Practical Radiation Oncology (2013) 3, 301–306
www.practicalradonc.org
Original Report
Stereotactic body radiation therapy-based treatment model for stage I medically inoperable small cell lung cancer Gregory M.M. Videtic MD, CM a,⁎, Kevin L. Stephans MD a , Neil M. Woody MD a , Nathan A. Pennell MD, PhD b , Marc Shapiro MD b , Chandana A. Reddy MS a , Toufik Djemil PhD a a
Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
b
Received 13 August 2012; revised 1 October 2012; accepted 2 October 2012
Abstract Purpose: To report on medically inoperable stage I small cell lung cancer (SCLC) patients for whom stereotactic body radiation therapy (SBRT) was employed to manage the primary tumor. Methods and Materials: Review of our institutional review board approved SBRT registry revealed 6 cases of stage I SCLC out of 430 patients over a 6-year interval (2004-2010). All patients had biopsy proven disease and deemed medically inoperable by a thoracic surgeon. Our institutional approach was to treat with a combination of SBRT, platinum-etoposide chemotherapy (CHT) and prophylactic cranial irradiation (PCI). SBRT was delivered using a Novalis/BrainLAB platform and ExacTrac (BrainLab, Westchester, IL) for image guidance. Results: Patient characteristics included a median Karnofsky performance scale of 80, a median age of 68 years, 4 females, and 1 patient still smoking at presentation. Impaired pulmonary function caused inoperability in 50% of cases. Tumor characteristics included median tumor size of 2.6 cm and median positron emission tomography-standard uptake valuemax of 9. The SBRT was 60 Gy/3 fractions (3 patients), 50 Gy/5 fractions (2 patients), 30 Gy/1 fraction (1 patient). Median follow-up was 11.9 months. There was no grade 3 or higher, and 1 grade 2, toxicity. Three patients were alive at analysis and 3 patients had died of non-cancer causes. At 1 year, local control was 100%, there was no regional nodal failure, and 1 patient had distant failure (liver). Overall and disease-free survivals at 1 year were 63% and 75%, respectively. Conclusions: Employing SBRT for stage I medically inoperable SCLC is rational, with excellent local control and encouraging disease-specific survival. The absence of regional nodal failure supports positron emission tomography for mediastinal staging. Platinum-based CHT may be feasible in vulnerable populations. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Presented in part at the 14th World Conference on Lung Cancer (WCLC 2011), July 3-7, 2011, Amsterdam, The Netherlands. Conflicts of interest: None. ⁎ Corresponding author. Cleveland Clinic Lerner College of Medicine, Staff Physician, Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Ave, Mailroom T28, Cleveland, OH 44195. E-mail address: [email protected] (G.M.M. Videtic). 1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.10.003
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Introduction Small cell lung cancer (SCLC) represents approximately 15% of all lung cancer cases diagnosed in the United States. 1 Of these, about 30% of SCLC patients present with limited disease (LD). 1 Concurrent chemoradiation therapy followed by prophylactic cranial irradiation is used for the curative management of LD-SCLC and results in a median survival of 23 months and a 5-year survival rate of 26%. 2 There is a small subset of LD-SCLC patients (5%-15%) who present with disease limited to the lung, without regional nodal involvement (T1/T2N0, or stage I). 3 Patients with this localized SCLC are managed like their counterparts with the equivalent stage of non-small cell lung cancer (NSCLC), in that they undergo surgical resection of the lung lesion along with a mediastinal nodal dissection since their overall prognosis is felt to be the best with this approach. 4 However, unlike NSCLC patients, medically fit resected stage I SCLC patients are routinely offered adjuvant chemotherapy, followed by prophylactic cranial irradiation (PCI). 1 Regarding surgical resection, a significant proportion of early-stage NSCLC patients presents with impaired cardiopulmonary reserve, placing them at increased risk of perioperative complications and long-term disability with standard anatomic resections; these patients are deemed medically inoperable. 5 Over the past decade, stereotactic body radiation therapy (SBRT) has emerged as a novel radiation modality with significant applications in the medically inoperable, early-stage NSCLC population. 6 For this population SBRT consistently provides excellent local control, little acute toxicity, and improved overall survival compared to historic results seen with conventional fractionated radiation therapy. 6 The same phenomenon of medical inoperability is also occasionally seen with early-stage SCLC patients. In that respect, since initiating an SBRT lung program at our Institute in 2004 we have employed this technology in the care of such patients. Inasmuch as this is a rare disease presentation, we decided to report the outcomes for our series, albeit small, of medically inoperable early-stage SCLC patients because we believe it further characterizes the role and utility of SBRT in thoracic malignancies and describes the feasibility of integrating the other recognized SCLC treatment modalities, chemotherapy, and PCI into the care of poor risk patients, since there is no standardized approach.
