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D. Raben
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 15
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.01 - A Randomized Phase II Study of S-1 and Cisplatin vs Vinorelbine and Cisplatin with Concurrent Radiotherapy for Locally Advanced NSCLC: WJOG5008L (ID 544)
16:45 - 16:50 | Author(s): J. Shimizu, T. Kodaira, T. Seto, T. Sasaki, T. Yamanaka, N. Kunitake, F. Ohyanagi, T. Kozuka, M. Takeda, K. Nakamatsu, T. Takahashi, H. Harada, N. Yoshimura, S. Tsutsumi, H. Kitajima, M. Kataoka, K. Nakagawa, Y. Nishimura, Y. Nakanishi
- Abstract
- Presentation
Background:
Cisplatin-based chemotherapy and concurrent radiotherapy is the standard treatments for locally advanced non-small cell lung cancer ( LA-NSCLC). This trial evaluated two experimental regimens of chemotherapy with concurrent radiotherapy.
Methods:
Eligible patients (pts) with unresectable stage III NSCLC, 20 to 74 years of age, and ECOG PS of 0–1 were randomized to either Arm SP, S-1 (40 mg/m[2]/dose per oral, b.i.d, on days 1-14) and cisplatin (60 mg/m[2] on day 1) repeated every 4 weeks or Arm VP, vinorelbine ( 20mg/m[2] on day 1, 8) and cisplatin (80 mg/m[2] on day) repeated every 4 weeks with early concurrent thoracic radiotherapy of 60Gy at 2 Gy per daily fraction. The primary endpoint was overall survival rate at 2-year (2yr-OS). A pick-the-winner design was used to identify the treatment regimen most likely to be superior. The planned sample size was 55 patients per arm, assuming in each arm that the null hypothesis for 2yr- OS was 50% versus an alternative hypothesis for 65% with one-sided alpha of 0.10 and power of 80%. All the radiation treatment plans were reviewed at quality assurance committee meetings. (Study ID: UMIN000002420)
Results:
One hundred eleven patients were registered between Sep 2009 and Sep 2012. Of 108 patients for efficacy analysis, the 2yr-OS was 76% (95% CI, 62-85%) for SP and 69% (95% CI, 54-79%) for VP. The hazard ratio (HR) of death between the two arms was 0.85 (0.48-1.49). The median progression-free survival (PFS) was 14.8 months for SP and 12.3 months for VP with a HR of 0.92 (0.58-1.44). 80% and 48% of pts completed the protocol treatment in SP and VP, respectively. Common grade 3-4 toxicities of both SP and VP were neutropenia 33%, 75%, platelets 9%, 4%, hemoglobin 26%, 28%, febrile neutropenia 9%, 17%, diarrhea 6%, 0% respectively. There were 4 and 5 treatment-related deaths in Arms SP and VP, respectively. The quality assurance committee judged that 74% of radiation treatment plans had no deviation and 24% had a minor deviation.
Conclusion:
Both arms rejected the null hypothesis for 2yr-OS. In this study Arm SP was declared the winner in terms of 2yr-OS, PFS, treatment completion, and toxicity.
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MINI07.02 - Chemoradiotherapy versus Radiotherapy Alone in Elderly Patients with Stage III Non-Small Cell Lung Cancer: A Systematic Review (ID 3163)
16:50 - 16:55 | Author(s): D.E. Dawe, D. Christiansen, R. Zarychanski, A. Abou-Setta, P.M. Ellis, A. Swaminath, J. Rothney, R. Rabbani, S. Mahmud
- Abstract
- Presentation
Background:
Approximately 30% of non-small cell lung cancer (NSCLC) patients present with locally advanced (stage III) disease, and half are elderly (age ≥70). Young, fit patients with stage III NSCLC have improved survival with the use of combined chemotherapy and radiation therapy (CRT) over radiation therapy (RT) alone – HR 0.74 in a 2010 Cochrane systematic review. Elderly patients have more comorbid illnesses and suffer greater treatment toxicity, thus it is unclear whether they benefit more from CRT over RT. The objective of this systematic review is to explore the evidence base for using CRT in elderly patients with stage III NSCLC.
Methods:
We performed a systematic review including trials identified in MEDLINE, EMBASE and CENTRAL databases from inception to March 8, 2015, plus relevant conference proceedings since 2000. We included randomized controlled trials (RCTs) of elderly patients (≥70 years old) with stage III NSCLC or elderly subgroups from individual patient meta-analyses comparing CRT versus RT alone. We excluded studies that treated patients with palliative intent, included surgical patients, or in which both arms received chemotherapy. We did not restrict language. Two reviewers independently extracted summary outcome data. Risk of bias was assessed using the Cochrane Risk of Bias tool. We used a random effects model and inverse variance method to pool time-to-event outcomes. We calculated Peto Odds Ratios (POR) using RevMan 5.3 to pool dichotomous outcomes with a zero cell and otherwise calculated Risk Ratios (RR).
Results:
We screened 2951 citations identifying 68 articles for full text evaluation, 16 of which have not been accessible yet. Four reports of three studies met inclusion criteria (n = 407 elderly patients). All trials were evaluated as having a high risk of bias due primarily to lack of blinding. Overall survival in elderly patients was superior in those treated with CRT compared to RT (HR 0.66, 95%CI 0.53 to 0.82, I[2] 0%, p 0.0009). Progression-free survival was also improved with CRT (HR 0.67, 95%CI 0.53 to 0.85, I[2] 0%, p 0.001). Toxicity assessments were available in two studies with 119 patients receiving CRT and 121 RT. Treatment-related death occurred in 6 (5%) with CRT and 5 (4%) with RT (RR 1.22, 95%CI 0.38 to 3.88) and grade ≥3 pneumonitis was seen in 6 patients in each group, (RR 1.01, 95%CI 0.34 to 3.06) – neither was significantly different between treatments. Neutropenia – 57% v 2% (POR 14.38, 95%CI 8.26 to 25.04) and thrombocytopenia – 30% v 3% (RR 7.62, 95%CI 2.09 to 27.79) were more common with CRT. Febrile neutropenia occurred in 3 (2.5%) patients with CRT and zero patients with RT, but this did not meet significance (POR 7.54, 95%CI 0.78 to 72.82). No studies included patient-reported quality of life.
Conclusion:
CRT in elderly patients with stage III NSCLC results in improved survival as compared to RT alone, at the expense of increased treatment-related hematologic toxicity. Quality of life assessment should be included in any future trial design. CRT can be considered for fit patients ≥70 years of age with stage III NSCLC.
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MINI07.03 - The NARLAL2 Phase III Trial: Heterogeneous FDG-Guided Dose Escalation of Advanced NSCLC. A Clinical Trial by the Danish Lung Cancer Group (ID 2248)
16:55 - 17:00 | Author(s): D.S. Møller, J.L. Andersen, A.L. Appelt, C. Brink, O. Hansen, L. Hoffmann, N.K.G. Jensen, M. Josipovic, A.A. Khalil, M.M. Knap, M.D. Lund, C.M. Lutz, M.S. Nielsen, S.K. Nielsen, T.B. Nielsen, C.H. Nyhus, W. Ottosson, G.F. Persson, P. Sibolt, K. Wedervang, T. Schytte
- Abstract
- Presentation
Background:
Locally advanced lung cancer lacks effective treatment options and requires aggressive radiotherapy (RT) with higher doses. In the light of RTOG 0617, multi-center dose escalation trials should avoid increasing organ at risk (OAR) toxicity and require strict quality assurance (QA). Exploiting the predictive value of FDG-PET, sub-volumes can be dose escalated, and by implementing image-guided adaptive RT, the total treatment volume (PTV) can be reduced. Incorporating these elements, the randomized multicenter trial NARLAL2 aims at increasing loco-regional control at 30 months without increasing major toxicity.
Methods:
Figure 1 In the standard arm, the PTV is treated with a homogenous dose of 66 Gy/33 fractions. In the experimental arm, the dose is heterogeneously escalated to the FDG-PET avid volumes, with mean doses up to 95 Gy/33 fractions and 74 Gy/33 fractions to the escalated volumes in the tumor and malignant lymph nodes, respectively. The escalation dose will be limited in favor of OAR constraints. A standard and an experimental treatment plan with similar mean lung doses of maximum 20 Gy are made for each patient prior to randomization. Quality Assurance: FDG-PET scans of a standard phantom (NEMA) and PET signal processing software from all centers were compared and acceptable agreement achieved. Multicenter delineation of OARs was performed and consensus achieved. Treatment planning and adaptive strategy consensus were based on a study including five patients with repeated CT-scans, requiring several steps before the achievable level of dose escalation and the number of patients needed in the trial could be defined. Daily online tumor set-up and adaptive strategies were mandatory. A QA committee for evaluation of RT plans and treatments and a central committee for evaluation of all non-biopsy-verified recurrences were established.
