Stereotactic ablative radiotherapy for early stage lung cancer and lung metastases in a New Zealand population
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Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted external beam radiation in a shorter time period and with fewer treatments than conventional radiotherapy. Leksell first described the concept of stereotactic radiosurgery in 1951.1 Initially, however, its use was restricted to intracranial targets. With advancements in linear accelerator technology, the use of stereotactic techniques was expanded to extracranial targets in the 1990s.2
Lung cancer remains the leading cause of cancer death in New Zealand.3 Only 16.5% of lung cancer in New Zealand is diagnosed at an early stage. Māori patients are more likely to be diagnosed at a later stage4,5 and less likely to receive curative surgery than non-Māori patients.6 Early international studies investigating the use of SABR for inoperable patients with early stage lung cancer demonstrated a local control rate of >85% at three years with a grade three or higher toxicity rate of <4%.7
Meanwhile, increased interest and evidence in treating oligometastatic disease with curative intent has led to the application of SABR in the metastatic setting.8–10 SABR is sometimes considered more favourable than pulmonary metastasectomy due to its non-invasive nature and low morbidity. Two-year local control rates for pulmonary metastases have been found to be in the region of 80% internationally.11
The aim of our study was to compare the outcomes of lung-based SABR treatment in a New Zealand cohort to the global literature.
Methods
Study design
A retrospective analysis was performed on all patients who received SABR to a lung mass between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included patients treated in the primary and metastatic setting. Data on patient demographics, tumour characteristics and dosing schedules were collected from electronic medical records. Outcomes, including recurrence and toxicity rates, were collected by review of clinical letters and imaging reports. Toxicities were graded as per the RTOG 0236 schema.12
Patient selection
All patients were discussed through the lung cancer multidisciplinary meeting (MDM), and their eligibility for SABR was based on the departmental guideline. Patients with T1N0M0 or T2aN0M0 (<5cm) non-small cell lung cancer who had an expected survival of more than one year and were not fit for or refused surgery were assessed for SABR. Each patient’s performance status was considered in the context of the underlying morbidity and life expectancy. Patients with oligometastatic lung disease with <2 lesions <5cm in size with stable extra-thoracic disease were included. Staging with PET-CT was performed less than six weeks prior to SABR. Attempts were routinely made to obtain a histologic diagnosis, unless that was deemed not possible for safety or other technical reasons.
Procedures
Patient immobilisation was achieved using an extended vacuum bag with the patient in the supine position with elevated arms. A planning scan with a 4D CT and standard 3D CT without contrast was performed. An internal target volume (ITV) was directly contoured at maximal intensity projection. The planning target volume (PTV) was defined by adding a 5mm margin to the ITV.
The default dosing schedule was 54Gy in three fractions. If the PTV included the chest wall, a dose of 48Gy in four fractions was selected, and if the PTV was within 2cm of the central mediastinal structures, a dose of 60Gy in eight fractions was utilised. This reflects the protocols in the CHISEL study and a Dutch study, respectively.13,14 Deviation from this guideline was permitted at the discretion of the treating radiation oncologist. Dose constraints to at-risk organs were defined as per the RTOG 0618 protocol.15
Outcomes
Follow-up time was defined as the time from completion of SABR to the latest clinic visit or thoracic imaging (whichever was more recent). The primary outcome measured was the local control rate. Secondary outcomes were progression-free survival (PFS), overall survival and toxicity profile. Local failure was determined on serial CT chest imaging every three to six months. Local failure was defined as an enlarging lesion with radiological features consistent with recurrence, such as an enlarging solid or necrotic component or a bulging margin. Progression-free survival was defined as the time from completion of the SABR treatment to progression or death from any cause. Overall survival was defined as the time from treatment completion to death from any cause.
Statistical analysis
Statistical analysis was executed using Microsoft Excel and IBM SPSS Statistics Subscription version 1.0.0.1327. The Kaplan–Meier method was used to report overall survival and progression-free survival. Univariate Cox regression analysis was performed to investigate the association of survival time with other variables. Age and tumour size were analysed as continuous variables. ECOG (<2; >2), smoking status (current smoker; not current smoker), ethnicity (Māori; non-Māori) and tumour location (central; peripheral) were analysed as categorical variables. A central tumour was defined as that with a PTV within 2cm of central mediastinal structures.16
Results
Baseline characteristics
Between May 2015 and September 2019, 102 patients (116 lesions) received SABR treatment. One patient received treatment to four lesions. This patient had sequential treatment to two lesions followed by concurrent SABR to a further two lesions at relapse. Eleven patients received SABR to two lesions: seven concurrently, three sequentially and one at relapse. The mean age of the cohort was 70 years (interquartile range: 63–75). Median follow-up was 19 months (95%CI 17–22; range: 0–52 months). Table 1 details the baseline patient characteristics.
Table 1: Patient characteristics.
Following discussion at MDMs, 86 (74%) of the lesions were considered early stage lung cancer and 30 (26%) were considered metastatic disease to the lung. The number of lesions that measured less than or equal to three centimetres was 101 (87%). Of those considered lung cancer primaries, 45 (52%) did not have confirmative histology. Tumour characteristics are detailed in Table 2.
Table 2: Tumour characteristics.
Twenty-two patients received SABR treatment to 30 oligometastatic lung lesions. The majority of patients (13, 59%) had a colorectal primary. Two patients had metastatic melanoma, and there was one case each of breast cancer, liposarcoma, pancreatic cancer (neuroendocrine), mixed follicular/papillary thyroid carcinoma, lung cancer (squamous cell carcinoma), meningioma and pheochromocytoma. Eight (27%) of the metastatic lesions had confirmative histology.
Of all early stage lung cancer lesions, 64 (74%) were considered medically inoperable and 11 (13%) were considered clinically inappropriate for surgery. Eleven (13%) patients were offered surgery but opted against it. Patients were considered clinically inappropriate for surgery at MDM if there were multiple suspicious pulmonary nodules, a history of another active malignancy or prior thoracic surgery. A PET-CT was used in the diagnostic work-up of 96% of all primary lesions.
Radiotherapy treatment
The most common dose, received by 50% of the cohort, was 48Gy in four fractions with two fractions per week. Thirty percent of the cohort received 60Gy in eight fractions and 10% received 54Gy in three fractions. The other 10% were prescribed a different dosing schedule. Table 3 details the dosing schedules used. One patient abandoned treatment after one fraction due to the progression of the disease noted during the planning process. Five patients in the primary lung cancer cohort received a biologically effect dose (BED) of <100Gy. A BED of >100Gy (p=0.68) was received by 93% of Māori and 95% of non-Māori. There was no observed difference in local control with increased BED (HR0.99 (0.95–1.04) p=0.88).
Table 3: Dosing schedules.
Local control
Local failure developed in 9% (8/86) of lesions in the primary lung cancer cohort and 13% (4/30) of lesions in the metastatic disease cohort. The median time to local failure was 16 months (95%CI: 8–19). Figure 1 details the local control for all lesions. The actuarial three-year rate of local control was 85% (95%CI: 73–97%) in early stage lung cancer and 82% (95%CI: 66–98%) in oligometastatic disease. Central early stage lung cancers had a significantly higher risk of local recurrence than peripheral lesions on univariate Cox regression analysis (HR6.4 (95%CI: 1.3–31.5) p=0.02). Table 4 details the rate and type of locoregional recurrence in each cohort at end of follow-up.
Figure 1: Local control for all lesions.
Table 4: Locoregional recurrence.
Survival outcomes in early stage lung cancer
The first site of recurrence in patients with early stage lung cancer was local in 22% and regional or distant in 78%. Of the patients originally treated for a primary tumour, 11 (14%) had developed distant metastasis and 16 (20%) had died at end of follow-up. The actuarial three-year rate of progression-free survival and overall survival in early stage lung cancer was 56% (95%CI: 40–72%) and 71% (95%CI: 57–85%) respectively. Figure 2 demonstrates the progression-free survival and overall survival in this cohort. There was no difference in progression-free survival with tumour size (HR1.3 p=0.18), increased age (HR1.02 p=0.46), smoking status (HR0.8 p=0.61) or ECOG performance status (HR1.4 p=0.46).
Figure 2: Progression-free survival and overall survival in early stage lung cancer.
Māori ethnicity
Māori patients with early stage lung cancer had a worse progression-free survival compared to non-Māori patients (HR2.4 (95%CI: 1.1–5.1) p=0.03). Median PFS in Māori and non-Māori patients was 24 months and 41 months, respectively. There was no significant difference in overall survival between Māori and non-Maori Māori patients: median 42 months (95% CI: 21–62) vs 46 months (95% CI: 32–59), respectively (HR1.6 (95%CI: 0.6–4.2) p=0.34). The mean primary lung cancer lesion size in the Māori and non-Māori cohorts was 2.3cm and 2.18cm respectively (p=0.78). Central tumours accounted for 40.7% and 34.5% of the Māori and non-Māori cohorts respectively (p=0.58).
Confirmative histology
The presence of confirmative histology in patients with primary lung cancer was not associated with a difference in local control (HR3.2 (95%CI: 0.6–15.8) p=0.16) or overall survival (HR1.6 (95%CI: 0.6–4.2) p=0.35).
Survival outcomes in the oligometastatic cohort
Of the metastatic cohort, 8/22 patients (36%) had developed further distant metastasis and three patients (14%) had died at end of follow-up. The actuarial three-year progression-free survival and overall survival rates were 26% (95%CI: 3–49%) and 73% (95%CI: 46–100%), respectively. Figure 3 illustrates the corresponding Kaplan–Meier curves. Median progression-free survival was 19 months (95%CI: 10–27). Of the twelve patients who progressed after receiving SABR for metastatic disease, eight proceeded to further antineoplastic therapy and four did not. Colorectal malignancies represented 7/12 (58%) of those that progressed. The median time to subsequent therapy was 13 months.
Figure 3: Progression-free survival and overall survival in oligometastatic disease.
Toxicity profile
There were no reported grade three side effects. The most common toxicity reported was chest wall pain (9%). Two patients developed a grade two rib fracture (2%). All five patients who developed grade two chest wall pain or rib fracture had received SABR to a peripheral lesion. The rate of pneumonitis was 4.7% in central lesions and 1.3% in peripheral lesions.
