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L. Ashcroft



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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.02 - Age as a prognostic factor in small cell lung cancer. A pooled analysis of randomized clinical trials from the Manchester lung cancer group (MLCG) and the UK Medical Research Council Clinical Trials Unit (MRC CTU). (ID 2270)

      10:30 - 12:00  |  Author(s): L. Ashcroft

      • Abstract
      • Presentation
      • Slides

      Background
      About 40% of all cases of small cell lung cancer (SCLC) occur in the over 70 year age group (70+), and 10% in patients aged over 80 years. A SEER database reports decreasing SCLC 5-year survival with age (7.1%, 3.9% and 2.2% in the <70, 70-79 and 80+ age groups, respectively). However age has been inconsistently reported as a prognostic factor in SCLC trials. Recently a series of randomized trials of chemotherapy (CT) in SCLC were pooled to analyze the prognostic impact of patient sex (Wheatley-Price et al, Annals of Oncology 2009). We used the same dataset to investigate the impact of age.

      Methods
      Five randomized phase II and III CT trials, performed by the MLCG and MRC CTU between 1993 and 2005, were pooled for analysis (one study from the previous analysis was excluded as it did not contain elderly patients). One trial investigated a dose-dense approach and 4 trials compared CT regimens. The primary endpoints were overall survival (OS) in limited stage (LS) and extensive stage (ES) and the rates of haematological and non-haematological toxicity.

      Results
      In total 1439 patients were included, of whom 45% were female and 36% had ES disease. The median age was 63 years (range 30-88), and 343 (24%) were 70+, and only 33 (2%) were 80+. Anthracycline-based CT was given in 61%, versus platinum-based CT in 38% of patients. More patients in the younger group had a good performance status (ECOG 0-1, Karnofsky 80-100); 65% versus 39% (p=0.0007). Baseline hyponatremia was present in 35% and did not differ by age group. Overall, median OS was significantly longer in younger patients in univariate analysis (9.3 months versus 7.4 months; HR 0.79, 95% CI 0.66-0.95, p=0.01). By disease stage, median OS in LS patients was significantly longer in younger patients (HR 0.88, 95% CI 0.79-0.99, p=0.04), and a similar effect was observed in ES (HR 0.75, 95% CI 0.55-1.01, p=0.06). However in multivariate analysis (age, stage, sex, hyponatremia, anemia), factors significantly associated with longer survival were LS, female sex, good PS and absence of hyponatremia, but younger age was no longer prognostic (HR 0.96, 95% CI 0.86-1.08, p=0.52). The elderly were more likely to experience grade 3 or 4 leucopenia (52% versus 40%, p=0.0035), neutropenia (36% versus 31%, p=0.045) and thrombocytopenia (34% versus 22%, p=0.0003), but less likely to experience grade 3 or 4 emesis (8% versus 14%, p=0.022) or mucositis (5% versus 11%, p=0.021). There were no differences in infection rates or blood transfusion rates, although the elderly required more platelet transfusions (p<0.0001). The dose intensity (total number of CT cycles delivered divided by the planned number of cycles) was higher in the younger group (p<0.0001).

      Conclusion
      In a large pooled analysis of CT trials in SCLC, age was not a prognostic factor for survival. However the elderly experienced higher rates of grade 3 and 4 hematological toxicity. Further analysis is ongoing.

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    P1.09 - Poster Session 1 - Combined Modality (ID 212)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-011 - Phase I clinical trial assessing the MEK inhibitor selumetinib (AZD6244; ARRY-142886) with concomitant thoracic radiotherapy (RT) in patients with Stage III-IV non small cell lung cancer (NSCLC) (ID 1415)

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

      • Abstract

      Background
      The RAS/RAF/MEK/ERK signalling cascade has a central role in cancer proliferation and in modulating response to treatment. RAS mutations can confer a radiation-refractory phenotype and MAPK signaling can be stimulated by treatment with ionizing radiation in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244; ARRY-142886) is an orally available inhibitor of MEK1/2 which was shown to enhance the effect of radiotherapy in preclinical studies. This effect was due to the ability of selumetinib to directly sensitize tumor cells to the cytotoxic effect of radiation and to modulate tumor vessel functionality by reducing VEGF-A expression. In a Phase II study, selumetinib given in combination with docetaxel showed promising activity in NSCLC patients with KRAS activating mutations. Aim To determine the recommended Phase II dose (RP2D) of selumetinib in combination with standard dose thoracic radiotherapy (RT) in NSCLC.