Results:
A mean dose of 91,9 Gy to the FDG-PET avid part of the tumor and 80 Gy to the clinical target volume was achieved in the planning study, corresponding to 16% estimated increase in locoregional control at 30 months. Assuming a loco-regional control of 56% at 30 months in the standard arm, a total of 330 patients were needed in order to resolve this effect with a power of 80% (95% significance level). Recalculation of escalated plans on CT-scans acquired at fraction 20 revealed an increase in OAR doses of 4-7Gy for two of five patients, endorsing the need for adaptive strategies.
Conclusion:
A dose escalation trial with strict QA has been set up. Patient enrollment started January 2015.
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MINI07.04 - Dynamic Changes in Cell-Free Circulating Tumor DNA to Track Tumor Response and Risk of Recurrence in Stage III Non-Small Cell Lung Cancer (ID 2499)
17:00 - 17:05 | Author(s): S.H. Lin, T. Xu, J. He, K. Banks, R.B. Lanman, D. Sebisanovic, A.A. Talasaz, C. Lu, T. Buchholz, S. Hahn, R.U. Komaki, Z. Liao
- Abstract
- Presentation
Background:
While the curative management of unresectable stage III non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy, clinical outcomes remain poor. Cellular heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific mutant allelic frequency in cell-free DNA from plasma quantifies tumor heterogeneity and that tracking allelic evolution via blood from patients during and after treatment can serve as a non-invasive means to monitor treatment response and recurrence.
Methods:
Between 2009-2013, 156 patients with unresectable NSCLC who received definitive radiotherapy or chemoradiotherapy were consented to have blood drawn at baseline before starting radiotherapy, once or twice during treatment, and once or twice during follow up visits. Cell-free plasma DNA was sequenced using a cell-free circulating tumor DNA (ctDNA) next generation sequencing (NGS) assay (Guardant360) that uses digital sequencing to report single nucleotide variants (SNVs) in 68 genes and amplifications in 16 genes. This ctDNA assay has high sensitivity (detects 85%+ of the SNVs detected in tissue in advanced cancer patients) and analytic specificity (>99.9999%). Over 670 serial samples were collected from these patients. Here we report the initial analysis of the first 26 patients of this ongoing study.
Results:
Among this initial cohort, 23 (88%) had a recurrence (PFS ranged from 1.2 – 27.9 months) and three (12%) had no evidence of recurrence as of last contact (32.8 – 42.8 months post-radiotherapy completion). Twenty-one patients (81%) had ctDNA alterations present pre-radiotherapy, of which six had a classic driver mutation: KRAS G12F x2; KRAS G12S; PIK3CA E545K x2; PIK3CA H1047R. These six patients had significantly shorter PFS compared to patients without a driver mutation present pre-radiotherapy: average PFS of 4.2 months (1.2 - 8.3) vs. 18.6 months (4.4 - 42.8) respectively (p=0.002). All six had the driver mutation disappear during radiotherapy, four had new alterations appear during and/or post-treatment. One patient had the driver mutation reappear in ctDNA post-radiotherapy and had the shortest PFS (1.2 months) of all patients. Ten patients (38%) had no ctDNA alterations present in the post-radiotherapy blood sample and a trend was observed of improved PFS among patients without ctDNA alterations post-treatment (average PFS 52.3 vs. 75.5 months respectively) however this was not statistically significant (p=0.1). Of note, the three patients without evidence of recurrence as of last contact had no ctDNA alterations identified in the post-treatment sample. This trend is anticipated to become significant with larger sample size.
Conclusion:
In this interim analysis, we found that the dynamic alterations of specific mutant alleles strongly correlated with clinical response and that persistence of ctDNA mutant allele concentrations post-definitive treatment is likely a marker of early metastatic recurrence. Undetectable ctDNA in post-treatment sample was seen in the three patients with approximately three years of PFS. These initial results suggest that serial ctDNA analysis may be useful to monitor treatment response and identify patients at high risk for early recurrence who may benefit from additional systemic therapy.
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MINI07.05 - Discussant for MINI07.01, MINI07.02, MINI07.03, MINI07.04 (ID 3311)
17:05 - 17:15 | Author(s): J. Schiller
- Abstract
- Presentation
Abstract not provided
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MINI07.06 - Pattern of Loco-Regional Failure after Definitive Chemo Radiotherapy for NSCLC. Results from NARLAL, a Phase II Randomized Trial (ID 1042)
17:15 - 17:20 | Author(s): T. Schytte, T.B. Nielsen, M. Knap, A. Khalil, C. Nyhus, T. McCulloch, B. Holm, C. Brink, O. Hansen
- Abstract
- Presentation
Background:
Concurrent chemo-radiotherapy (CRT) is the treatment of choice in loco-regional advanced non-small cell lung cancer (LA-NSCLC). Even though the patients are treated with curative intend the loco-regional control at 2 year is only about 30% in clinical trials. The aim of this study is to compare the loco-regional failure in patients treated with 66 Gy vs 60 Gy in the randomized phase II trial, NARLAL. Furthermore to analyze the localization of relapse compared to the original treatment plan.
Methods:
From 2009-2013 117 patients with LA-NSCLC were randomized in a national multicentre protocol between 60 Gy/ 30 F (arm A) and 66 Gy/ 33 F (Arm B), 5 FW. Navelbine[®] 50 mg 3 days a week was given as concomitant regimen. Patients were followed with CT scans every 3[rd] month in 2 years and hereafter every 6[th] month for another 3 years. As part of the protocol a PET-CT scan was performed 9 months after randomization. In case recurrent disease was suspected a biopsy was done from the lesion if possible. The recurrence gross tumor volume will be delineated and registered with the original radiation treatment plan to identify the site of failure.
Results:
Fifty-nine patients were treated in arm A and 58 patients in arm B. The median local recurrence free interval was 10 months in arm A and 10.9 months in arm B (p=0.57). At the end of this analysis 22 patients were alive with no evidence of loco-regional disease, 16 patients had died with no evidence of loco-regional failure. Loco-regional failure in high-dose area was diagnosed in 60 (51%) patients (33 patients in arm A and 27 patients in arm B). Loco-regional failure outside high-dose area was diagnosed in 19 patients. Fig 1. Treatment plan 60 Gy/ 30 F and PET-CT with relapse (verified by biopsy) Figure 1
Conclusion:
Although this treatment was with curative intend, the loco-regional control was disappointingly poor in both treatment arms. This is in line with other newly published clinical dose-escalations trials for NSCLC. In order to improve loco-regional control and hopefully survival homogeneous dose-escalation is not the choice. Inhomogenous dose-escalation may be an alternative. A phase III trial on this subject has just started enrolment in Denmark (NARLAL II, www.clinicaltrials.gov). Acknowledgements Supported by CIRRO- The Lundbeck Foundation Center for Interventional Research in Radiation Oncology.
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- Abstract
- Presentation
Background:
Surgical resection after neoadjuvant chemoradiation therapy for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) carries high postoperative complications. Careful selection of candidate for surgery should be based on analysis of proven risk factors.
Methods:
We retrospectively reviewed all consecutive patients with clinical stage IIIA-N2 non-small cell lung cancer who underwent surgical resection after neoadjuvant chemoradiation therapy from 1997 to 2013. Preoperative, perioperative, and outcome variables which related to the morbidity and mortality were assessed. Univariate and multivariate analysis was done to identify predictors of postoperative morbidity and mortality.
Results:
During the study period, 574 patients underwent major pulmonary resection after induction therapy. The median time interval between the end of induction therapy and surgery was 33 days (range, 5-79 days). Thirty-day and ninety-day postoperative mortality were 1.4% (8 patients), and 7.1% (41 patients), respectively. The most common cause of In-hospital mortality was acute respiratory distress syndrome (n=6, 4.5%). Morbidity rate was 34.7 % (199 patients). Median hospital stay was 8 days (interquartile range, 7-11 days). Significant predictors of morbidity by multivariable analysis included patient age more than 70 years (odds ratio- 1.82;p=0.040), low body mass index <18.5 (odds ratio - 2.62;p=0.022), and pneumonectomy (odds ratio – 1.8;p=0.026). Significant predictors of mortality by multivariable analysis included patient age more than 70 years (odds ratio – 1.82; p=0.022), and pneumonectomy (odds ratio – 3.256; p=0.003). Ninety-day mortality was 15.8 % (9/57) in patient age more than 70 years, and 17.8 % (13/73) in patients who underwent pneumonectomy.
Conclusion:
Surgical outcomes after neoadjuvant CCRT for patients who are older than 70 year or undergo pneumonectomy are relatively poor. For those patients, there should be extra concern about the respiratory complications. And for the elderly patients with limited pulmonary reserves, other possible alternative treatment options, such as definitive CCRT rather than surgery should be considered.