Practical Radiation Oncology: October-December 2013
All patients were staged using computed tomography (CT) of the chest, abdomen and pelvis, magnetic resonance imaging of the brain and positron emission tomography (PET). Mediastinoscopy was not required but any abnormal mediastinal nodes on PET were expected to be characterized by a bronchoscope-guided ultrasound approach. The institutional approach to SBRT has been previously described. 8–10 In brief, patients were treated on a Novalis-
Methods and materials A survey of our institutional review board approved SBRT data registry for the period 2004-2010 revealed 6 cases out of 430 patients (1.4%) diagnosed with stage I (American Joint Committee on Cancer 6th edition 7) SCLC. All patients had biopsy proven disease. Medical inoperability was established by an experienced thoracic surgeon.
Figure 1 Representative axial computed tomographic images of the chest for an early-stage small cell lung cancer (arrow). (A) Prior to SBRT; (B) 4-months post SBRT; (C) 23-months post SBRT, demonstrating the evolving fibrotic response. SBRT, stereotactic body radiation therapy.
Practical Radiation Oncology: October-December 2013
SBRT and small cell lung cancer
BrainLAB system (BrainLab, Westchester, IL) using a vacuum bag restriction system (Bodyfix; Medical Intelligence Inc, Phoenix, AZ) and an abdominal compression device to limit the maximum range of tumor motion to b 1 cm in all directions. Treatment planning was carried out with BrainLAB planning software and referenced to the free-breathing study. Patient setup and target localization were verified daily prior to delivery using the ExacTrac image-guidance system (BrainLAB). Dose schedules were selected at the treating physician's discretion and reflected tumor location, distinguishing “peripheral” from “central” tumors per the criteria of RTOG 0236. 11 The timing of chemotherapy with respect to SBRT was at the discretion of the treating medical oncologist, with the expectation that the patient would receive 4 cycles of a platinum agent with etoposide every 3 weeks. On completion of SBRT and chemotherapy, PCI (25 Gy/10 fractions) was planned once the patient had demonstrated response in the chest and had reimaging of the brain for restaging. First follow-up was generally 6 to 8 weeks after completion of PCI, with same-day pulmonary function tests and chest CT. Thereafter, routine follow-up was every 3 months with CT imaging at each visit and pulmonary function tests twice yearly. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. 12 Local failure was defined as progressive and increasing CT scan abnormalities confirmed by progressive and incremental increases in a lesion's standardized uptake values (SUVs) on serial PET imaging, with or without biopsy. Nodal failure was defined as radiographic (PET or CT) Table 1
303
progression in the hilum or mediastinum. Distant failure was defined as the presence of distant metastases on clinical examination or imaging. The primary outcomes were local control and survival, which were measured from the initiation of SBRT until death or last patient contact. Local, nodal, and distant control and survival estimates were calculated using Kaplan-Meier analysis. Statistical analyses were performed using StatView 5.0 (SAS Institute, Cary, NC), and a P value less than .05 was considered statistically significant.
Results Patient No. 4 (see Fig 1) is a representative case in the present series. He is a 69-year-old male patient, with longstanding chronic obstructive pulmonary disease who had been undergoing yearly screening by CT scan for nodules first detected in 2005. In March 2009, a previously noted left upper lobe nodule increased in size from 8 mm to 14 mm. A PET-CT done at that time showed a maximum SUV of 2.8 for the nodule and no other abnormalities. In May 2009, the patient underwent a bronchoscopy with brushings of the lesion revealing SCLC. The workup was otherwise negative. A thoracic surgeon deemed the patient medically inoperable because his forced expiratory volume in 1 second was 46% of predicted. Following a multidisciplinary thoracic assessment, SBRT was recommended and delivered as 60 Gy in 3 fractions (per the Radiation Therapy Oncology Group
Patient, tumor, and treatment characteristics of medically inoperable small cell lung cancer patients treated with SBRT
Patient Sex Age KPS Inoperable— Inoperable— no. reason details
“Central” SBRT dose CHT Stage Tumor Smoker BMI T location in Gy/no. cycles (cm) PET at (n; type) of fx SUVmax SBRT
1
M
57
50
Vascular
No
28.6 2.9
IA
2
F
68
80
Pulmonary
Yes
20.1 2.3
IA
3
F
63
80
Pulmonary
No
21.8 3.6
4
M
68
90
Pulmonary
No
5
F
73
90
Cardiac
6
F
72
90
Pulmonary
CHF, MI, active PVD with amputation FEV1 46% pred. DLCO 20% pred. FEV1 17% pred. DLCO 24% pred. FEV1 46% pred. requiring pneumonectomy Acute ischemia during med'scopy FEV1 25% pred. DLCO 40% pred.