      Methods
      Selumetinib (Hyd-Sulfate capsule) was administered orally twice daily as a single agent for one week and then in combination with thoracic RT for 6 to 6.5 weeks (60 to 66 Gy in 30 to 33 fractions) in a single institution, open label Phase I trial using a modified Fibonacci sequence. Prior standard chemotherapy was permitted with a minimum interval between day8 of the last cycle of chemotherapy and day1 of administration of selumetinib of ≥ 2weeks. Other eligibility included: histologic or cytologic diagnosis of NSCLC, stage III not suitable for concurrent chemo-radiotherapy or stage IV with dominant thoracic symptoms, disease encompassable within a radical RT treatment volume, ECOG PS 0-1., no prior RT or investigational agents.

      Results
      A total of six consecutive patients with inoperable stage III (n=3) or stage IV (n=3) NSCLC were given selumetinib 50 mg twice daily (dose level 1) with concomitant thoracic RT (59.8-66 Gy in 30-33 fractions). All patients completed the combined treatment. Selumetinib delivery was > 80%. Four out of the six patients had dose interruptions of 2-3 days due to expected adverse events (AEs). Skin rash (6/6), diarrhoea (5/6) and fatigue (4/6) were the most common toxicities. Grade 3/4 AEs included hypertension (2/6), diarrhoea (2/6), skin rash (1/6), pulmonary embolism (1/6), fatigue (1/6) and pericardial effusion (1/6). Pulmonary embolism (grade 3) was considered not related to the study treatment. One patient experienced dose limiting toxicity (DLT) consisting of a combination of diarrhoea (grade 3) and fatigue (grade 3). Response to treatment was assessed 4 weeks post RT. Distant recurrence was seen in 1 patient; 3 patients had SD, 1 patient experienced a PR and 1 a CR. Median duration of response was 2 months (range 1-4 months).

      Conclusion
      Selumetinib given at 50 mg twice daily with concomitant radical thoracic RT was tolerated with no unexpected toxicities or enhancement of expected RT toxicities. Although the protocol-defined criteria to further escalate the selumetinib dose were met, because of the heterogeneous and small patient cohort and AEs encountered further evaluation of the 50 mg twice daily was preferred in order to obtained additional safety data. An expanded cohort of 15 patients having additional FLT-PET scans.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-008 - Concurrent chemoradiotherapy (cCTRT) for locally advanced Non Small Cell Lung Cancer (NSCLC) followed by consolidation Pemetrexed: a phase II study (ID 1545)

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

      • Abstract

      Background
      cCTRT is the current standard treatment for good Performance Status (PS) unresectable locally advanced NSCLC. A phase III study demonstrated that Docetaxel consolidation does not improve overall survival (OS) after cCTRT (Hanna. JCO 2008). The role of consolidation chemotherapy after cCTRT is still investigational and our study was set up to evaluate the role of pemetrexed in this setting. A less toxic consolidation chemotherapy may enable a higher proportion of patients to comply to planned treatment which may improve outcome.

      Methods
      This was a single-institution prospective phase II study. Treatment comprised cisplatin (50 mg/m[2] days 1, 8, 29, 36), etoposide (50 mg/m[2] days 1-5 and 29-33) and concurrent thoracic radiotherapy starting on day 1 chemotherapy (66 Gy in 33 daily fractions; 3D conformal radiotherapy or IMRT) followed by consolidation pemetrexed (500 mg/m[2] on days 71, 92 and 133). The primary endpoint was 1 year OS. Secondary endpoints were progression-free survival (PFS), 2 yr OS, acute/late toxicity (CTCAE v3.0), compliance to treatment.

