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L. Gaspar

Moderator of

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    E06 - Issues in Current Multidisciplinary Practice (ID 6)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Combined Modality
    • Presentations: 4
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      E06.1 - Optimal Chemotherapy in Combined Modality Therapy for NSCLC (ID 398)

      14:05 - 14:25  |  Author(s): E. Vokes

      • Abstract
      • Slides

      Abstract
      Over the last decade, combined modality therapy has been established as standard of care for patients with locoregionally advanced unresectable non-small cell lung cancer (1). Both induction chemotherapy followed by radiation as well as concomitant chemoradiotherapy have been shown to be superior to radiotherapy alone and both approaches extend progression-free and overall survival. In direct comparison, concomitant chemoradiotherapy has been shown to be superior to induction in several randomized phase III trials as well as meta-analyses, likely due to enhanced locoregional control due to the chemotherapy radiation sensitization effect (2, 3). Currently about 20 to 30% of patients can be cured. While there are established clinical prognostic factors, very little information exists to more precisely guide prognosis or therapeutic approach for individual patients. In trying to improve survival outcomes induction chemotherapy was added to concomitant chemoradiotherapy but failed to result in superior outcome compared to concomitant chemoradiotherapy alone.(4). Similarly, consolidation chemotherapy or maintenance therapy with erlotinib in patients unselected for molecular characteristics did not improve survival compared with concomitant chemoradiotherapy alone (5,6). Several chemotherapy regimens have been investigated in the concomitant setting including the mitomycin/vinblastine/cisplatin (MVP) regimen, carboplatin/paclitaxel given weekly (and this regimen has consolidation chemotherapy for two cycles built in) and cisplatin/etoposide. The latter two are frequently used standards in control arms for current randomized trials. There has also been interest in the combination of carboplatin and pemetrexed given the superior single modality activity of the platinum/pemetrexed regimen in non-squamous cell tumors (7). It has been demonstrated that this drug combination can be given at full systemic doses in combination with radiation, thus providing good systemic coverage to eradicate micro-metastases as well as locoregional radiation enhancement. Whether any of these regimens is superior to another is not clear and few direct comparisons have been completed. Japanese investigators compared carboplatin/taxol with carboplatin/irinotecan and the MVP regimen in combination with concomitant radiation and reported equivalent outcomes with these regimens(8). In a small trial comparing carboplatin/taxol with cisplatin/etoposide and radiotherapy, the platinum/etoposide regimen appeared to be superior; however, the number of patients was very limited at approximately 30 per arm (9). Cisplatin/pemetrexed vs. carboplatin/pemetrexed has also been compared in a randomized phase II format supporting a trend for superiority of cisplatin-based therapy as has been shown for other stages of non-small cell lung cancer as well (10). A large randomized phase III trial comparing cisplatin/etoposide with cisplatin/pemetrexed each with concomitant radiotherapy to 66 Gy has been completed. This study was closed after a futility analysis at near completion of planned accrual and a full analysis of this trial is awaited for the future. Targeted therapies have also been of interest. While they have matured to be standard therapy for many patients with stage IV disease their role in earlier stages remains under-investigated. In a number of uncontrolled trial, the addition of erlotinib or gefitinib to radiation therapy with or without additional chemotherapy has been shown to be feasible. In the Alliance Cooperative Group (formerly CALGB), a recent trial looking at induction chemotherapy with carboplatin and albumin-bound paclitaxel followed by erlotinib and concomitant radiotherapy for patients with poor-risk stage III non-small cell lung cancer was completed. Median progression-free and overall survival times of 11 months and 16 months respectively were encouraging. However, no comparative arm of radiotherapy alone was included in the trial design (11). Similarly, cetuximab has been integrated into this treatment approach. RTOG 0324 reported encouraging pilot data from the addition of cetuximab to carboplatin/paclitaxel-based concurrent chemoradiation and consolidation chemotherapy(12). A randomized trial comparing the base regimen vs. the base regimen plus cetuximab in this setting has been completed and mature results are expected in the near future. It should be cautioned however, that the larger clinical experience with the addition of cetuximab to concurrent chemoradiotherapy regimens to date has been disappointing. A randomized phase II study conducted by the CALGB (CALGB#30407) found no obvious clinically significant benefit from the addition of cetuximab to carboplatin/pemetrexed radiotherapy (7). Median survival times were 21.2 and 22.4 months respectively for the two study arms. Similarly, controlled trials investigating the addition of cetuximab in patients with esophageal or head and neck cancer to concomitant chemoradiotherapy have not shown a statistically significant benefit compared to chemoradiotherapy alone. Current research interest is focused on the treatment of patients with molecular abnormalities, in particular EGFR mutations or EML/alk translocation. For these patients, a study investigating induction chemotherapy with either erlotinib or crizotinib, respectively followed by standard concurrent chemoradiation vs concurrent chemoradiation alone is about to be activated. Similarly, immunological approaches are of interest. At present, no data from studies investigating CTLA-4 or PD1 inhibitors are available. However, a randomized trial investigating the BLP25 vaccine, a liposome MUC1-based vaccine, has recently been reported. This vaccine attempts to induce a proliferative T-cell response to the MUC1 antigen which is frequently overexpressed and hyper-glycosylated in non-small cell lung cancer. In this trial, patients completed standard combined modality therapy (either induction or concomitant chemoradiotherapy) and were then randomized to either a placebo or the active vaccine. For the overall study cohort a trend in survival was observed which was more pronounced in a planned subset analysis of patients receiving concomitant chemoradiotherapy (13). This study adds support to further investigations to vaccine-based approaches. While current standard therapy approaches do result in consistent cure rates of 20-30% of patients, further progress will depend on the development of more specific combined modality approaches. Immunological and molecularly driven clinical trials will be of particular interest in this regard.