Discussion
This single-centre retrospective study evaluated the use of SABR in a typical radiotherapy setting in New Zealand. This is the largest series to date on the use of SABR in New Zealand. Reflecting its typical use, the study included SABR treatments to both early stage lung cancer and pulmonary metastases.
Surgery is generally considered the treatment of choice in medically operable early stage lung cancers. The American Society for Radiation Oncology guidelines state that SABR is not recommended for patients with standard operative risk.7 To date, there are no completed randomised controlled trials that directly compare the outcomes of surgery and SABR in the treatment of early stage lung cancer. However, Chang et al combined data from two such trials that closed early (due to slow accrual) and reported no significant difference in local or distant control between the surgical and SABR cohorts.17 A meta-analysis that examined 40 SABR studies and 23 surgery studies demonstrated no difference in estimated overall or disease-free survival after adjustment for the proportion of operable patients and age.18 After discussion at MDM, 13% of our primary cohort were deemed medically operable but opted against surgery.
Two randomised studies, the CHISEL and SPACE trials, compared SABR and conventional external beam radiotherapy (EBRT) for the treatment of inoperable early stage lung cancer.13,19 The CHISEL trial demonstrated a significant improvement in local control with SABR compared to EBRT: the two-year rates were 89% and 65%, respectively. The SPACE trial demonstrated a local control rate of 86% in both arms at the end of a three-year median follow-up. Our study demonstrates a reproducible local control rate of 85% at three years in patients who were treated with SABR for early stage lung cancer.
Fifty-two percent of our cohort who were treated for an early stage lung cancer proceeded to SABR without confirmative histology. There was no significant difference in local control or overall survival when confirmative histology was available. A Dutch study, with a larger cohort, has also demonstrated no difference in local control or overall survival in patients who had a pathological or clinical diagnosis of early stage lung cancer.20 The clinical diagnosis was based on a new or increasing FDG avid mass on PET-CT. Ninety-six percent of all primary lesions had a PET-CT as part of their diagnostic work-up in our study.
National statistics report that the incidence of lung cancer in Māori is over three times higher than in non-Māori and that Māori are more likely to be diagnosed at a later stage.5 Māori also have a significantly higher risk of cancer-specific mortality, even after the statistics are adjusted for age and stage at diagnosis. In our study, progression-free survival was significantly worse in the Māori cohort with early stage lung cancer, and although it was not statistically significant, overall survival was lower in the Māori cohort. This raises the question of possible differences in tumour biology or a genetic susceptibility to aggressive disease. Further research to evaluate this variability may ultimately guide clinical practice.
The site of first recurrence was outside the local treatment field in 78% in our study and 55% in the CHISEL trial.13 No patient or tumour factor, other than ethnicity, was associated with a worse progression-free survival.
Hellman and Weichselbaum first described the term ‘oligometastases‘ in 1995 as an intermediate tumour state between localised and widely metastatic disease, with limited metastatic capacity and the potential for treatment with curative intent.21 The SABR-COMET trial demonstrated a significant improvement in progression-free survival and overall survival in patients with oligometastatic disease who were randomly assigned to SABR or standard palliative care.9 Median progression-free survival with SABR was 12 months in the SABR-COMET trial and 19 months in our study. At three years, approximately one quarter of patients in our cohort with oligometastatic disease had not developed progression. In patients who did developed progression, the use of SABR delayed the need for subsequent therapy by a median of 13 months.
A German study that investigated the use of SABR for pulmonary metastases in seven hundred patients reported a local control rate of 81% and an overall survival rate of 54% at two years.22 In this study, pulmonary metastases treated with SABR had a three-year actuarial local control of 82% and an overall survival rate of 73%.
The disparity between rates of local control and progression-free survival in both the primary and metastatic cohorts highlights the risk of distant metastasis despite achieving local control. Several practical aspects need to be considered with regard to pursuing systemic therapies after SABR in this population. First, there is currently insufficient evidence to support the use of adjuvant systemic therapy after definitive SABR for limited lung metastases or early stage lung cancer. Thus, subjecting patients to potentially toxic therapies may not be justified when the benefit is unclear. Second, in the absence of measurable primary disease, it is difficult to determine whether an oligometastatic lesion is truly representative of an isolated single clone, or whether it is a part of a more widely disseminated disease process. For example, distant recurrences in breast cancer have been shown to have an evolutionary root from late drivers of resected primary tumours.23 Third, determination of histopathology and mutational profile is increasingly important in treatment decisions in early stage lung cancer, and there is emerging data to support the use of adjuvant targeted therapies after complete resection.24 Given many uncertainties remain unanswered, pragmatic trials should be designed to assess the benefits of systemic therapy after SABR in this heterogeneous, co-morbid population.
Timmerman et al demonstrated an 11-fold increased risk of severe toxicity when SABR was targeted to central compared to peripheral tumours.25 No grade three or higher toxicity was identified in our study. The adjustment of dosing schedules for central tumours may have contributed to this outcome. In contrast, the RTOG 0236 study reported a grade three to grade four toxicity rate of 16%. However, the toxicity rates in this RTOG study included a decline in pulmonary function tests, which were not routinely evaluated in our cohort.12
The limitations of this study include its retrospective nature, the frequent absence of confirmative histology and the variability of the dosing schedules used. However, this variability reflects real-world use of SABR outside the clinical trial setting.
This series demonstrates that the use of SABR in the New Zealand population largely mirrors the outcomes in the global literature. The challenges faced in the clinical decision-making of these patients stem from the scarcity of randomised trials available, the frequent failure to acquire confirmative histology and the complexity of detecting recurrent disease on imaging after treatment. Further randomised studies could determine whether the use of SABR is equivalent to surgery in early stage lung cancer or oligometastatic disease and define the threshold of both the number and size of lesions effectively treated with SABR.
Summary
Abstract
AIM: Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted radiation in a shorter time period than conventional radiotherapy. The aim of this study was to compare the outcomes of lung-based SABR in a New Zealand cohort to the global literature. METHODS: A single-institution retrospective analysis was performed on all patients who received lung-based SABR between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included both early stage lung cancer and lung oligometastases that measured less than 5cm. RESULTS: 102 patients received SABR to 116 lesions. Median follow-up was 19 months. The three-year rate of local control in the primary and metastatic cohorts was 85% and 82%, respectively. This reflects the three-year local control rate of 86% for primary lung cancer in the SPACE trial and the two-year local control rate of 81% for pulmonary oligometastases in a German study. Central primary lung cancer was associated with a higher risk of local recurrence (HR6.4 (1.3–31.5) p=0.02). The three-year progression-free survival rate in patients with early stage lung cancer and oligometastases was 56% and 26%, respectively. Māori patients with primary lung cancer had a significantly worse progression free survival (HR2.4 (1.1–5.1) p=0.03). There were no reported grade three toxicities. CONCLUSION: The use of lung-based SABR in a typical radiotherapy setting in New Zealand mirrors global outcomes.
Aim
Method
Results
Conclusion
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand. 1951;102(4);316-9
2. White A, Swanson SJ. Surgery versus stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer: less is not more. J Thorac Dis. 2016;8(Suppl 4):S399-S405. doi:10.21037/jtd.2016.04.40
3. Elwood JM, Aye PS, Tin S. Increasing Disadvantages in Cancer Survival in New Zealand Compared to Australia, between 2000-05 and 2006-10. PLoS One. 2016;11:e0150734. doi:10.1371/journal.pone.0150734
4. Lawrenson R, Lao C, Brown L, et al. Characteristics of lung cancers and accuracy and completeness of registration in the New Zealand Cancer Registry. N Z Med J. 2018;131:13-23.
5. Health.govt.nz. New Zealand: Unequal Impact: Maori and Non Maori Cancer Statistics 1996-2001; c2006-05. Available from: https://www.health.govt.nz/publication/unequal-impact-maori-and-non-maori-cancer-statistics-1996-2001
6. Lawrenson R, Lao C, Brown L et al. Management of patients with early stage lung cancer – why do some patients not receive treatment with curative intent? BMC Cancer. 2020;20(1):109). doi: 10.1186/s12885-020-6580-6
7. Videtic GMM, Donington J, Giuliani M, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7:295-301. doi:10.1016/j.prro.2017.04.014
8. Agolli L, Bracci S, Nicosia L, Valeriani M, De Sanctis V, Osti MF. Lung Metastases Treated With Stereotactic Ablative Radiation Therapy in Oligometastatic Colorectal Cancer Patients: Outcomes and Prognostic Factors After Long-Term Follow-Up. Clin Colorectal Cancer. 2017;16:58-64. doi:10.1016/j.clcc.2016.07.004
9. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838. doi:10.1200/JCO.20.00818
10. Buglione M, Jereczek-Fossa BA, Bonù ML, et al. Radiosurgery and fractionated stereotactic radiotherapy in oligometastatic/oligoprogressive non-small cell lung cancer patients: Results of a multi-institutional series of 198 patients treated with "curative" intent. Lung Cancer. 2020;141:1-8. doi:10.1016/j.lungcan.2019.12.019
11. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol. 2013;14:e28-e37. doi:10.1016/S1470-2045(12)70510-7
12. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070-1076. doi:10.1001/jama.2010.261
13. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019;20:494-503. doi:10.1016/S1470-2045(18)30896-9
14. Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol. 2011;6:2036-2043. doi:10.1097/JTO.0b013e31822e71d8
15. Timmerman RD, Paulus R, Pass HI, et al. Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial. JAMA Oncol. 2018;4:1263-1266. doi:10.1001/jamaoncol.2018.1251
16. Chang JY, Beezjak A, Mornex F. Stereotactic Ablative Radiotherapy for Centrally Located Early Stage Non-Small Cell Lung Cancer: What We Have Learned. J Thorac Oncol. 2015;10(4):577-85. doi: 10.1097/JTO.0000000000000453
17. Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials [published correction appears in Lancet Oncol. 2015 Sep;16(9):e427]. Lancet Oncol. 2015;16:630-637. doi:10.1016/S1470-2045(15)70168-3
18. Zheng X, Schipper M, Kidwell K, et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis. Int J Radiat Oncol Biol Phys. 2014;90:603-611. doi:10.1016/j.ijrobp.2014.05.055
19. Nyman J, Hallqvist A, Lund JÅ, et al. SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiother Oncol. 2016;121:1-8. doi:10.1016/j.radonc.2016.08.015
20. Verstegen NE, Lagerwaard FJ, Haasbeek CJ et al. Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: comparison with a contemporaneous cohort with pathologically proven disease. Radiother Oncol. 2011;101:250-254. doi:10.1016/j.radonc.2011.09.017
21. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13:8-10. doi:10.1200/JCO.1995.13.1.8
22. Rieber J, Streblow J, Uhlmann L, et al. Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy". Lung Cancer. 2016;97:51-58. doi:10.1016/j.lungcan.2016.04.012
23. Yates LR, Knappskog S, Wedge D, et al. Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell. 2017;32:169-184.e7. doi:10.1016/j.ccell.2017.07.005
24. Herbst RS, Tsuboi M, John T et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38:18 suppl (abstr). doi: 10.1200/JCO.2020.38.18_suppl.LBA5
25. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833-4839. doi:10.1200/JCO.2006.07.5937
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Stereotactic ablative radiotherapy for early stage lung cancer and lung metastases in a New Zealand population
View Article PDF
Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted external beam radiation in a shorter time period and with fewer treatments than conventional radiotherapy. Leksell first described the concept of stereotactic radiosurgery in 1951.1 Initially, however, its use was restricted to intracranial targets. With advancements in linear accelerator technology, the use of stereotactic techniques was expanded to extracranial targets in the 1990s.2
Lung cancer remains the leading cause of cancer death in New Zealand.3 Only 16.5% of lung cancer in New Zealand is diagnosed at an early stage. Māori patients are more likely to be diagnosed at a later stage4,5 and less likely to receive curative surgery than non-Māori patients.6 Early international studies investigating the use of SABR for inoperable patients with early stage lung cancer demonstrated a local control rate of >85% at three years with a grade three or higher toxicity rate of <4%.7
Meanwhile, increased interest and evidence in treating oligometastatic disease with curative intent has led to the application of SABR in the metastatic setting.8–10 SABR is sometimes considered more favourable than pulmonary metastasectomy due to its non-invasive nature and low morbidity. Two-year local control rates for pulmonary metastases have been found to be in the region of 80% internationally.11
The aim of our study was to compare the outcomes of lung-based SABR treatment in a New Zealand cohort to the global literature.
