Dose-Intensive Thoracic Radiation Therapy for Patients at High Risk with Early-Stage Non–Small-Cell Lung Cancer

o riginal contribution Dose-Intensive Thoracic Radiation Therapy for Patients at High Risk with Early-Stage Non–Small-Cell Lung Cancer Jeffrey A. Bogart,1 Tracy E. Alpert,1 Mary C. Kilpatrick,1 Bonnie L. Keshler,1 Surjeet S. Pohar,1 Hemangini Shah,1 Elisabeth Dexter,2 Jesse N. Aronowitz3 Abstract Recent studies suggest that radiation therapy (RT) dose escalation in early-stage non–small-cell lung cancer (NSCLC) is feasible when 3-dimensional therapy is used. However, the accompanying prolongation of the treatment course when standard fractionation is used could be suboptimal from a practical and biologic standpoint. We report results of a compressed course of RT for patients with pathologically documented clinical stage 1 NSCLC who were unsuitable for curative surgery because of pulmonary dysfunction or other medical comorbidities. Thirty-one lesions were treated with dose-intensive RT (eg, fraction ≥ 2.25 Gy and nominal total dose ≥ 60 Gy) and have been followed up for ≥ 6 months from the completion of treatment. All patients completed therapy without interruption. Three patients developed grade 3 pulmonary toxicity 1-3 months after therapy. The overall tumor response rate was 88% (35% complete response and 53% partial response), whereas in-field tumor progression was documented for 5 of 31 lesions. Actuarial median survival was 38 months and 3-year overall survival was 60%, and most deaths were secondary to intercurrent disease. Moderately accelerated single daily fractionated RT is feasible for high-risk patients with early-stage NSCLC and merits further investigation. Clinical Lung Cancer, Vol. 6, No. 6, 350-354, 2005

Key words: Conformal radiation therapy, 3-Dimensional therapy, Hypofractionation

Introduction

al lymph nodes).2 The prospects for cure are excellent for fit patients treated with standard surgery (eg, lobectomy), with 5year survival rates generally ranging from 50% to 80% for pathologic stage I disease, but many patients are considered medically inoperable secondary to cardiopulmonary dysfunction and/or other underlying medical comorbidities.3 For example, approximately 25% of patients ≥ 65 years of age with earlystage NSCLC do not undergo surgery.4 There is also reason to believe this population could increase in the coming years given the projected growth in the elderly population and the recent increased use of lung cancer screening.5,6 External-beam radiation therapy (RT) is the most frequently employed alternative therapy for patients with early-stage NSCLC, and widely variable results have been reported following treatment with standard doses of conventionally fractionated thoracic RT (TRT).7 Technologic advances during the past decade, in particular 3-dimensional conformal RT planning, have the potential to shift the therapeutic index for medically

Lung cancer remains the most common cause of cancer death in the United States, and an estimated 91,000 men and 73,000 women will die from lung cancer in 2005.1 According to the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute (NCI), approximately 15% of patients with non–small-cell lung cancer (NSCLC) are diagnosed with localized disease (ie, no evidence of spread to region1Department of Radiation Oncology 2Department of Surgery

SUNY Upstate Medical University, Syracuse, NY 3Department of Radiation Oncology, University of Massachusetts

Medical Center, Worcester, MA Submitted: Mar 25, 2005; Revised: May 4, 2005; Accepted: May 4, 2005 Address for correspondence: Jeffrey A. Bogart, MD, Department of Radiation Oncology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY 13210 Fax: 315-464-5943; e-mail: [email protected]

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inoperable patients through more precise treatment delivery. However, whether the improved tumor targeting provided by conformal RT, on its own, can lead to improved outcomes remains to be seen. For instance, a recent retrospective review from the Netherlands Cancer Institute did not suggest improved outcomes with conformal RT techniques for stage I NSCLC.8 Preliminary results of prospective dose-escalation trials have also been reported and demonstrate that very high doses of externalbeam RT can be delivered with conventional fractionation if the irradiated lung volume is limited.9,10 However, markedly protracting the treatment course may not be an optimal approach for patients with NSCLC, as evidence from prospective trials suggests that the biologic efficacy of RT is diminished with prolongation of the treatment course.11,12 Moreover, these regimens are impractical for many patients at high risk, who typically have substantial medical comorbidities. Thus, a TRT regimen that delivers an intense biologic dose with a limited duration could be of particular interest in this population. We report our institutional experience administering a moderately compressed TRT regimen for clinical stage I NSCLC.