5.37
No
50/5
None
12.7
No
60/3
4 × PE
IB
4.2
No
60/3
4 × PE
31.9 1.4
IA
2.8
No
60/3
4 × PE
No
26.7 3.5
IB
21.1
Yes
50/5
No
28.4 2.2
IA
13.5
No
30/1
1 x PE then 3 × CpE None
BMI, body mass index; “Central”, tumor location per Radiation Therapy Oncology Group 0236; CHF, congestive heart failure; CHT, chemotherapy; CpE, carboplatin-etoposide; DLCO, diffusing capacity of lung for carbon monoxide; F, female, FEV1, forced expiratory volume in 1 second; fx, fraction; Gy, Gray; KPS, Karnofsky performance status; M, male; MI, myocardial infarction; med'scopy, mediastinoscopy; PE, cisplatin-etoposide; PETSUVmax, positron emission tomography-derived maximum standardized uptake value; pred., predicted; PVD, peripheral vascular disease; SBRT, stereotactic body radiation therapy; T, tumor.
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0236 approach 11), completed in June 2009. Four cycles of cisplatin-etoposide were subsequently administered every 3 weeks and completed in September 2009. PCI (25 Gy/10 fractions) was completed November 2009. A complete response was achieved in the chest, with serial CT imaging revealing disappearance of the tumor and evolving postSBRT fibrotic response (Fig 1). The patient remains alive (as of May 2012), without evidence of disease. Table 1 provides details on patient and tumor characteristics. In summary, the median Karnofsky performance status was 80 (range, 50-90), the median age was 68 years (range, 57-73), 4 patients were female, the median BMI was 27.55 (range, 20.1-31.9), and 1 patient was still smoking at the time of treatment. Impaired pulmonary function was the reason for inoperability in 4
Practical Radiation Oncology: October-December 2013
cases. Median tumor size was 2.6 cm (range, 1.4-3.6). By American Joint Committee on Cancer criteria, 4 tumors were T1 and 2 T2. One lesion was “central.” The median PET-SUVmax for tumor was 9 (range, 2.8-21.1). With respect to the specifics of individual treatment, 1 patient had a mediastinoscopy. SBRT dose schedules were the following: 60 Gy/3 fractions (3 patients); 50 Gy/5 fractions (2 patients); and 30 Gy/1 fraction (1 patient). One patient received chemotherapy (CHT) before SBRT. One patient died of a brain aneurysm soon after SBRT and never received either planned CHT or PCI. This patient was also 1 of the total 2 patients who died before receiving PCI. With respect to outcomes, median follow-up at the time of analysis was 11.9 months. No grade 3 or higher toxicity was noted, with 1 grade 2 toxicity (chest wall). Figure 2 presents overall and disease-free survival curves for this series. Three patients were alive at analysis and 3 had died of non-cancer causes, although 1 did have distant disease at time of death. At 1 year, local control was 100%, there were no regional nodal failures, and 1 patient developed distant failure in the form of liver metastases. Overall and disease-free survivals at 1 year were 63% and 75%, respectively.
Discussion
Figure 2 (A) Overall and (B) disease-free survival for 6 medically inoperable early-stage small cell lung cancer patients treated with stereotactic body radiation therapy (SBRT), chemotherapy, and prophylactic cranial irradiation. MST, median survival time.