Methods
Study design
A retrospective analysis was performed on all patients who received SABR to a lung mass between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included patients treated in the primary and metastatic setting. Data on patient demographics, tumour characteristics and dosing schedules were collected from electronic medical records. Outcomes, including recurrence and toxicity rates, were collected by review of clinical letters and imaging reports. Toxicities were graded as per the RTOG 0236 schema.12
Patient selection
All patients were discussed through the lung cancer multidisciplinary meeting (MDM), and their eligibility for SABR was based on the departmental guideline. Patients with T1N0M0 or T2aN0M0 (<5cm) non-small cell lung cancer who had an expected survival of more than one year and were not fit for or refused surgery were assessed for SABR. Each patient’s performance status was considered in the context of the underlying morbidity and life expectancy. Patients with oligometastatic lung disease with <2 lesions <5cm in size with stable extra-thoracic disease were included. Staging with PET-CT was performed less than six weeks prior to SABR. Attempts were routinely made to obtain a histologic diagnosis, unless that was deemed not possible for safety or other technical reasons.
Procedures
Patient immobilisation was achieved using an extended vacuum bag with the patient in the supine position with elevated arms. A planning scan with a 4D CT and standard 3D CT without contrast was performed. An internal target volume (ITV) was directly contoured at maximal intensity projection. The planning target volume (PTV) was defined by adding a 5mm margin to the ITV.
The default dosing schedule was 54Gy in three fractions. If the PTV included the chest wall, a dose of 48Gy in four fractions was selected, and if the PTV was within 2cm of the central mediastinal structures, a dose of 60Gy in eight fractions was utilised. This reflects the protocols in the CHISEL study and a Dutch study, respectively.13,14 Deviation from this guideline was permitted at the discretion of the treating radiation oncologist. Dose constraints to at-risk organs were defined as per the RTOG 0618 protocol.15
Outcomes
Follow-up time was defined as the time from completion of SABR to the latest clinic visit or thoracic imaging (whichever was more recent). The primary outcome measured was the local control rate. Secondary outcomes were progression-free survival (PFS), overall survival and toxicity profile. Local failure was determined on serial CT chest imaging every three to six months. Local failure was defined as an enlarging lesion with radiological features consistent with recurrence, such as an enlarging solid or necrotic component or a bulging margin. Progression-free survival was defined as the time from completion of the SABR treatment to progression or death from any cause. Overall survival was defined as the time from treatment completion to death from any cause.
Statistical analysis
Statistical analysis was executed using Microsoft Excel and IBM SPSS Statistics Subscription version 1.0.0.1327. The Kaplan–Meier method was used to report overall survival and progression-free survival. Univariate Cox regression analysis was performed to investigate the association of survival time with other variables. Age and tumour size were analysed as continuous variables. ECOG (<2; >2), smoking status (current smoker; not current smoker), ethnicity (Māori; non-Māori) and tumour location (central; peripheral) were analysed as categorical variables. A central tumour was defined as that with a PTV within 2cm of central mediastinal structures.16
Results
Baseline characteristics
Between May 2015 and September 2019, 102 patients (116 lesions) received SABR treatment. One patient received treatment to four lesions. This patient had sequential treatment to two lesions followed by concurrent SABR to a further two lesions at relapse. Eleven patients received SABR to two lesions: seven concurrently, three sequentially and one at relapse. The mean age of the cohort was 70 years (interquartile range: 63–75). Median follow-up was 19 months (95%CI 17–22; range: 0–52 months). Table 1 details the baseline patient characteristics.
Table 1: Patient characteristics.
Following discussion at MDMs, 86 (74%) of the lesions were considered early stage lung cancer and 30 (26%) were considered metastatic disease to the lung. The number of lesions that measured less than or equal to three centimetres was 101 (87%). Of those considered lung cancer primaries, 45 (52%) did not have confirmative histology. Tumour characteristics are detailed in Table 2.
Table 2: Tumour characteristics.
Twenty-two patients received SABR treatment to 30 oligometastatic lung lesions. The majority of patients (13, 59%) had a colorectal primary. Two patients had metastatic melanoma, and there was one case each of breast cancer, liposarcoma, pancreatic cancer (neuroendocrine), mixed follicular/papillary thyroid carcinoma, lung cancer (squamous cell carcinoma), meningioma and pheochromocytoma. Eight (27%) of the metastatic lesions had confirmative histology.
Of all early stage lung cancer lesions, 64 (74%) were considered medically inoperable and 11 (13%) were considered clinically inappropriate for surgery. Eleven (13%) patients were offered surgery but opted against it. Patients were considered clinically inappropriate for surgery at MDM if there were multiple suspicious pulmonary nodules, a history of another active malignancy or prior thoracic surgery. A PET-CT was used in the diagnostic work-up of 96% of all primary lesions.
Radiotherapy treatment
The most common dose, received by 50% of the cohort, was 48Gy in four fractions with two fractions per week. Thirty percent of the cohort received 60Gy in eight fractions and 10% received 54Gy in three fractions. The other 10% were prescribed a different dosing schedule. Table 3 details the dosing schedules used. One patient abandoned treatment after one fraction due to the progression of the disease noted during the planning process. Five patients in the primary lung cancer cohort received a biologically effect dose (BED) of <100Gy. A BED of >100Gy (p=0.68) was received by 93% of Māori and 95% of non-Māori. There was no observed difference in local control with increased BED (HR0.99 (0.95–1.04) p=0.88).
Table 3: Dosing schedules.
Local control
Local failure developed in 9% (8/86) of lesions in the primary lung cancer cohort and 13% (4/30) of lesions in the metastatic disease cohort. The median time to local failure was 16 months (95%CI: 8–19). Figure 1 details the local control for all lesions. The actuarial three-year rate of local control was 85% (95%CI: 73–97%) in early stage lung cancer and 82% (95%CI: 66–98%) in oligometastatic disease. Central early stage lung cancers had a significantly higher risk of local recurrence than peripheral lesions on univariate Cox regression analysis (HR6.4 (95%CI: 1.3–31.5) p=0.02). Table 4 details the rate and type of locoregional recurrence in each cohort at end of follow-up.
Figure 1: Local control for all lesions.
Table 4: Locoregional recurrence.
Survival outcomes in early stage lung cancer
The first site of recurrence in patients with early stage lung cancer was local in 22% and regional or distant in 78%. Of the patients originally treated for a primary tumour, 11 (14%) had developed distant metastasis and 16 (20%) had died at end of follow-up. The actuarial three-year rate of progression-free survival and overall survival in early stage lung cancer was 56% (95%CI: 40–72%) and 71% (95%CI: 57–85%) respectively. Figure 2 demonstrates the progression-free survival and overall survival in this cohort. There was no difference in progression-free survival with tumour size (HR1.3 p=0.18), increased age (HR1.02 p=0.46), smoking status (HR0.8 p=0.61) or ECOG performance status (HR1.4 p=0.46).
Figure 2: Progression-free survival and overall survival in early stage lung cancer.
Māori ethnicity
Māori patients with early stage lung cancer had a worse progression-free survival compared to non-Māori patients (HR2.4 (95%CI: 1.1–5.1) p=0.03). Median PFS in Māori and non-Māori patients was 24 months and 41 months, respectively. There was no significant difference in overall survival between Māori and non-Maori Māori patients: median 42 months (95% CI: 21–62) vs 46 months (95% CI: 32–59), respectively (HR1.6 (95%CI: 0.6–4.2) p=0.34). The mean primary lung cancer lesion size in the Māori and non-Māori cohorts was 2.3cm and 2.18cm respectively (p=0.78). Central tumours accounted for 40.7% and 34.5% of the Māori and non-Māori cohorts respectively (p=0.58).
Confirmative histology
The presence of confirmative histology in patients with primary lung cancer was not associated with a difference in local control (HR3.2 (95%CI: 0.6–15.8) p=0.16) or overall survival (HR1.6 (95%CI: 0.6–4.2) p=0.35).
