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I. Tham

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    MS15 - Extending the Limits of Combined Modality Treatment for NSCLC (ID 32)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Combined Modality
    • Presentations: 4
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      MS15.1 - Targeted Therapy in Combined Modality Therapy for Intrathoracic NSCLC with Activating Mutations (ID 526)

      14:00 - 15:30  |  Author(s): E. Smit

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS15.2 - Dose Escalation of Radiation in Combined Modality Therapy of NSCLC (ID 527)

      14:00 - 15:30  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract
      Chemo-radiotherapy (CT-RT) is the presently the standard of care in patients presenting with a stage III-N2 NSCLC, with surgery being considered an option in selected patient subgroups [ESMO Guidelines 2013]. Improved local disease control in stage III disease translated into improved overall survival [Auperin A, 2010; Machtay M, 2012]. The best median survival reported to date in a randomized phase III trial of concurrent CT-RT is 28.7 months in RTOG 0617, when concurrent carboplatin-paclitaxel was combined with delivery of 60 Gy in once-daily fractions of 2 Gy [Bradley J, 2013]. At this dose, 25% of patients developed a local failure at 18 months follow-up. Therefore, both the optimization of radiation delivery and dose escalation are areas of active research. Evidence supporting radiation dose escalation comes from retrospective analyses and pooled studies. The randomized RTOG 0617 study compared 60 Gy (in 6 weeks) versus 74 Gy (in 7.5 weeks), in a 2x2 design where patients were also randomized to receive additional cetuximab or none [Bradley J, ASCO 2013]. Analysis of the impact of cetuximab has yet to be reported, but a difference in favor of the 60 Gy arm was seen for progression-free survival (36.6% vs. 26.3% at 18 months), median overall survival (28.7 vs. 19.5 months). A higher incidence of grade 3 esophagitis in the 74 Gy arm (21% vs. 7%, p=0.0003) was not unexpected, but the higher rates of local disease progression (34.3% vs. 25.1%, HR = 1.37, p = 0.0319) was a surprise. The latter raises the possibility of unsafe planning practices being applied when higher (and more toxic) doses have to be delivered. On multivariate analysis, factors predictive of a poorer overall survival were higher radiation doses, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volumes receiving >5 Gy. While publication of full data from the RTOG 0617 study is awaited, some issues related to toxicity and techniques should considered (below). 1. Improved radiotherapy planning using intensity modulated radiotherapy (IMRT) has permitted some parameters for lung toxicity (V20, mean lung dose) to be improved. However, not all recent or ongoing studies have applied constraints for lung volumes undergoing low-dose irradiation (V5). Furthermore, the choice of chemotherapy may increase lung toxicity, as reported by a recent meta-analysis showing that the risk of radiation pneumonitis is highest after concurrent CT-RT in patients aged >65 years, who also received carboplatin-paclitaxel [Palma D, 2012]. This meta-analysis revealed that predictors of fatal pneumonitis were use of daily dose fractions exceeding 2 Gy, the V~20~ parameter, and lower-lobe tumor locations. 