To our knowledge, this is the first reported series describing the utility of SBRT in the management of medically inoperable early-stage SCLC. Mindful of the rarity of this disease presentation and the smallness of this present series, this report was intended to highlight new perspectives on expanding the range of the role of SBRT in treating lung cancer in selected high-risk patients. First, it demonstrates that the same outcomes that have now become expected with SBRT for medically inoperable early-stage NSCLC; ie, feasibility, safety, excellent disease control, minimal toxicity, and potential survival benefits, 6 may be achievable for special presentations of SCLC. Given the generic mechanisms by which radiation therapy works combined with the recognized radiosensitivity of small cell disease, we hoped to produce at least equivalent local control rates for SCLC from SBRT as seen for NSCLC. The local control rate of 100% seen for this series supports this hypothesis, although we recognize that the number of patients is small and the follow-up ongoing. Second, as with the medically inoperable NSCLC population, this study supports the utility of PET in staging patients specifically with respect to the mediastinum. Although the gold standard in lung cancer remains mediastinoscopy, this procedure is rarely used in SBRT NSCLC patients given the fragility of this population, and clinical results to date suggest that regional nodal failure
Practical Radiation Oncology: October-December 2013
after PET staging prior to SBRT is b 10%, with distant failure predominating. 6 This same pattern is now seen in the current series of SCLC patients such that regional nodal failure after SBRT was not seen for the 5 of 6 patients who had no pathologic staging of the nodes. This series also suggests that in the event of undetectable or occult microscopic nodal disease, chemotherapy may be sufficient to control the PET-negative mediastinum, without the need for radiation therapy. Third, it suggests that the feasibility role of systemic therapy in vulnerable populations needs to be carefully studied. Prospective randomized data do not in general support the routine use of adjuvant platinum-based chemotherapy for patients with resected stage I NSCLC. 13 In the medically inoperable NSCLC population treated with SBRT, there has been even less expectation of defining a role for adjuvant chemotherapy since the population has been generally judged too frail to tolerate conventional systemic therapies. However, since the dominant form of failure after SBRT, like surgery, appears to be distant metastatic disease, 6 there has been interest in exploring the possibility of adjuvant agents in selected inoperable patients, especially with the advent of “targeted” or biologic therapies to mitigate toxicities. In contrast, there has been routine use of adjuvant chemotherapy in the setting of resected early-stage SCLC, based on a number of historical series that have suggested improvements in survival when it is used. 1 Likewise, PCI has also been recommended for such patients because high relapse rates in the brain have also been observed with pathologic stage I disease. 1 The present series suggests that for some medically inoperable populations, curative systemic therapies may be possible to administer and can be tolerated by patients. Our observation has encouraged us to more actively investigate the role of adjuvant therapies in properly selected medically inoperable NSCLC patients. Fourth, a SBRT-based approach to stage I SCLC appears to have many advantages over the form of conventional chemoradiation therapy used in limitedstage disease, especially with respect to toxicity. Radiation therapy and chemotherapy are not given concurrently, thus preventing additive toxicities. SBRT by definition involves no elective nodal irradiation and therefore does not produce significant mediastinal or esophageal toxicity. Also, unlike conventional limited-stage radiation therapy, the timing of SBRT need not be linked to the initiation of chemotherapy in order to still achieve excellent locoregional control. Lastly, among the most provocative findings published in the lung cancer SBRT literature have been the results of Onishi et al, 14 in which the survival of a subgroup of medically operable patients treated with SBRT was comparable with similar-stage patients treated with video-assisted thorascopic surgery or lobectomy and defining the role of SBRT in potentially operable
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patients is becoming an active area of investigation. As with SBRT in NSCLC, it may be appropriate to consider the utility of SBRT in operable early-stage SCLC patients to mitigate surgery-related morbidity in order to be able to transition more rapidly to the adjuvant chemotherapy and PCI required for improving survival in this disease.
Conclusions This novel case series suggests that SBRT for stage I medically inoperable SCLC results in an excellent rate of local control, which is comparable with the data reported for medically inoperable early-stage NSCLC patients treated with SBRT. Disease-specific survival is encouraging, and as with medically inoperable NSCLC patients, non-cancer comorbidities contribute significantly to mortality. The absence of regional nodal failure lends support to the sole use of PET for characterizing the mediastinal nodes and suggests that radiation therapy is not needed to control a PET-negative mediastinum. Administration of platinum-based CHT was feasible in this inoperable series and lends support to the possibility of adjuvant chemotherapy in selected inoperable early-stage NSCLC patients managed with SBRT.
References 1. Anraku M, Waddell TK. Surgery for small-cell lung cancer. Semin Thorac Cardiovasc Surg. 2006;18:211-216. 2. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340:265-271. 3. Urschel JD. Surgical treatment of peripheral small cell lung cancer. Chest Surg Clin N Am. 1997;7:95-103. 4. Dusmet M, Goldstraw P. Surgery for small cell lung cancer. Hematol Oncol Clin North Am. 2004;18:323-341. 5. Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg. 2005;80:2051-2056. 6. Videtic GM, Stephans KL. The role of stereotactic body radiotherapy in the management of non-small cell lung cancer: an emerging standard for the medically inoperable patient? Curr Oncol Rep. 2010;12:235-241. 7. Lung. In: Greene FL, Page DL, Fleming D, et al, eds. AJCC Cancer Staging Handbook, 6th Ed. New York: Springer; 2002:191-204. 8. Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol. 2009;4:976-982. 9. Videtic GM, Stephans K, Reddy C, et al. Intensity-modulated radiotherapy-based stereotactic body radiotherapy for medically inoperable early-stage lung cancer: excellent local control. Int J Radiat Oncol Biol Phys. 2010;77:344-349. 10. Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac Oncol. 2009;4:838-844.