Survival outcomes in the oligometastatic cohort
Of the metastatic cohort, 8/22 patients (36%) had developed further distant metastasis and three patients (14%) had died at end of follow-up. The actuarial three-year progression-free survival and overall survival rates were 26% (95%CI: 3–49%) and 73% (95%CI: 46–100%), respectively. Figure 3 illustrates the corresponding Kaplan–Meier curves. Median progression-free survival was 19 months (95%CI: 10–27). Of the twelve patients who progressed after receiving SABR for metastatic disease, eight proceeded to further antineoplastic therapy and four did not. Colorectal malignancies represented 7/12 (58%) of those that progressed. The median time to subsequent therapy was 13 months.
Figure 3: Progression-free survival and overall survival in oligometastatic disease.
Toxicity profile
There were no reported grade three side effects. The most common toxicity reported was chest wall pain (9%). Two patients developed a grade two rib fracture (2%). All five patients who developed grade two chest wall pain or rib fracture had received SABR to a peripheral lesion. The rate of pneumonitis was 4.7% in central lesions and 1.3% in peripheral lesions.
Discussion
This single-centre retrospective study evaluated the use of SABR in a typical radiotherapy setting in New Zealand. This is the largest series to date on the use of SABR in New Zealand. Reflecting its typical use, the study included SABR treatments to both early stage lung cancer and pulmonary metastases.
Surgery is generally considered the treatment of choice in medically operable early stage lung cancers. The American Society for Radiation Oncology guidelines state that SABR is not recommended for patients with standard operative risk.7 To date, there are no completed randomised controlled trials that directly compare the outcomes of surgery and SABR in the treatment of early stage lung cancer. However, Chang et al combined data from two such trials that closed early (due to slow accrual) and reported no significant difference in local or distant control between the surgical and SABR cohorts.17 A meta-analysis that examined 40 SABR studies and 23 surgery studies demonstrated no difference in estimated overall or disease-free survival after adjustment for the proportion of operable patients and age.18 After discussion at MDM, 13% of our primary cohort were deemed medically operable but opted against surgery.
Two randomised studies, the CHISEL and SPACE trials, compared SABR and conventional external beam radiotherapy (EBRT) for the treatment of inoperable early stage lung cancer.13,19 The CHISEL trial demonstrated a significant improvement in local control with SABR compared to EBRT: the two-year rates were 89% and 65%, respectively. The SPACE trial demonstrated a local control rate of 86% in both arms at the end of a three-year median follow-up. Our study demonstrates a reproducible local control rate of 85% at three years in patients who were treated with SABR for early stage lung cancer.
Fifty-two percent of our cohort who were treated for an early stage lung cancer proceeded to SABR without confirmative histology. There was no significant difference in local control or overall survival when confirmative histology was available. A Dutch study, with a larger cohort, has also demonstrated no difference in local control or overall survival in patients who had a pathological or clinical diagnosis of early stage lung cancer.20 The clinical diagnosis was based on a new or increasing FDG avid mass on PET-CT. Ninety-six percent of all primary lesions had a PET-CT as part of their diagnostic work-up in our study.
National statistics report that the incidence of lung cancer in Māori is over three times higher than in non-Māori and that Māori are more likely to be diagnosed at a later stage.5 Māori also have a significantly higher risk of cancer-specific mortality, even after the statistics are adjusted for age and stage at diagnosis. In our study, progression-free survival was significantly worse in the Māori cohort with early stage lung cancer, and although it was not statistically significant, overall survival was lower in the Māori cohort. This raises the question of possible differences in tumour biology or a genetic susceptibility to aggressive disease. Further research to evaluate this variability may ultimately guide clinical practice.
The site of first recurrence was outside the local treatment field in 78% in our study and 55% in the CHISEL trial.13 No patient or tumour factor, other than ethnicity, was associated with a worse progression-free survival.
Hellman and Weichselbaum first described the term ‘oligometastases‘ in 1995 as an intermediate tumour state between localised and widely metastatic disease, with limited metastatic capacity and the potential for treatment with curative intent.21 The SABR-COMET trial demonstrated a significant improvement in progression-free survival and overall survival in patients with oligometastatic disease who were randomly assigned to SABR or standard palliative care.9 Median progression-free survival with SABR was 12 months in the SABR-COMET trial and 19 months in our study. At three years, approximately one quarter of patients in our cohort with oligometastatic disease had not developed progression. In patients who did developed progression, the use of SABR delayed the need for subsequent therapy by a median of 13 months.
A German study that investigated the use of SABR for pulmonary metastases in seven hundred patients reported a local control rate of 81% and an overall survival rate of 54% at two years.22 In this study, pulmonary metastases treated with SABR had a three-year actuarial local control of 82% and an overall survival rate of 73%.
The disparity between rates of local control and progression-free survival in both the primary and metastatic cohorts highlights the risk of distant metastasis despite achieving local control. Several practical aspects need to be considered with regard to pursuing systemic therapies after SABR in this population. First, there is currently insufficient evidence to support the use of adjuvant systemic therapy after definitive SABR for limited lung metastases or early stage lung cancer. Thus, subjecting patients to potentially toxic therapies may not be justified when the benefit is unclear. Second, in the absence of measurable primary disease, it is difficult to determine whether an oligometastatic lesion is truly representative of an isolated single clone, or whether it is a part of a more widely disseminated disease process. For example, distant recurrences in breast cancer have been shown to have an evolutionary root from late drivers of resected primary tumours.23 Third, determination of histopathology and mutational profile is increasingly important in treatment decisions in early stage lung cancer, and there is emerging data to support the use of adjuvant targeted therapies after complete resection.24 Given many uncertainties remain unanswered, pragmatic trials should be designed to assess the benefits of systemic therapy after SABR in this heterogeneous, co-morbid population.
Timmerman et al demonstrated an 11-fold increased risk of severe toxicity when SABR was targeted to central compared to peripheral tumours.25 No grade three or higher toxicity was identified in our study. The adjustment of dosing schedules for central tumours may have contributed to this outcome. In contrast, the RTOG 0236 study reported a grade three to grade four toxicity rate of 16%. However, the toxicity rates in this RTOG study included a decline in pulmonary function tests, which were not routinely evaluated in our cohort.12
The limitations of this study include its retrospective nature, the frequent absence of confirmative histology and the variability of the dosing schedules used. However, this variability reflects real-world use of SABR outside the clinical trial setting.
This series demonstrates that the use of SABR in the New Zealand population largely mirrors the outcomes in the global literature. The challenges faced in the clinical decision-making of these patients stem from the scarcity of randomised trials available, the frequent failure to acquire confirmative histology and the complexity of detecting recurrent disease on imaging after treatment. Further randomised studies could determine whether the use of SABR is equivalent to surgery in early stage lung cancer or oligometastatic disease and define the threshold of both the number and size of lesions effectively treated with SABR.
Summary
Abstract
AIM: Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted radiation in a shorter time period than conventional radiotherapy. The aim of this study was to compare the outcomes of lung-based SABR in a New Zealand cohort to the global literature. METHODS: A single-institution retrospective analysis was performed on all patients who received lung-based SABR between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included both early stage lung cancer and lung oligometastases that measured less than 5cm. RESULTS: 102 patients received SABR to 116 lesions. Median follow-up was 19 months. The three-year rate of local control in the primary and metastatic cohorts was 85% and 82%, respectively. This reflects the three-year local control rate of 86% for primary lung cancer in the SPACE trial and the two-year local control rate of 81% for pulmonary oligometastases in a German study. Central primary lung cancer was associated with a higher risk of local recurrence (HR6.4 (1.3–31.5) p=0.02). The three-year progression-free survival rate in patients with early stage lung cancer and oligometastases was 56% and 26%, respectively. Māori patients with primary lung cancer had a significantly worse progression free survival (HR2.4 (1.1–5.1) p=0.03). There were no reported grade three toxicities. CONCLUSION: The use of lung-based SABR in a typical radiotherapy setting in New Zealand mirrors global outcomes.
Aim
Method
Results
Conclusion
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand. 1951;102(4);316-9
2. White A, Swanson SJ. Surgery versus stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer: less is not more. J Thorac Dis. 2016;8(Suppl 4):S399-S405. doi:10.21037/jtd.2016.04.40
3. Elwood JM, Aye PS, Tin S. Increasing Disadvantages in Cancer Survival in New Zealand Compared to Australia, between 2000-05 and 2006-10. PLoS One. 2016;11:e0150734. doi:10.1371/journal.pone.0150734
4. Lawrenson R, Lao C, Brown L, et al. Characteristics of lung cancers and accuracy and completeness of registration in the New Zealand Cancer Registry. N Z Med J. 2018;131:13-23.