2. Cardiac doses exceeding 5 Gy correlated with poorer survival in RTOG 0617 trial, and future studies must pay more attention to cardiac toxicity. Following concurrent CT-RT, cardiac doses of 45 Gy or higher correlated with myocardial hypoperfusion [Gayed 2006], and a higher risk of ischemic heart disease and cardiac dysfunction was seen patients undergoing CT-RT for left-sided lung cancer [Hardy D, 2010]. 3. After radiation doses of 74 Gy and 86 Gy delivered after chemotherapy, the incidence of bronchial stenosis was 4 and 25%, respectively, (Millar KL, 2005]. This complication may increase in incidence if higher doses of radiation are administered concurrent with chemotherapy. 4. When evaluating the results dose escalation studies, one must also consider the impact of tumor volume on survival in stage III NSCLC. For example, planning target volumes (PTV) correlated significantly with overall survival, with PTV values <350cc, 350-700cc, >700-1050cc and >1050cc having corresponding median overall survivals of 35.6 months (95% CI=0-71.3), 24.2 months (95% CI=18.3-30.2), 15.7 months (95% CI=10.5-20.9) and 10.3 months (95% CI=6.0-14.7), respectively [van Reij E, 2013]. Survival for tumors measuring 350-700cc differed significantly from the groups 700-1050 and >1050 cc (p=0.039 and p=0.002, respectively). In addition, larger tumor volumes are also associated with an increased risk of dying in the first 18 months, independently of T and N stage, but not beyond that time point [Ball D, 2012]. The latter finding suggests that a better characterization of tumor characteristics that correlate with radiocurability should be a research priority. 5. In RTOG 0617, the dose of 74 Gy arm was delivered in 7.5 weeks. A recent meta-analysis suggested that the accelerated delivery of radiation, i.e. delivering a higher higher dose in a shorter overall time, led to superior tumor control [Mauguen 2013]. Such accelerated delivery can be delivered using multiple fractions per day, or larger doses/fraction, both approaches which can increase the toxicity of concurrent CT-RT. For some subgroups of stage III-N2 disease, e.g. large volume tumors, where the benefits of concurrent CT-RT are modest [Wiersma T, 2013], sequential delivery may be a less toxic manner for investigating dose escalation. 6. Tumor volumes not infrequently regress during a course of CT-RT, and may also shift in position during the course of treatment [Lim G, 2011]. Volumetric imaging on modern treatment machines can allow for such changes to be detected, and treatment plans be adapted when required. Many recent clinical studies have not studied this aspect of treatment delivery. With dose escalation in fractions of 2 Gy falling out of favor, some groups are exploring the ‘dose painting’ hypothesis [Bentzen S, 2011]. Briefly, the former assumes that local recurrences arise from relatively radiation-resistant sub-regions; that reliable spatio-temporal mapping of such sub-regions is possible (e.g. using FDG-PET); that boosting radiation delivery to these egions improves local tumor control with acceptable side effects. Others groups are exploring the use of protons to improve local control in stage III NSCLC. A critical evaluation of the results emerging from ongoing trials is required, even if early outcomes from pioneering centers appear promising. Quality assurance data from radiotherapy trials, in which a broad range of institutions participate, reveals that a failure to comply with protocol requirements is associated lead to decreased survival, poorer local control and potentially increased toxicity [Weber DC, 2012].

