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L. Hendriks



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-015 - EGFR mutated patients: different pattern and outcome of metastatic bone disease and brain metastases? (ID 1596)

      09:30 - 16:30  |  Author(s): L. Hendriks

      • Abstract

      Background
      Bone and brain are frequent and problematic sites of metastasis in metastatic non-small cell lung cancer (mNSCLC). Conflicting studies exist whether patients with EGFR mutations develop brain metastases (BM) more often or have a longer survival after diagnosis of mNSCLC than EGFR/KRAS wild type (WT) or KRAS+ patients. For metastatic bone disease (MBD) this is not known. In this retrospective matched control study we compared in EGFR+, KRAS+ and WT patients time from mNSCLC to development of MBD/BM, skeletal related events (SREs) and subsequent survival.

      Methods
      In this retrospective case-control study all EGFR+ patients diagnosed at two molecular pathology departments were selected (VUMC 01-11-2004 to 01-01-2012, MUMC 01-10-2008 to 01-08-2012). For every EGFR+ patient a consecutive KRAS+ and WT mNSCLC patient was selected. Patients with another malignancy within 2 years of mNSCLC diagnosis or no follow up were excluded. Data regarding age, gender, histology, performance score, treatment, MBD and BM diagnosis, SRE and subsequent survival were collected.

      Results
      222 patients were included: 73 EGFR+, 76 KRAS+ and 73 WT (table 1). Respectively 56.2%, 51.3% and 50.7% had MBD (p=0.768) of which respectively 41.5%, 25.6% and 40.5% were diagnosed during follow up (p=0.262). Time to MBD was (mean, [SD]) respectively 13.4 [±10.6], 20.7 [±17.8], 16.8 [±9.6] months (p=0.360). Post MBD survival was (median, [95% confidence interval (CI)]) 15.0 [11.0-19.0], 7.1 [1.3-12.8], 3.2 [0.0-8.3] months respectively (p=0.008). Time to 1[st] SRE was not significantly different (p=0.164). Respectively 28.8%, 39.5% and 34.2% had BM (p=0.444) of which 76.2%, 60.0% and 48.0% were diagnosed during follow up (p=0.148). Mean time to BM was 20.3 [±11.7], 10.8 [±9.3], 14.3 [±10.8] months respectively (EGFR+-KRAS+ p=0.013, EGFR+-WT p=0.176). Post BM survival was 11.0 [2.2-19.8], 6.9 [0-14.1], 12.5 [5.6-19.5] months respectively (p=0.969). Results did not change significantly when patients with only best supportive care were excluded nor when in the EGFR+ group only exon 19/21 patients were included.

      table: patient characteristics and results bone and brain metastasis
      Characteristics EGFR+ N = 73 KRAS+ N = 76 Wildtype N = 73 p-value
      Female N (%) 51 (72.6) 44 (57.9) 29 (39.7) 0.001
      Mean age, years (range) 59.6 (29.3-90.7)
      60.6 (35.1-83.3)
      		62.5 (39.6– 81.8) 0.228
      Never smoker N (%) 29 (45.3) 2 (2.7) 10 (15.2) <0.001
      WHO PS 0-2 N (%) 63 (98.4) 72 (97.3) 60 (92.3) 0.270
      Adenoca N (%) 67 (91.8) 63 (84.0) 55 (76.4) 0.209
      1[st] line no treatment 1[st] line chemo 1[st] line EGFR-TKI 3 ( 4.1) 23 (31.5) 47 (64.4) 10 (13.2) 64 (84.2) 2 ( 2.6) 14 (19.2) 54 (74.0) 5 ( 6.8) 0.069 <0.001 <0.001
      MBD N (%) Yes - at diagnosis - during follow up No 41 (56.2) -24 (58.5) -17 (41.5) 32 (43.8) 39 (51.3) -29 (74.4) -10 (25.6) 37 (48.7) 37 (50.7) - 22 (59.5) - 15 (40.5) 36 (49.3) 0.768 0.262
      SRE+ N (%) 22 (53.7) 23 (59.0) 21 (55.3) 0.887
      BM N (%) Yes -at diagnosis -during follow up No 21 (28.8) - 5 (23.8) -16 (76.2) 52 (72.2) 30 (39.5) -12 (40.0) -18 (60.0) 46 (60.5) 25 (34.2) - 13 (52.0) - 12 (48.0) 48 (65.8) 0.444 0.148