5. Health.govt.nz. New Zealand: Unequal Impact: Maori and Non Maori Cancer Statistics 1996-2001; c2006-05. Available from: https://www.health.govt.nz/publication/unequal-impact-maori-and-non-maori-cancer-statistics-1996-2001
6. Lawrenson R, Lao C, Brown L et al. Management of patients with early stage lung cancer – why do some patients not receive treatment with curative intent? BMC Cancer. 2020;20(1):109). doi: 10.1186/s12885-020-6580-6
7. Videtic GMM, Donington J, Giuliani M, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7:295-301. doi:10.1016/j.prro.2017.04.014
8. Agolli L, Bracci S, Nicosia L, Valeriani M, De Sanctis V, Osti MF. Lung Metastases Treated With Stereotactic Ablative Radiation Therapy in Oligometastatic Colorectal Cancer Patients: Outcomes and Prognostic Factors After Long-Term Follow-Up. Clin Colorectal Cancer. 2017;16:58-64. doi:10.1016/j.clcc.2016.07.004
9. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838. doi:10.1200/JCO.20.00818
10. Buglione M, Jereczek-Fossa BA, Bonù ML, et al. Radiosurgery and fractionated stereotactic radiotherapy in oligometastatic/oligoprogressive non-small cell lung cancer patients: Results of a multi-institutional series of 198 patients treated with "curative" intent. Lung Cancer. 2020;141:1-8. doi:10.1016/j.lungcan.2019.12.019
11. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol. 2013;14:e28-e37. doi:10.1016/S1470-2045(12)70510-7
12. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070-1076. doi:10.1001/jama.2010.261
13. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019;20:494-503. doi:10.1016/S1470-2045(18)30896-9
14. Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol. 2011;6:2036-2043. doi:10.1097/JTO.0b013e31822e71d8
15. Timmerman RD, Paulus R, Pass HI, et al. Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial. JAMA Oncol. 2018;4:1263-1266. doi:10.1001/jamaoncol.2018.1251
16. Chang JY, Beezjak A, Mornex F. Stereotactic Ablative Radiotherapy for Centrally Located Early Stage Non-Small Cell Lung Cancer: What We Have Learned. J Thorac Oncol. 2015;10(4):577-85. doi: 10.1097/JTO.0000000000000453
17. Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials [published correction appears in Lancet Oncol. 2015 Sep;16(9):e427]. Lancet Oncol. 2015;16:630-637. doi:10.1016/S1470-2045(15)70168-3
18. Zheng X, Schipper M, Kidwell K, et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis. Int J Radiat Oncol Biol Phys. 2014;90:603-611. doi:10.1016/j.ijrobp.2014.05.055
19. Nyman J, Hallqvist A, Lund JÅ, et al. SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiother Oncol. 2016;121:1-8. doi:10.1016/j.radonc.2016.08.015
20. Verstegen NE, Lagerwaard FJ, Haasbeek CJ et al. Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: comparison with a contemporaneous cohort with pathologically proven disease. Radiother Oncol. 2011;101:250-254. doi:10.1016/j.radonc.2011.09.017
21. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13:8-10. doi:10.1200/JCO.1995.13.1.8
22. Rieber J, Streblow J, Uhlmann L, et al. Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy". Lung Cancer. 2016;97:51-58. doi:10.1016/j.lungcan.2016.04.012
23. Yates LR, Knappskog S, Wedge D, et al. Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell. 2017;32:169-184.e7. doi:10.1016/j.ccell.2017.07.005
24. Herbst RS, Tsuboi M, John T et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38:18 suppl (abstr). doi: 10.1200/JCO.2020.38.18_suppl.LBA5
25. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833-4839. doi:10.1200/JCO.2006.07.5937
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Stereotactic ablative radiotherapy for early stage lung cancer and lung metastases in a New Zealand population
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Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted external beam radiation in a shorter time period and with fewer treatments than conventional radiotherapy. Leksell first described the concept of stereotactic radiosurgery in 1951.1 Initially, however, its use was restricted to intracranial targets. With advancements in linear accelerator technology, the use of stereotactic techniques was expanded to extracranial targets in the 1990s.2
Lung cancer remains the leading cause of cancer death in New Zealand.3 Only 16.5% of lung cancer in New Zealand is diagnosed at an early stage. Māori patients are more likely to be diagnosed at a later stage4,5 and less likely to receive curative surgery than non-Māori patients.6 Early international studies investigating the use of SABR for inoperable patients with early stage lung cancer demonstrated a local control rate of >85% at three years with a grade three or higher toxicity rate of <4%.7
Meanwhile, increased interest and evidence in treating oligometastatic disease with curative intent has led to the application of SABR in the metastatic setting.8–10 SABR is sometimes considered more favourable than pulmonary metastasectomy due to its non-invasive nature and low morbidity. Two-year local control rates for pulmonary metastases have been found to be in the region of 80% internationally.11
The aim of our study was to compare the outcomes of lung-based SABR treatment in a New Zealand cohort to the global literature.
Methods
Study design
A retrospective analysis was performed on all patients who received SABR to a lung mass between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included patients treated in the primary and metastatic setting. Data on patient demographics, tumour characteristics and dosing schedules were collected from electronic medical records. Outcomes, including recurrence and toxicity rates, were collected by review of clinical letters and imaging reports. Toxicities were graded as per the RTOG 0236 schema.12
Patient selection
All patients were discussed through the lung cancer multidisciplinary meeting (MDM), and their eligibility for SABR was based on the departmental guideline. Patients with T1N0M0 or T2aN0M0 (<5cm) non-small cell lung cancer who had an expected survival of more than one year and were not fit for or refused surgery were assessed for SABR. Each patient’s performance status was considered in the context of the underlying morbidity and life expectancy. Patients with oligometastatic lung disease with <2 lesions <5cm in size with stable extra-thoracic disease were included. Staging with PET-CT was performed less than six weeks prior to SABR. Attempts were routinely made to obtain a histologic diagnosis, unless that was deemed not possible for safety or other technical reasons.
Procedures
Patient immobilisation was achieved using an extended vacuum bag with the patient in the supine position with elevated arms. A planning scan with a 4D CT and standard 3D CT without contrast was performed. An internal target volume (ITV) was directly contoured at maximal intensity projection. The planning target volume (PTV) was defined by adding a 5mm margin to the ITV.
The default dosing schedule was 54Gy in three fractions. If the PTV included the chest wall, a dose of 48Gy in four fractions was selected, and if the PTV was within 2cm of the central mediastinal structures, a dose of 60Gy in eight fractions was utilised. This reflects the protocols in the CHISEL study and a Dutch study, respectively.13,14 Deviation from this guideline was permitted at the discretion of the treating radiation oncologist. Dose constraints to at-risk organs were defined as per the RTOG 0618 protocol.15
Outcomes
Follow-up time was defined as the time from completion of SABR to the latest clinic visit or thoracic imaging (whichever was more recent). The primary outcome measured was the local control rate. Secondary outcomes were progression-free survival (PFS), overall survival and toxicity profile. Local failure was determined on serial CT chest imaging every three to six months. Local failure was defined as an enlarging lesion with radiological features consistent with recurrence, such as an enlarging solid or necrotic component or a bulging margin. Progression-free survival was defined as the time from completion of the SABR treatment to progression or death from any cause. Overall survival was defined as the time from treatment completion to death from any cause.
Statistical analysis
Statistical analysis was executed using Microsoft Excel and IBM SPSS Statistics Subscription version 1.0.0.1327. The Kaplan–Meier method was used to report overall survival and progression-free survival. Univariate Cox regression analysis was performed to investigate the association of survival time with other variables. Age and tumour size were analysed as continuous variables. ECOG (<2; >2), smoking status (current smoker; not current smoker), ethnicity (Māori; non-Māori) and tumour location (central; peripheral) were analysed as categorical variables. A central tumour was defined as that with a PTV within 2cm of central mediastinal structures.16
Results
Baseline characteristics
Between May 2015 and September 2019, 102 patients (116 lesions) received SABR treatment. One patient received treatment to four lesions. This patient had sequential treatment to two lesions followed by concurrent SABR to a further two lesions at relapse. Eleven patients received SABR to two lesions: seven concurrently, three sequentially and one at relapse. The mean age of the cohort was 70 years (interquartile range: 63–75). Median follow-up was 19 months (95%CI 17–22; range: 0–52 months). Table 1 details the baseline patient characteristics.
Table 1: Patient characteristics.
Following discussion at MDMs, 86 (74%) of the lesions were considered early stage lung cancer and 30 (26%) were considered metastatic disease to the lung. The number of lesions that measured less than or equal to three centimetres was 101 (87%). Of those considered lung cancer primaries, 45 (52%) did not have confirmative histology. Tumour characteristics are detailed in Table 2.
Table 2: Tumour characteristics.
Twenty-two patients received SABR treatment to 30 oligometastatic lung lesions. The majority of patients (13, 59%) had a colorectal primary. Two patients had metastatic melanoma, and there was one case each of breast cancer, liposarcoma, pancreatic cancer (neuroendocrine), mixed follicular/papillary thyroid carcinoma, lung cancer (squamous cell carcinoma), meningioma and pheochromocytoma. Eight (27%) of the metastatic lesions had confirmative histology.
Of all early stage lung cancer lesions, 64 (74%) were considered medically inoperable and 11 (13%) were considered clinically inappropriate for surgery. Eleven (13%) patients were offered surgery but opted against it. Patients were considered clinically inappropriate for surgery at MDM if there were multiple suspicious pulmonary nodules, a history of another active malignancy or prior thoracic surgery. A PET-CT was used in the diagnostic work-up of 96% of all primary lesions.
Radiotherapy treatment
The most common dose, received by 50% of the cohort, was 48Gy in four fractions with two fractions per week. Thirty percent of the cohort received 60Gy in eight fractions and 10% received 54Gy in three fractions. The other 10% were prescribed a different dosing schedule. Table 3 details the dosing schedules used. One patient abandoned treatment after one fraction due to the progression of the disease noted during the planning process. Five patients in the primary lung cancer cohort received a biologically effect dose (BED) of <100Gy. A BED of >100Gy (p=0.68) was received by 93% of Māori and 95% of non-Māori. There was no observed difference in local control with increased BED (HR0.99 (0.95–1.04) p=0.88).
Table 3: Dosing schedules.
Local control
Local failure developed in 9% (8/86) of lesions in the primary lung cancer cohort and 13% (4/30) of lesions in the metastatic disease cohort. The median time to local failure was 16 months (95%CI: 8–19). Figure 1 details the local control for all lesions. The actuarial three-year rate of local control was 85% (95%CI: 73–97%) in early stage lung cancer and 82% (95%CI: 66–98%) in oligometastatic disease. Central early stage lung cancers had a significantly higher risk of local recurrence than peripheral lesions on univariate Cox regression analysis (HR6.4 (95%CI: 1.3–31.5) p=0.02). Table 4 details the rate and type of locoregional recurrence in each cohort at end of follow-up.
Figure 1: Local control for all lesions.
Table 4: Locoregional recurrence.
Survival outcomes in early stage lung cancer
The first site of recurrence in patients with early stage lung cancer was local in 22% and regional or distant in 78%. Of the patients originally treated for a primary tumour, 11 (14%) had developed distant metastasis and 16 (20%) had died at end of follow-up. The actuarial three-year rate of progression-free survival and overall survival in early stage lung cancer was 56% (95%CI: 40–72%) and 71% (95%CI: 57–85%) respectively. Figure 2 demonstrates the progression-free survival and overall survival in this cohort. There was no difference in progression-free survival with tumour size (HR1.3 p=0.18), increased age (HR1.02 p=0.46), smoking status (HR0.8 p=0.61) or ECOG performance status (HR1.4 p=0.46).
Figure 2: Progression-free survival and overall survival in early stage lung cancer.