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11. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303: 1070-1076. 12. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at: http://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/ctcaev3.pdf. Accessed February 13, 2012.
Practical Radiation Oncology: October-December 2013 13. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559. 14. Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi institutional study. J Thorac Oncol. 2007;2(7 Suppl 3):S94-S100.
www.practicalradonc.org
Original Report
Stereotactic body radiation therapy-based treatment model for stage I medically inoperable small cell lung cancer Gregory M.M. Videtic MD, CM a,⁎, Kevin L. Stephans MD a , Neil M. Woody MD a , Nathan A. Pennell MD, PhD b , Marc Shapiro MD b , Chandana A. Reddy MS a , Toufik Djemil PhD a a
Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
b
Received 13 August 2012; revised 1 October 2012; accepted 2 October 2012
Abstract Purpose: To report on medically inoperable stage I small cell lung cancer (SCLC) patients for whom stereotactic body radiation therapy (SBRT) was employed to manage the primary tumor. Methods and Materials: Review of our institutional review board approved SBRT registry revealed 6 cases of stage I SCLC out of 430 patients over a 6-year interval (2004-2010). All patients had biopsy proven disease and deemed medically inoperable by a thoracic surgeon. Our institutional approach was to treat with a combination of SBRT, platinum-etoposide chemotherapy (CHT) and prophylactic cranial irradiation (PCI). SBRT was delivered using a Novalis/BrainLAB platform and ExacTrac (BrainLab, Westchester, IL) for image guidance. Results: Patient characteristics included a median Karnofsky performance scale of 80, a median age of 68 years, 4 females, and 1 patient still smoking at presentation. Impaired pulmonary function caused inoperability in 50% of cases. Tumor characteristics included median tumor size of 2.6 cm and median positron emission tomography-standard uptake valuemax of 9. The SBRT was 60 Gy/3 fractions (3 patients), 50 Gy/5 fractions (2 patients), 30 Gy/1 fraction (1 patient). Median follow-up was 11.9 months. There was no grade 3 or higher, and 1 grade 2, toxicity. Three patients were alive at analysis and 3 patients had died of non-cancer causes. At 1 year, local control was 100%, there was no regional nodal failure, and 1 patient had distant failure (liver). Overall and disease-free survivals at 1 year were 63% and 75%, respectively. Conclusions: Employing SBRT for stage I medically inoperable SCLC is rational, with excellent local control and encouraging disease-specific survival. The absence of regional nodal failure supports positron emission tomography for mediastinal staging. Platinum-based CHT may be feasible in vulnerable populations. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Presented in part at the 14th World Conference on Lung Cancer (WCLC 2011), July 3-7, 2011, Amsterdam, The Netherlands. Conflicts of interest: None. ⁎ Corresponding author. Cleveland Clinic Lerner College of Medicine, Staff Physician, Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Ave, Mailroom T28, Cleveland, OH 44195. E-mail address: [email protected] (G.M.M. Videtic). 1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.10.003
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Introduction Small cell lung cancer (SCLC) represents approximately 15% of all lung cancer cases diagnosed in the United States. 1 Of these, about 30% of SCLC patients present with limited disease (LD). 1 Concurrent chemoradiation therapy followed by prophylactic cranial irradiation is used for the curative management of LD-SCLC and results in a median survival of 23 months and a 5-year survival rate of 26%. 2 There is a small subset of LD-SCLC patients (5%-15%) who present with disease limited to the lung, without regional nodal involvement (T1/T2N0, or stage I). 3 Patients with this localized SCLC are managed like their counterparts with the equivalent stage of non-small cell lung cancer (NSCLC), in that they undergo surgical resection of the lung lesion along with a mediastinal nodal dissection since their overall prognosis is felt to be the best with this approach. 4 However, unlike NSCLC patients, medically fit resected stage I SCLC patients are routinely offered adjuvant chemotherapy, followed by prophylactic cranial irradiation (PCI). 1 Regarding surgical resection, a significant proportion of early-stage NSCLC patients presents with impaired cardiopulmonary reserve, placing them at increased risk of perioperative complications and long-term disability with standard anatomic resections; these patients are deemed medically inoperable. 5 Over the past decade, stereotactic body radiation therapy (SBRT) has emerged as a novel radiation modality with significant applications in the medically inoperable, early-stage NSCLC population. 6 For this population SBRT consistently provides excellent local control, little acute toxicity, and improved overall survival compared to historic results seen with conventional fractionated radiation therapy. 6 The same phenomenon of medical inoperability is also occasionally seen with early-stage SCLC patients. In that respect, since initiating an SBRT lung program at our Institute in 2004 we have employed this technology in the care of such patients. Inasmuch as this is a rare disease presentation, we decided to report the outcomes for our series, albeit small, of medically inoperable early-stage SCLC patients because we believe it further characterizes the role and utility of SBRT in thoracic malignancies and describes the feasibility of integrating the other recognized SCLC treatment modalities, chemotherapy, and PCI into the care of poor risk patients, since there is no standardized approach.
