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A. Bezjak
Moderator of
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PC 03 - Pro vs Con: Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response / Pro vs Con: Is There a Role for Radiation in Oligometastatic Disease? (ID 49)
- Event: WCLC 2015
- Type: Pro Con
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:A. Brade, K. Rosenzweig, A. Bezjak, J.S. Lee
- Coordinates: 9/09/2015, 14:15 - 15:45, 708+710+712
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PC03.01 - Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response - Pro (ID 2034)
14:20 - 14:40 | Author(s): B. Slotman
- Abstract
- Presentation
Abstract:
Background Brain metastases are an important clinical problem in patients with small cell lung cancer (SCLC), with 20% of patients having them at diagnosis and about 80% at autopsy. In patients with LS-SCLC, prophylactic cranial irradiation (PCI) significantly reduces the risk of brain metastases, and it improves survival [1]. A meta-analysis showed a survival benefit of almost 6% at 3 years with PCI (21 vs 15%). A subsequent international multi-center study comparing higher and lower dose PCI found no improvement in outcomes with higher doses [2]. Consequently, a dose of 25 Gy in 10 fractions remains the standard dose for PCI. Since the risk of brain metastases is even higher in patients with ES-SCLC, PCI has also been investigated in these patients.A randomized EORTC study showed that PCI both reduced the risk of brain metastases and improved overall survival [3]. Survival at 1 year was 27% for the patients who received PCI compared to 13% for the controls. Interestingly, patients who received PCI were more likely to receive 2[nd] or 3[rd] line chemotherapy with subsequent disease progression (68 vs45%), presumably because they remained fitter without brain metastases. PCI was well tolerated in the effect on quality of life was small and transient [4]. The beneficial effect of of PCI was underscored in the recent CREST trial, where the risk of brain metastases was less than 5% [5]. Controversies surrounding the use of PCI Firstly, PCI can have a negative effect on cognition [6], with important risk factors being advanced age, pre-existing cerebrovascular problems, diabetes and the use of anti-epileptics. It should however be appreciated that brain metastases by themselves also have an important negative effect on cognition and quality of life. Moreover, SCLC patients may have impaired cognitive functioning in comparison with healthy controls, independent of the use of chemotherapy or radiotherapy. Another point to consider is that metastases in SCLC, often are multiple with limited options for high dose (stereotactic) radiotherapy, in contrast to NSCLC. Use of radiotherapy techniques that reduce doses to the hippocampus [7], as well as the use of Alzheimer drugs drugs such as memantine and donezepil [8] may further mitigate the effect of PCI. The effectiveness and safety of these approaches remains to be be evaluated in prospective clinical trials. Second, it has been questioned whether PCI will continue to show a beneficial effect if a brain MRI is repeated after completion of chemotherapy, in order to eliminate some subclinical metastases. This is discussion intensified after the presentation of a Japanese study in 2014 [9]. In the study, MRI brain was not only performed after chemotherapy, but also at regular intervals during the follow-up. Any brain metastases detected were treated with radiotherapy or radiosurgery. The study was designed as a superiority study for PCI, with overall survival as primary endpoint, but closed early due to futility. The likelihood of finding a survival benefit of PCI was less than 0,1%, but the discussion was fueled by the incorrect and misleading title using the word ‘detrimental’. Due to slow accrual, the Japanese study enrolled 160 patients entered from 40 centers in 4 years, thereby suggesting that patient selection may have played a roll. The publication of this analysis is awaited with interest. In order to address this topic from another angle, we have re-analyzed the effect of PCI on brain metastases and survival in a previous EORTC PCI study, after excluding patients who either died or developed brain metastases in the first 8 weeks after randomization, as such patients may have had asymptomatic brain metastases, visible if an MRI would have been performed. Even after exclusion of these patients, the EORTC PCI trial found a significant effect on brain metastases (HR 0.40; p<0.001) and overall survival (HR0.74; p=0.035) [unpublished data]. Conclusion In conclusion, PCI should remain standard of care in SCLC patients who have responded to chemotherapy. The pros and cons of PCI should be individually weighted and discussed with the patient. Some promising new techniques undergoing evaluation now may reduce the side-effects of PCI. References 1. Aupérin A, Arriagada R, Pignon JP, et al.. