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Joe Y Chang
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.08 - Long Term Follow-up on NRG Oncology RTOG 0915 (NCCTG N0927): a Randomized Phase II Study of 2 SBRT Schedules for Lung Cancer (ID 7390)
15:45 - 17:30 | Author(s): Joe Y Chang
- Abstract
- Presentation
Background:
NRG Oncology RTOG 0915/NCCTG N0927 was a randomized lung stereotactic body radiotherapy (SBRT) trial of 34 Gy in 1 fraction (arm 1) versus 48 Gy in 4 fractions (arm 2) designed to select the better of the 2 regimens by comparing them at 1 year (yr): first by rates of pre-specified protocol-specified adverse events (psAEs), then by primary tumor control for each arm. 34 Gy emerged as the least toxic yet equally efficacious regimen. Herein, we update those results with long-term follow-up.
Method:
This phase II North American multicenter study of patients aged 18 yrs or older with medically inoperable non-small cell lung cancer with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors was designed to detect 1-yr psAEs rates >17% as primary endpoint. Primary tumor failure (PTF) (either infield or marginal failure) and local failure (either infield, marginal, or involved lobe failure) [with death without failure considered as a competing event]; overall survival (OS); disease-free survival (DFS) and progression-free survival (PFS) were secondary endpoints, but the study was not designed for statistical comparisons of these outcomes. The study opened in September 2009 and closed in March 2011. Updated data were analyzed through November 14, 2016.
Result:
Ninety four patients were accrued, with 86 eligible for analysis: 41 in arm 1 and 45 in arm 2, after 8 cases were excluded. Median follow-up time was 3.8 yrs for all patients, and 5.1 yrs for those alive at analysis. The grade 3 and higher treatment-related toxicity profile was unchanged since previous report, with specifically no new high grade chest wall or grade 5 events. Four of 48 Gy patients had subsequent grade 3 changes in spirometry since meeting the primary endpoint. Medians (in yrs) for 34 Gy and 48 Gy were: 4.1 vs. 4.0 for OS, and 2.6 vs. 2.8 for DFS, respectively. Five-yr outcomes as % (95% CI) for 34 Gy and 48 Gy were: PTF rate of 7.9 (2.0, 19.5) vs. 6.8 (1.7, 16.9); OS of 28.8 (15.4, 43.8) vs. 40.2 (24.9, 55.0); PFS of 19.1 (8.5, 33.0) vs. 31.8 (18.6, 45.9); and second primary rate of 15.5 (6.1, 28.9) vs. 13.3 (5.3, 25.1), respectively. Distant failure as the sole failure or a component of first failure was numerically higher in the 34 Gy arm (7 (46.7%)), but in the 48 Gy arm, rate of second primary development was higher (7 (43.8%)). Approximately 1/3 of patients’ causes of death was unknown, and another 1/3 was related to causes other than cancer or treatment.
Conclusion:
No excess in late-appearing toxicity was seen in either arm. Primary tumor control rates at 5 yrs were similar by arm. Median survival times of 4 yrs for each arm suggest similar efficacy pending any larger studies appropriately powered to detect survival differences.
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MS 03 - Best Practice for Small-Sized Early Stage Lung Cancer: Standard Surgery, Limited Resection, SBRT (ID 525)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:H.Y. Lee, Masami Sato
- Coordinates: 10/16/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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MS 03.05 - SBRT Experience (ID 7652)
11:00 - 12:30 | Presenting Author(s): Joe Y Chang
- Abstract
- Presentation
Abstract:
In the early 2000s, the revolution in computer-driven radiotherapy technology enabled exquisitely precise direction of radiation beams to specific tumor targets. The advent of 4-dimensional computed tomography (CT), MRI and on-board image-guided intensity-modulated radiotherapy (IMRT), stereotactic ablative radiotherapy (SABR), particle therapy have equipped radiation oncologists with novel tools to tightly conform ablative radiation doses to targets while avoiding inadvertent irradiation of surrounding critical normal structures. SABR, also called stereotactic body radiation therapy (SBRT), as a non-invasive curative therapy, achieves >90% local control, improves survival with minimal toxicity and has become standard therapy in medical inoperable peripheral located stage I NSCLC (1, 2). Particularly for elderly patient, SABR’s effectiveness based on lung cancer-specific survival and progression-free survival is the same in the elderly (>75 year old) as it is the average age population (<75 year old). It also poses no increased toxicity. Compared to historical outcomes with surgery in the elderly, SABR outcome is considered comparable for stage I disease but has less morbidity (3). The pattern of failure study showed that the dominant failure of SABR in stage I NSCLC is distant metastasis (10 to 20%), followed by regional lymph node recurrence (10 to 15%) and then local failure ( 5 to 10%) (4). Up to 1 in 6 patients who received SABR for early-stage NSCLC may develop isolated local-regional recurrence that could be salvaged with definitive treatment. The first long-term results for the largest group of salvaged patients with local-regional recurrence after SABR (n=103) was reported in ASCO 2017 annual meeting (Brooks et al, ASCO 2017 oral presentation in Chicago). 