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J.S. Lee

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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
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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
      • Slides

      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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    MINI 07 - ChemoRT and Translational Science (ID 110)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      MINI07.09 - Incorporating Erlotinib Into Chemoradiation Therapy for Unresectable Stage IIIA/B NSCLC: Interim Results of Ongoing Phase II Randomized Trial (ID 1761)

      17:30 - 17:35  |  Author(s): J.S. Lee

      • Abstract
      • Presentation
      • Slides

      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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    MINI 21 - Novel Targets (ID 133)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI21.09 - Discussant for MINI21.06, MINI21.07, MINI21.08 (ID 3422)

      17:30 - 17:40  |  Author(s): J.S. Lee

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 32 - EGFR WT and MT Targeting (ID 144)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL32.07 - Randomized Phase II Trial of Sequential Gefitinib and Pemetrexed/Cisplatin Chemotherapy for Stage IIIB/IV Lung Adenocarcinoma in Never Smokers (ID 1332)

      17:50 - 18:01  |  Author(s): J.S. Lee

      • Abstract
      • Presentation
      • Slides

      Background:
      While concurrent administration of EGFR-TKI and chemotherapy failed to improve the survival outcome, preclinical and clinical data suggested that sequential administration of EGFR-TKI within a chemotherapy cycle might improve the clinical outcome by avoiding the putative antagonism of TKI-induced G1 arrest of the cell cycle phase-dependent activity of chemotherapy. This study was designed to evaluate this idea with gefitinib and Pemetrexed/Cisplatin (Pem/Cis), the best known regimen for lung adenocarcinoma (ADC), in never-smokers with chemo-naive ADC of the lung.

      Methods:
      Eligible patients (pts) were never-smokers with chemo-naive stage IIIB/IV ADC, performance status of 0-2 and adequate organ functions, who were randomized after stratification by the EGFR mutation status (positive vs. negative/unknown) to receive either gefitinib (G) 250 mg/day or placebo (P) on days 5-18 of a 3-weekly cycle of chemotherapy, which consisted of Pem 500 mg/m[2] and cisplatin(Cis) 75mg/m[2] given iv on day 1, every 3 weeks for a maximum of 9 cycles. Responding patients continued to receive either G or P every day until PD or unacceptable toxicity. After documentation of PD, pts who had been on P arm were crossed over to receive G. The primary endpoint was progression-free survival (PFS).

      Results:
      Between 06/2012 and 12/2014, 76 pts (M/F: 9/67) with median age of 58.0 years (range 32-75) were enrolled; 72 pts had stage IV and 4 had IIIB tumors. EGFR mutation was (+) in 29, (-) in 43, and unknown in 4. As of 03/17/2015, while randomization code is not broken yet, 53 pts are off treatment (48 due to PD, 2 deaths, 2 patient’s refusal, and 1 due to intercurrent brain tumor) and 19 pts are known dead (17 due to PD and 2 due to other causes). Overall, more pts with EGFR mt(+) tumor received 6 cycles of therapy than those with EGFR mt(-) tumor [28/29 (97%) vs. 32/43 (73%)] and completed 9 cycles of therapy as planned [19/29 (66%) vs. 14/43 (33%)]. The treatment was well tolerated with less G-associated skin toxicities, due to intermittent administration schedule of G per protocol. The most common G3/4 adverse events were: anemia (17.1%), neutropenia (15.8%), vomiting (5.3%), thrombocytopenia (3.9%), and peripheral neuropathy (3.9%). There was no unexpected safety issue except for more Cis-associated peripheral neuropathy which became more noticeable as the treatment continued beyond 6 cycles of therapy. Median PFS was 8.2 months (mos) for the entire group, and 10.6 mos and 6.6 mos for EGFR mt(+) and mt(-) groups, respectively. Overall median survival has not been reached yet with an estimated 2-year survival rate of 56.3%.

      Conclusion:
      First-line sequential administration of G with Pem/Cis chemotherapy was well tolerated with no undue side effects or any compromise in efficacy parameters. Detailed data will be presented to see whether this strategy warrants further investigation in a certain subset of pts with advanced NSCLC.

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