Practical Radiation Oncology: October-December 2013
All patients were staged using computed tomography (CT) of the chest, abdomen and pelvis, magnetic resonance imaging of the brain and positron emission tomography (PET). Mediastinoscopy was not required but any abnormal mediastinal nodes on PET were expected to be characterized by a bronchoscope-guided ultrasound approach. The institutional approach to SBRT has been previously described. 8–10 In brief, patients were treated on a Novalis-
Methods and materials A survey of our institutional review board approved SBRT data registry for the period 2004-2010 revealed 6 cases out of 430 patients (1.4%) diagnosed with stage I (American Joint Committee on Cancer 6th edition 7) SCLC. All patients had biopsy proven disease. Medical inoperability was established by an experienced thoracic surgeon.
Figure 1 Representative axial computed tomographic images of the chest for an early-stage small cell lung cancer (arrow). (A) Prior to SBRT; (B) 4-months post SBRT; (C) 23-months post SBRT, demonstrating the evolving fibrotic response. SBRT, stereotactic body radiation therapy.
Practical Radiation Oncology: October-December 2013
SBRT and small cell lung cancer
BrainLAB system (BrainLab, Westchester, IL) using a vacuum bag restriction system (Bodyfix; Medical Intelligence Inc, Phoenix, AZ) and an abdominal compression device to limit the maximum range of tumor motion to b 1 cm in all directions. Treatment planning was carried out with BrainLAB planning software and referenced to the free-breathing study. Patient setup and target localization were verified daily prior to delivery using the ExacTrac image-guidance system (BrainLAB). Dose schedules were selected at the treating physician's discretion and reflected tumor location, distinguishing “peripheral” from “central” tumors per the criteria of RTOG 0236. 11 The timing of chemotherapy with respect to SBRT was at the discretion of the treating medical oncologist, with the expectation that the patient would receive 4 cycles of a platinum agent with etoposide every 3 weeks. On completion of SBRT and chemotherapy, PCI (25 Gy/10 fractions) was planned once the patient had demonstrated response in the chest and had reimaging of the brain for restaging. First follow-up was generally 6 to 8 weeks after completion of PCI, with same-day pulmonary function tests and chest CT. Thereafter, routine follow-up was every 3 months with CT imaging at each visit and pulmonary function tests twice yearly. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. 12 Local failure was defined as progressive and increasing CT scan abnormalities confirmed by progressive and incremental increases in a lesion's standardized uptake values (SUVs) on serial PET imaging, with or without biopsy. Nodal failure was defined as radiographic (PET or CT) Table 1
303
progression in the hilum or mediastinum. Distant failure was defined as the presence of distant metastases on clinical examination or imaging. The primary outcomes were local control and survival, which were measured from the initiation of SBRT until death or last patient contact. Local, nodal, and distant control and survival estimates were calculated using Kaplan-Meier analysis. Statistical analyses were performed using StatView 5.0 (SAS Institute, Cary, NC), and a P value less than .05 was considered statistically significant.