      Results
      35 patients were recruited between March 2008 and October 2010. Median age was 61 years (range 42-76). M:F ratio was 23(66%):12(34%). ECOG PS was 0:1 11(31%):24(69%). Histology: squamous 21(60%), adenocarcinoma 8(23%), undifferentiated 4(11%), other 2(6%). Stage: IIB 1(3%), IIIA 19(54%), IIIB 15(43%). All 35(100%) had PETCT staging. All 35 patients received concurrent chemotherapy (dose reduction in 3 patients) and 32 (91%) received the planned 66Gy (range 56-66 Gy). The number of patients who completed pemetrexed were: cycle 1=25 (71%), cycle 2=22 (63%), cycle 3=16 (46%). Radiation parameters: Gross Tumour Volume (GTV) was median 60.2 cm[3] (range 11.4-274.4 cm[3]), V~20Gy ~median 30.4% (range 10.5-35.3%), During the concurrent phase, grade 3/4 toxicity was noted for: neutropenia 17(49%) anaemia 1(3%), thrombocytopenia 1(3%), infection 8(23%), fatigue 6(17%), nausea±vomiting 4(11%), mucositis 3(9%), anorexia 3(9%). During the pemetrexed consolidation phase, the only grade 3/4 toxicities were: infection 5(20%), anaemia 3(12%), neutropenia 2(8%) and fatigue 2(8%). Acute radiotherapy toxicity (<3months): oesophagitis grade 3/4 10(29%) and late toxicity (>3months): pneumonitis grade 3/4 2(7%), oesophageal stricture 2 (7%), pulmonary fibrosis 1(3%). Median follow up was 25months. Median OS was 34months, with 1yr OS 77% (95% CI 60-88%), and 2yr OS 61% (95% CI 37-72%). Median PFS was 22months, with 1yr PFS 62% (95% CI 43-76%) and 2yr 49% (95% CI 31-65%). Of the 14 deaths, causes were, 1 suicide during radiotherapy, 2 treatment-related deaths (1 grade 5 pneumonitis and 1 grade 5 haemoptysis) and 13 due to lung cancer.

      Conclusion
      In an unselected locally advanced NSCLC population, staged with PETCT a median survival of 34 months can be achieved. The study reinforces the challenge of delivering consolidation chemotherapy and suggests that improved staging contributes to improved outcomes. Although there was failure to deliver all planned cycles of consolidation pemetrexed after cCTRT in 54% of patients, these are encouraging results that warrant further investigation.

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    P3.13 - Poster Session 3 - SCLC (ID 202)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.13-005 - CONVERT - the challenges of opening centres and recruiting patients to an international multi-centre chemo-radiotherapy trial in limited-stage small cell lung cancer (ID 1366)

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

      • Abstract

      Background
      CONVERT is a multicentre, randomised, phase III trial open in Europe and Canada in limited-stage small cell lung cancer. Patients are randomised to twice (45 Gy in 30 fractions) or once-daily radiotherapy (66 Gy in 33 fractions) given concurrently with 4-6 cycles of chemotherapy. This study is funded by Cancer Research UK and involves centres from the UK NCRI, the ‘Groupe Francais de Pneumo-Cancerologie’, the Spanish Lung Cancer Group, the EORTC and NCIC CTG.

      Methods
      To identify and review the challenges in site set-up. To review time taken from site initiation to first patient randomised, number of centres opened that included 0-2 patients and number of centres that recruited the majority of all patients.

      Results
      In June 2013, 519/532 patients had been recruited in 9 countries; 299 from 32 UK centres, 100 from 17 French centres, 39 from 9 Canadian centres, 27 from 6 Spanish centres, 26 from 3 Belgian centres, 13 patients from 1 centre in Slovenia, 9 from 2 centres in The Netherlands and 6 patients from 1 centre in Poland. Figure 1 shows the number of centres open and patients recruited. 96 sites are currently open to recruitment (5 sites opened in 2008, 34 in 2009, 31 in 2010, 17 in 2011, 8 in 2012 & 3 in 2013, 2 sites subsequently closed early) of which 74 (77%) have randomised at least 1 patient. 24 sites (25%) recruited only 1 or 2 patients. 10 sites have recruited 49% of the total number of patients with a single site recruiting 18.5% of all patients randomised. Time taken from site initiation to 1[st] patient randomised ranged from 0–1029 days with a median of 144 days. Time taken to complete the QA exercise from initial information sent to site ranged from 14-1181 days with a median of 290.5 days. Figure 1

      Conclusion
      Recruitment to an academic trial in LS-SCLC is a challenge but accrual has improved considerably since 2008. This can be directly related to the increasing number of sites opened to recruitment. Duration of site set-up and completion of the QA exercise are factors explaining slower than anticipated accrual rates particularly between 2008 and 2010. We anticipate that the study will close to recruitment in July 2013. International participation has been a key factor to the success of the trial and the experience gained will be of value to the design of future radiotherapy studies to ensure target accrual.