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      MS15.3 - Management of Patients with Oligometastatic/Resectable Stage IV NSCLC (ID 528)

      14:00 - 15:30  |  Author(s): L. Liu

      • Abstract
      • Presentation
      • Slides

      Abstract
      For the past decade, the standard first-line therapy for stage IV non-small-cell lung cancer (NSCLC) patients with adequate ECOG performance status (<2) has been platinum-based doublet chemotherapy with a reported median overall survival (OS) of 8–10 months, which has slightly improved to 12 months with the addition of bevacizumab. More recently, tyrosine kinase inhibitors of epidermal growth factor receptor, gefitinib and erlotinib, and anaplastic lymphoma kinase, crizotinib, have been shown to provide longer progression-free survival (PFS) and fewer side effects as first-line therapy, compared with chemotherapy in patients with certain histological subtypes and activating mutations. However, despite therapeutic developments, palliative treatment is standard for many stage IV NSCLC patients and the prognosis remains poor, with relative 5-year survival rates ≤4%, compared with an average of approximately 17% for all patients with NSCLC. Oligometastatic NSCLC is a subgroup of stage IV NSCLC with a limited number/number of sites of metastatic disease, usually 1–5 metastatic lesions. While only a small subset of patients present with such limited metastases (brain metastasis <50%, adrenal gland metastasis ~7%), they may be suitable for, and achieve long-term survival following, eradication of both the primary and metastatic tumours. For example, reported 5-year survival rates for NSCLC patients with solitary brain or adrenal metastasis who underwent surgical removal of both primary lung and metastatic disease ranged from 7–24% and 25–34%, respectively, which is higher than the average of ≤4% for all stage IV NSCLC patients. In addition to having an adequate performance status, there are additional key prognostic factors for identifying oligometastatic NSCLC patients likely to benefit from aggressive therapy; staging of the metastatic lesions, lymph node involvement and status of the primary lung tumour. A lower number of metastatic sites is predictive of good clinical outcome, with >2 metastatic sites associated with shorter PFS. The organ involved in metastatic spread may also impact clinical outcome as, for instance, patients with brain and adrenal gland metastases are more suitable for surgical intervention compared with bone or liver. Given the importance of number and site of metastatic lesions, positron emission tomography and magnetic resonance imaging are vital for accurate staging of oligometastatic disease. An association between N0 disease and increased long-term survival compared with N1/N2 disease has been observed. For example, following surgical treatment of one cohort of patients with solitary NSCLC adrenal gland metastasis, those with N2 disease had 0% median 5-year survival rate, compared with 52% for N0/N1 patients (P=0.001). Pathologic staging of lymph nodes is therefore critical. The status of the primary lung tumour also impacts clinical outcome, as the primary tumour must itself be resectable. Stage III primary disease is associated with worse survival outcome than stage I or II in patients undergoing surgical excision of brain and adrenal gland metastases, with a reported 5-year survival rate of 0% for stage III, compared with 63% and 77% for stage I and II, respectively. Similarly, patients with oligometastatic disease and a controlled primary site, or ‘oligorecurrance’, have better prognosis than those with an uncontrolled primary tumour. Histological subtype of NSCLC may also impact prognosis in oligometastatic NSCLC, with adenocarcinoma associated with the most favourable outcomes. Although an optimal disease-free interval (DFI) to define synchronous and metachronous disease has not been agreed upon, synchronous oligometastasis is generally associated with poorer survival outcomes. Patients receiving adrenalectomy for oligometastatic NSCLC with DFI ≤6 months had median OS of 12 months versus 31 months for DFI >6 months. Similar results were reported for isolated brain metastasis. Oligometastatic NSCLC is a stage IV cancer and as a guiding principle therapy should be simple and minimally invasive. Furthermore, given the diffuse nature of this disease state, management should ideally involve a multidisciplinary team as the primary and metastatic cancer must be treated, requiring a wide range of expertise. Surgery and radiosurgery (stereotactic radiosurgery [SRS] in the brain and stereotactic body radiotherapy [SBRT] in extracranial sites) are the two most common methods of tumour ablation. In general, radiosurgery is less invasive than surgery and is therefore useful for patients ineligible for surgery. Additionally, evidence suggests SBRT may be more applicable to limited extracranial metastasis to multiple organs compared with surgery. The treatment of limited brain metastases has been evaluated through several randomised clinical trials. Surgical resection plus whole brain radiotherapy (WBRT) of oligometastasis in the brain led to significantly prolonged OS compared with WBRT alone – as high as 40 weeks in one trial, compared with 15 weeks for WBRT (P<0.01). Further, a study of SRS with WBRT in patients with 1–4 brain metastases showed improved survival outcomes for patients with solitary brain metastases and improved clinical outcomes for patients with >1 site of metastatic disease, compared with WBRT alone. Overall, SRS plus WBRT is considered an acceptable choice for those patients with limited brain metastasis who are not suitable for surgery. Adrenalectomy is the standard of care for adrenal gland metastases, with OS ranging from 11–31 months. There have been no randomised trials of the use of SBRT in the adrenal gland setting, although one retrospective study reported OS of 23 months for isolated adrenal metastases treated with SBRT. Further, a recent review article of extracranial oligometastatic disease from various primary cancers suggests that survival following SBRT compares favourably to surgery. One of the key challenges for the management of oligometastatic NSCLC is continuing to improve diagnosis and prognostic factors to more accurately identify those patients with oligometastatic NSCLC who are likely to benefit from ablative treatment, as well as distinguish truly isolated metastatic disease from early-stage metastasis that later develops into widely disseminated disease. Continuing advances in imaging technology will play a role in refining diagnosis and prognosis. From a treatment perspective, challenges include cognitive problems associated with WBRT and the current lack of randomised trial data comparing surgery, radiosurgery and standard of care. To this end, there are several ongoing clinical trials, such as the randomized SABR-COMET study, which compares palliative radiation with stereotactic ablative radiation for ≤3 metastatic tumours to any single organ.

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      MS15.4 - Surgery after Induction Chemo/Radiation Therapy (ID 529)

      14:00 - 15:30  |  Author(s): W. Weder

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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