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C. Faivre-Finn
Moderator of
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ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 8
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
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ORAL10.01 - A DLL3-Targeted ADC, Rovalpituzumab Tesirine, Demonstrates Substantial Activity in a Phase I Study in Relapsed and Refractory SCLC (ID 1598)
11:05 - 11:16 | Author(s): C.M. Rudin, M.C. Pietanza, D.R. Spigel, T. Bauer, B. Glisson, F. Robert, N. Ready, D. Morgensztern, M.D. Kochendoerfer, M. Patel, R. Salgia, D.K. Strickland, R. Govindan, H. Burris, S.J. Dylla
- Abstract
Background:
Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.
Methods:
SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.
Results:
52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.
Conclusion:
Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.
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ORAL10.02 - A Prospective Randomized Phase III Study of Continuum Chemotherapy versus Chemo-Radiotherapy in ES-SCLC in Asian Indian (ID 2854)
11:16 - 11:27 | Author(s): S. Narayan, M. Singhal, S. Beniwal, A. Kapoor, N. Sharma, R. Saught, A. Sharma
- Abstract
Background:
Selected patients with good responses to platinum based chemotherapy and good performance status were candidates for continuum platinum based chemotherapy versus chemo-radiotherapy in Extensive-stage small cell lung cancer (ES-SCLC). To evaluate the efficacy and toxicity of continuum platinum based chemotherapy versus chemo-radiotherapy in ES-SCLC in Asian Indian patient population.
Methods:
Between July 2008 and December 2009, 358 patients with ES-SCLC treated with induction Cisplatin (60-80mg/m2 d1) + Etoposide (80-120 mg/m2 d1-3) × 3 cycles for every 3 weeks. Patients with CR at both local as well as distant sites or PR at the local site, but CR at distant sites were randomized 1:1 to two treatment groups (n=287). A total of 287 patients with response were randomized to accelerated hyperfraction thoracic RT (45Gy/1.5 Gy twice daily) plus PE × 4 (144) versus PE × 4 alone without radiation (n=143). The PE doses were similar as in induction. All patients received prophylactic cranial irradiation (25Gy/10 fraction/5/week). The primary endpoint was the comparison of progression free survival (PFS) between the two arms and the secondary endpoints included overall survival (OS). All statistical analyses were performed by using SPSS version 20.0.
Results:
Baseline characteristics were well balanced. Mean age was 58 years (range 32-69), 78% had ECOG 0-1; 22% ECOG 2. In the CRT arm 66.67% and in CT only arm 57.34% patients were smoker. Median PFS 15 months (CRT arm) versus 10 months (CT only) (HR, 0.78; 95% CI, 0.56-1.18; p=0.06) and 5-year OS 10.3% (CRT arm) versus 6.2% (CT only) (HR, 0.83; 95% CI, 0.49 to 1.29; p=0.47) respectively. The survival difference at 1 year was not statistically significant (39% vs 31%; HR=0.89, CI 0.69-1.13; p=0.091). The survival difference at 3 years was just significant (18% vs 11%; HR=0.83, CI 0.72-1.08; p=0.047). Local control trended better in CRT arm, but no difference in distant metastasis control in both arms.
Conclusion:
CRT arm showed better PFS and OS than CT only arm within Asian Indian patient population. Thus, the CRT may be used as a continuum treatment in Asian Indian patients of ES-SCLC after induction chemotherapy.
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ORAL10.03 - Which Patients with ES-SCLC Should Receive Thoracic Radiotherapy (TRT) Routinely? (ID 41)
11:27 - 11:38 | Author(s): B. Slotman, C. Faivre-Finn, H. Van Tinteren, J. Praag, J. Knegjens, S. El Sharouni, M. Hatton, A. Keijser, S. Senan
- Abstract
- Presentation
Background:
Although TRT in patients with ES-SCLC did not lead to a statistically significant difference in overall survival (p=0.066), it did improve 2-year survival rates (p=0.004) in the CREST trial (Slotman et al., Lancet 385:36-42:2015). The failure to meet the primary study endpoint has evoked some controversy in the lung cancer community as to which patients should be offered TRT routinely. To define which patients benefit most from radiotherapy, analysis for overall survival (OS), progression free survival (PFS) and recurrence pattern was performed in patients with and without RITD, which was one of the stratification factors in the randomized study.