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MINI07.08 - Mutation Profile Prognostic Value in Stage III Non Small Cell Lung Cancer (NSCLC) Patients Treated with Chemo-Radiotherapy (CRT) (ID 2262)
17:25 - 17:30 | Author(s): A. Boros, L. Lacroix, B. Lancas, J. Adam, J. Pignon, C. Caramella, D. Planchard, A. Levy, V. De Montpreville, E. Deutsch, B. Besse, C. Le Pechoux
- Abstract
- Presentation
Background:
Molecular profiling is a standard procedure in advanced non squamous NSCLC. Gene alteration in EGFR, BRAF or ALK gene can lead to prescription of targeted therapies and prolongs survival. The influence of molecular abnormalities on the survival of stage III NSCLC patients definitely treated by CRT is unknown.
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intent for stage III NSCLC in a single institution. Paraffin embedded tissue block were collected. DNA was extracted for gene mutation analysis by next generation sequencing and ALK, ROS1 and RET rearrangements were detected by FISH analysis. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method.
Results:
Between January2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Platinum-based chemotherapy was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Seventy-eight patients were evaluable for mutation profile, 20 (26%) were female, 47 (60%) were current smoker, 40 (51%) had adenocarcinoma and there were 47/31 stage IIIA/IIIB. Mutations were positive as follow: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/66), PI3KCA 2% (1/58), HER2 0% (0/65), NRAS 3% (1/32), CTNNB1 3% (1/32). FISH was positive for ALK in 5% (3/56) of the NSCLC. In 32 NSCLC for which the test was performed, there was no alteration in ROS1, RET, HRAS and AKT1. Median Follow-up was 3.1 years (minimum 0.9 year). EGFR mutated or ALK+ (EGFR/ALK) group (n=11) and other mutation group (n=17) had a poorer progression free survival (median 0.8[95%CI: 0.6 ; 0.9] year and 0.5 [0.4 ; 0.8] year ; multivariate hazard ratio (HR)= 1.8 [0.8 ; 3.8] and 2.8 [1.5 ; 5.1] respectively, p=0.004) compared to the wild group (n=50) (median 1 year [0.9;1.3]). There was no significant difference (p=0.23, multivariate Cox) in overall survival: median 2.4 years [1.3 ; NR] for EGFR/ALK group, 1.1 [0.6 ; 2.5] for other mutation group and 1.9 [1.5 ; 2.5] for wild type. In multivariate analysis, only the dose of radiotherapy was significantly associated with overall survival (HR=0.5 [0.3 ; 1.0], p=0.04 in contrast with performance status or stage.
Conclusion:
This study suggests that selected gene alterations could be associated with a poorer survival in stage III NSCLC patients treated by combined modality treatment or radiotherapy alone. Their prognostic and/or predictive value should be further evaluated in a larger population.
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- Abstract
- Presentation
Background:
Combined chemoradiotherapy (CCRT) improves long-term outcome of patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC). However, most pts die from distant failure due to preexisting occult metastases. Based on the premise that EGFR-TKI would improve the outcome of pts with stage III NSCLC that harbors sensitive EGFR mutations, as for the pts with stage IV NSCLC, we initiated a randomized phase II pilot trial that incorporated erlotinib (E) into CCRT treatment paradigms.
Methods:
Eligible pts over 18 years old with unresectable stage IIIA or IIIB NSCLC, ECOG PS 0–1, and adequate organ function were screened for EGFR mutation in axons 18–21 in the tumor sample. Those with EGFR mutation (+) tumors were randomized upfront to receive 3 cycles of 3-weekly E 150 mg/day treatment, and then either E x2 cycles concurrently with CCRT and x6 more cycles after CCRT (Arm A) or CCRT with 2 cycles of irinotecan-cisplatin (IP) but no additional therapy after CCRT (Arm B). When disease progression (PD) is documented during follow-up, E was re-instituted. Pts with EGFR mutation (-) or unknown tumors were randomized to receive either 3 cycles of IP induction followed by CCRT concurrently with 2 cycles of IP (Arm C) or CCRT with IP x2 first then consolidation with IP x3 (Arm D). IP chemo dose-schedule was irinotecan 60 mg/m[2] and cisplatin 30mg/m[2] iv on days 1 and 8 when given concurrently with RT (2.4 Gy/fx, total 60 Gy); irinotecan 65 mg/m[2] and cisplatin 30 mg/m[2] iv on days 1 and 8 when given every 3 weeks as induction or consolidation. The primary endpoint was overall response rate (ORR), toxicity, and overall survival (OS).
Results:
From 02/2008 to 03/2015, 59 pts (44 men and 8 women) with median age of 62 years (range: 37-78) were enrolled. There were 13 never smokers, 28 had adenocarcinoma, and 44 had IIIB tumors. EGFR mutation was (+) in 12, (-) in 28, and unknown in 19. There was apparent imbalance in histology and smoking status between the pts assigned to Arms A&B and C&D. ORR after induction E therapy was 75.0% for the 12 pts with EGFR mutation(+) tumors (Arm A, n=7; B, n=5). ORR after IP induction therapy was 63.6% for pts with EGFR mutation(-) or unknown tumors in Arm C (n=22). After completion of upfront CCRT therapy with IP in Arm D (n=25), ORR was 68.0%. There were no noticeable unusual side-effects. Median PFS for Arm A, B, C, and D, was 11.84, 8.09, 8.36, and 11.81 months respectively, with a trend toward better OS for pts with EGFR mutation(+) tumors (Arm A: not reached, B: 31.18 mos) than those EGFR mutation(-) or unknown tumors (Arm C: 17.93 mos, Arm D: 25.33 mos).
Conclusion:
The combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC patients. Although the number is rather small, pts with EGFR mutation (+) tumors seem to be a distinct subset with better overall survival than the others, which warrants careful consideration in chemoradiation therapy trial design and outcome evaluation.
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MINI07.10 - Discussant for MINI07.06, MINI07.07, MINI07.08, MINI07.09 (ID 3312)
17:35 - 17:45 | Author(s): B. Loo
- Abstract
- Presentation
Abstract not provided
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MINI07.11 - Isotoxic Dose Escalation and Acceleration in Lung Cancer Chemoradiotherapy (ID 1522)
17:45 - 17:50 | Author(s): D. Landau, I. Khan, A. Baker, A.T. Bates, M.C. Bayne, N. Counsell, A. Garcia-Alonso, S.V. Harden, J. Hicks, L. Hughes, M.C. Illsley, S.R. Hughes, V. Laurence, Z. Malik, H. Mayles, P.W.M. Mayles, E. Miles, N. Mohammed, Y. Ngai, E. Parsons, J. Spicer, P. Wells, D. Wilkinson, J.D. Fenwick
- Abstract
Background:
RTOG 0617 investigated standard dose radiotherapy (RT) versus higher dose in the context of concurrent chemoRT with no advantage to higher dose treatment. IDEAL CRT investigated an alternative RT dose-escalation strategy with concurrent chemoRT in locally advanced NSCLC. Dose-per-fraction-escalation was used to achieve intensification without treatment prolongation. The trial would determine the maximum tolerable dose (MTD) deliverable to esophagus, and assess toxicity and early clinical outcomes for the schedule.
Methods:
Patients were enrolled to 2 groups, depending on maximum esophageal dose. Tumor doses were determined by esophageal constraints in Group 1 and other normal tissue constraints in Group 2. Patients received 63-73Gy in 30 once-daily fractions / 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. Group 1 esophageal dose-escalation followed a 6+6 design, increasing maximum dose to 1cc esophagus from 65Gy, 68Gy then 71Gy in successive cohorts, defining MTD by early and late toxicity. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and tumor response.
Results:
8 centres recruited 84 patients, treating 13, 12 and 10 in 65Gy, 68Gy and 71Gy group 1 cohorts. Prescribed RT doses are shown in figure 1. Median follow-up 24 months. 57 patients (68%) were stage IIIa and 21 (25%) IIIb. 5 grade 3 esophagitis events observed across both groups and 3 grade 3 pneumonitis. Following 1 fatal esophageal perforation in the 71Gy cohort, 68Gy was declared as esophageal MTD. Overall Survival (OS) and Progression Free Survival (PFS) were 87.8% and 72.0% at 1 year, and 67.1% and 50.4% at 2 years, median OS 39.3 months. OS is shown in figure 2. Figure 1 Figure 2
Conclusion:
Acceptable toxicity rates and promising survival were achieved. The isotoxic design proved practical, allowing significant treatment intensification and definition of MTD with relatively few patients. Results from longer follow-up are required and will be presented at the meeting.
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MINI07.12 - Stage III NSCLC in the Elderly: Patient Characteristics Predictive for Tolerance and Survival of Chemoradiation in Daily Clinical Practice (ID 1512)
17:50 - 17:55 | Author(s): E. Driessen, G. Bootsma, L. Hendriks, F. Van Den Berkmortel, B. Bogaarts, J. Van Loon, A. Dingemans, M. Janssen-Heijnen
- Abstract
- Presentation
Background:
Although the mean age at diagnosis of stage III non-small cell lung cancer (NSCLC) is 70 years, trials mainly include younger patients. Therefore, a lack of knowledge remains regarding tolerance and survival of standard treatment (concurrent chemoradiation (cCHRT)) and other treatment options for the elderly. The aim of this study was to evaluate administered treatment, assess motivations to omit cCHRT, and determine predictors for treatment tolerance and survival among unselected elderly with stage III NSCLC.