Māori ethnicity
Māori patients with early stage lung cancer had a worse progression-free survival compared to non-Māori patients (HR2.4 (95%CI: 1.1–5.1) p=0.03). Median PFS in Māori and non-Māori patients was 24 months and 41 months, respectively. There was no significant difference in overall survival between Māori and non-Maori Māori patients: median 42 months (95% CI: 21–62) vs 46 months (95% CI: 32–59), respectively (HR1.6 (95%CI: 0.6–4.2) p=0.34). The mean primary lung cancer lesion size in the Māori and non-Māori cohorts was 2.3cm and 2.18cm respectively (p=0.78). Central tumours accounted for 40.7% and 34.5% of the Māori and non-Māori cohorts respectively (p=0.58).
Confirmative histology
The presence of confirmative histology in patients with primary lung cancer was not associated with a difference in local control (HR3.2 (95%CI: 0.6–15.8) p=0.16) or overall survival (HR1.6 (95%CI: 0.6–4.2) p=0.35).
Survival outcomes in the oligometastatic cohort
Of the metastatic cohort, 8/22 patients (36%) had developed further distant metastasis and three patients (14%) had died at end of follow-up. The actuarial three-year progression-free survival and overall survival rates were 26% (95%CI: 3–49%) and 73% (95%CI: 46–100%), respectively. Figure 3 illustrates the corresponding Kaplan–Meier curves. Median progression-free survival was 19 months (95%CI: 10–27). Of the twelve patients who progressed after receiving SABR for metastatic disease, eight proceeded to further antineoplastic therapy and four did not. Colorectal malignancies represented 7/12 (58%) of those that progressed. The median time to subsequent therapy was 13 months.
Figure 3: Progression-free survival and overall survival in oligometastatic disease.
Toxicity profile
There were no reported grade three side effects. The most common toxicity reported was chest wall pain (9%). Two patients developed a grade two rib fracture (2%). All five patients who developed grade two chest wall pain or rib fracture had received SABR to a peripheral lesion. The rate of pneumonitis was 4.7% in central lesions and 1.3% in peripheral lesions.
Discussion
This single-centre retrospective study evaluated the use of SABR in a typical radiotherapy setting in New Zealand. This is the largest series to date on the use of SABR in New Zealand. Reflecting its typical use, the study included SABR treatments to both early stage lung cancer and pulmonary metastases.
Surgery is generally considered the treatment of choice in medically operable early stage lung cancers. The American Society for Radiation Oncology guidelines state that SABR is not recommended for patients with standard operative risk.7 To date, there are no completed randomised controlled trials that directly compare the outcomes of surgery and SABR in the treatment of early stage lung cancer. However, Chang et al combined data from two such trials that closed early (due to slow accrual) and reported no significant difference in local or distant control between the surgical and SABR cohorts.17 A meta-analysis that examined 40 SABR studies and 23 surgery studies demonstrated no difference in estimated overall or disease-free survival after adjustment for the proportion of operable patients and age.18 After discussion at MDM, 13% of our primary cohort were deemed medically operable but opted against surgery.
Two randomised studies, the CHISEL and SPACE trials, compared SABR and conventional external beam radiotherapy (EBRT) for the treatment of inoperable early stage lung cancer.13,19 The CHISEL trial demonstrated a significant improvement in local control with SABR compared to EBRT: the two-year rates were 89% and 65%, respectively. The SPACE trial demonstrated a local control rate of 86% in both arms at the end of a three-year median follow-up. Our study demonstrates a reproducible local control rate of 85% at three years in patients who were treated with SABR for early stage lung cancer.
Fifty-two percent of our cohort who were treated for an early stage lung cancer proceeded to SABR without confirmative histology. There was no significant difference in local control or overall survival when confirmative histology was available. A Dutch study, with a larger cohort, has also demonstrated no difference in local control or overall survival in patients who had a pathological or clinical diagnosis of early stage lung cancer.20 The clinical diagnosis was based on a new or increasing FDG avid mass on PET-CT. Ninety-six percent of all primary lesions had a PET-CT as part of their diagnostic work-up in our study.
National statistics report that the incidence of lung cancer in Māori is over three times higher than in non-Māori and that Māori are more likely to be diagnosed at a later stage.5 Māori also have a significantly higher risk of cancer-specific mortality, even after the statistics are adjusted for age and stage at diagnosis. In our study, progression-free survival was significantly worse in the Māori cohort with early stage lung cancer, and although it was not statistically significant, overall survival was lower in the Māori cohort. This raises the question of possible differences in tumour biology or a genetic susceptibility to aggressive disease. Further research to evaluate this variability may ultimately guide clinical practice.
The site of first recurrence was outside the local treatment field in 78% in our study and 55% in the CHISEL trial.13 No patient or tumour factor, other than ethnicity, was associated with a worse progression-free survival.
Hellman and Weichselbaum first described the term ‘oligometastases‘ in 1995 as an intermediate tumour state between localised and widely metastatic disease, with limited metastatic capacity and the potential for treatment with curative intent.21 The SABR-COMET trial demonstrated a significant improvement in progression-free survival and overall survival in patients with oligometastatic disease who were randomly assigned to SABR or standard palliative care.9 Median progression-free survival with SABR was 12 months in the SABR-COMET trial and 19 months in our study. At three years, approximately one quarter of patients in our cohort with oligometastatic disease had not developed progression. In patients who did developed progression, the use of SABR delayed the need for subsequent therapy by a median of 13 months.
A German study that investigated the use of SABR for pulmonary metastases in seven hundred patients reported a local control rate of 81% and an overall survival rate of 54% at two years.22 In this study, pulmonary metastases treated with SABR had a three-year actuarial local control of 82% and an overall survival rate of 73%.
The disparity between rates of local control and progression-free survival in both the primary and metastatic cohorts highlights the risk of distant metastasis despite achieving local control. Several practical aspects need to be considered with regard to pursuing systemic therapies after SABR in this population. First, there is currently insufficient evidence to support the use of adjuvant systemic therapy after definitive SABR for limited lung metastases or early stage lung cancer. Thus, subjecting patients to potentially toxic therapies may not be justified when the benefit is unclear. Second, in the absence of measurable primary disease, it is difficult to determine whether an oligometastatic lesion is truly representative of an isolated single clone, or whether it is a part of a more widely disseminated disease process. For example, distant recurrences in breast cancer have been shown to have an evolutionary root from late drivers of resected primary tumours.23 Third, determination of histopathology and mutational profile is increasingly important in treatment decisions in early stage lung cancer, and there is emerging data to support the use of adjuvant targeted therapies after complete resection.24 Given many uncertainties remain unanswered, pragmatic trials should be designed to assess the benefits of systemic therapy after SABR in this heterogeneous, co-morbid population.
Timmerman et al demonstrated an 11-fold increased risk of severe toxicity when SABR was targeted to central compared to peripheral tumours.25 No grade three or higher toxicity was identified in our study. The adjustment of dosing schedules for central tumours may have contributed to this outcome. In contrast, the RTOG 0236 study reported a grade three to grade four toxicity rate of 16%. However, the toxicity rates in this RTOG study included a decline in pulmonary function tests, which were not routinely evaluated in our cohort.12
The limitations of this study include its retrospective nature, the frequent absence of confirmative histology and the variability of the dosing schedules used. However, this variability reflects real-world use of SABR outside the clinical trial setting.
This series demonstrates that the use of SABR in the New Zealand population largely mirrors the outcomes in the global literature. The challenges faced in the clinical decision-making of these patients stem from the scarcity of randomised trials available, the frequent failure to acquire confirmative histology and the complexity of detecting recurrent disease on imaging after treatment. Further randomised studies could determine whether the use of SABR is equivalent to surgery in early stage lung cancer or oligometastatic disease and define the threshold of both the number and size of lesions effectively treated with SABR.
Summary
Abstract
AIM: Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted radiation in a shorter time period than conventional radiotherapy. The aim of this study was to compare the outcomes of lung-based SABR in a New Zealand cohort to the global literature. METHODS: A single-institution retrospective analysis was performed on all patients who received lung-based SABR between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included both early stage lung cancer and lung oligometastases that measured less than 5cm. RESULTS: 102 patients received SABR to 116 lesions. Median follow-up was 19 months. The three-year rate of local control in the primary and metastatic cohorts was 85% and 82%, respectively. This reflects the three-year local control rate of 86% for primary lung cancer in the SPACE trial and the two-year local control rate of 81% for pulmonary oligometastases in a German study. Central primary lung cancer was associated with a higher risk of local recurrence (HR6.4 (1.3–31.5) p=0.02). The three-year progression-free survival rate in patients with early stage lung cancer and oligometastases was 56% and 26%, respectively. Māori patients with primary lung cancer had a significantly worse progression free survival (HR2.4 (1.1–5.1) p=0.03). There were no reported grade three toxicities. CONCLUSION: The use of lung-based SABR in a typical radiotherapy setting in New Zealand mirrors global outcomes.
Aim
Method
Results
Conclusion
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand. 1951;102(4);316-9
2. White A, Swanson SJ. Surgery versus stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer: less is not more. J Thorac Dis. 2016;8(Suppl 4):S399-S405. doi:10.21037/jtd.2016.04.40
3. Elwood JM, Aye PS, Tin S. Increasing Disadvantages in Cancer Survival in New Zealand Compared to Australia, between 2000-05 and 2006-10. PLoS One. 2016;11:e0150734. doi:10.1371/journal.pone.0150734
4. Lawrenson R, Lao C, Brown L, et al. Characteristics of lung cancers and accuracy and completeness of registration in the New Zealand Cancer Registry. N Z Med J. 2018;131:13-23.