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-84. 2. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009 May;10(5):467-74. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. 4. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol. 2009 Jan 1;27(1):78-84. 5. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3;385(9962):36-42. 6. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):656-64. 7. Kundapur V, Ellchuk T, Ahmed S, Gondi V. Risk of hippocampal metastases in small cell lung cancer patients at presentation and after cranial irradiation: a safety profile study for hippocampal sparing during prophylactic or therapeutic cranial irradiation. Int J Radiat Oncol Biol Phys. 2015 Mar 15;91(4):781-6 8. Day J, Zienius K, Gehring K, et al. Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. Cochrane Database Syst Rev. 2014 Dec 18;12:CD011335. 9. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial. J Clin Oncol 32 (Suppl) Jun 11, 2014, abstract 7503
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PC03.02 - Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response - Con (ID 2035)
14:40 - 15:00 | Author(s): N. Yamamoto
- Abstract
- Presentation
Abstract not provided
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PC03.03 - Is There a Role for Radiation in Oligometastatic Disease? - Pro (ID 2036)
15:00 - 15:20 | Author(s): C. Le Pechoux
- Abstract
- Presentation
Abstract:
Fewer than 20% of all lung cancers are small cell lung carcinomas (SCLCs). As SCLC is an aggressive tumor because of its high and early risk of dissemination, most patients (60-70%) have metastatic disease at diagnosis. Given the high propensity of SCLC for early metastatic dissemination, chemotherapy has been and still is the cornerstone of treatment based on etoposide and platinum, but SCLC is also very sensitive to radiotherapy. Median survival for patients with non-metastatic disease for whom the standard treatment is combined chemotherapy and thoracic radiotherapy, as well as prophylactic cranial irradiation (PCI), is currently 15–20 months, with 20–40% surviving to 2 years, and 25% surviving at 5 years in the best series. For metastatic patients, median survival is 8–13 months and 2 year survival is around 5%. Recent advances in SCLC management derive mostly from a better integration of chemotherapy and radiotherapy. So patients with a limited number of metastases in number and location may have an intermediate outcome; and local treatment of both the primary tumor as well as oligometastatic disease could be discussed. Such an approach is supported by the fact that many patients in early studies that established the role of thoracic radiation therapy in limited disease would now be considered as having metastatic disease. The percentage of such metastatic patients seems to have increased partly because of stage migration with the more frequent use of PET scan and brain MRI. Thus there is a category of patients with oligometastatic disease for whom local treatment may be envisaged. The oligometastatic status was first described by Hellman and Weichselbaum as an intermediate clinical state between locoregionally confined and widespread cancer in 1995. There has been strong interest lately in this subgroup of non-small cell lung cancer oligometastatic patients, with the development of stereotactic ablative radiotherapy. Until recently, there were few data supporting the role of radiation therapy in metastatic small cell lung cancer, except PCI. As there are few therapeutic options in second line, local treatment approaches have been evaluated in extensive disease. Prophylactic cranial irradiation is now part of the standard treatment in responders and more recently a phase III trial has shown that consolidation thoracic radiotherapy could improve outcome. The 2-year survival rate was 13% in the investigational arm versus 3% in the control arm where patients had 4-6 cycles of chemotherapy and PCI [Auperin, 1999; Slotman 2007; Slotman, 2015]. A randomized phase II trial (RTOG 0937) went further in the local approach of metastatic disease after systemic chemotherapy and really addressed the issue of oligometastatic disease [Gore, RTOG 0937]. It compared PCI to PCI and consolidative radiation therapy not only to the primary intrathoracic disease but also to residual extracranial metastatic lesions (1-4 extracranial metastases who achieve a CR/PR following chemotherapy). The trial has included 96 patients and has closed recently after a planned protocol interim analysis. Results are eagerly awaited. Even if there are studies supporting the role of radiotherapy in metastatic SCLC, new strategies are needed for this category of patients. There are promising preclinical data showing a strong synergy between radiotherapy and immune treatments. Such approaches are starting to be explored in SCLC in prospective studies.