Methods:
Patients with confirmed ES-SCLC who responded to 4-6 cycles of platinum-etoposide were randomized to TRT (30 Gy/10fx) or control. All received prophylactic cranial irradiation (PCI). The primary study endpoint was OS. Secondary endpoints were PFS, intrathoracic control. relapse pattern and toxicity.
Results:
Out of 495 patients in the intent-to-treat analysis, 434 had RITD (215 allocated to TRT and 219 to the control arm) and 61 had not (32 allocated to TRT and 29 to the control arm). No significant differences in patient characteristics were observed between the groups. In patients with RITD, OS was significantly longer in the TRT-arm (HR 0.81,95% CI 0.66-1.00;p=0.044). Survival rates in the TRT and control arm were 33% (95%CI 27-40) vs 26% (95%CI 21-33) at 1 year, and 12% (95%CI 8-19) vs. 3% (95%CI 1-8) at 2 years, respectively. PFS was also significantly longer in the TRT-arm (HR=0.70, 95%CI 0.57-0.85; p<0.001). Intrathoracic progression was reported in 43.7% of the TRT arm vs. 81.3% in the control arm (p<0.001). There was no significant difference in the risk of brain metastases (10.2% vs. 5.5%). Exclusive progression outside thorax and brain occurred in 37.2% in the TRT arm, compared to 5.9% in the control arm (P<0.001). In patients without RITD, there was no significant difference in OS (HR 1.02, 95%CI 0.59-1.77, p=0.937) and PFS (HR=1,00, 95%CI 0.59-1.70, NS) between the TRT and control arms.
Conclusion:
This additional analysis of the CREST data shows that ES-SCLC patients with RITD after chemotherapy have a statistically significant improvement in OS, PFS and risk of intrathoracic progression if they undergo TRT. No such benefit for TRT is seen in patients without RITD. These findings support the routine use of TRT in patients who respond to chemotherapy but still have residual intrathoracic disease.
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ORAL10.04 - Pembrolizumab for ED SCLC: Efficacy and Relationship with PD-L1 Expression (ID 3285)
11:38 - 11:49 | Author(s): P.A. Ott, E. Elez, S. Hiret, D. Kim, R.A. Moss, T. Winser, S.S. Yuan, M. Dolled-Filhart, J. Cheng, B. Piperdi, J.M. Mehnert
- Abstract
- Presentation
Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized IgG4 monoclonal antibody against PD-1 designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2, has demonstrated robust antitumor activity and a manageable toxicity profile in several advanced cancers, including NSCLC. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive SCLC in the ongoing, multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov, NCT02054806).
Methods:
Key eligibility criteria for the SCLC cohort include failure of or inability to receive standard therapy, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0 or 1, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1–positive bands in stroma as assessed by IHC using the 22C3 antibody at a central laboratory, no autoimmune disease, no interstitial lung disease, and no prior anti–PD-1 or anti–PD-L1 therapy. Pembrolizumab is given at 10 mg/kg every 2 weeks for 24 months or disease progression, intolerable toxicity, or investigator decision. Patients with progressive disease who are clinically stable may continue treatment until confirmation of progression 4 weeks later. Response will be assessed per RECIST v1.1 by investigator review every 8 weeks for the first 6 months, then every 12 weeks thereafter. Adverse events (AEs), including potentially immune-related adverse events, will be collected throughout the study and for 30 days (90 days for serious AEs) thereafter. Primary end points are safety and tolerability and the overall response rate. The relationship between pembrolizumab antitumor activity and potential biomarkers, including the level of PD-L1 expression, is an exploratory end point.
Results:
Of the 147 patients with SCLC who had evaluable tumor samples and were screened for PD-L1 expression, 42 (29%) had PD-L1–positive tumors. Overall, 24 patients with SCLC were enrolled and received ≥1 pembrolizumab dose. Among the 20 patients treated as of March 13, 2015, median age was 59.5 years, 55% were men, and 75% had an ECOG performance status of 1. All patients had received prior chemotherapy with a platinum + etoposide.
Conclusion:
Analyses of safety and tolerability and response are ongoing, as are analyses on the relationship between the level of PD-L1 expression and pembrolizumab response. These data will be available for presentation.