5. Health.govt.nz. New Zealand: Unequal Impact: Maori and Non Maori Cancer Statistics 1996-2001; c2006-05. Available from: https://www.health.govt.nz/publication/unequal-impact-maori-and-non-maori-cancer-statistics-1996-2001
6. Lawrenson R, Lao C, Brown L et al. Management of patients with early stage lung cancer – why do some patients not receive treatment with curative intent? BMC Cancer. 2020;20(1):109). doi: 10.1186/s12885-020-6580-6
7. Videtic GMM, Donington J, Giuliani M, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7:295-301. doi:10.1016/j.prro.2017.04.014
8. Agolli L, Bracci S, Nicosia L, Valeriani M, De Sanctis V, Osti MF. Lung Metastases Treated With Stereotactic Ablative Radiation Therapy in Oligometastatic Colorectal Cancer Patients: Outcomes and Prognostic Factors After Long-Term Follow-Up. Clin Colorectal Cancer. 2017;16:58-64. doi:10.1016/j.clcc.2016.07.004
9. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838. doi:10.1200/JCO.20.00818
10. Buglione M, Jereczek-Fossa BA, Bonù ML, et al. Radiosurgery and fractionated stereotactic radiotherapy in oligometastatic/oligoprogressive non-small cell lung cancer patients: Results of a multi-institutional series of 198 patients treated with "curative" intent. Lung Cancer. 2020;141:1-8. doi:10.1016/j.lungcan.2019.12.019
11. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol. 2013;14:e28-e37. doi:10.1016/S1470-2045(12)70510-7
12. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070-1076. doi:10.1001/jama.2010.261
13. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019;20:494-503. doi:10.1016/S1470-2045(18)30896-9
14. Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol. 2011;6:2036-2043. doi:10.1097/JTO.0b013e31822e71d8
15. Timmerman RD, Paulus R, Pass HI, et al. Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial. JAMA Oncol. 2018;4:1263-1266. doi:10.1001/jamaoncol.2018.1251
16. Chang JY, Beezjak A, Mornex F. Stereotactic Ablative Radiotherapy for Centrally Located Early Stage Non-Small Cell Lung Cancer: What We Have Learned. J Thorac Oncol. 2015;10(4):577-85. doi: 10.1097/JTO.0000000000000453
17. Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials [published correction appears in Lancet Oncol. 2015 Sep;16(9):e427]. Lancet Oncol. 2015;16:630-637. doi:10.1016/S1470-2045(15)70168-3
18. Zheng X, Schipper M, Kidwell K, et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis. Int J Radiat Oncol Biol Phys. 2014;90:603-611. doi:10.1016/j.ijrobp.2014.05.055
19. Nyman J, Hallqvist A, Lund JÅ, et al. SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiother Oncol. 2016;121:1-8. doi:10.1016/j.radonc.2016.08.015
20. Verstegen NE, Lagerwaard FJ, Haasbeek CJ et al. Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: comparison with a contemporaneous cohort with pathologically proven disease. Radiother Oncol. 2011;101:250-254. doi:10.1016/j.radonc.2011.09.017
21. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13:8-10. doi:10.1200/JCO.1995.13.1.8
22. Rieber J, Streblow J, Uhlmann L, et al. Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy". Lung Cancer. 2016;97:51-58. doi:10.1016/j.lungcan.2016.04.012
23. Yates LR, Knappskog S, Wedge D, et al. Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell. 2017;32:169-184.e7. doi:10.1016/j.ccell.2017.07.005
24. Herbst RS, Tsuboi M, John T et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38:18 suppl (abstr). doi: 10.1200/JCO.2020.38.18_suppl.LBA5
25. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833-4839. doi:10.1200/JCO.2006.07.5937
Contact diana@nzma.org.nz
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Stereotactic ablative radiotherapy for early stage lung cancer and lung metastases in a New Zealand population
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Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted external beam radiation in a shorter time period and with fewer treatments than conventional radiotherapy. Leksell first described the concept of stereotactic radiosurgery in 1951.1 Initially, however, its use was restricted to intracranial targets. With advancements in linear accelerator technology, the use of stereotactic techniques was expanded to extracranial targets in the 1990s.2
Lung cancer remains the leading cause of cancer death in New Zealand.3 Only 16.5% of lung cancer in New Zealand is diagnosed at an early stage. Māori patients are more likely to be diagnosed at a later stage4,5 and less likely to receive curative surgery than non-Māori patients.6 Early international studies investigating the use of SABR for inoperable patients with early stage lung cancer demonstrated a local control rate of >85% at three years with a grade three or higher toxicity rate of <4%.7
Meanwhile, increased interest and evidence in treating oligometastatic disease with curative intent has led to the application of SABR in the metastatic setting.8–10 SABR is sometimes considered more favourable than pulmonary metastasectomy due to its non-invasive nature and low morbidity. Two-year local control rates for pulmonary metastases have been found to be in the region of 80% internationally.11
The aim of our study was to compare the outcomes of lung-based SABR treatment in a New Zealand cohort to the global literature.
Methods
Study design
A retrospective analysis was performed on all patients who received SABR to a lung mass between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included patients treated in the primary and metastatic setting. Data on patient demographics, tumour characteristics and dosing schedules were collected from electronic medical records. Outcomes, including recurrence and toxicity rates, were collected by review of clinical letters and imaging reports. Toxicities were graded as per the RTOG 0236 schema.12
Patient selection
All patients were discussed through the lung cancer multidisciplinary meeting (MDM), and their eligibility for SABR was based on the departmental guideline. Patients with T1N0M0 or T2aN0M0 (<5cm) non-small cell lung cancer who had an expected survival of more than one year and were not fit for or refused surgery were assessed for SABR. Each patient’s performance status was considered in the context of the underlying morbidity and life expectancy. Patients with oligometastatic lung disease with <2 lesions <5cm in size with stable extra-thoracic disease were included. Staging with PET-CT was performed less than six weeks prior to SABR. Attempts were routinely made to obtain a histologic diagnosis, unless that was deemed not possible for safety or other technical reasons.
Procedures
Patient immobilisation was achieved using an extended vacuum bag with the patient in the supine position with elevated arms. A planning scan with a 4D CT and standard 3D CT without contrast was performed. An internal target volume (ITV) was directly contoured at maximal intensity projection. The planning target volume (PTV) was defined by adding a 5mm margin to the ITV.
The default dosing schedule was 54Gy in three fractions. If the PTV included the chest wall, a dose of 48Gy in four fractions was selected, and if the PTV was within 2cm of the central mediastinal structures, a dose of 60Gy in eight fractions was utilised. This reflects the protocols in the CHISEL study and a Dutch study, respectively.13,14 Deviation from this guideline was permitted at the discretion of the treating radiation oncologist. Dose constraints to at-risk organs were defined as per the RTOG 0618 protocol.15
Outcomes
Follow-up time was defined as the time from completion of SABR to the latest clinic visit or thoracic imaging (whichever was more recent). The primary outcome measured was the local control rate. Secondary outcomes were progression-free survival (PFS), overall survival and toxicity profile. Local failure was determined on serial CT chest imaging every three to six months. Local failure was defined as an enlarging lesion with radiological features consistent with recurrence, such as an enlarging solid or necrotic component or a bulging margin. Progression-free survival was defined as the time from completion of the SABR treatment to progression or death from any cause. Overall survival was defined as the time from treatment completion to death from any cause.
Statistical analysis
Statistical analysis was executed using Microsoft Excel and IBM SPSS Statistics Subscription version 1.0.0.1327. The Kaplan–Meier method was used to report overall survival and progression-free survival. Univariate Cox regression analysis was performed to investigate the association of survival time with other variables. Age and tumour size were analysed as continuous variables. ECOG (<2; >2), smoking status (current smoker; not current smoker), ethnicity (Māori; non-Māori) and tumour location (central; peripheral) were analysed as categorical variables. A central tumour was defined as that with a PTV within 2cm of central mediastinal structures.16
Results
Baseline characteristics
Between May 2015 and September 2019, 102 patients (116 lesions) received SABR treatment. One patient received treatment to four lesions. This patient had sequential treatment to two lesions followed by concurrent SABR to a further two lesions at relapse. Eleven patients received SABR to two lesions: seven concurrently, three sequentially and one at relapse. The mean age of the cohort was 70 years (interquartile range: 63–75). Median follow-up was 19 months (95%CI 17–22; range: 0–52 months). Table 1 details the baseline patient characteristics.
Table 1: Patient characteristics.
Following discussion at MDMs, 86 (74%) of the lesions were considered early stage lung cancer and 30 (26%) were considered metastatic disease to the lung. The number of lesions that measured less than or equal to three centimetres was 101 (87%). Of those considered lung cancer primaries, 45 (52%) did not have confirmative histology. Tumour characteristics are detailed in Table 2.
Table 2: Tumour characteristics.
Twenty-two patients received SABR treatment to 30 oligometastatic lung lesions. The majority of patients (13, 59%) had a colorectal primary. Two patients had metastatic melanoma, and there was one case each of breast cancer, liposarcoma, pancreatic cancer (neuroendocrine), mixed follicular/papillary thyroid carcinoma, lung cancer (squamous cell carcinoma), meningioma and pheochromocytoma. Eight (27%) of the metastatic lesions had confirmative histology.
Of all early stage lung cancer lesions, 64 (74%) were considered medically inoperable and 11 (13%) were considered clinically inappropriate for surgery. Eleven (13%) patients were offered surgery but opted against it. Patients were considered clinically inappropriate for surgery at MDM if there were multiple suspicious pulmonary nodules, a history of another active malignancy or prior thoracic surgery. A PET-CT was used in the diagnostic work-up of 96% of all primary lesions.
Radiotherapy treatment
The most common dose, received by 50% of the cohort, was 48Gy in four fractions with two fractions per week. Thirty percent of the cohort received 60Gy in eight fractions and 10% received 54Gy in three fractions. The other 10% were prescribed a different dosing schedule. Table 3 details the dosing schedules used. One patient abandoned treatment after one fraction due to the progression of the disease noted during the planning process. Five patients in the primary lung cancer cohort received a biologically effect dose (BED) of <100Gy. A BED of >100Gy (p=0.68) was received by 93% of Māori and 95% of non-Māori. There was no observed difference in local control with increased BED (HR0.99 (0.95–1.04) p=0.88).
Table 3: Dosing schedules.
Local control
Local failure developed in 9% (8/86) of lesions in the primary lung cancer cohort and 13% (4/30) of lesions in the metastatic disease cohort. The median time to local failure was 16 months (95%CI: 8–19). Figure 1 details the local control for all lesions. The actuarial three-year rate of local control was 85% (95%CI: 73–97%) in early stage lung cancer and 82% (95%CI: 66–98%) in oligometastatic disease. Central early stage lung cancers had a significantly higher risk of local recurrence than peripheral lesions on univariate Cox regression analysis (HR6.4 (95%CI: 1.3–31.5) p=0.02). Table 4 details the rate and type of locoregional recurrence in each cohort at end of follow-up.