Methods:
In this multicenter retrospective study, all stage III NSCLC patients aged ≥70 and diagnosed in 2009-2013 in three Dutch teaching hospitals were included. Data on patient and tumor characteristics were derived from the Netherlands Cancer Registry and medical records regarding treatment details, geriatric patient characteristics, tolerance (completing treatment and/or no unplanned hospitalizations) and survival. Treatment and motives for omitting cCHRT were described. Univariate and multivariable analyses were performed to gain insight into predictive factors.
Results:
In the 219 included patients, mean age was 76 years, 78% was male and 51% had squamous cell carcinoma. Sixty-eight percent had a WHO Performance Status (PS) of 0-1, 22% PS 2, and 11% PS 3. Serious co-morbidity (severe organ decompensation or ≥2 moderate decompensations) was present in 59%, average co-morbidity (moderate organ compensation or ≥2 mild decompensations) in 16%, mild co-morbidity (mild organ decompensation) in 11% and 15% had no co-morbidities. Chemoradiation (CHRT) was administered in 55% of patients (33% cCHRT and 22% sequential CHRT (sCHRT)), 16% received only radical radiotherapy (RT) and 29% Best Supportive Care (BSC). CHRT was less often administered to patients aged ≥75 and those with a PS 2-3 (p<0.001). Also, patients with serious co-morbidity were less likely to receive CHRT, although not significant (p=0.10). The most common motives for omitting cCHRT were co-morbidity and/or poor PS (57%) and patient refusal (15%). Multivariable analyses showed that treatment and co-morbidity were predictive for tolerance. In comparison to cCHRT, tolerance was significantly better for RT (Odds Ratio (OR) = 5.1(95% Confidence Interval (95%CI) 2.1-13)) and non-significantly better for sCHRT (OR=2.2 (0.97-4.9)). Patients with serious co-morbidity had significantly worse tolerance compared to no co-morbidity (OR=0.28 (0.11-0.68). Even when corrected for patient characteristics, survival was not significantly better after cCHRT compared to sCHRT (Hazard Ratio (HR) = 1.1 (95%CI 0.76-1.7)) or compared to RT (HR=1.3 (0.81-2.0)). The 1-and 3-year Overall Survival (OS) rates for cCHRT were respectively 56% and 17%, for sCHRT 54% and 16%, and for RT 48 % and 9%.
Conclusion:
Co-morbidity, poor PS and patient refusal were the most common motives for omitting cCHRT. Although relatively fit and younger elderly were assigned to cCHRT, treatment tolerance was worse. OS was not significantly different between cCHRT, sCHRT and even RT. Since limited information on geriatric characteristics was available in this retrospective study, prospective studies including geriatric assessments are urgently needed to gather evidence on treatment options, resulting in the most optimal balance between quality of life and survival.
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MINI07.13 - Clinical Impact of Frequent Surveillance Imaging in the First Year following Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer (ID 2538)
17:55 - 18:00 | Author(s): N.K. Harandi, M.E. Daly
- Abstract
- Presentation
Background:
Uncertainty exists regarding the optimal surveillance strategy following definitive chemoradiation (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) with regards to both frequency and modality. We sought to determine the efficacy of frequent (q2-4 month) post-treatment imaging in detecting asymptomatic recurrent disease and document the clinical impact of frequent surveillance imaging.
Methods:
The records of all patients treated with CRT for stage IIIA/IIIB NSCLC between August 1999 and April 2014 at our institution were reviewed. Patients were included if they underwent frequent (Q2-4 month) chest computed tomography (CT) or positron emission tomography (PET/CT) for routine surveillance following CRT for at least one year following CRT or until disease progression or death. Radiographic findings and clinical interventions from the first year following CRT were identified.
Results:
We identified 145 patients with LA-NSCLC treated with CRT, 65 of whom underwent Q2-4 month surveillance imaging for at least one year or until progression or death. Median age was 63.6 years (range, 41.0-86.9 years). Forty-nine (75.4%) also underwent an initial baseline CT within the first 6 weeks following CRT. An asymptomatic recurrence was detected by surveillance imaging within the first year in 40 (61.5%) patients, 31 (77.5%) by CT and 9 (22.5%) by PET/CT. Among these patients, 21 (52.5%) initiated palliative systemic therapy. Three (7.5%) underwent attempted definitive therapy for isolated disease, including one patient treated with definitive lobectomy for what was found to be a histologically distinct new primary early stage NSCLC, and two patients treated with stereotactic ablative radiotherapy for isolated recurrences, both of whom subsequently developed metastatic disease. Urgent palliative local therapies (radiotherapy and bronchoscopy) were performed in 2 patients for impending neurologic and airway compromise, respectively. Ten patients (25%) with recurrences detected on surveillance imaging were not candidates for or declined additional cancer-directed therapy. Seven patients (10.8%) developed a symptomatic recurrence detected between planned scans. Five patients (7.7%) underwent additional diagnostic procedures for false-positive surveillance imaging findings.
Conclusion:
Frequent surveillance imaging within the first year following CRT for LA-NSCLC detected asymptomatic recurrences in a high proportion of patients in our population. However, definitive interventions were attempted in less than 5%, and were successful in only one patient. The predominant potential benefit of frequent radiographic surveillance appears to be the expedient initiation of palliative systemic therapy. Evidence-based algorithms for follow-up imaging among this population are needed, and should account for patient-specific factors including expected tolerance of, benefit from, and willingness to undergo systemic therapies.
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- Abstract
- Presentation
Background:
Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC).
Methods:
Nineteen patients with unresectable stage III NSCLC, ECOG performance status 0-l, and adequate organ function were treated with 60–66 Gy thoracic radiation therapy over 30–33 fractions concurrent with weekly 7.5 mg/m[2] endostatin for 14 days, 50 mg/m[2] paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m[2] endostatin for 14 days, 150 mg/m[2] paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment (Fig.1). The objective response rate was recorded according to the RECIST criteria, and the toxicity was evaluated using the NCI Common Toxicity Criteria. Figure 1
Results:
Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 13 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% [95% CI, 51%–97%]. The median progression-free survival was 10 months (95% CI, 7.6–12.3 months), and the median overall survival was 14 months (95% CI, 10.7–17.2 months) (Tab.1). The toxicity analysis of 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity. Figure 1
Conclusion:
The results demonstrated no evidence of the efficacy of endostatin concurrent with chemoradiotherapy of locally advanced unresectable NSCLC. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined.
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MINI07.15 - Discussant for MINI07.11, MINI07.12, MINI07.13, MINI07.14 (ID 3325)
18:05 - 18:15 | Author(s): C.J. Langer
- Abstract
- Presentation
Abstract not provided
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MINI 18 - Radiation Topics in Localized NSCLC (ID 139)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 15
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MINI18.01 - Stereotactic Body Radiation v. Observation for Early-Stage NSCLC in Elderly Patients (ID 137)
16:45 - 16:50 | Author(s): R.H. Nanda, T.W. Gillespie, J.L. Mikell, Y. Liu, J. Libscomb, S.S. Ramalingam, F. Fernandez, W.J. Curran, K.A. Higgins
- Abstract
- Presentation
Background:
Stereotactic body radiotherapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the new standard of care for medically inoperable, early-stage non-small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing co-morbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT in patients 70 and older improves survival relative to observation alone.
Methods:
The NCDB, a retrospective national database capturing up to 80% of all patients treated for cancer, was queried for patients ages 70 or higher with early stage (T1-T3N0M0) NSCLC from years 2003-2006. Overall survival was compared between patients treated with stereotactic body radiotherapy alone and patients receiving no treatment. Extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT.
Results:
A total of 3,147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%) and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the two groups (p=0.076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (HR 0.64, p<0.001), as well as for each age group as follows: 70-74, HR=0.72; 75-79, HR=0.66; 80-84, HR=0.59; 85 and above, HR=0.56.
Conclusion:
SBRT is associated with improved survival in elderly patients with early stage NSCLC with concurrent comorbid conditions compared to observation alone . The data support the use of SBRT for treatment of elderly patients with early stage NSCLC that have limiting co-morbid conditions.
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MINI18.02 - Stereotactic Body Radiotherapy Is Safe and Effective in Octo- and Nonagenarians for the Treatment of Early Stage Lung Cancer (ID 3072)
16:50 - 16:55 | Author(s): M. Giuliani, A. Hope, M. Johnson, M. Guckenberger, F. Mantel, H. Peulen, J. Sonke, J. Belderbos, M. Werner-Wasik, H. Ye, I. Grills
- Abstract
Background:
To determine the safety and efficacy of lung SBRT in older patients and to compare their outcomes to those of younger patients.