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ORAL10.05 - Discussant for ORAL10.01, ORAL10.02, ORAL10.03, ORAL10.04 (ID 3560)
11:49 - 11:59 | Author(s): P. Lara Jr.
- Abstract
- Presentation
Abstract not provided
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ORAL10.06 - Long-Term Survival after Surgery for Pathologic N1 and N2 Small Cell Lung Cancer: A Comparison with Nonoperative Management (ID 3089)
11:59 - 12:10 | Author(s): C.J. Yang, D.Y. Chan, P.J. Speicher, B.C. Gulack, M.W. Onaitis, M.G. Hartwig, B.C. Tong, M.F. Berry, T.A. D'Amico, D. Harpole
- Abstract
- Presentation
Background:
With the advent of modern chemotherapy, patients previously thought to have unresectable small cell lung cancer (SCLC) may have tumors amenable to surgery. This study was undertaken to test the hypothesis of whether surgery, in the setting of modern adjuvant therapies, offers a survival advantage among patients with node-positive SCLC.
Methods:
Overall survival (OS) of patients with pT1-2 pN1-2 M0 SCLC who underwent non-operative management (chemotherapy ± radiation) vs surgery (with adjuvant chemotherapy ± radiation) in the National Cancer Data Base (NCDB) from 2003-2011 was assessed using propensity-score-matched analysis. Groups were matched for common prognostic co-variates (year of diagnosis, age, sex, race, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, pathologic T and N status, and tumor location). NCDB data is prospectively collected by certified tumor registrars and include over 70% of cancer cases diagnosed annually in the U.S.
Results:
Of 1,071 patients who met inclusion criteria, 359 (33.5%) patients underwent surgery with adjuvant chemotherapy ± radiation and 712 (66.5%) underwent non-operative management. After propensity-score matching, 11 covariates were balanced between the surgery (n=231) and non-operative (n=231) groups. Surgery was associated with a significantly higher OS than non-operative management (5-year OS 28.1% vs 18.3, log-rank p<0.01) (Figure 1). To minimize treatment selection bias due to comorbidities, we limited the propensity-matched analysis to patients with no comorbidities; surgery remained significantly associated with a higher OS than non-operative management (5-year OS 32.1% vs 21.8%, log-rank p<0.01) (Figure 2). Figure 1 Figure 2
Conclusion:
In a propensity-matched analysis of a national population-based cancer database, surgery followed by adjuvant chemotherapy ± radiation for SCLC pT1-3 pN1-2 patients had improved outcomes when compared to non-operative medical treatment. These results support an increased role of surgery in multimodality therapy for more advanced limited-stage small cell lung cancer.
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ORAL10.07 - Clinical and Molecular Profiling of Surgically Resected Small Cell Lung Cancer (ID 2235)
12:10 - 12:21 | Author(s): K. Takamura, H. Yokouchi, H. Nishihara, H. Suzuki, H. Uramoto, S. Yamazaki, H. Kikuchi, K. Akie, F. Sugaya, Y. Fujita, M. Harada, T. Harada, M. Higuchi, T. Kojima, T. Fukuhara, Y. Matsuura, O. Honjo, Y. Minami, N. Watanabe, H. Dosaka-Akita, H. Isobe, M. Nishimura, M. Munakata
- Abstract
- Presentation
Background:
NCCN, ACCP and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), while ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). In addition, the clinical impact of surgery with other variables on patients with early-stage SCLC has yet to be determined. Therefore, clarification of the clinical profile of surgically resected SCLC is required. Suppression of MED12, a subunit of the transcriptional MEDIATOR complex in conjunction with cell surface expression of TGF-βRII was reported to be correlated with the resistance mechanism of EGFR-TKIs, crizotinib, and chemotherapy. Few investigators examined the expression profile of MED12 as well as receptor tyrosine kinases in SCLC. A next-generation sequencing (NGS) system is a novel technology for sequencing genomes at high-throughput and with great accuracy using deep sequencing. It has been instrumental for translational study integrating the detection of genetic alteration analysis into the better understanding of tumor biology, as well as treatment of various types of cancers. Recently, SOX-2 amplification, histone modification, and genetic alterations in the PI3K/AKT/mTOR pathway were reported to be potential targets of SCLC using NGS through whole exon analysis. However, further investigation is needed for the personalized treatment of SCLC. We updated the molecular data using NGS, which had been presented at ESMO 2014 (abstract ID: 5724).
