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G.P. Bootsma



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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.07 - Early onset body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancer is not due to dysphagia or reduced calorie intake (ID 3409)

      11:10 - 11:15  |  Author(s): G.P. Bootsma

      • Abstract
      • Presentation
      • Slides

      Background
      Increased treatment-associated esophagitis could be responsible for concurrent chemo-radiotherapy (CT-RT)-induced weight loss in patients with non-small cell lung cancer (NSCLC). However, based on clinical observations, we hypothesized that weight loss already starts early after initiation of concurrent CT-RT and might therefore be not solely dependent on decreased intake due to esophagitis symptoms.

      Methods
      In a retrospective cohort, the onset and frequency of weight changes and their association with esophagitis grade ≥2 were assessed in patients with NSCLC treated with concurrent (n=102) or sequential (n=92) CT-RT. The findings in the retrospective cohort were validated in a prospective study in which weight loss and esophagitis grade ≥2 was assessed over a longer time period and additional data on nutritional intake, muscle strength and quality of life was obtained of patients treated with concurrent CT-RT (n=9).

      Results
      In the retrospective cohort, both the number of patients with weight loss and the magnitude of weight loss was significantly higher in concurrent than sequential treated patients in week 2, 3 and 4 of (CT-)RT (p<0.05). Longitudinal data analysis showed no significant associations between weight loss and grade esophagitis ≥2 in patients treated with concurrent CT-RT (p=0.10). In the prospective cohort, a similar pattern of ‘early’ weight loss was observed in the first weeks of concurrent CT-RT (p<0.05). This early weight loss was not accompanied by significant decreases in nutritional intake but muscle strength did already decline in this early stage (p<0.05). In the following weeks of concurrent CT-RT, the weight further decreased and reached its minimum at the end of treatment (p<0.05), while the number of patients with grade esophagitis ≥2 increased during this time period. During the later part of concurrent CT-RT, dietary intake was significantly lower and patients became more reliant on supplemental nutrition (p<0.05). Although the weight increased again in the weeks after concurrent CT-RT, it had still not reached the baseline level after 4 weeks post treatment (p<0.05).

      Conclusion
      Weight loss is a common complication of concurrent CT-RT for locally advanced NSCLC, starts early after initiation of CT-RT and is not dependent of esophagitis. It is presumably caused by active catabolism as this ‘early’ weight loss is accompanied by decreased muscle strength, despite stable dietary intake. In the later weeks of treatment, concurrent CT-RT is characterized by a further decline in body weight, decreased dietary intake and higher reliance on nutritional support. In this phase the occurrence of radiation-induced esophagitis grade ≥2 increases. In the weeks following concurrent CT-RT, partial recovery of body weight takes place but this is still not complete after 4 weeks post CT-RT. The sustained weight loss during and following concurrent CT-RT might have major negative consequences as weight loss in patients with underlying malignant disease might has been associated with higher mortality, lower treatment responses and decreases in quality of life. Though the origin of weight loss during concurrent CT-RT seems to be different in the subsequent phases, more aggressive supportive nutritional support throughout the treatment course seems conceivable to prevent negative energy balances and optimize concurrent CT-RT management.

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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 - 09:30  |  Author(s): G.P. Bootsma

      • 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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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-022 - Number of pathologic nodes in regions closest to the oesophagus is the strongest predictor for esophagitis in small cell lung cancer patients treated with concurrent chemo-radiation: an analysis of 170 patients. (ID 2711)

      09:30 - 09:30  |  Author(s): G.P. Bootsma

      • Abstract

      Background
      Radiation esophagitis grade III caused by chemo-radiation for small-cell lung cancer is a burden for patients and thus of concern to radiation oncologists. Neutropenia and radiation dose to the esophagus are known treatment factors influencing the rate of esophagitis during treatment, but currently the only factors that can be discussed with the patient at diagnosis are the choice of concurrent versus sequential chemo-radiation and the radiation dose fractionation schedule. In order to build predictive models to more accurately tailor treatment and advise patients on treatment options, more prognostic factors known at the moment of diagnosis are needed.

      Methods
      Analysis of all patients in our prospective database with stage I-III SCLC referred for concurrent chemo-radiotherapy between 5-2004 and 1-2012. All patients were PET-staged and received 45 Gy in 1.5 Gy fractions twice daily to the tumour and PET-or pathologically proven positive lymph nodes. Chemotherapy consisted of carboplatin-etoposide given concurrently with radiotherapy. All pathological lymph node regions were noted for each patient. Based on the Mountain Dressler atlas, the lymph node regions closest to the oesophagus were designated ``high risk`` regions for esophagitis, namely: 1R, 1L, 3P, 4L, 7, 8 and 9. Toxicity was scored according to CTC AE 3.0. Univariate analysis was done using the Chi-square test, reporting for p-value the Fischer exact Test for small numbers of events. Multivariate analysis was done using logistic regression. .

      Results
      170 patients were included in the present analysis. Thirty-seven (20%) patients developed grade III esophagitis. In univariate analysis the number of nodal regions (0, 1-4, ≥5) (p=0.02) and the number of high risk nodal regions (0, 1-2, ≥3) (p=0.001) had a significant effect on the risk of grade III esophagitis whereas the location of the primary tumour or having a T4 tumour did not. In multivariate analysis including age, gender and T4 tumour, the number of pathological nodal stations lost significance. In the multivariate analysis using age, gender, T4 tumour and the ``high risk`` count (0, 1-2, ≥3 areas) having nodes in ≥3 high risk areas was the only significant factor (p=0.002), with a hazard ratio (HR) of 7.4 for developing oesophagitis grade III (95% CI for HR: 2.2-25.2). The absolute rates of esophagitis grade III were: 5/51 (10%), 19/91 (21%), 12/28 (43%) for patients with respectively 0, 1-2 and ≥3 pathological high risk nodal areas.

      Conclusion
      In this series of stage I-III small cell lung cancer treated with radical chemo-radiation, the strongest predictor for esophagitis grade III known at diagnosis is the presence of nodal disease in ``high-risk regions`` 1R, 1L, 3P, 4L, 7, 8 and 9. Analysis of the correlation of this finding with the dose to the esophagus (Dmax/ Dmean) is ongoing and will also be presented at the conference.