Patients and Methods Patients were eligible for inclusion in this retrospective review if they had pathologically documented clinical stage I NSCLC, were judged to be unsuitable for curative surgery because of pulmonary dysfunction or other medical comorbidities, and received treatment with definitive dose-intensive RT. For the purposes of this study, dose-intensive RT was defined as a minimum radiation fraction of 2.25 Gy and a minimum nominal total dose of 60 Gy. The minimum follow-up was 6 months from the completion of RT. Patients with a history of malignancy were not excluded as long as active disease was not present at the time of diagnosis of lung cancer. Patients who refused surgery but were considered medically operable were not included in this analysis. Since 2002, a prospective trial for medically inoperable NSCLC has been open at our institution, and patients treated in that study are not included in this review. This retrospective review was approved by our institutional review board.

Pretreatment Evaluation A complete history and physical examination of all patients was performed. Pathologic documentation was obtained in all cases via computed tomography (CT)–guided needle biopsy, but bronchoscopy and mediastinoscopy were not routinely performed. Staging evaluation included a posteroanterior (PA) and lateral chest radiograph and a CT scan of the chest and abdomen. Bone and/or CT scans of the brain were obtained only if clinically indicated. Six patients underwent a [18F]fluorodeoxyglucose positron emission tomography examination as part of the staging evaluation. The majority of patients (25 of 29) were evaluated by a thoracic surgeon and were determined to be unsuitable for standard treatment with lobectomy, though surgical evaluation was not mandated for patients with severe preexisting pulmonary dysfunction or other medical comorbidities.

Thoracic Radiation Therapy Planning Patients underwent formal RT simulation in the supine position. Custom immobilization devices, either a low-density foam cradle or vacuum locked bag, were routinely constructed to assist in patient positioning. During simulation, tumor motion was visualized and noted for expansion of the target volume at the time of RT planning. Computed tomography scans with intravenous contrast medium were obtained in the treatment position for development of conformal RT plans. The gross tumor volume (GTV) was outlined on the lung windows of all relevant CT slices. The planning target volume (PTV) typically included the GTV plus 1-1.5 cm but was expanded if tumor motion was noted during simulation. Regional lymph nodes were not targeted. A multifield plan was then devised with the goal of encompassing the PTV within the 95% isodose line while limiting the dose to the surrounding functioning lung and other normal structures. Strict limits were not in place regarding the volume of functioning lung irradiation, though an attempt was made to limit the percentage of total lung volume receiving > 20 Gy (V20) to < 15% in patients treated with RT during the past 3 years.13 The maximum allowed spinal cord dose did not exceed 50 Gy.

Follow-up and Response Measurement Patients and portal radiographs were evaluated weekly during therapy. Subsequent to the completion of therapy, patients were typically evaluated at 3-month intervals in the first year after treatment and at 6-month intervals thereafter. Response evaluation was performed by means of radiography and/or CT of the chest. Additional studies, including formal pulmonary function testing, were obtained as clinically indicated. The criteria for complete response were the disappearance of all disease including signs, symptoms, and radiographic changes related to the tumor. For patients with all disease measurements in 2 dimensions, partial response was defined as a reduction of 50% of the sum of the longest diameters of all measured target lesions without the development of new lesions or enlargement of any existing lesion. Acute radiation-induced toxicity arising in the first 3 months after RT was graded according to the NCI Common Toxicity Criteria, and subsequent toxic effects of therapy were graded according to guidelines set forth by the Radiation Therapy Oncology Group (RTOG).14

Statistical Analysis Kaplan-Meier curves were used to describe overall survival and failure-free survival. Survival time was defined as the time between initiation of TRT and death. Failure-free survival time was computed as the time between initiation of TRT and disease progression or death.

Results Thrity-one clinical stage I NSCLC lesions were irradiated in 29 eligible patients between February 1997 and November 2003. One patient received RT to bilateral stage I lesions simultaneously, and another patient received sequential definitive courses of RT for metachronous stage I lesions.

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Thoracic Radiation Therapy for Early-Stage Lung Cancer Table 1

Selected Patient and Tumor Characteristics Characteristic

Number of Patients (%)

Figure 1

A

Survival Data of Patients Treated with TRT

Overall Survival

Age (Years)

100

< 60

1 (3)

60-69

10 (35)

70-79

10 (35)

≥ 80

8 (28)

Survival (%)

80

Sex Female

16 (55)

Male

13 (45)

60 40 20

0

10

20

30

Performance Status

40

50

60

70

80

50

60

70

80

50

60

70

80

Months

1

13 (45)

2

16 (55)

B

Progression-Free Survival 100

Oxygen Requirement 14 (48)

Yes

15 (52)

Survival (%)

80

No

Previous Malignancy No

21 (72)

Yes

8 (28)

60 40 20

Stage

0

IA (T1N0)

19 (61)

IB (T2N0)

12 (39)

Histology

10

20

30

4

Months

C

Local Progression-Free Survival 100

9 (29)

Squamous cell carcinoma

8 (26)

Large cell carcinoma

1 (3)