Methods:
We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 through January 2013. One hundred twenty-five formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using seven antibodies (MED12 and TGF-βRII, ALK, c-Met, EGFR, c-kit, and VEGFRII) and to NGS systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 cancer-specific genes. (UMIN registration No. 000010116 /10117).
Results:
Median relapse-free survival and overall survival (OS) were 15.6 (95%CI=6.8-24.5) and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without a history or presence of other types of cancer (HR: 0.545, 95%CI=0.335-0.887, p=0.014), with preoperative diagnosis (HR: 0.510, 95%CI=0.299-0.871, p=0.014), with c-stage II and under (HR: 0.288, 95%CI=0.154-0.541, p<0.001) and with prophylactic cranial irradiation (HR: 0.300, 95%CI=0.092-0.976, p=0.045). Of the 125 patients whose samples were available, MED12 and TGF-βRII were highly expressed in nucleus and cytoplasm, respectively in 92% and 55% of the samples. None of the tumors expressed ALK. There was no relationship between the expression of c-Met, EGFR, and VEGFRII and either of RFS or OS. Multivariate analysis demonstrated that high expression of c-kit in tumor is an independent factor for longer OS (HR=0.543, 95%CI: 0.310-0.953, p=0.033). Seventy-nine samples have been subjected to NGS. Three actionable gene mutations, EGFR (E746_A750del), KRAS (G12D), and AKT1 (E17K) were found.
Conclusion:
These results supported the ESMO guidelines for the management of early-stage SCLC, and indicated that presence or history of other types of cancer might be a major decisive factor for surgery. The results of immunohistochemistry using antibodies of selective molecules and NGS assist us in gaining a better understanding of the biology and treatment strategy of SCLC.
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ORAL10.08 - Discussant for ORAL10.06, ORAL10.07 (ID 3330)
12:21 - 12:31 | Author(s): D. Ball
- Abstract
- Presentation
Abstract not provided
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Author of
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GR 04 - Problems in Advanced Metastatic Disease (ID 18)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Kelly, R. Pirker
- Coordinates: 9/09/2015, 14:15 - 15:45, 702+704+706
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GR04.01 - Case of a Patient with EGFR Mutation Positive Disease and Two Small Brain Metastases (ID 1844)
14:20 - 14:40 | Author(s): C. Faivre-Finn
- Abstract
- Presentation
Abstract:
Non-small-cell lung cancer (NSCLC) is the leading cause of brain metastases. The development of brain metastases in this group of patients represents an important public health issue, as 20-40% of NSCLC patients present with or will develop brain metastasis during the course of their treatment. The prognosis of NSCLC patients with brain metastases is generally extremely poor and brain metastases have a major impact on quality of life. The incidence of brain metastases has been increasing over time as a consequence of better neuroimaging modalities and also prolonged survival in the locally advanced and metastatic setting with improved therapies. This is particularly relevant in the group of patients with somatic aberrations within driver oncogenes, such as epidermal growth factor receptor (EGFR) as targeted therapy using tyrosine kinase inhibitors (TKIs) are producing high response rates and progression free survival. Patients with EGFR mutations therefore represent a population at higher risk of brain metastases than the overall NSCLC population, with a risk of developing intra-cranial disease as the first site of progression in approximately 20-30%, and a lifetime risk >50%. Of note, brain metastases in this group of patients present more and more in the context of well controlled systemic disease and are more likely to be treatable than in the historic paradigm where brain metastases developed in concert with progressive multi-organ metastatic disease.Furthermore, there is a suggestion that the prognosis of EGFR mutated patients and brain metastases is better compared to wild type . In the context of stable thoracic and systemic disease treatment options for oligometastatic brain disease include; surgery, stereotactic radiotherapy, whole brain radiotherapy, and systemic treatments. Surgery can play an important role in patients with brain metastases and particularly patients with mass effect from a large symptomatic lesion. Randomised controlled trials with single brain metastases have demonstrated that the addition of surgery to WBRT improves survival. Stereotactic radiosurgery (SRS) is increasingly used as the sole treatment rather than as a ‘booster therapy’ in addition to WBRT to improve local control. Typically, SRS is reserved for patients with controlled extracranial disease and life expectancy >6 months, 1 to 4 brain metastases less than 3cm in maximum diameter. Treatment with EGFR TKIs is generally considered in patients with EGFR mutations but the evidence to support the optimal sequencing with local therapies is limited. In my talk I will discuss the following points: • Risk of developing brain metastases in EGFR mutated NSCLC • Prognostic factors (including EGFR mutation) • The role of local treatment (SRS, WBRT and neurosurgery) • The role of prophylactic cranial irradiation • The role of systemic treatment • Future directions
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MINI 28 - Psychological Impact of Lung Cancer and its Treatment (ID 150)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:A. Oton
- Coordinates: 9/09/2015, 16:45 - 18:15, 102+104+106
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MINI28.09 - Can WBRT Be Omitted in NSCLC Patients with Inoperable Brain Metastases? Results from the UK MRC QUARTZ Randomised Clinical Trial (ID 2914)
17:35 - 17:40 | Author(s): C. Faivre-Finn
- Abstract
- Presentation
Background:
Brain metastases affect up to 40% of patients with non-small cell lung cancer (NSCLC), and for patients not suitable for surgical resection or stereotactic radiosurgery, whole brain radiotherapy (WBRT) and dexamethasone is standard treatment. However there are no randomised clinical trials showing whether WBRT improves either quality of life (QoL) or survival.
