
Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0.³⁶ Given that the trial was carried out under the guidelines of a National Institutes of Health Quick Trials grant, an independent Data Safety Monitoring Committee was formed within our institution to review control and toxicity data. This committee, consisting of a medical oncologist, radiation oncologist, pulmonary physician, and statistician, reviewed all unexpected adverse events experienced by treated patients to make final assignment regarding relation to treatment and toxicity grade.

SBRT Dosage
The final assignment of T stage status was made based on the CT for treatment planning rather than on the pretreatment diagnostic CTs done for routine staging. Patients with T1 tumors were assigned a dose to the periphery of the PTV of 20 Gy per fraction x 3 (60 Gy total), whereas patients with T2 tumors were treated at 22 Gy per fraction x 3 (66 Gy total).

Statistical Analysis
Follow-up was determined from the date of the last stereotactic treatment, rather than from the date of diagnosis, to determine median follow-up and Kaplan-Meier time-to-event estimates³⁷ of outcome data. Two-sided tests were used for statistical significance assigned to correspond to .05 or less.

	RESULTS

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Seventy patients (34 men and 36 women) with a median age of 70 years (range, 51 to 86 years) were enrolled onto the study between January 2002 and July 2004. Patient characteristics are listed in Table 1. The most common characteristic making a patient medically inoperable was a baseline FEV₁ less than 40% predicted, which was identified in 43 patients. Other medical problems making the patients poor surgical candidates included severe heart disease (14 patients) and severely impaired diffusing capacity (six patients). Twenty three of the patients enrolled required supplemental home oxygen before the treatment. All but one patient enrolled had a greater than 20 pack-year smoking history and 18 admitted to ongoing cigarette smoking after the treatment. Pretreatment pulmonary function characteristics are shown in Table 2.

Response and Imaging Changes
The 3-month post-treatment major response rate (complete and partial) was 60%. The remaining 40% of patients had stable disease at 3 months. After 3 months, 17 patients had local enlargement of CT radiographic abnormalities in the vicinity of the treated tumor, prompting a PET scan or biopsy.

Disease Control and Survival
Ten patients have had recurrence of cancer. Tumors recurred in the local site alone in three patients, locally and disseminated tumors recurred in zero patients, and disseminated tumors recurred only in seven patients. In the three patients with local recurrence, time to recurrence was 9, 16, and 33 months, respectively, from treatment. Figure 1 shows Kaplan-Meier local tumor control. The 24-month local tumor control was 95%. A total of 28 people have died. Seventeen patients died as a result of what the data safety monitoring committee determined to be comorbid medical problems and not as a result of cancer recurrence or toxicity. Of these seventeen patients, 10 died as a result of noncardiopulmonary dysfunction (eg, kidney problems, cerebrovascular disease, second primary malignancies, esophageal varices, and so on), four died as a result of cardiac problems, and three died as a result of respiratory problems determined to be unrelated to the treatment. Eleven patients died as a result of lung cancer (five patients) or lung cancer treatment (six patients). The Kaplan-Meier overall survival curve is shown in Figure 2, which indicates a median survival of 32.6 months.

View larger version (5K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of time from treatment until local failure (percent with local control).

View larger version (5K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of overall survival (OS).

Eight patients were identified as having grade 3 to 4 toxicity resulting from the SBRT treatment. These grade 3 to 4 toxicities included decline in pulmonary function tests, pneumonias, pleural effusions, apnea, and skin reaction. Among these eight patients, the time from treatment to toxicity ranged from 1.1 to 25.1 months from completion of therapy (median, 7.6 months).

The data safety monitoring committee believed the SBRT treatment may have contributed to the events leading to the death of six patients (grade 5 toxicity). These deaths as a result of toxicity occurred at 0.6, 3.9, 12.1, 12.8, 13.8, and 19.5 months after SBRT treatment. Four of these deaths were associated with a bacterial pneumonia, and patients were receiving antibiotics at the time of death. One patient died as a result of complications from a pericardial effusion after treatment of a tumor adjacent to the mediastinum superior to the hilum. One death occurred in a patient who experienced a local recurrence next to the carina previously and subsequently had massive hemoptysis and death at 19.5 months after SBRT. This patient was scored as having died as a result of a treatment complication rather than progressive cancer.

Predictors of Control and Toxicity
Neither univariate nor multivariate analysis was carried out to find predictors of local tumor control, given that only three patients experienced local tumor recurrence.

In relation to overall survival, the following variables were examined: tumor location in the chest, T stage, GTV, histology, laterality, pulmonary function tests, sex, age, cardiac versus pulmonary cause of inoperability, oxygen dependence, performance status at treatment, ongoing smoking, and PTV. There was no factor significantly predicting overall survival in the univariate analysis, although T stage (outcome with T2 was worse), cardiac versus pulmonary cause of inoperability (outcome with cardiac was worse), and FEV₁ (outcome with < 40% predicted was worse) were all significant in a subset of 41 patients with complete data in all fields. In the multivariate analysis, pretreatment oxygen dependence (P = .073) and cardiac dysfunction as reasons for medically inoperable status (P = .045) were both predictors of poorer survival.