Not specified

13 (42)

Patient and Tumor Characteristics Patient characteristics are shown in Table 1. There was a slight female predominance. Median age was 73 years, and 8 patients (28%) were ≥ 80 years of age. Fifteen patients were oxygen dependent before the initiation of therapy, and the majority of patients (55%) had an Eastern Cooperative Oncology Group performance status of 2. Eight patients had a history of malignancy, including lung cancer in 5 patients, breast cancer in 1 patient, prostate cancer in 1 patient, and non-Hodgkin’s lymphoma in 1 patient. The vast majority of patients were unsuitable for curative resection as a result of pulmonary or cardiac dysfunction. One patient had a previous pneumonectomy and was therefore ineligible for additional surgery. The results of pulmonary function testing demonstrated a median pretreatment forced expiratory volume in 1 second of 0.98 L (range, 0.38-1.59 L). Nineteen lesions were categorized as stage IA (T1N0) and 12 were categorized as stage IB (T2N0). The maximum tumor dimension ranged from 1.5 cm to 5 cm (median, 2.5 cm).

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80

Survival (%)

Adenocarcinoma

60 40 20

0

10

20

30

40

Months

Radiation Therapy Schedule and Technique Treatment was administered once daily on consecutive weekdays without a planned treatment break. The most commonly employed schedule was 2.5 Gy in daily fractions over 5.5 weeks to a nominal dose of 70 Gy, but fraction size ranged from 2.25 Gy to 3.7 Gy, and the nominal total dose ranged from 60 Gy to 78.5 Gy. Conformal RT planning was used for 94% of lesions. Beam energy ranged from 6 MV to 18 MV, and a median of 4 RT fields were used (range, 2-6 fields). Treatmentfield size ranged from 5 cm × 5 cm to 11 cm × 8 cm. The median V20 was 12% for patients treated with conformal tech-

Jeffrey A. Bogart et al Table 2

Select Studies of Radiation Therapy for Early-Stage Non–Small-Cell Lung Cancer8,10,19-22 Study

Lagerwaard et al8 Bradley et

al10

Bradley et al19 Rosenzweig et

al20

Number of Patients

Stage

Total Dose (Gy)

Fraction Size (Gy)

Local Tumor Control (%)

Overall Survivial (%)

113

I

66-70

2

43 (3-year)

25 (3-year)

73

I

70.9-90.3

2.15

62 (3-year)†

35 (3-year)†

45

I

70

2

NS

49 (3-year)*

32

I/IIA

70.2

1.8

43 (5-year)

33 (5-year)

al21

11

I

92.4-102.9

2.1

76 (2-year)

NS

Maguire et al22

22

I/II

73.6-80

1.6 twice daily

42 (4-year)†

35 (4-year)†

Current Study

31

I

70

2.5

83 (3-year)

60 (3-year)

Henning et

*Disease-free survival. †Estimated from survival curve. Abbreviation: NS = not stated

niques. Three patients received chemotherapy consisting of paclitaxel (50 mg/m2) and carboplatin (area under the curve of 2) administered weekly during RT.

Toxic Effects of Therapy All patients completed therapy without interruption related to the toxic effects of therapy. Three patients developed grade 3 pneumonitis 1-3 months after therapy, and 1 patient developed grade 3 soft tissue fibrosis in the anterior chest wall following treatment with PA parallel opposed fields. Radiation pneumonitis resolved with supportive measures in 1 patient, whereas 2 patients had persistent increased dyspnea on exertion. Post-therapy forced expiratory volume in 1 second was equally likely to worsen (range, 2%-16%) or improve (range, 1%-17%), and post-therapy lung diffusion for carbon monoxide decreased an average of 13% (range, 0-40%). Two of 3 patients receiving concurrent chemotherapy developed grade 3 pneumonitis, compared with 1 of 26 patients treated with RT alone.

Response and Survival Complete radiographic disappearance following therapy was observed for 10 lesions (35%), whereas partial regression was noted for an additional 17 lesions (53%), for an overall response rate of 88%. Local tumor control has been maintained in 26 of 31 lesions, and subsequent in-field tumor progression following response to TRT has been observed in only 1 patient. Local tumor control was similar for T1 and T2 lesions. Relapse in the unirradiated mediastinum was documented in 2 patients in conjunction with local tumor progression, but no isolated nodal recurrences were observed. The median potential duration of follow-up for all patients was 44 months, and 17 patients remained alive with a median follow-up of 29 months. Five patients died from progressive disease and 7 patients died as a result of intercurrent illness. Kaplan-Meier actuarial median survival is 38 months whereas 2and 3-year overall survival rates were 74% and 60%, respectively (Figure 1A). Three-year relapse-free survival and local progression–free survival rates were 54% and 82%, respectively (Figure 1B and Figure 1C).