Methods:
A phase III randomised non-inferiority trial with a primary outcome measure of quality adjusted life years (QALYs). Patients with brain metastases from NSCLC who were not suitable for resection or stereotactic radiotherapy, irrespective of any other clinical characteristics, were randomly allocated to either optimal supportive care, including dexamethasone, plus WBRT 20 Gy/5f (OSC+WBRT) or OSC alone. QALYs were generated from overall survival and patients’ weekly completion of the EQ-5D questionnaire. OSC alone was considered non-inferior if not greater than 7 QALY days worse than OSC+WBRT (80% power and a one sided significance level of 5% requiring 534 patients). Secondary outcome measures include sub-group analyses to identify/validate predictive classifications.
Results:
From 2007-2014 538 patients were recruited from 69 UK and 3 Australian centres. Summary trial information is presented in table 1, with baseline characteristics well balanced between trial arms. Median survival was 65 days (OSC+WBRT) vs 57 days (OSC), hazard ratio 1.05 (95% CI 0.89 – 1.26). The mean QALY was 43.3 days (OSC+WBRT) vs 41.4 days (OSC), difference -1.9 days (90% CI -9.1 – +6.6). More OSC patients received additional anti-cancer treatment (39% vs 25%, p-value=0.0004), particularly radiotherapy (22% vs 13%, p-value=0.0067), with palliative thoracic irradiation in the two weeks following randomisation accounting for most of the difference. At 4 weeks post-randomisation, 36% of patients in each arm were alive with maintained or improved QoL compared to baseline. This fell to 17% in each arm at 8 weeks. The most commonly reported problems at 4 weeks concerned mobility (73% WBRT vs 79% OSC) and the ability to perform usual activities (68% vs 67%). Table 1. Summary of main trial dataOSC+WBRT (N=269) OSC (N=269) Sex Male 157 (58%) 157 (58%) Age Median 66 67 IQR 60 – 72 62 – 72 Range 38 – 84 45 – 85 KPS <70 101 (38%) 102 (38%) ≥70 168 (62%) 167 (62%) Extra-cranial mets No 122 (45%) 124 (46%) Number of brain mets Solitary 80 (30%) 82 (30%) Time since brain mets diagnosis <= 4 weeks 165 (61%) 153 (57%) > 4 weeks 104 (39%) 116 (43%) Median (days) 23 26 Range (days) 2 – 235 0 – 196 Survival (weeks) Deaths 260 262 One-year (95% CI) 2.6% (1.1%, 5.1%) 2.7% (1.2%, 5.3%)
Conclusion:
This is the only large randomised trial evaluating the utility of WBRT in this disease. Although the results include the pre-specified non-inferiority margin, the estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients. Additionally there were no significant differences in overall survival or quality of life. .