Methods:
Patients with primary lung cancer treated with SBRT were identified from a multi-institutional (5) database of 1192 cases. Details of patient factors, treatment specifics, toxicity and clinical outcomes were extracted from the database. All events were calculated from the end of radiotherapy. Estimates of local (LR), regional (RR), and distant metastases (DM) were calculated using the competing risk method. Cause specific (CSS) and overall survival (OS) were calculated using the Kaplain-Meier method. Outcomes were compared for those <70, 70-79, >=80. Toxicity was graded per CTCAE V3.0. The 90 day mortality was reported for those <70, 70-79, >=80. Univariable analysis was performed to determine associations with CSS in patients aged >70.
Results:
The median follow-up was 1.7years (1-10y) and median age 75 (41-94). There were 364 patients age <70 (28%), 546 age 70-79 (42%) and 387 age ³80 (48%). 621(48%) were female, 1125(87%) were peripheral and 852(66%) were biopsied. There was no difference in baseline SUV (p=0.6), histology (p=0.4), radiation dose (p=0.1), gender (p=0.3) or biopsy rate (p=0.2) among the three age groups. Patients aged >=80 had significantly more T2 tumors 21% vs 23% vs 32 % (p<0.01). There was no difference in 5 year LR (10% vs 11.5% vs 10%, p=0.7), RR (22% vs 10% vs 9%, p=0.1), DM (17% vs 16% vs 21%, p=0.07) or CSS (80% vs 80% vs 75%, p=0.6). Those age ³80 had significantly lower 5 year OS (75% vs 44% vs 23%, p<0.01). The grade 3+ pneumonitis rate was 1.3% vs 1.6% vs 1.5% (p=0.9) in patients ages <70,70-79, >=80 respectively. The 90 day mortality rates for patients aged <70,70-79, >=80 were 1.4%, 2.7%, and 2.6% respectively. In patients aged >70 CSS was associated with tumor size (p<0.01; HR1.4) and baseline SUV max (p=0.03; HR1.04).
Conclusion:
SBRT is a safe treatment modality in elderly patients (aged >80). Despite larger tumor volumes, the tumor control outcome were identical to the younger patients treated with SBRT. All patients, regardless of age, should be considered for treatment of early stage lung cancer (T1-T2) with SBRT.
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MINI18.03 - Immune Activation in Early Stage Non-Small Cell Lung Cancer (NSCLC) following Stereotactic Ablative Radiotherapy (SABR) and Surgery (ID 2123)
16:55 - 17:00 | Author(s): J.G. Aerts, P. De Goeje, M. Schram, K. Bezemer, M. Kaijen-Lambers, J. Hegmans, J. De Langen, A. Maat, J. Nuyttens, R. Hendriks, E. Smit, S. Senan
- Abstract
- Presentation
Background:
An anatomical surgical resection is considered to be the standard of care in fit patients, but non-randomized comparative effectives studies suggest that survival outcomes may be similar following SABR. An antitumor immune microenvironment was found to be a prognostic factor in surgically resected early stage NSCLC. SABR has been reported to activate the immunesystem in malignant diseases via a number of mechanisms. We investigated the impact of both surgery and SABR in early stage NSCLC on the immunesystem, studied in peripheral blood over time.
Methods:
This is a non-randomised trial. Treatment by either surgery or SABR treatment for early stage (cT1-T2aN0M0) were determined by an institutional multi-disciplinary tumorboard, and in accordance with the patient’s preference . SABR was typically delivered in 3-8 fractions in 1-2 weeks, based on risk-adapted radiotherapy schemes that delivered a biologically effective dose of >100 Gy. Surgery generally involved a VATS lobectomy. Blood was collected prior to treatment, and at weeks 1, 2, 3 and 6 after start of treatment. The peripheral blood mononuclear cell (PBMC) fraction was isolated and was stimulated for 4 hours with phorbol 12-myristate 13-acetate (PMA) and ionomycin, to activate the T cells. Subsequently, the T-cells cells were harvested and analyzed by flow cytometry on the expression of CD4 and/or CD8, granzyme B and interferon (IFN) γ. As PD-1 expression is induced in T-cells after antigen exposure the expression of PD-1 was determined. Changes of population proportions between the different time points were analyzed with the related-samples Wilcoxon signed rank test.
Results:
23 early stage non-small cell lung cancer (NSCLC) patients were included in the study. Of these, 13 patients underwent surgical resection at a mean age (±standard deviation) of 62,9± 8,4 years, and 10 patients who underwent SABR at a median age of 70,0 ±10,4 years. SABR patients had more comorbidities, and a poorer WHO performance score, but clinical tumor stage was comparable. A significant increase in the proportion of IFNγ[+]Granzyme B[+] CD8 T cells (p<.05) was observed at week 2 in the SABR treated group, whereas no difference was found after surgical resection. The PD1[+] fraction of CD4[+] T cells was significantly increased at week 2 in the SABR treated group (p<.05), whereas no differences were seen at two weeks after surgical resection. Proportions of PD1[+ ]CD4 T cells remained elevated in the SABR group at week 3 and 6. A similar trend was observed in the CD8[+] T cell population, although this did not reach statistical significance (p<.1).
Conclusion:
SABR but not surgery, enhances T-cell activation and PD-1 upregulation. The results of our study warrant further investigation as to whether SABR induces an anti-tumor response in patients with early stage NSCLC . The upregulation of PD-1 inherently accompanied with this activation of the immune system potentially warrants combination treatment with PD-(L)1 blockade.
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MINI18.04 - Tumor Volume Variations and Related Dosimetric Impact During Stereotactic Body Radiation Therapy for Lung Cancer (ID 958)
17:00 - 17:05 | Author(s): L. Moretti, Y. Jourani, F. Charlier, T. De Brouwer, P. Van Houtte
- Abstract
Background:
This study aimed to evaluate the importance of interfraction variations in gross tumor volume (GTV) during stereotactic body radiotherapy (SBRT) for early lung cancer patients and assess its impact on dosimetric GTV coverage
Methods:
Forty-seven consecutive patients undergoing SBRT were treated with 48 Gy in 4 fractions (group 1: n=35) or 60 Gy in 8 fractions (group 2: n=12). For each patient, Cone-Beam Computed Tomography (CBCT) imaging obtained at each fraction and initial planning 4DC (CT) were analyzed. GTVs were delineated on all CBCTs, and individual treatment planning was recalculated on each CBCT. Statistical analyses were performed to compare differences between independent samples: the Mann-Whitney U test was used for non-normal continuous variables analyses between groups and the χ2 test for proportions within each SBRT group. Wilcoxon signed rank test was also used to assess changes in volume, dosimetric parameters, and tumor localization. All significance tests were two-tailed and p<0.05 was considered significant
Results:
A total of 236 CBCTs were processed and analyzed. Median total treatment times were 8 days for group 1 and 19.5 days for group 2. There was a significant tumor volume change between the initial CT and the 1st CBCT (p=0.003) in group 1. This was not found in group 2 (p=0.67). GTV was significantly larger at the 2nd CBCT (p=0.003 for group 1 and p=0.049 for group 2) compared to the 1st CBCT. Volume changes were not significantly different at the 3rd fraction compared to 1st CBCT. In group 1, GTV volume significantly decreases at the 4th fraction compared to the 2nd (p=0.047). In group 2, the significant decrease in volume occurs at the 6th fraction (p=0.026). There was no association between the overall treatment time and tumor volume variations. Taken individually (n=47) 83% of tumors have at least one occurrence of a greater than 15% volume change during SBRT compared to the 1[st] CBCT. Variations of more than 20%, 30% and even 40% were observed in ~60%, 40%, and 17% of treatments, respectively. No factor that would predict a significant volume change during SBRT for the patients analyzed could be identified. In group 1, tumor coverage factor (>95%) for any given fraction deviated no more than 5% from optimised coverage obtained in the initial treatment plan. Although sample size is smaller, there was a trend towards lower tumor coverage factors in group 2 compared to group 1. Conformity index for all tumors still ranged from 3.41 to 13.35 in group 1, and 0.95 to 10.48 in group2, without any association with tumor volume variations or treatment time
Conclusion:
There was considerable variation in tumor volumes and more frequent than initially expected for patients undergoing lung SBRT. However, these volume changes did not significantly impact dosimetric parameters. Whether these results affect treatment and/or patient outcome remains to be investigated in prospective clinical trials
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MINI18.05 - Discussant for MINI18.01, MINI18.02, MINI18.03, MINI18.04 (ID 3407)
17:05 - 17:15 | Author(s): H. Choy
- Abstract
- Presentation
Abstract not provided
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MINI18.06 - Validation of High Risk Features on CT for Detection of Local Recurrence After SBRT for Stage I NSCLC (ID 2138)
17:15 - 17:20 | Author(s): H. Peulen, F. Mantel, M. Rossi, B. Stam, I. Grills, M. Giuliani, M. Werner-Wasik, A. Hope, J. Belderbos, M. Guckenberger, J. Sonke
- Abstract
- Presentation
Background:
Fibrotic changes after SBRT for stage I NSCLC are difficult to distinguish from local recurrences (LR), hampering proper selection for salvage therapy. Huang et al. (1) defined CT high risk features (HRF) for detection of LR. This study attempts to validate these HRFs in an independent patient cohort.