Figure 1: Local control for all lesions.
Table 4: Locoregional recurrence.
Survival outcomes in early stage lung cancer
The first site of recurrence in patients with early stage lung cancer was local in 22% and regional or distant in 78%. Of the patients originally treated for a primary tumour, 11 (14%) had developed distant metastasis and 16 (20%) had died at end of follow-up. The actuarial three-year rate of progression-free survival and overall survival in early stage lung cancer was 56% (95%CI: 40–72%) and 71% (95%CI: 57–85%) respectively. Figure 2 demonstrates the progression-free survival and overall survival in this cohort. There was no difference in progression-free survival with tumour size (HR1.3 p=0.18), increased age (HR1.02 p=0.46), smoking status (HR0.8 p=0.61) or ECOG performance status (HR1.4 p=0.46).
Figure 2: Progression-free survival and overall survival in early stage lung cancer.
Māori ethnicity
Māori patients with early stage lung cancer had a worse progression-free survival compared to non-Māori patients (HR2.4 (95%CI: 1.1–5.1) p=0.03). Median PFS in Māori and non-Māori patients was 24 months and 41 months, respectively. There was no significant difference in overall survival between Māori and non-Maori Māori patients: median 42 months (95% CI: 21–62) vs 46 months (95% CI: 32–59), respectively (HR1.6 (95%CI: 0.6–4.2) p=0.34). The mean primary lung cancer lesion size in the Māori and non-Māori cohorts was 2.3cm and 2.18cm respectively (p=0.78). Central tumours accounted for 40.7% and 34.5% of the Māori and non-Māori cohorts respectively (p=0.58).
Confirmative histology
The presence of confirmative histology in patients with primary lung cancer was not associated with a difference in local control (HR3.2 (95%CI: 0.6–15.8) p=0.16) or overall survival (HR1.6 (95%CI: 0.6–4.2) p=0.35).
Survival outcomes in the oligometastatic cohort
Of the metastatic cohort, 8/22 patients (36%) had developed further distant metastasis and three patients (14%) had died at end of follow-up. The actuarial three-year progression-free survival and overall survival rates were 26% (95%CI: 3–49%) and 73% (95%CI: 46–100%), respectively. Figure 3 illustrates the corresponding Kaplan–Meier curves. Median progression-free survival was 19 months (95%CI: 10–27). Of the twelve patients who progressed after receiving SABR for metastatic disease, eight proceeded to further antineoplastic therapy and four did not. Colorectal malignancies represented 7/12 (58%) of those that progressed. The median time to subsequent therapy was 13 months.
Figure 3: Progression-free survival and overall survival in oligometastatic disease.
Toxicity profile
There were no reported grade three side effects. The most common toxicity reported was chest wall pain (9%). Two patients developed a grade two rib fracture (2%). All five patients who developed grade two chest wall pain or rib fracture had received SABR to a peripheral lesion. The rate of pneumonitis was 4.7% in central lesions and 1.3% in peripheral lesions.
Discussion
This single-centre retrospective study evaluated the use of SABR in a typical radiotherapy setting in New Zealand. This is the largest series to date on the use of SABR in New Zealand. Reflecting its typical use, the study included SABR treatments to both early stage lung cancer and pulmonary metastases.
Surgery is generally considered the treatment of choice in medically operable early stage lung cancers. The American Society for Radiation Oncology guidelines state that SABR is not recommended for patients with standard operative risk.7 To date, there are no completed randomised controlled trials that directly compare the outcomes of surgery and SABR in the treatment of early stage lung cancer. However, Chang et al combined data from two such trials that closed early (due to slow accrual) and reported no significant difference in local or distant control between the surgical and SABR cohorts.17 A meta-analysis that examined 40 SABR studies and 23 surgery studies demonstrated no difference in estimated overall or disease-free survival after adjustment for the proportion of operable patients and age.18 After discussion at MDM, 13% of our primary cohort were deemed medically operable but opted against surgery.
Two randomised studies, the CHISEL and SPACE trials, compared SABR and conventional external beam radiotherapy (EBRT) for the treatment of inoperable early stage lung cancer.13,19 The CHISEL trial demonstrated a significant improvement in local control with SABR compared to EBRT: the two-year rates were 89% and 65%, respectively. The SPACE trial demonstrated a local control rate of 86% in both arms at the end of a three-year median follow-up. Our study demonstrates a reproducible local control rate of 85% at three years in patients who were treated with SABR for early stage lung cancer.
Fifty-two percent of our cohort who were treated for an early stage lung cancer proceeded to SABR without confirmative histology. There was no significant difference in local control or overall survival when confirmative histology was available. A Dutch study, with a larger cohort, has also demonstrated no difference in local control or overall survival in patients who had a pathological or clinical diagnosis of early stage lung cancer.20 The clinical diagnosis was based on a new or increasing FDG avid mass on PET-CT. Ninety-six percent of all primary lesions had a PET-CT as part of their diagnostic work-up in our study.
National statistics report that the incidence of lung cancer in Māori is over three times higher than in non-Māori and that Māori are more likely to be diagnosed at a later stage.5 Māori also have a significantly higher risk of cancer-specific mortality, even after the statistics are adjusted for age and stage at diagnosis. In our study, progression-free survival was significantly worse in the Māori cohort with early stage lung cancer, and although it was not statistically significant, overall survival was lower in the Māori cohort. This raises the question of possible differences in tumour biology or a genetic susceptibility to aggressive disease. Further research to evaluate this variability may ultimately guide clinical practice.
The site of first recurrence was outside the local treatment field in 78% in our study and 55% in the CHISEL trial.13 No patient or tumour factor, other than ethnicity, was associated with a worse progression-free survival.
Hellman and Weichselbaum first described the term ‘oligometastases‘ in 1995 as an intermediate tumour state between localised and widely metastatic disease, with limited metastatic capacity and the potential for treatment with curative intent.21 The SABR-COMET trial demonstrated a significant improvement in progression-free survival and overall survival in patients with oligometastatic disease who were randomly assigned to SABR or standard palliative care.9 Median progression-free survival with SABR was 12 months in the SABR-COMET trial and 19 months in our study. At three years, approximately one quarter of patients in our cohort with oligometastatic disease had not developed progression. In patients who did developed progression, the use of SABR delayed the need for subsequent therapy by a median of 13 months.
A German study that investigated the use of SABR for pulmonary metastases in seven hundred patients reported a local control rate of 81% and an overall survival rate of 54% at two years.22 In this study, pulmonary metastases treated with SABR had a three-year actuarial local control of 82% and an overall survival rate of 73%.
The disparity between rates of local control and progression-free survival in both the primary and metastatic cohorts highlights the risk of distant metastasis despite achieving local control. Several practical aspects need to be considered with regard to pursuing systemic therapies after SABR in this population. First, there is currently insufficient evidence to support the use of adjuvant systemic therapy after definitive SABR for limited lung metastases or early stage lung cancer. Thus, subjecting patients to potentially toxic therapies may not be justified when the benefit is unclear. Second, in the absence of measurable primary disease, it is difficult to determine whether an oligometastatic lesion is truly representative of an isolated single clone, or whether it is a part of a more widely disseminated disease process. For example, distant recurrences in breast cancer have been shown to have an evolutionary root from late drivers of resected primary tumours.23 Third, determination of histopathology and mutational profile is increasingly important in treatment decisions in early stage lung cancer, and there is emerging data to support the use of adjuvant targeted therapies after complete resection.24 Given many uncertainties remain unanswered, pragmatic trials should be designed to assess the benefits of systemic therapy after SABR in this heterogeneous, co-morbid population.
Timmerman et al demonstrated an 11-fold increased risk of severe toxicity when SABR was targeted to central compared to peripheral tumours.25 No grade three or higher toxicity was identified in our study. The adjustment of dosing schedules for central tumours may have contributed to this outcome. In contrast, the RTOG 0236 study reported a grade three to grade four toxicity rate of 16%. However, the toxicity rates in this RTOG study included a decline in pulmonary function tests, which were not routinely evaluated in our cohort.12
The limitations of this study include its retrospective nature, the frequent absence of confirmative histology and the variability of the dosing schedules used. However, this variability reflects real-world use of SABR outside the clinical trial setting.
This series demonstrates that the use of SABR in the New Zealand population largely mirrors the outcomes in the global literature. The challenges faced in the clinical decision-making of these patients stem from the scarcity of randomised trials available, the frequent failure to acquire confirmative histology and the complexity of detecting recurrent disease on imaging after treatment. Further randomised studies could determine whether the use of SABR is equivalent to surgery in early stage lung cancer or oligometastatic disease and define the threshold of both the number and size of lesions effectively treated with SABR.
Summary
Abstract
AIM: Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted radiation in a shorter time period than conventional radiotherapy. The aim of this study was to compare the outcomes of lung-based SABR in a New Zealand cohort to the global literature. METHODS: A single-institution retrospective analysis was performed on all patients who received lung-based SABR between May 2015 and September 2019 at Waikato Hospital, New Zealand. The study included both early stage lung cancer and lung oligometastases that measured less than 5cm. RESULTS: 102 patients received SABR to 116 lesions. Median follow-up was 19 months. The three-year rate of local control in the primary and metastatic cohorts was 85% and 82%, respectively. This reflects the three-year local control rate of 86% for primary lung cancer in the SPACE trial and the two-year local control rate of 81% for pulmonary oligometastases in a German study. Central primary lung cancer was associated with a higher risk of local recurrence (HR6.4 (1.3–31.5) p=0.02). The three-year progression-free survival rate in patients with early stage lung cancer and oligometastases was 56% and 26%, respectively. Māori patients with primary lung cancer had a significantly worse progression free survival (HR2.4 (1.1–5.1) p=0.03). There were no reported grade three toxicities. CONCLUSION: The use of lung-based SABR in a typical radiotherapy setting in New Zealand mirrors global outcomes.
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Stereotactic ablative radiotherapy for early stage lung cancer and lung metastases in a New Zealand population
Stereotactic ablative radiotherapy (SABR) involves the delivery of high doses of precisely targeted external beam radiation in a shorter time period and with fewer treatments than conventional radiotherapy.
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