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ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
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ORAL10.03 - Which Patients with ES-SCLC Should Receive Thoracic Radiotherapy (TRT) Routinely? (ID 41)
11:27 - 11:38 | Author(s): C. Faivre-Finn
- Abstract
- Presentation
Background:
Although TRT in patients with ES-SCLC did not lead to a statistically significant difference in overall survival (p=0.066), it did improve 2-year survival rates (p=0.004) in the CREST trial (Slotman et al., Lancet 385:36-42:2015). The failure to meet the primary study endpoint has evoked some controversy in the lung cancer community as to which patients should be offered TRT routinely. To define which patients benefit most from radiotherapy, analysis for overall survival (OS), progression free survival (PFS) and recurrence pattern was performed in patients with and without RITD, which was one of the stratification factors in the randomized study.
Methods:
Patients with confirmed ES-SCLC who responded to 4-6 cycles of platinum-etoposide were randomized to TRT (30 Gy/10fx) or control. All received prophylactic cranial irradiation (PCI). The primary study endpoint was OS. Secondary endpoints were PFS, intrathoracic control. relapse pattern and toxicity.
Results:
Out of 495 patients in the intent-to-treat analysis, 434 had RITD (215 allocated to TRT and 219 to the control arm) and 61 had not (32 allocated to TRT and 29 to the control arm). No significant differences in patient characteristics were observed between the groups. In patients with RITD, OS was significantly longer in the TRT-arm (HR 0.81,95% CI 0.66-1.00;p=0.044). Survival rates in the TRT and control arm were 33% (95%CI 27-40) vs 26% (95%CI 21-33) at 1 year, and 12% (95%CI 8-19) vs. 3% (95%CI 1-8) at 2 years, respectively. PFS was also significantly longer in the TRT-arm (HR=0.70, 95%CI 0.57-0.85; p<0.001). Intrathoracic progression was reported in 43.7% of the TRT arm vs. 81.3% in the control arm (p<0.001). There was no significant difference in the risk of brain metastases (10.2% vs. 5.5%). Exclusive progression outside thorax and brain occurred in 37.2% in the TRT arm, compared to 5.9% in the control arm (P<0.001). In patients without RITD, there was no significant difference in OS (HR 1.02, 95%CI 0.59-1.77, p=0.937) and PFS (HR=1,00, 95%CI 0.59-1.70, NS) between the TRT and control arms.
Conclusion:
This additional analysis of the CREST data shows that ES-SCLC patients with RITD after chemotherapy have a statistically significant improvement in OS, PFS and risk of intrathoracic progression if they undergo TRT. No such benefit for TRT is seen in patients without RITD. These findings support the routine use of TRT in patients who respond to chemotherapy but still have residual intrathoracic disease.
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-034 - Lung v5 Does Not Predict for Lung Toxicity after Fixed-Beam Intensity Modulated Radiotherapy (IMRT) (ID 709)
09:30 - 09:30 | Author(s): C. Faivre-Finn
- Abstract
Background:
Intensity Modulated Radiotherapy (IMRT) facilitates superior dose conformity, due to sculpting of the high dose volume and reduction of dose to normal tissues. However, the use of IMRT for lung cancer in the U.K. remains low, as a result of the paucity of clinical data and concerns about the impact of the low dose bath on toxicity. Our institution has treated 738 lung cancer patients with IMRT since 2008. Here we report the results of 227 patients, focusing on toxicity. Survival will be reported at a later date.
Methods:
A retrospective review of the first 227 patients receiving 6MV inversely planned (6-8 field) step and shoot IMRT for lung cancer from 2008-2013 was carried out. A database was interrogated to correlate planning parameters with toxicity. Toxicity was collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Results:
227 patients with a median age of 66 (36-87) were included. Patients received a dose of 50-68 Gy in 20-33 fractions. One hundred and sixty (70%) had non-small cell lung cancer, 47 (21%) small cell lung cancer, 8 (4%) mixed histology and 12 (5%) no histology. At presentation, 6 (3%), 27 (12%), 184 (81%) and 9 patients (4%) had stage I, II, III and IV disease respectively. Treatment modalities were split evenly between concurrent (37%), sequential (31%) chemo-radiotherapy and radiotherapy alone (32%). Median PTV volume was 502.7 cc (67.3-1297.2). Median lung V20, V10 and V5 were 27.7% (6.8-35.3), 50.4% (9.8-83.1) and 64.3% (12.9-98.9). Mean dose to the oesophagus was 23.8 Gy (3.1-51.0); oesophageal V55 and V35 were 2.9% (0-70.8) and 36.8% (0-79.8). Heart V30 and V5 were 23.6% (0-60.6) and 57.6% (0-100) respectively. Despite 104 patients (46%) with V5 values > 65%, acute G3 pneumonitis was observed in only 7 (3.1%) patients. Acute G3 oesophagitis was observed in 31 (13.7%) patients. Late toxicity was not available in all patients. 6/154 (4%) developed late G3 pneumonitis, 8/154 (5.3%) had late G3 dyspnoea and late G2 cough was reported in 12/154 (8.1%). Grades 1, 2 and 3 pulmonary fibrosis occurred in 68/178 (30%), 13/178 (6%) and 1/178 (0.4%) patients respectively. Oesophageal stricture was evident in 7/173 (3%) and 4 patients developed an oesophageal fistula. There was no significant correlation between lung V5 and acute or late lung toxicity, using >65% as a cut off. Similar results were found with lung V10. There was also no relationship between mean oesophageal dose/V35/V55 and fistula or oesophageal stricture.