912 patients with clinically early-stage I-II NSCLC from MDACC were treated with SABR with isolated local recurrence (LR, n = 49) or regional recurrence (RR, n = 53). Salvage was performed in 79.6% of LR and 90.6% of RR patients. Median follow-up from time of initial SABR was 57.2 months. 5-year OS was 52% for LR and 27.8% for RR patients. Of LR and RR patients, those receiving salvage had significantly better 5-year OS compared to those not receiving salvage (57.9% LR, 31.1% RR, 0% no salvage; p = 0.006). 5-year OS for LR salvaged patients was not statistically different from patients with NR (53.5% NR, p = 0.92) and 5-year OS for salvaged RR was lower than that of NR (p=0.022). 60% patients never recurred after salvage but subsequent DM occurred in 27.6% of local-regional recurrent patients at a median of 10.5 months. No salvaged patient experienced grade 5 toxicity. There is debate about what is the optimal treatment for operable stage I NSCLC. Majority of the population-based retrospective propensity-matched studies have indicated that SABR has effectiveness comparable to that of surgery for this population, with reported 3-year overall survival rates of 48-91% and local control rates of 85-96% that is significantly better than conventional radiotherapy (5). A pooled analysis of two prospective randomized trials for operable patients showed a better overall survival rate at 3 years for SABR than for surgery (6); however, the efficacy, pattern of failure, and toxicity reported were mostly based upon relatively short follow-up and patient’s number is small; therefore, larger studies with longer follow up are needed and are ongoing around the world. Recently, a phase II prospective study investigating SABR for early-stage NSCLC with median follow-up of 7 years demonstrated outstanding OS of 47% with low rates of local (8%), regional (14%) and distant failure (14%) 7 years after SABR, comparable to those of surgery but with lower toxicity (7). Second malignancy remains one of the most common issues with longer follow-up (21%), again consistent with surgical data. There are two major limitations of SABR in treating early stage NSCLC. First, critical nearby normal tissue dose constraints such as esophagus, bronchial tree, brachial plexus, heart, major vessels etc. may limit the ablative dose that could be safely delivered (8); second, the efficacy of SABR is reduced and toxicity is increased with increasing size of the lesion, particularly when the lesion is >5 cm (9). Most of outstanding clinical outcome with SABR reported in the literature are based on lesions less than 5 cm, typically <3 cm, and not close/next to critical normal structures. Finally, we need to keep in mind that cancer is a biological disease, not just a technologic challenge. As our ability to control local tumors improves with the use of new technology, the importance of systemic disease control grows in parallel—after all, in most cases it is metastatic disease that kills the patient. During the past decade, the development of genomic profile–based targeted therapy and immune checkpoint pathway– based immunotherapy has revolutionized the management of stage IV lung cancer. More and more data indicated that cancer cells killed by radiation release tumor-associated antigens and immunoregulatory cytokines, thereby functioning as a kind of cancer-specific vaccine in situ; they further activate tumor-specific systemic immune responses to eradicate tumors even outside the radiation field (the abscopal effect). These effects seem to be more prominent when the radiation used with immunotherapy involves giving high (ablative) doses, a type of therapy for which we coined the term “I-SABR” (immunotherapy and stereotactic ablative radiotherapy, 10). I-SABR protocols are underway for both early-stage disease and advanced cancer. In summary: SABR/SBRT, a novel non-invasive approach with low toxicity, achieves outstanding clinical outcome and is the standard treatment in medical inoperable stage I NSCLC. It remains controversial whether SABR should be used for operable early stage NSCLC and more randomized studies are ongoing. The dominant pattern of failure after SABR is distant metastasis, followed by regional or intra-lobar failure. Patient with isolated local/regional recurrence should be salvaged aggressively and long-term surveillance is crucial to detect early recurrence and the secondary lung cancer. Combined SABR with systemic therapy such as immunotherapy may further improve the efficacy and cure rate. REFERENCES 1. Timmerman R, et al. Jama. 2010;303(11):1070-6. 2. Onishi H, et al. Cancer. 2004;101(7):1623-31. 3. Brooks ED,et al. Int J Radiat Oncol Biol Phys. 2017;98(4):900-907 4. Senthi S, et al. Lancet Oncol. 2012;13(8):802-9. 5. Shirvani SM, et al JAMA Surg. 2014;149(12):1244-53. 6. Chang JY, et al.Lancet Oncol. 2015;16(6):630-7. 7. Sun B, et al. Cancer. 2017. E-pub ahead of print 8. Timmerman R, et al. JCO. 2006;24(30):4833-9. 9. Tekatli H,et al. J Thorac Oncol. 2017;12(6):974-982. 10. Bernstein MB, el al. Nat Rev Clin Oncol. 2016;13(8):516-24
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