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      E06.2 - Staging and Early Response Assessment in Combined Modality Therapy for NSCLC (ID 399)

      14:25 - 14:45  |  Author(s): D. Ball, S. Everitt, T. Kron, S. Siva, M. Macmanus

      • Abstract
      • Presentation
      • Slides

      Abstract
      For years radiation oncologists have dreamed of being able to dynamically adapt treatment to the response of normal and tumor tissues observed during a protracted course of radiotherapy. An obvious goal is to adjust the PTV as the GTV shrinks during treatment, which may improve dose volume metrics in the organs at risk, especially lung. Reinflation of atelectatic lung in response to tumour size reduction may require adjustment of PTV size and position to avoid geographic miss. Cone beam CT (CBCT) has revolutionised the ability to regularly image soft tissue, although it is less useful for targets within the mediastinum or those defined primarily by FDG PET. The main limiting step is the time required to develop an adaptive treatment plan without interrupting treatment. Experience suggests that tumor reduction needs to be substantial to have a meaningful impact on the dose volume metrics. The use of serial FDG PET during treatment to detect residual activity and to use this as a surrogate for persistent disease for adaptive radiotherapy is under investigation. This is however based on an unproven assumption that such FDG activity is due to tumor and not inflammation. Tumor motion adds further uncertainty, affecting both SUV and intrafraction location of the residual FDG uptake. CBCT may also detect tumor progression. This seems to be uncommon.(1) When it occurs, apart from discontinuing futile treatment to avoid unnecessary toxicity, can anything else be done? Our group has investigated the use of PET tracers to detect functional changes in tumour during treatment, including FDG and the thymidine based tracer FLT which we hypothesise images tumour proliferation. Preliminary results indicate that FLT detects functional changes in the tumour earlier than FDG, but the clinical implications of this are unknown.(2) One patient with clinical progression had increased uptake of FLT detected at 20 Gy, suggesting accelerated repopulation. The rate of treatment was accelerated with twice daily fractionation, resulting in a reduction in FLT uptake, providing anecdotal proof of principle. Accelerated repopulation has also been indirectly observed with induction chemotherapy.(3) Imaging with FLT may present an opportunity to detect altered proliferation pre-radiotherapy which may benefit from accelerated fractionation.(4) A further change that may occur during fractionated treatment is reoxygenation. We have observed changes in uptake of the hypoxia PET tracer FAZA during a course of radiotherapy,(5) indicating that hypoxia is present in some tumors pre-treatment, although surprisingly little use is made of this knowledge in clinical practice. Changes observed in normal tissue response may also present opportunities for adaptive treatment. The patient can be used as a biological dosemeter, and the occasional patient will require truncation of treatment because of esophagitis. Is this increased sensitivity a surrogate for inherently increased radiosensitivity within the tumor, indicating that a higher tumor dose is unnecessary for such patients? Our group has observed changes in normal lung during treatment using ventilation/perfusion imaging, opening up prospects of avoiding functioning (as opposed to anatomical) lung with beam redirection.(6) Conclusions: A number of tools are now available to detect tumor and normal tissue response to radiotherapy during treatment. These changes may be anatomic or functional, including changes in tumor kinetics or the micro-environment. The challenge now is to turn these observations into clinically useful patient benefits. References 1. Lim G, Bezjak A, Higgins J, Moseley D, Hope AJ, Sun A, et al. Tumor regression and positional changes in non-small cell lung cancer during radical radiotherapy. J Thorac Oncol. 2011;6:531-6. 2. Ball D, Everitt S, Hicks R, Callahan J, Plumridge N, Collins M, et al. Differential Uptake of F18-fluoro-deoxy-glucose (FDG) and F18-fluoro-deoxy-l-thymidine (FLT) Detected by Serial PET/CT Imaging During Radical Chemoradiation for Non-Small Cell Lung Cancer (NSCLC). . J Thorac Oncol 2012;7:S238. 3. El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer. 2003;89:2184-9. 4. Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76-85. 5. Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, et al. Imaging of hypoxia with (18) F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57:475-81. 6. Siva S, Callahan J, Hofman MS, Eu P, Martin O, Pope K, Ball D, MacManus M, Kron T, Hicks RJ. Technical considerations and preliminary experience of a pilot study of Gallium-68 VQ 4D-PET/CT in lung radiotherapy. J Thorac Oncol 2012;7: S1182.