      Conclusion
      Incidence of MBD or BM was not different between EGFR+, KRAS+ and WT patients. Time from diagnosis of mNSCLC to MBD, 1[st] SRE or post-BM survival did not differ. However, survival after MBD was significantly longer in EGFR+ patients. This stresses the impact of bone management in these patients and probably warrant more intense screening for MBD. In EGFR+ patients BM remain a serious event with short survival. This should stimulate investigators to search for BM specific treatments in order to prolong survival post BM in EGFR+ patients.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-029 - Progression of radiation induced esophageal stenosis in a non-small cell lung cancer (NSCLC) patient treated with sorafenib (ID 1882)

      09:30 - 16:30  |  Author(s): L. Hendriks

      • Abstract

      Background
      Sorafenib is an orally available multikinase inhibitor with antiproliferative and anti-angiogenic activity. Reported oral adverse events of any grade are stomatitis/mucositis (11-38%, mostly ≤ CTC-AE grade 2), oral mucosal pain and dysphagia in the absence of clinical lesions. Sorafenib is under investigation in NSCLC. We report a patient who developed symptomatic progression of an esophageal stenosis during sorafenib treatment.

      Methods
      not appicable

      Results
      Case: A 67-year old male presented at the outpatient clinic with dysphagia CTC-AE grade 3. He was diagnosed with a cT3N3M1a (oligometastatic adenocarcinoma, KRAS mutated) NSCLC in January 2011 for which he was treated with concurrent chemoradiotherapy. Treatment was complicated with grade 3 radiation esophagitis (confirmed with duodenogastroscopy) for which he was treated with a feeding tube and proton pump inhibition. Because of remaining grade 1 dysphagia, duodenogastroscopies were performed in August 2011 and February 2012. A stable relative stenosis of the upper esophagus was found, easy to pass with the duodenogastroscope. Because of progressive disease he was subsequently treated with erlotinib/ pemetrexed (September 2011, study) and docetaxel monotherapy (August 2012). February 2013 he progressed again with subsequent participation in a phase II study with sorafenib 400 mg BID and metformin 1000 mg BID. Within three weeks he developed dysphagia for solid foods. A chest computed tomography showed no external compression of the esophagus and no tumor progression. Duodenogastroscopy revealed a stenosis with ulceration in the upper part of the esophagus, passing the stenosis was only possible with a baby-duodenogastroscope. Because of swallowing problems, sorafenib was temporarily stopped and placement of a percutaneous feeding tube was planned. However, two days after stopping sorafenib, his dysphagia completely resolved and food passage was normal. So, ten days later sorafenib was restarted with dose reduction (200 mg BID). After restarting sorafenib his dysphagia returned with grade 3 within six weeks. Again, sorafenib was temporarily stopped and in a couple of days his dysphagia resolved. After another restart of sorafenib at the latter dose he again developed dysphagia, but this time manageable.

      Conclusion
      We present a patient who developed a grade 3 stenosis of the esophagus during treatment with sorafenib which clinically resolved shortly after stopping sorafenib but reoccurred after rechallenge with sorafenib at a lower dose. Dysphagia resolved again after stopping the sorafenib with again complaints after restarting. No other explanation was found (e.g. progression of malignancy, external compression). 1.5 year before, after concurrent chemoradiotherapy, he was diagnosed with a relative stenosis of the upper esophagus, but this remained stable until sorafenib treatment was started. He scored 8/13 points on the Naranjo score, making sorafenib a probable cause of the stenosis. The underlying mechanism is unknown. A possible explanation is sorafenib inhibition of the VEGF and MAP-kinase pathway. These pathways are both involved in the process of mucosal defense and repair, and it could be that blocking this pathway combined with sensitization by previous irradiation caused progression of the stenosis. This case stresses the importance of being aware of unusual side effects of medication and taking into account possible interactions with previous treatments.