Discussion Our results suggest the administration of a modestly hypofractionated dose-intensive RT regimen is feasible for highrisk patients with early-stage NSCLC. The attraction of a compressed treatment course for patients with early-stage NSCLC who are unable to undergo curative surgery is obvious. Recent trials from the RTOG and Hayman et al demonstrate the feasibility of marked dose escalation (in some instances surpassing 100 Gy) when the volume of irradiated functioning lung is limited.9,10 In these studies, median survival for patients with earlystage NSCLC ranged from 20 months to 27 months. However, the requirement for an extended course of therapy, which could approach 10 weeks, can deter patients at high risk from deciding to undergo treatment. A recent review emphasizes the potential impact of therapy for patients with early-stage NSCLC who are not candidates for standard surgery, as median survival was doubled for treated patients compared with patients who were not treated (eg, 22 months vs. 11 months).15 Moreover, despite the presence of comorbid medical illness in this patient population, the majority of patients with medically inoperable stage I NSCLC die from disease progression.7 The paradigm of conventional dose escalation for the treatment of NSCLC remains open to question. Interruptions in the RT course have been implicated in reducing tumor control for squamous cell cancer of the head and neck as well as NSCLC, and a recent analysis of data from past RTOG trials suggests the loss of survival rate was 1.6% per day of prolongation beyond 6 weeks.11,12,16 Conversely, accelerating the completion of the treatment course could lead to enhanced tumor control. For example, the schedule of 70 Gy in 5.5 weeks results in a predicted biologic dose increase of approximately 24% compared with conventional fractionation.17 Whether the underlying molecular characteristics of early-stage NSCLC will identify patients most likely to benefit from accelerated RT is unclear, but it will be an important future research consideration. The intermediate-term results of this retrospective study are encouraging, with actuarial median survival surpassing 3 years and excellent local tumor control. Local tumor control has been exhibited in 26 of 31 lesions, an important consideration given the

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Thoracic Radiation Therapy for Early-Stage Lung Cancer direct relationship between local tumor control and cause-specific survival noted in the published literature.18 Most deaths were a result of intercurrent disease. The fact that no patient had treatment failure in the untreated nodal stations suggests that the toxicity of prophylactic mediastinal irradiation can be avoided even in patients who did not undergo mediastinoscopy. A summary of select trials using conformal RT for early-stage NSCLC is shown in Table 2.8,10,19-22 As with all retrospective studies, there are obvious limitations to our review. Patient selection could have impacted outcomes, and although our study population had some favorable characteristics (female predominance, clinical stage IA tumors), its underlying health was poor (> 50% had poor functional status and/or oxygen dependence). The impact of chemotherapy on tumor control and toxicity is difficult to assess because few patients received chemotherapy, and these patients tended to have larger tumors and correspondingly larger target volumes. The administration of fewer large RT fractions (eg, hypofractionation) has often been reflexively associated with an enhanced risk of late normal tissue toxicity by many in the radiation oncology community.23 Although this relationship could be pertinent when large volumes of functioning lung are irradiated, the advent of advanced imaging and RT planning technologies could limit the functioning lung irradiated and permit safe administration of high doses to small target volumes. Even before the introduction of conformal RT, retrospective studies suggested that hypofractioned therapy (eg, 48 Gy in 4-Gy daily fractions) could be safely administered when involved-field (eg, limited volume) techniques were used for early-stage NSCLC.24,25 Although we were able to achieve a modest reduction in treatment, further compression of the treatment course should be feasible. The optimal schedule for this population remains to be defined, and whether higher nominal total doses could be advantageous is not clear. The Cancer and Leukemia Group B is presently conducting a multi-institutional prospective trial to define the maximum accelerated course of RT when the total nominal dose is held constant at 70 Gy.26 The current cohort is receiving 17 fractions of 4.1 Gy, though the safety of this regimen remains to be determined. An alternate approach of extreme hypofractionation, using stereotactic body radiation surgery, requires increased technologic resources and sophistication compared with conformal RT. Stereotactic body radiosurgery has been explored extensively in Japan, with encouraging initial results, and the preliminary results of a prospective trial in the United States were recently reported.27,28 Whether this technology can be safely employed in a multi-institutional setting will be assessed in a recently activated RTOG trial.29

Conclusion Our experience demonstrates that acceleration of the RT course is feasible for patients at high risk who have early-stage NSCLC. Outcomes, including local tumor control and survival, appear encouraging but need confirmation in prospective trials. This approach could be an attractive alternative to prolonged high-dose conventionally fractionated RT. Ongoing clinical trials are currently evaluating alternate-dose and fractionation schemes, and the results of these trials will provide further guid-

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ance regarding the optimal management of the significant population of patients with medically inoperable early-stage NSCLC.

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