Results Patient No. 4 (see Fig 1) is a representative case in the present series. He is a 69-year-old male patient, with longstanding chronic obstructive pulmonary disease who had been undergoing yearly screening by CT scan for nodules first detected in 2005. In March 2009, a previously noted left upper lobe nodule increased in size from 8 mm to 14 mm. A PET-CT done at that time showed a maximum SUV of 2.8 for the nodule and no other abnormalities. In May 2009, the patient underwent a bronchoscopy with brushings of the lesion revealing SCLC. The workup was otherwise negative. A thoracic surgeon deemed the patient medically inoperable because his forced expiratory volume in 1 second was 46% of predicted. Following a multidisciplinary thoracic assessment, SBRT was recommended and delivered as 60 Gy in 3 fractions (per the Radiation Therapy Oncology Group
Patient, tumor, and treatment characteristics of medically inoperable small cell lung cancer patients treated with SBRT
Patient Sex Age KPS Inoperable— Inoperable— no. reason details
“Central” SBRT dose CHT Stage Tumor Smoker BMI T location in Gy/no. cycles (cm) PET at (n; type) of fx SUVmax SBRT
1
M
57
50
Vascular
No
28.6 2.9
IA
2
F
68
80
Pulmonary
Yes
20.1 2.3
IA
3
F
63
80
Pulmonary
No
21.8 3.6
4
M
68
90
Pulmonary
No
5
F
73
90
Cardiac
6
F
72
90
Pulmonary
CHF, MI, active PVD with amputation FEV1 46% pred. DLCO 20% pred. FEV1 17% pred. DLCO 24% pred. FEV1 46% pred. requiring pneumonectomy Acute ischemia during med'scopy FEV1 25% pred. DLCO 40% pred.
5.37
No
50/5
None
12.7
No
60/3
4 × PE
IB
4.2
No
60/3
4 × PE
31.9 1.4
IA
2.8
No
60/3
4 × PE
No
26.7 3.5
IB
21.1
Yes
50/5
No
28.4 2.2
IA
13.5
No
30/1
1 x PE then 3 × CpE None
BMI, body mass index; “Central”, tumor location per Radiation Therapy Oncology Group 0236; CHF, congestive heart failure; CHT, chemotherapy; CpE, carboplatin-etoposide; DLCO, diffusing capacity of lung for carbon monoxide; F, female, FEV1, forced expiratory volume in 1 second; fx, fraction; Gy, Gray; KPS, Karnofsky performance status; M, male; MI, myocardial infarction; med'scopy, mediastinoscopy; PE, cisplatin-etoposide; PETSUVmax, positron emission tomography-derived maximum standardized uptake value; pred., predicted; PVD, peripheral vascular disease; SBRT, stereotactic body radiation therapy; T, tumor.
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0236 approach 11), completed in June 2009. Four cycles of cisplatin-etoposide were subsequently administered every 3 weeks and completed in September 2009. PCI (25 Gy/10 fractions) was completed November 2009. A complete response was achieved in the chest, with serial CT imaging revealing disappearance of the tumor and evolving postSBRT fibrotic response (Fig 1). The patient remains alive (as of May 2012), without evidence of disease. Table 1 provides details on patient and tumor characteristics. In summary, the median Karnofsky performance status was 80 (range, 50-90), the median age was 68 years (range, 57-73), 4 patients were female, the median BMI was 27.55 (range, 20.1-31.9), and 1 patient was still smoking at the time of treatment. Impaired pulmonary function was the reason for inoperability in 4
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cases. Median tumor size was 2.6 cm (range, 1.4-3.6). By American Joint Committee on Cancer criteria, 4 tumors were T1 and 2 T2. One lesion was “central.” The median PET-SUVmax for tumor was 9 (range, 2.8-21.1). With respect to the specifics of individual treatment, 1 patient had a mediastinoscopy. SBRT dose schedules were the following: 60 Gy/3 fractions (3 patients); 50 Gy/5 fractions (2 patients); and 30 Gy/1 fraction (1 patient). One patient received chemotherapy (CHT) before SBRT. One patient died of a brain aneurysm soon after SBRT and never received either planned CHT or PCI. This patient was also 1 of the total 2 patients who died before receiving PCI. With respect to outcomes, median follow-up at the time of analysis was 11.9 months. No grade 3 or higher toxicity was noted, with 1 grade 2 toxicity (chest wall). Figure 2 presents overall and disease-free survival curves for this series. Three patients were alive at analysis and 3 had died of non-cancer causes, although 1 did have distant disease at time of death. At 1 year, local control was 100%, there were no regional nodal failures, and 1 patient developed distant failure in the form of liver metastases. Overall and disease-free survivals at 1 year were 63% and 75%, respectively.
Discussion
Figure 2 (A) Overall and (B) disease-free survival for 6 medically inoperable early-stage small cell lung cancer patients treated with stereotactic body radiation therapy (SBRT), chemotherapy, and prophylactic cranial irradiation. MST, median survival time.