In the analysis of patients experiencing high-grade (grade 3 to 5) toxicity, both univariate and multivariate analysis showed that tumor location (hilar/pericentral v peripheral) was a strong predictor of toxicity (P = .004). A schematic diagram of the hilar/pericentral region of the lungs is shown in Figure 3. As demonstrated in Figure 4, patients with peripheral tumor locations had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with perihilar/central tumors. Patients with perihilar/central tumors have an 11-fold increased risk of experiencing severe toxicity compared with more peripheral locations. In addition, four of the six deaths as a result of toxicity observed in the study were in patients with perihilar/central tumors. Although not as strong as tumor location, on multivariate analysis in 53 patients with complete data sets in all fields, the size of the GTV was a significant predictor of grade 3 to 5 toxicity. Tumors with GTV volume of more than 10 mL had an eight-fold risk of high-grade toxicity compared with smaller tumors (P = .017).

View larger version (36K): [in this window] [in a new window]   Fig 3. Diagram of lung showing definition of the perihilar/central tumor region. In the ongoing Radiation Therapy Oncology Group protocols, this area is referred to as the zone of the proximal bronchial tree.

View larger version (6K): [in this window] [in a new window]   Fig 4. Kaplan-Meier plot of time from treatment until grade 3 to 5 treatment related toxicity comparing patients with tumors in the central (perihilar and central mediastinal) regions from those with more peripheral tumors.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

In our previous phase I study, we showed that a surprisingly large dose per fraction and total dose could be delivered to a frail population of patients with early-stage lung cancer.^34,35 This phase II trial builds on that experience by treating larger numbers of similarly selected patients at the most potent tolerable doses from our phase I experience. As shown clearly by this experience, negative events, including high-grade toxicity and local tumor recurrence, occur after long durations after therapy. These late negative events would be missed easily by short-duration, incomplete, or less thorough follow-up.

As an example, this report describes 14 patients who experienced grade 3 to 5 toxicity. However, this prospective trial did not define a limit on the period of observation of toxicity related to therapy. As observed, most of these high-grade toxicities were recorded many months, sometimes years, after therapy was complete. In a population prone to medical problems related to their other serious conditions such as emphysema and heart disease, hospitalizations or even deaths occurring more than a year after therapy might not be attributed to therapy. The application of the data safety monitoring committee carried out in this trial as required by the National Institutes of Health funding mechanism served to scrutinize all adverse events carefully and potentially assign them as possibly related to therapy in many cases.

This trial, along with the previously reported phase I trial, constitutes the basis for the ongoing multicenter Radiation Therapy Oncology Group (RTOG) trial 0236. By the time that trial was designed, concern that SBRT treatments with the 60 to 66 Gy in three fractions dose level might be too toxic for hilar/pericentral was already expressed by our group at symposia and meetings. The formal analysis of this trial confirms that observation. Although the RTOG data are still immature, we are optimistic that excluding the zone of the proximal bronchial tree might allow avoidance of high-grade toxicity.

The SBRT regimen used in this protocol showed a remarkably high rate of tumor local control of 95% at 2 years. This rate of local control, measured on a prospective and controlled trial, rivals the best surgical local control rates in operable patients. Furthermore, it appears superior to local control after wedge resections commonly done in patients with compromised pulmonary function. This was accomplished via an outpatient and noninvasive treatment carried out in a convenient three-fraction regimen. Still, readers should be cautioned that these results are preliminary and more follow-up for both control and toxicity is required. In operable patients with early-stage lung cancer, anatomic dissection with lobectomy or pneumonectomy remains the standard therapy.

Although these data are promising, they reflect an initial report that was written mainly to warn clinicians of the excessive toxicities seen in patients with central lesion locations. Indeed, until the results mature, caution should be taken in interpretation of long-term toxicity and efficacy as reported in this initial report. Several other trials are under development in the RTOG, including trials with different fractionation for central tumors, the addition of systemic therapy, and a phase II trial in operable patients. The conclusion that SBRT is prone to late effects requires that these patients be observed longer to characterize accurately local control, toxicity, and survival.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Robert Timmerman National Institutes of Health (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Robert Timmerman, Constantin Yiannoutsos, Lech Papiez, Mark Williams, James Fletcher Administrative support: Mark Williams Provision of study materials or patients: Robert Timmerman, Ronald McGarry, Kathy Tudor, Jill DeLuca, Marvene Ewing, Ramzi Abdulrahman, Colleen DesRosiers, James Fletcher Collection and assembly of data: Robert Timmerman, Lech Papiez, Kathy Tudor, Jill DeLuca, Marvene Ewing, Ramzi Abdulrahman, Colleen DesRosiers, James Fletcher Data analysis and interpretation: Robert Timmerman, Ronald McGarry, Constantin Yiannoutsos, Lech Papiez Manuscript writing: Robert Timmerman Final approval of manuscript: Robert Timmerman, Ronald McGarry, Constantin Yiannoutsos, Lech Papiez, Mark Williams, James Fletcher

 

	NOTES

 
Supported by Grant No. 5R21CA097721-02 from the United States National Institutes of Health.

Presented in an oral format at the Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), Denver, CO, October 16-20, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 25, 2006; accepted August 9, 2006.

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  Suresh Senan, Niels J.A. Haasbeek, Egbert F. Smit, and Frank J. Lagerwaard
  JCO 2007 25: 464 [Full Text]

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