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PC03.04 - Is There a Role for Radiation in Oligometastatic Disease? - Con (ID 2037)
15:20 - 15:40 | Author(s): W.J. Curran
- Abstract
- Presentation
Abstract not provided
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Author of
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ORAL 19 - Radiation for Localized Lung Cancer (ID 126)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:D. De Ruysscher, M. Hiraoka
- Coordinates: 9/08/2015, 10:45 - 12:15, 102+104+106
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ORAL19.03 - NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiotherapy (SBRT) for Central Tumors - Adverse Events (ID 1458)
11:07 - 11:18 | Author(s): A. Bezjak
- Abstract
- Presentation
Background:
The safety of SBRT for medically inoperable patients with centrally located early stage non-small cell lung cancer (NSCLC) was evaluated in this phase I/II multicenter RTOG study that completed accrual in Sept 2013. This is the first report of adverse events (AE) observed on the study.
Methods:
Eligible patients were medically inoperable with biopsy proven, PET staged T1-2N0M0 NSCLC, ≤ 5 cm in size, centrally located tumors (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura). Patients were successively accrued onto dose-escalating 5 fraction SBRT schedules delivered over 1.5-2 weeks, starting with 10 Gy per fraction (fr), then 10.5Gy/fr, 11 Gy/fr, 11.5 Gy/fr and 12 Gy /fr. Toxicity was graded using CTCAE v4.0; any potential dose-limiting toxicity within the initial 365 days post SBRT could have led to dose reduction for subsequent patients accrued, using TITE-CRM (time-to-event continual reassessment method) statistical design.
Results:
120 patients (100 evaluable) from 43 centers were accrued between 2/2009 and 9/2013. 12 were excluded as they did not receive protocol treatment (6 of these on the 12Gy/fr cohort) and another 8 did not meet eligibility criteria. Cohort sizes were 8 (10Gy/fr), 8 (10.5Gy/fr), 18 (11Gy/fr), 43 (11.5Gy/fr), and 43 pts (12Gy/fr). Median age was 72 (range 52- 89) years, 57% were female, 45% had squamous cell carcinoma, 39% had adenocarcinoma, 65% had T1 tumors. Median follow up was 26.6 months. Most adverse events were grade (G) 1 or 2. 5/8 pts in lowest SBRT dose cohort (10 Gy/fr) experienced G2 toxicity, none had G>3. Of 7 pts in 10.5 Gy/fr, 1 had G2 and 1 had G5 toxicity. Of 14 pts in 11 Gy/fr cohort, 4 had G2 and 1 had G3. Of 38 pts in 11.5Gy/fr cohort, 11 had G2, 4 had G3 and 2 had G5. Of 33 pts in 12Gy/fr, 4 had G2, 5 had G3, 1 G4 and 1Gr 5 as the worst overall toxicity definitely, probably or possibly related to SBRT. All Gr 5 toxicities were due to hemoptysis, occuring at a mean of 13 mo post SBRT (range 5.5-14mo). G2+ GI toxicity only occurred in the 11.5Gy/fr (1/38) and 12.0Gy/fr (2/33) cohorts. G2+ pulmonary toxicity occurred in 4/8 10.0Gy/fr, 0/8 10.5Gy/fr, 5/14 11.0Gy/fr, 15/38 11.5Gy/fr, and 10/33 12.0Gy/fr pts.
Conclusion:
This phase I/II trial of SBRT provides data to inform patients of the potential toxicities with a 5 fraction SBRT schedule for centrally located NSCLC. Although SBRT was well tolerated, 4/100 pts (4%) had fatal hemoptysis potentially attributable to SBRT. Determination of the optimal SBRT dose needs to await analysis of tumor locations, DVH data and efficacy data. This project was supported by grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422 from the National Cancer Institute (NCI).
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ORAL 20 - Chemoradiotherapy (ID 124)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, J.Y. Chang
- Coordinates: 9/08/2015, 10:45 - 12:15, 201+203
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ORAL20.08 - Discussant for ORAL20.06, ORAL20.07 (ID 3353)
11:50 - 12:00 | Author(s): A. Bezjak
- Abstract
- Presentation
Abstract not provided
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