Methods:
From a multicenter combined database of patients treated with SBRT for stage I NSCLC between 2006 and 2012, 53 LR were detected of which 14 were biopsy proven. The biopsy proven LR (N=14) were matched 1:2 to patients without LR (n=28) based on: 1) dose 2) PTV 3) follow up time 4) central/peripheral location 5) lung lobe. Of the resulting 42 patients 18 were male and 24 female with a median age of 73 years (range 56-89years). Median tumor size, PTV and dose were 2.3 cm (range 1.0-4.9cm), 49cc (range 9-166cc), 48 Gy (range 48-60Gy) in 4 fractions (range 3-8) respectively. Most tumors were peripheral (76%) and located in the upper lobes (55%). Median follow up (FU) was 36 months (range 14-78months) and median time to LR was 18 months (range 12-45months). For all patients, planning CT scans and at least two follow up scans were available. Two blinded observers scored eight HRFs for each scan. Sensitivity and specificity in predicting LR were assessed and compared using Fisher’s exact test. Analysis for best fit was done using AUC.
Results:
Results of sensitivity and specificity are shown in Table 1. The best performing HRF was cranio-caudal growth: sensitivity 86%, specificity 82%. The odds of LR increased on average by 2.6 (95%CI1.5-4.3) for each additional HRF detected, while the AUC was 0.86. The presence of ≥ 3 HRFs resulted in the best cut-off with sensitivity 79% and specificity 86%. Loss of linear margin and bulging margin were scored identical and therefore only the latter was included in the model. The two best combinations of HRFs were: 1) bulging margin & cranio-caudal growth, with a sensitivity of 93% and specificity of 82% or 2) bulging margin & enlarging opacity after 12 months, with a sensitivity of 86% and specificity of 89%. Table 1CT high risk factor for local recurrence Sensitivity (%) Specificity (%) p-value Any HRF 93 64 .001 enlarging opacity (≥5mm and ≥20%) 86 68 .003 sequential enlarging opacity 57 89 .002 enlarging opacity after 12 months 71 89 <.001 bulging margin 64 100 <.001 loss of linear margin 64 100 <.001 loss of air bronchograms 7 100 0.33 cranio-caudal growth (≥5mm and ≥20%) 86 82 <.001 new pleural effusion 14 93 0.59
Conclusion:
In this matched group of biopsy proven LR and controls, cranio-caudal growth was the best individual predictor of LR after SBRT. Combining HRF bulging margin with either cranio-caudal growth or enlarging opacity after 12 months resulted in higher sensitivities and specificities than number of HRFs. 1)Huang et al. Radiotherapy&Oncology 2013
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MINI18.07 - Early Results of a Quality Assurance Program in a Randomized Trial of Stereotactic Body Radiotherapy for Stage I Medically Inoperable Lung Cancer (ID 2887)
17:20 - 17:25 | Author(s): A. Swaminath, M. Wierzbicki, J. Wright, T. Tsakiridis, K. Cline, C. Bucci, O. Ostapiak, S. Parpia, J. Julian, T. Whelan
- Abstract
- Presentation
Background:
A large Canadian multicentre randomized trial (LUSTRE) has recently opened to determine if stereotactic body radiotherapy (SBRT) to 48 Gy in 4 fractions (peripheral) or 60 Gy in 8 fractions (central) improves outcomes compared to conventionally hypofractionated radiotherapy (CRT) to 60 Gy in 15 fractions in early stage non-small cell lung cancer. Given the rapid diffusion of lung SBRT technology across Canada, a unique radiotherapy quality assurance (RTQA) program was devised to minimize variations in practice. This study describes the RTQA experience to date.
Methods:
Centres participating in LUSTRE are required to satisfy three RTQA requirements prior to being accredited: (a) Respond to a survey describing treatment equipment, planning system details and image guidance parameters in order to confirm that their centre is compliant with protocol guidelines; (b) Assess SBRT delivery accuracy using a thoracic phantom produced by IROC (Imaging and Radiation Oncology Core); and (c) Successfully complete four treatment plans from the developed trial planning guide using SBRT and CRT for one centrally and one peripherally located cancer.
Results:
Currently 13 centres are undergoing RTQA: (a) Surveys have been completed in 8 centres, 2 require revision, and 3 are incomplete. (b) Phantom testing has been completed in 9 centres, 2 are incomplete, 1 has results pending, and 1 is being resubmitted. Although 6/13 centres were identified as having active SBRT programs (>3 patients/month), only 2/6 had completed the IROC phantom prior to study accreditation (most having in-house end-to-end tests). (c) 8/13 centres have successfully submitted their test cases. All 8 submitting centres passed on SBRT/CRT distributions and conformality indices. However, 5/8 centres required resubmission for contouring revisions. In one case, the GTV/ITV was incorrectly contoured. In another case, it was contoured on the incorrect dataset. In the remainder, normal organs (lungs, bronchi, esophagus) had contouring errors, particularly the bronchial tree; contours excluded the major bronchi, and in 2 cases, normal lung parenchyma was included. Some centres did not follow standardized nomenclature for targets and normal organs, as they were likely new to this naming convention. Some issues were related to misinterpretation of the planning guide, prompting the trial group to work with centres to ensure a seamless future workflow.
Conclusion:
Preliminary results show that most well-established lung SBRT centres rely on their own in-house standards, while others are using LUSTRE RTQA to implement new SBRT programs. Our experience shows that when centres participate in an independent review, alterations are recommended that can improve their own existing QA processes, and contribute to standardized practice nationwide. Such an RTQA process can be a model worth considering in future radiotherapy randomized trials, and also when instituting new radiotherapy technologies into existing clinical programs.
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MINI18.08 - A Systematic Review of Comparative Effectiveness Studies of Surgery versus SABR in Early Stage Lung Cancer: How Good Is the Data? (ID 1549)
17:25 - 17:30 | Author(s): A.V. Louie, C.D. Goodman, H. Chen, G.B. Rodrigues, D.A. Palma, B. Slotman, S. Senan
- Abstract
- Presentation
Background:
Three prospective randomized control trials (RCTs) comparing stereotactic ablative radiotherapy (SABR) and surgery in early stage non-small cell lung cancer (ES-NSCLC) failed to complete accrual. Numerous other comparative effectiveness studies have been published, but such studies may be more prone to bias, and conclusions may vary based on study quality. The goal of this study was to perform a systematic review of comparative effectiveness studies that compare both treatment modalities in this patient population, to assess study quality and conclusions.
Methods:
In accordance with PRISMA guidelines, a systematic review was conducted on studies reporting on comparative outcomes of surgery versus SABR for ES-NSCLC. Studies published in the English language over a 10-year period (April 2006-March 2015) were identified using PUBMED with an inclusive search strategy, using the National Library of Medicine’s medical subject headings. Eligible study designs included RCTs, population analyses, match pair comparisons, propensity-match score comparisons, retrospective case-control series, decision analyses, and cost-effectiveness analyses. Letters, editorial and systematic reviews were excluded. Abstracts identified were independently reviewed by two investigators to determine eligibility, with discrepancies settled by a third investigator. Using a standardized data abstraction form, study, patient, tumor, and treatment characteristics were abstracted. As patients undergoing surgery and SABR often differ in their baseline characteristics, we determined the proportion of studies reporting statistical adjustment for baseline characteristic imbalances (e.g. matching in patient studies, sensitivity analyses in modeling studies). The Fisher’s exact test was used to determine if there was an association between the use of statistical adjustment and differences in overall survival (OS) findings.
Results:
Of the 568 studies identified by our search strategy, 22 were eligible for analysis. Primary study design was retrospective (n=11), population-based (n=7), or model-based (n=4). Most patient studies (n=17) reported on a statistical adjustment for differences in baseline characteristics, with propensity score matching (n=12) being the most common technique employed. All studies, except for 1, reported details of the type of surgery performed. SABR doses employed ranged from 30 Gy in 1 fraction, to 60 Gy in 3 fractions. The weighted average pathologic confirmation of malignancy rate for SABR patients was 72% (range 22-100%). Of the 20 studies reporting on overall survival, 12 found that SABR and surgery were equal, or sensitive to variability in baseline patient, treatment, or tumor factors. The remaining 8 studies reported an overall survival benefit of surgery over SABR, however, 4 of these studies did not employ statistical adjustments for baseline characteristics. In the other 4 studies reporting overall survival superiority of surgery when controlling for various co-variates, at least one other recurrence endpoint (local, regional, or distant) was found to be equal between surgery and SABR. All but 2 studies stated in their conclusion that future clinical trials are warranted to investigate the role of SABR in the potentially operable ES-NSCLC patient.