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      E06.3 - Management of NSCLC Involving the Chest Wall (ID 400)

      14:45 - 15:05  |  Author(s): D.H. Grunenwald

      • Abstract
      • Presentation
      • Slides

      Abstract

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      E06.4 - Treating the 'Borderline' Patient (Moderate PS, Large Tumour, etc.) (ID 401)

      15:05 - 15:25  |  Author(s): L. Gaspar

      • Abstract
      • Presentation
      • Slides

      Abstract
      There is no general agreement on the definition of the “borderline” patient with stage III non-small cell lung cancer (NSCLC). Patients judged to be unsuitable for standard treatment could be of advanced age, unable to undergo cisplatin-based chemotherapy, poor performance status, poor pulmonary function and/or bulky tumors requiring large radiation fields. Since the combination of chemotherapy and radiation therapy (RT) has been adopted as the standard of care, there has been an increased portion of elderly patients who receive it. [1]. Cooperative group studies have demonstrated that the elderly have more toxicity then their younger counterparts and that age is a negative prognostic factor for survival. [2, 3, 4] However, the elderly with good PF still have improved survival with combined chemoRT as opposed to radiation only. Prospective studies in the “borderline” patient by cooperative groups in North America and Asia have had various eligibility criteria. [5, 6, 7, 8]. Those studies accrued slowly or poorly, perhaps due to the 6-7 week RT required in most studies. One RTOG study combining celecoxib and RT did allow either 60 Gy in 6 weeks or 45 Gy in 3 weeks but few patients were treated with the short course. [8] A short of course of RT may be more acceptable to patients who are elderly or have a poor performance status. A retrospective study of patients who did not receive concurrent chemoRT showed that similar survival was seen in patients treated with 45 Gy in 3 weeks as in patients treated with >60 Gy in 6 weeks. [9] Few prospective studies have been done in patients with poor pulmonary function. A retrospective study found that pre-treatment FEV1 was not statistically correlated with symptomatic lung toxicity following concurrent chemoradiation.[10] However, the combination of poor FEV1, advanced age and high mean lung dose correlated positively with pulmonary toxicity. Prospective studies are also lacking in patients with bulky disease for whom large radiation fields are required. Retrospective studies suggest that bulky disease is associated with a higher risk for the early development of metastases and death. [11] Future efforts to improve the therapeutic ratio for borderline patients likely involve the improved ability to predict both benefit and risk for an individual patient. Studies are ongoing using molecular methods to better predict distant metastases-free survival and pulmonary toxicity. [12, 13] 1. van der Drift MA, Karim-Kos HE, Siesling S, et al. Progress in standard of care therapy and modest survival benefits in the treatment of non-small cell lung cancer patients in the Netherlands in the last 20 years. J Thorac Oncol. 2012;7(2):291-8. 2. Schild SE, Mandrekar SJ, Jatoi A, et al. The value of combined-modality therapy in elderly patients with stage III non-small cell lung cancer. Cancer. 2007;110(2):363-8. 3. Langer CJ, Manola J, Bernardo P, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst. 2002;94(3):173-81. 4. Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individuals patients from 52 randomized clinical trials.. BMJ. 7;311(7010) 1995: 8099-909. 5. Lau DH, Crowley JJ, Gandara DR, et al. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol. 1998;16(9):3078-81. 6. Atagi S, Kawahara M, Tamura T, et al. Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812). Jpn J Clin Oncol. 2005;35(4):195-201. 7. Jatoi A, Schild SE, Foster N, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol. 2010;21(10):2040-4. 8. Gore E, Bae K, Langer C, et al. Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213. Clin Lung Cancer. 2011;12(2):125-30. 9. Amini A, Lin SH, Wei C, et al. Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer. Radiat Oncol. 2012;7:33. 10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. 11. Wiersma TG, Dahele M, Verbakel WF, et al. Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer. Lung Cancer. 2013;80(1):62-7. 12. Yuan X, Wei Q, Komaki R,et al. TGFβ1 Polymorphisms Predict Distant Metastasis-Free Survival in Patients with Inoperable Non-Small-Cell Lung Cancer after Definitive Radiotherapy. PLoS One. 2013;8(6):e65659. 13. Yin M, Liao Z, Yuan X, et al. Polymorphisms of the vascular endothelial growth factor gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy. Cancer Sci. 2012;103(5):945-50.