Conclusion:
From our experience, IMRT to the thorax is well tolerated, with minimal grade 3 toxicity. Contrary to reports, we did not observe a correlation between lung V5 and acute/late lung toxicity. However the heterogeneous population, retrospective nature of this study and small number of grade 3+ events limit the scope for multivariate analysis of toxicity. The data needs to be confirmed with a larger number of patients and integrated within predictive models of radiation-induced toxicity using patient reported outcome tools to facilitate collection of prospective toxicity data in the routine clinical setting. Data will be updated prior to the meeting.
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P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.07-009 - Effect of Accurate Heart Outlining on Cardiac Dose - the CONVERT Trial Experience (ID 1378)
09:30 - 09:30 | Author(s): C. Faivre-Finn
- Abstract
Background:
RTOG 0617 showed greater one year overall survival of 81% in the 60Gy group versus 70.4% in the 74Gy group, supporting the hypothesis that cardio pulmonary effects of radiotherapy can contribute to death. It has demonstrated that the percentage of heart receiving ≥5 and ≥30Gy is correlated with survival. Hence there is a need to improve planning and delivery of radiotherapy to avoid irradiating normal lung and heart wherever possible. This current study investigates the effect on cardiac dose of inaccurate cardiac outlining (non compliant to protocol) for a selection of plans submitted as part of the CONVERT Trial quality assurance programme.
Methods:
The CONVERT Trial is a multicentre phase III study which recruited 547 patients with limited-stage small cell lung cancer from April 2008 to November 2013. Patients were randomised to receive once daily (66Gy in 33 fractions) or twice daily (45Gy in 30 fractions) radiotherapy concurrently with chemotherapy. The primary endpoint was overall survival. The spinal canal, lungs, oesophagus and heart were contoured as organs at risk for dose-volume histograms. The trial protocol specified that the heart and pericardial sac should be contoured. Outlining should extend superiorly to the inferior aspect of the aortic arch and inferiorly to the apex of the heart. An atlas was provided to each centre which included example organ at risk contours. In this current study, heart outline volumes (in cm[3]) provided by participating centres have been compared to gold standard heart outlines (in cm[3]) drawn according to the trial protocol for 50 patients. The impact of the change in heart volume on heart dose (V30) is also presented. The CT and structure set for each case was imported into Eclipse (Version 11), and the heart was re-outlined according to the trial protocol. The plan data were then imported into Vodca along with the dose cube provided by the centre so that DVH data could be extracted.
Results:
The mean difference in cardiac volume between the gold standard and that provided by the centre was 80.0cm[3 ](range: 1.9cm[3] to 248.2cm[3]). In the experimental trial arm (66Gy), an increase in calculated cardiac dose (V30/%) was seen in 22/28 cases (78.6%) by using the gold standard cardiac outline rather than that provided by the centre. The mean increase in V30 was 5.7% (range: 0.92% to 15.29%). In the control dose arm (45Gy), an increase in calculated cardiac dose (V30/%) was seen in 17/22 cases (77.3%). The mean increase in V30 was 6.9% (range: 0.93% to 14.1%).
Conclusion:
In this study we have shown that in 86% of cases reviewed the heart was not delineated according to protocol. As a result the mean heart dose was underestimated by an average of 2.3Gy. In conclusion, this study highlights the importance of collecting radiotherapy plans to check heart contours as part of a QA programme and to feedback deviations to investigators.