Conclusion:
A systematic review of the comparative effectiveness literature indicates that the results of well-controlled studies comparing surgery and SABR argue for clinical equipoise. Results of a pooled analysis of two international RCTs that closed prematurely are expected shortly.
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MINI18.09 - Survival of Elderly Patients after SABR for Early Lung Cancers - A Population Based Retrospective Comparison of Survival among Age Cohorts (ID 3113)
17:30 - 17:35 | Author(s): D. Schellenberg, M. Dosani, R. Yang, A. Houle, S. Thomas, C. Lund, H. Carolan
- Abstract
- Presentation
Background:
As Stereotactic Ablative Body Radiotherapy (SABR) is increasingly used to treat early non-small cell lung cancer, a larger proportion of elderly patients are now receiving radical therapy. This review aims to assess whether age significantly influences overall survival (OS) in patients with early stage lung cancer treated by SABR according to a standard provincial protocol, and to determine if a maximum age guideline should be introduced.
Methods:
Using a population database all lung-SABR patients were divided into age categories <70 yo (n=45), 70-74 (n=28). 75-79 (n=39),80-84 (n=33) and ≥85 (n=22). Patient and tumor characteristics were collected including: sex, Charlson comorbidity index (CCI), ECOG performance status, tumor diameter, maximum tumor SUV (SUVmax), forced expiratory volume in 1 second (FEV1), and whether a pathologic diagnosis was obtained. For each cohort, OS from date of SABR was calculated. Variability among tumor characteristics between cohorts was evaluated by Chi-squared test and OS was calculated by Kaplan-Meier.
Results:
185 patients were treated from 2009 to 2013. Median age was 76 (range 49-94). The percentage of patients with pathologic diagnoses and the percentage of males was similar among age categories. FEV1 values, ECOG status, SUVmax values and tumor length were not significantly different among the age categories. Older patients had significantly greater CCI scores (see table p=0.001). Median OS for all patients was 36 months and was not reduced in the oldest cohorts (<70: 34 months, 70-74: 24 months: 75-80: 39 months, 80-84:36 months, ≥85: 36 months).Age Categories (years old) <70 70-74 75-79 80-84 85+ CCI 0-1 5 (%) 0 0 0 0 2-4 59 (%) 39 35 15 10 5-7 34 (%) 54 57 76 60 8 or more 2 (%) 7 8 9 30
Conclusion:
Based on 5 years of population based data, an age cutoff for lung-SABR is not endorsed. In our treated population, patients ≥85 yo have similar OS as younger patients despite greater CCI scores.
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MINI18.10 - Discussant for MINI18.06, MINI18.07, MINI18.08, MINI18.09 (ID 3542)
17:35 - 17:45 | Author(s): S.S. Yom
- Abstract
- Presentation
Abstract not provided
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MINI18.11 - Does Motion Management Technique for Lung SBRT Influence Local Control? (ID 177)
17:45 - 17:50 | Author(s): G.M.M. Videtic, N. Woody, C. Reddy, K. Stephans
- Abstract
- Presentation
Background:
Abdominal compression (COMP) for motion management began with our lung stereotactic body radiotherapy (SBRT) practice. From 11/2009, breath hold technique by automatic breath control (ABC) device is selectively employed typically for fit oligometastatic patients (pts). We now compare local failure (LF) results for COMP versus ABC.
Methods:
Our IRB-approved SBRT registry was queried for pts. treated for either a primary lung cancer (PRIME) or an oligometastatic (OLIGO) diagnosis with a minimum 6 months follow up. SBRT was delivered by a stereotactic-specific LINAC platform with vacuum-bag based immobilization, and infrared-based X-ray positioning system+/- CBCT for image-guidance. With COMP, tumor excursion was limited to <1cm and the ITV was created one of two way dependent on treatment era: 1. Fused GTV excursion CTs from free breathing, fixed inhale and exhale travel or 2. by 4DCT, with PTV created from the MIP ITV after adding a 5mm margin. With ABC, 3 serial CT image sets confirmed target immobilization, with the PTV generated after 5 mm was added to the static GTV. SBRT was delivered either with dynamic arcs or step-and-shoot intensity–modulated beams. SBRT dose/fractionation schedules evolved over time and reflected treatment era, tumor location, clinician preference, and trial-based experience. LF was defined as progressive and increasing CT scan abnormalities confirmed by progressive and incremental increases in a lesion’s SUVs on serial PET imaging, with or without biopsy.
Results:
For the interval 10/2003 to 7/2014, 873 pts with 931 lesions were treated. Overall pt. characteristics were: 455 (52.1%) female; 83.9% Caucasian; median age 73 years (range 37-97); median KPS 80 (range 40-100); median BMI 26.2 (range 12.1-56.3). Overall tumor characteristics were: median tumor size 2.2 cm (range 0.7-10.0); median PET SUVmax 7.5 (range 0.8-59), per RTOG 0813 definitions 234 (25.4%) were central lesions, with no significant tumor differences between COMP and ABC cohorts. 830 (89.2%) lesions were PRIME, 101 (10.8%) were OLIGO. ABC was used significantly more for OLIGO vs. COMP (34.4% vs.8.3%, p<0.0001). Median follow-up and SBRT dose were 16.4 months (0-109.5) and 50 G/5 fractions respectively. Overall crude rate of LF was 9.9%. Use of ABC was not associated with increased LF compared to COMP: hazard ratio (HR)=1.043 [95% CI 0.48-2.29; p=0.92] Three-year actuarial rates of LF for ABC vs. COMP were 13.8% and 16.5%, respectively. After stratifying by OLIGO/PRIME, neither ABC nor COMP was significantly associated with LF. There is a suggestion that centrality may be associated with LF with ABC (HR =2.087, p=0.066)On univariate analysis, BMI, tumor size, PET SUVmax and central location were associated with failure, with size the most significant.
Conclusion:
Although form of motion control overall did not predict for LF in lung SBRT, LF for central tumors may be associated with ABC use.
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MINI18.12 - Assessment of Dose Response via Regional Lung Perfusion following Stereotactic Radiotherapy for Lung Cancer (ID 910)
17:50 - 17:55 | Author(s): R. McGurk, S.K. Das, E. Schreiber, T. Zagar, A. Sheikh, W. McCartney, M. Lawrence, P. Rivera, R. Green, L. Marks
- Abstract
- Presentation
Background:
Radiation therapy (RT)-induced lung injury is one of the major causes of morbidity in patients with thoracic cancer. Extensive work has been done to understand the predictors of lung injury in patients receiving conventionally fractionated RT. However, less work has been done in the setting of hypo-fractionation. Further, conventional methods to consider lung injury typically assess global lung function (e.g. symptoms, pulmonary function tests), are affected by many other (non-radiation) factors, and are thus non-specific. Single photon emission computed tomography (SPECT) perfusion imaging affords an objective quantitative manner to assess the effects of RT on regional lung function. We herein report the preliminary results of a prospective study to assess the magnitude of RT-induced reductions in regional lung perfusion following hypo-fractionated stereotactic RT.
Methods:
Four patients undergoing hypo-fractionated stereotactic lung RT (SBRT: 12 Gy x 4 fractions or 10 Gy x 5 fractions) had a pre-treatment SPECT (single-photon emission computed tomography) perfusion scan providing a 3D map of regional lung perfusion. Scans were repeated 3-6 months post-treatment. Pre- and post SPECT scans were registered to the planning CT scan (and hence the 3D dose data). Changes in regional perfusion (counts per cc on the pre-post scans) were computed in regions of the lung exposed to different doses of radiation (in 5 Gy intervals), thus defining a dose-response function. SPECT scans were internally normalized such that total counts in the regions receiving <5 Gy were equal between pre- and post-treatment scans.
Results:
3 months post-RT, changes in perfusion are highly variable. At 6 months, there is a consistent dose-dependent reduction in regional perfusion. Average percent decline in regional perfusion was 10% at 15-20 Gy, 20% and 20-25 Gy, and 30% at 25-30 Gy representing a relatively linear dose response with an approximate 2% reduction per Gray for doses in excess of 10 Gy. Subtle increases in perfusion were seen in lung receiving <10 Gy. Figure 1
Conclusion:
Hypo-fractionated stereotactic RT appears to cause a dose-dependent reduction in regional lung perfusion. There appears to be a threshold effect with no apparent perfusion loss at doses <10 Gy, in both normalized and unnormalized dose-response curves. Additional data is needed from a larger number of patients to better assess this issue. This sort of data can be used to assist optimizing RT treatment plans that minimize the risk of lung injury.