To our knowledge, this is the first reported series describing the utility of SBRT in the management of medically inoperable early-stage SCLC. Mindful of the rarity of this disease presentation and the smallness of this present series, this report was intended to highlight new perspectives on expanding the range of the role of SBRT in treating lung cancer in selected high-risk patients. First, it demonstrates that the same outcomes that have now become expected with SBRT for medically inoperable early-stage NSCLC; ie, feasibility, safety, excellent disease control, minimal toxicity, and potential survival benefits, 6 may be achievable for special presentations of SCLC. Given the generic mechanisms by which radiation therapy works combined with the recognized radiosensitivity of small cell disease, we hoped to produce at least equivalent local control rates for SCLC from SBRT as seen for NSCLC. The local control rate of 100% seen for this series supports this hypothesis, although we recognize that the number of patients is small and the follow-up ongoing. Second, as with the medically inoperable NSCLC population, this study supports the utility of PET in staging patients specifically with respect to the mediastinum. Although the gold standard in lung cancer remains mediastinoscopy, this procedure is rarely used in SBRT NSCLC patients given the fragility of this population, and clinical results to date suggest that regional nodal failure
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after PET staging prior to SBRT is b 10%, with distant failure predominating. 6 This same pattern is now seen in the current series of SCLC patients such that regional nodal failure after SBRT was not seen for the 5 of 6 patients who had no pathologic staging of the nodes. This series also suggests that in the event of undetectable or occult microscopic nodal disease, chemotherapy may be sufficient to control the PET-negative mediastinum, without the need for radiation therapy. Third, it suggests that the feasibility role of systemic therapy in vulnerable populations needs to be carefully studied. Prospective randomized data do not in general support the routine use of adjuvant platinum-based chemotherapy for patients with resected stage I NSCLC. 13 In the medically inoperable NSCLC population treated with SBRT, there has been even less expectation of defining a role for adjuvant chemotherapy since the population has been generally judged too frail to tolerate conventional systemic therapies. However, since the dominant form of failure after SBRT, like surgery, appears to be distant metastatic disease, 6 there has been interest in exploring the possibility of adjuvant agents in selected inoperable patients, especially with the advent of “targeted” or biologic therapies to mitigate toxicities. In contrast, there has been routine use of adjuvant chemotherapy in the setting of resected early-stage SCLC, based on a number of historical series that have suggested improvements in survival when it is used. 1 Likewise, PCI has also been recommended for such patients because high relapse rates in the brain have also been observed with pathologic stage I disease. 1 The present series suggests that for some medically inoperable populations, curative systemic therapies may be possible to administer and can be tolerated by patients. Our observation has encouraged us to more actively investigate the role of adjuvant therapies in properly selected medically inoperable NSCLC patients. Fourth, a SBRT-based approach to stage I SCLC appears to have many advantages over the form of conventional chemoradiation therapy used in limitedstage disease, especially with respect to toxicity. Radiation therapy and chemotherapy are not given concurrently, thus preventing additive toxicities. SBRT by definition involves no elective nodal irradiation and therefore does not produce significant mediastinal or esophageal toxicity. Also, unlike conventional limited-stage radiation therapy, the timing of SBRT need not be linked to the initiation of chemotherapy in order to still achieve excellent locoregional control. Lastly, among the most provocative findings published in the lung cancer SBRT literature have been the results of Onishi et al, 14 in which the survival of a subgroup of medically operable patients treated with SBRT was comparable with similar-stage patients treated with video-assisted thorascopic surgery or lobectomy and defining the role of SBRT in potentially operable
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patients is becoming an active area of investigation. As with SBRT in NSCLC, it may be appropriate to consider the utility of SBRT in operable early-stage SCLC patients to mitigate surgery-related morbidity in order to be able to transition more rapidly to the adjuvant chemotherapy and PCI required for improving survival in this disease.
Conclusions This novel case series suggests that SBRT for stage I medically inoperable SCLC results in an excellent rate of local control, which is comparable with the data reported for medically inoperable early-stage NSCLC patients treated with SBRT. Disease-specific survival is encouraging, and as with medically inoperable NSCLC patients, non-cancer comorbidities contribute significantly to mortality. The absence of regional nodal failure lends support to the sole use of PET for characterizing the mediastinal nodes and suggests that radiation therapy is not needed to control a PET-negative mediastinum. Administration of platinum-based CHT was feasible in this inoperable series and lends support to the possibility of adjuvant chemotherapy in selected inoperable early-stage NSCLC patients managed with SBRT.
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