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Author of

  • +

    E06 - Issues in Current Multidisciplinary Practice (ID 6)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Combined Modality
    • Presentations: 1
    • +

      E06.4 - Treating the 'Borderline' Patient (Moderate PS, Large Tumour, etc.) (ID 401)

      15:05 - 15:25  |  Author(s): L. Gaspar

      • Abstract
      • Presentation
      • Slides

      Abstract
      There is no general agreement on the definition of the “borderline” patient with stage III non-small cell lung cancer (NSCLC). Patients judged to be unsuitable for standard treatment could be of advanced age, unable to undergo cisplatin-based chemotherapy, poor performance status, poor pulmonary function and/or bulky tumors requiring large radiation fields. Since the combination of chemotherapy and radiation therapy (RT) has been adopted as the standard of care, there has been an increased portion of elderly patients who receive it. [1]. Cooperative group studies have demonstrated that the elderly have more toxicity then their younger counterparts and that age is a negative prognostic factor for survival. [2, 3, 4] However, the elderly with good PF still have improved survival with combined chemoRT as opposed to radiation only. Prospective studies in the “borderline” patient by cooperative groups in North America and Asia have had various eligibility criteria. [5, 6, 7, 8]. Those studies accrued slowly or poorly, perhaps due to the 6-7 week RT required in most studies. One RTOG study combining celecoxib and RT did allow either 60 Gy in 6 weeks or 45 Gy in 3 weeks but few patients were treated with the short course. [8] A short of course of RT may be more acceptable to patients who are elderly or have a poor performance status. A retrospective study of patients who did not receive concurrent chemoRT showed that similar survival was seen in patients treated with 45 Gy in 3 weeks as in patients treated with >60 Gy in 6 weeks. [9] Few prospective studies have been done in patients with poor pulmonary function. A retrospective study found that pre-treatment FEV1 was not statistically correlated with symptomatic lung toxicity following concurrent chemoradiation.[10] However, the combination of poor FEV1, advanced age and high mean lung dose correlated positively with pulmonary toxicity. Prospective studies are also lacking in patients with bulky disease for whom large radiation fields are required. Retrospective studies suggest that bulky disease is associated with a higher risk for the early development of metastases and death. [11] Future efforts to improve the therapeutic ratio for borderline patients likely involve the improved ability to predict both benefit and risk for an individual patient. Studies are ongoing using molecular methods to better predict distant metastases-free survival and pulmonary toxicity. [12, 13] 1. van der Drift MA, Karim-Kos HE, Siesling S, et al. Progress in standard of care therapy and modest survival benefits in the treatment of non-small cell lung cancer patients in the Netherlands in the last 20 years. J Thorac Oncol. 2012;7(2):291-8. 2. Schild SE, Mandrekar SJ, Jatoi A, et al. The value of combined-modality therapy in elderly patients with stage III non-small cell lung cancer. Cancer. 2007;110(2):363-8. 3. Langer CJ, Manola J, Bernardo P, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst. 2002;94(3):173-81. 4. Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individuals patients from 52 randomized clinical trials.. BMJ. 7;311(7010) 1995: 8099-909. 5. Lau DH, Crowley JJ, Gandara DR, et al. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol. 1998;16(9):3078-81. 6. Atagi S, Kawahara M, Tamura T, et al. Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812). Jpn J Clin Oncol. 2005;35(4):195-201. 7. Jatoi A, Schild SE, Foster N, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol. 2010;21(10):2040-4. 8. Gore E, Bae K, Langer C, et al. Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213. Clin Lung Cancer. 2011;12(2):125-30. 9. Amini A, Lin SH, Wei C, et al. Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer. Radiat Oncol. 2012;7:33. 10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. 11. Wiersma TG, Dahele M, Verbakel WF, et al. Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer. Lung Cancer. 2013;80(1):62-7. 12. Yuan X, Wei Q, Komaki R,et al. TGFβ1 Polymorphisms Predict Distant Metastasis-Free Survival in Patients with Inoperable Non-Small-Cell Lung Cancer after Definitive Radiotherapy. PLoS One. 2013;8(6):e65659. 13. Yin M, Liao Z, Yuan X, et al. Polymorphisms of the vascular endothelial growth factor gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy. Cancer Sci. 2012;103(5):945-50.

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