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MINI18.13 - Can Stereotactic Ablative Radiotherapy (SABR) Improve Patient Selection for Lung Cancer Surgery and Reduce Perioperative Mortality? (ID 779)
17:55 - 18:00 | Author(s): N. Serrano, B. Adams, S. Szentpetery, C.L. Rogers, M. Chang, D. Moghanaki
- Abstract
- Presentation
Background:
Comparative effectiveness research has demonstrated similar rates of disease control and overall survival (OS) for patients with stage I non-small cell lung carcinoma (NSCLC) who are treated with either surgery or SABR. It was therefore hypothesized that the introduction of SABR might improve patient selection for surgery, lead to the referral of high operable risk patients for SABR, and consequently reduce the lung cancer surgery perioperative mortality rate.
Methods:
Cancer registry data identified all patients with stage I NSCLC who underwent surgery or SABR between 1993-2014 at a Veterans Affairs medical center. Mortality rates from the pre-SABR and post-SABR (after 2007) eras were compared. Clinical records in the Computerized Patient Record System were queried to analyze rates of disease control and overall survival (OS).
Results:
A total of 284 patients underwent surgery for stage I NSCLC in the pre-SABR (n=171) and post-SABR (n=113) eras. The majority of patients were male (96.6%) and the median follow-up was 4.1 years. Operative procedures included a pneumonectomy (n=10), lobectomy (n=206), or wedge resection (n=68). The 90-day mortality rate was 3.2%, whereas the 6-month mortality rate was 7.0%. Comparing mortality rates in the pre-SABR to post-SABR eras, there were no declines at 90-days (3.5% vs. 2.7%, p=0.47), or 6-months (7.0% vs. 7.1%, p=0.36). Patients referred for SABR have included 27 medically inoperable patients and 0 operable patients. The mortality rate after SABR was 0% at both 90-days and 6 months. Comparing SABR and surgery, the rate of disease progression was similar (p=0.47); found in 18.5% after SABR (1 distant, 4 regional), 23.4% after lobectomy (9 regional, 2 regional and distant, 11 distant), 33.3% after wedge (3 local, 3 distant), and 0% after pneumonectomy. Two-year OS was numerically superior with SABR (69.4% vs. 63.1%), although this was not statistically significant (p=0.52).
Conclusion:
The introduction of SABR neither influenced patient selection for surgery, nor reduced the perioperative mortality rate for patients with stage I NSCLC. These data suggest comparative effectiveness research alone may be insufficient to improve outcomes for this disease. Efforts to complete a prospective randomized trial of surgery vs. SABR should not be abandoned.
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MINI18.14 - Pre-Existing Pulmonary Fibrosis Increases the Risk of Radiation Pneumonitis (ID 557)
18:00 - 18:05 | Author(s): S. Campbell, G. Kerr, J. Murchison, G. Ritchie, S. Erridge, T. Evans, F. Little, M. McKean, A. Price
- Abstract
- Presentation
Background:
Radiation pneumonitis is a potentially life-threatening complication of curative radiotherapy in individuals with lung cancer. Predicting which patients are at higher risk of pneumonitis is constrained by limited understanding of its causes. The aim of this study was to examine patient characteristics and radiological factors associated with increased risk of radiation pneumonitis in individuals with lung cancer receiving curative radiotherapy.
Methods:
Individuals with lung cancer treated with curative radiotherapy between January and June 2009 were identified from our departmental database. Data were extracted on patient sex, age and smoking status, lobe affected by cancer, pathology, T and N stage, radiation dose delivered, the use of concurrent chemotherapy, and the grade of fibrosis present on the diagnostic CT scan. The CT scans were reviewed and the fibrosis scored by two pulmonary radiologists. CTCAEv3.0 toxicity scores were used to grade the pneumonitis. Mann-Whitney, chi-squared and Fisher exact tests were used to determine the impact of the various factors on the risk of developing pneumonitis.
Results:
84 patients were identified who underwent curative radiotherapy for lung cancer between January and June 2009. The minimum follow-up for the cohort was 5 years. One year and 3 year survival were 61.9% and 29.8% respectively. 8/84 patients (9.5%) developed significant pneumonitis (CTCAEv3 grade 3 - 5). 6/22 (27.3%) patients with fibrosis on their diagnostic CT developed grade 3 - 5 pneumonitis compared with 2/58 (3.4%) of patients with no fibrosis on the diagnostic CT (Fisher exact test, p=0.0042). Low grade pneumonitis had no impact on survival (grade 0, median survival 80 weeks, grade 1 - 2, median survival 78 weeks) whereas median survival was reduced to 16 weeks in those with grade 3 - 5 pneumonitis. One out of 8 patients in this group survived one year. Only the presence of fibrosis on the diagnostic CT scan and continued tobacco use affected the risk of developing pneumonitis with fibrosis increasing the risk of developing pneumonitis (relative risk 7.9, p < 0.04) and continued tobacco use reducing the risk (relative risk 0.3, p < 0.02). There appeared to be a trend between the fibrosis score on the baseline scan and the risk of developing pneumonitis which did not achieve statistical significance
Conclusion:
The data from this small study suggest radiation pneumonitis affects approximately 1 in 10 individuals receiving curative radiotherapy for lung cancer. The presence of pulmonary fibrosis on the diagnostic CT scan increased the risk of developing pneumonitis. Consideration should be given to alternative treatment options for these patients.
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MINI18.15 - Discussant for MINI18.11, MINI18.12, MINI18.13, MINI18.14 (ID 3474)
18:05 - 18:15 | Author(s): W.E.E. Eberhardt
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 33 - Radiotherapy and Complications (ID 164)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
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MINI33.05 - Discussant for MINI33.01, MINI33.02, MINI33.03, MINI33.04 (ID 3553)
18:55 - 19:05 | Author(s): D. Raben
- Abstract
- Presentation
Abstract not provided
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P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-002 - Effects of Eribulin and Radiation on a Panel of Small Cell Lung Cancer (SCLC) Cell Lines (ID 2154)
09:30 - 09:30 | Author(s): D. Raben
- Abstract
Background:
Background: Chemotherapy produces high response rates in extensive stage SCLC and a modest improvement in 5-year survival rates when combined with chest radiation in limited stage SCLC. Chemotherapeutic agents for SCLC have not changed in 20 years. Eribulin is a microtubule inhibitor that arrests cells in the G2/M fraction of the cell cycle with established activity in breast cancer. Radiobiological studies demonstrated that cells in the G2/M phase of the cell cycle are less efficient at repairing radiation induced DNA damage. Thus, we investigated the effects of eribulin, radiation and the combination on growth and cell cycle distribution in a panel of SCLC cell lines.
Methods:
Methods: Growth inhibition (GI) by varying concentrations of eribulin alone, radiation alone and the combination was assessed by MTS assay at 5 days post-treatment. Growth inhibition or fraction affected (FA) was determined by 1-(x/y) where x is the MTS signal for the experimental condition and y is the MTS signal for the untreated control cells. Our goal was to use a dose of radiation that alone induced a FA of about 0.5 allowing determination of the combination effects with eribulin. Changes in the G2/M distribution of cells treated with eribulin alone, radiation alone and the combination were evaluated at 24 and 48 hours post treatment by propidium iodine staining and analysis by FACS.
Results:
Results: Four of the eight SCLC cell lines were very sensitive to eribulin with half maximal growth inhibitory concentration (FA<0.5) of < 2nM. Four lines had 0.5 FA values > 2nM. 2 Gy radiation produced 32% to 58% growth inhibition in all 8 lines irrespective of their eribulin sensitivity. Low eribulin concentrations (≤ 1.25nM) and 2Gy radiation produced >70% growth inhibition in the 4 sensitive lines, which was significantly more growth inhibition than either alone. Eribulin concentrations of >2.5nM were required to increase growth inhibition over either alone in the 4 more resistant lines and the maximal GI was less in these lines (48%-70%) even at higher concentrations. With respect to G2/M, in the 4 most sensitive eribulin lines, there was a significant increase in the G2/M fraction following eribulin alone (0.625-1.25nM), radiation alone (2 or 3Gy) and a further increase occurred with the combination treatment. In these eribulin sensitive lines, 59% to 93% of the cells were in the G2/M phase by 48 hours. In 3 of the 4 less sensitive eribulin lines, higher concentrations of eribulin (>2.5nM) were required to increase the G2/M fraction to >50% and 2 or 3 Gy irradiation increased the G2/M fraction to 59% to 64%. The combination produced maximal G2/M fractions of 64%-79%. The one most eribulin resistance line never had more than 50% GI or > 40% of cells in G2/M at any concentration or radiation dose up to 4 Gy.
Conclusion:
Conclusions: SCLC cell lines are sensitive to eribulin and radiation and the combination produced significantly more growth inhibition and cell cycle arrest then either alone. The combination warrants further evaluation in in vivo models and potentially clinical trial study in patients with SCLC.
