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P. Mayles



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    O14 - Radiotherapy - Toxicity and Clinical Trials (ID 105)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      O14.07 - IDEAL CRT: Isotoxic Dose Escalation and Acceleration in Lung Cancer ChemoRadiotherapy - a phase I/II trial of concurrent chemoradiation with dose-escalated radiotherapy in patients with stage II or stage III Non-Small Cell Lung Cancer. (ID 1368)

      11:35 - 11:45  |  Author(s): P. Mayles

      • Abstract
      • Presentation
      • Slides

      Background
      The IDEAL-CRT trial uses an individual patient approach to radiotherapy (RT) dose escalation, escalating the dose within a fixed overall treatment time, 6 weeks, by increasing dose per fraction. Isotoxic RT is based on the calculated risk of RT-pneumonitis (RTPN), RT dose being escalated so that all patients are exposed to the same RTPN risk. We investigated the feasibility and safety of individualised, isotoxic dose escalation for once daily RT delivered in 30 once-daily fractions with concurrent chemotherapy.

      Methods
      Eligibility; NSCLC stage II/III, PS 0/1, FEV~1~ (≥40% predicted or ≥1L), DCLO (≥40% predicted). A radiobiological model was used to individualize RT dose-prescription – selecting a dose which, in 30# once daily for 6 weeks, is associated with a 10% risk of grade 3+ RTPN, but limiting prescribed doses to between 63Gy - 73Gy (2Gy dose equivalent α:β=10, 63.5Gy-86Gy). Dose constraints were fixed for spinal cord, heart, brachial plexus. In Arm 1, initially the maximum dose to 1cc oesophageal did not exceed 63Gy. Arm 2 comprised patients in whom oesophageal dose rather than lung dose limited the prescription dose: the oesophageal dose was raised from 65Gy to 68Gy, 71Gy and 73Gy in consecutive cohorts, the prescribed dose lying between 63Gy and 73Gy and being the highest consistent with the oesophageal limit. Dose escalation was determined using a 6+6 design. Dose limiting toxicity (DLT) was defined as Grade 3+ oesophagitis. MTD was determined if grade 3+ oesophagitis >42% (>5/12). Two cycles of Cisplatin-Vinorelbine chemotherapy given concurrently during RT. All contouring and dosimetry on planning CT scans was centrally reviewed. IMRT was introduced in November 2012. Primary endpoints: oesophagitis and RTPN. Serial pulmonary function tests and ECGs performed. Efficacy endpoints: overall survival (OS), progression free survival (PFS), and tumour response.

      Results
      Between October 2010 and February 2013, 84 patients recruited (9 UK centres), 49 patients Arm 1, 35 patients Arm 2 (13 at 65Gy, 12 at 68Gy, 10 at 71Gy; none at 73Gy as the 73Gy upper prescription dose limit was only rarely associated with an oesophageal dose higher than 71Gy). Median follow up was 11 months (range 2,24); median age 66 years (range 43-84); 74% male; 39%/60% WHO 0/1; 30% adenocarcinoma, 54% squamous. Mean GTV 121cc (range 14-602cc). Mean prescribed dose for patients completing RT (n=80) 67.6Gy (range 63-73Gy) in Arm 1 and 70.1 Gy (63-73) in Arm 2. Mean 1cc-oesophageal-dose in Arm 1 55.5Gy (range 14.2-68.0Gy). In Arm 1 grade 3+ oesophagitis was 6% (3/49). In Arm 2, Grade 3+ oesophagitis was 17% (2/12) at 68Gy; no Grade 3+ oesophagitis in 65Gy (0/12) and 71Gy (0/10) cohorts. Grade 3+ RTPN 2% (1/49) in Arm 1 and 6% (2/35) in Arm 2. 1 year OS and PFS rates were 92% and 74% respectively.

      Conclusion
      Isotoxic RT dose escalation was safe and feasible. The MTD for oesophagus was not reached. Acceleration of the IDEAL-CRT schedule to five weeks is under investigation in a second study, currently recruiting.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-012 - I-START Trial: A UK phase I/II trial of isotoxic accelerated radiotherapy in locally advanced non-small cell lung cancer (ID 1575)

      09:30 - 09:30  |  Author(s): P. Mayles

      • Abstract

      Background
      Approximately 35,000 people die from lung cancer each year in the UK, the majority from non-small cell lung cancer (NSCLC). Patients with locally advanced (LA) NSCLC are often not suitable for chemotherapy or combined chemo-radiotherapy treatment because of patient or tumour factors. In these cases radical radiotherapy alone is used. Increased radiation dose may improve both local tumour control and survival. The radiotherapy dose is limited by surrounding organs, which include the lungs, heart, spinal cord and oesophagus. The maximum radiotherapy dose that can safely be delivered to the oesophagus is not known. The I-START trial was therefore developed, on behalf of the UK National Cancer Research Institute Lung Clinical Studies Group, to establish oesophageal radiation dose limits and to investigate the feasibility and effectiveness of a novel approach to dose escalation in LA-NSCLC. The study is funded by Cancer Research UK (C25518/A11535), sponsored by Velindre NHS Trust and coordinated by the Wales Cancer Trials Unit.

      Methods
      Patients with histologically or cytologically confirmed stage II to IIIb NSCLC, suitable for radical radiotherapy, are eligible for the trial. Enrolled patients will receive 20 fractions of radiotherapy over 4 weeks. The trial is split into two phases: Phase I: To establish the maximum tolerated (MTD) dose of radiotherapy to the oesophagus in patients where the oesophagus overlaps with the planning target volume (PTV). Phase I patients will be split into 2 groups depending on the length of the oesophagus lying within the PTV (Group 1A is where the overlap ≤6.5cm and Group 1B is where the overlap >6.5cm). Cohorts of 6 or 12 patients are recruited to both groups at sequentially increasing dose levels (58, 61, 63, 65Gy). Progression to the next oesophageal dose level will depend on the number of patients in a cohort with grade 3 or 4 acute oesophagitis, or other grade 3 or 4 toxicity, occurring up to 2 months after radiotherapy. Once the MTD to the oesophagus is established for each group, all participants will follow the Phase II protocol with the determined oesophageal dose limit. Phase II: Patients will receive a maximum of 65Gy in 20 fractions and the dose prescribed will be the highest dose achievable without exceeding defined safe dose limits for organs at risk. Where the oesophagus does not overlap with the PTV, patients can immediately be treated in Phase II, whereas patients whose oesophagus overlaps with the PTV can only be entered into Phase II once Phase I is complete, i.e. the MTD to the oesophagus has been established. The primary outcome of Phase II is the toxicity rate (grade 3 or 4) at 3 months. The I-START trial will determine whether this novel method of increasing the radiotherapy dose in patients with NSCLC patients is tolerable, safe and effective. If the results are positive, then this new treatment may be compared against the best currently available standard treatment in a future larger randomised (Phase III) trial.

      Results
      Not applicable.

      Conclusion
      Not applicable.