Moving towards novel treatments in mesothelioma. Paul Baas, The Netherlands Cancer Institute Rolf Stahel, University Clinic Zurich

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1 Moving towards novel treatments in mesothelioma Paul Baas, The Netherlands Cancer Institute Rolf Stahel, University Clinic Zurich Malignant pleural mesothelioma (MPM) has proven to be quite resistant to different treatment modalities. Although some progress has been made in first-line treatment by combining platinum and anti-folates, 2-year survival is less than 20%. For secondline treatment, only a few studies have been published and have not yet led to any recommendation. Therefore, it is of great importance to find new therapies for both first- and second-line treatment. To improve the outcome of any treatment, improved patient selection is very important. Levels of thymidelate synthase (TS) might predict the outcome of a treatment with anti-folates, while biomarkers like VEGF (vascular endothelial growth factor) might have predictive and/or prognostic value. Most new studies include extensive translational research to identify underlying mechanisms of action as well as patients who are likely to benefit or not. Studies that focus on the addition of VEGF inhibition to standard therapy have either had negative results or are still in progress. The addition of small molecule VEGF receptor blockers in MPM is being tested in combination with chemotherapy. A randomized phase III maintenance study of thalidomide in MPM patients without progression after first-line treatment is expected to be reported on in This study has been powered to show an increase in progression-free survival (PFS) of 50% in the thalidomide arm compared to no treatment. One phase III study of second-line doxorubicin with or without ranpirnase (RNA degradation) failed to show any benefit. Another large phase III study is evaluating the effect of an oral histone deacetylase inhibitor (vorinostat) vs placebo in the second- or third-line setting. Side effects of this medication are relatively mild and the study has now accrued just over 50% of the planned number. For patients who are considered surgical candidates and present with a relative low tumor burden, multimodality approaches (chemotherapy with surgical resection and/or radiation) are offered as part of studies. Current studies focus on the usefulness of adjuvant radiation therapy or the role of surgery. Patients who are not considered

2 candidates for the multimodality approach, new drugs or adaptations of the standard first-line treatment should be included in trials. Besides the above mentioned approaches there are a large number of new targeted agents that are being tested in phase I-II studies, including a variety of drugs that influence specific cell processes (bortezomib) or modulate the immune response (dendritic cell therapy). It is clear that with the increasing knowledge of the involved cell processes and available new drugs, many new studies are possible, but the number of patients with MPM is small and choices have to be made.

3 Advances in radiotherapy in SCLC The CONVERT trial: Concurrent once-daily versus twicedaily radiotherapy for limited stage SCLC Dr Corinne Faivre-Finn Background Small cell lung cancer (SCLC) comprises 15 to 20% of all UK diagnosed lung cancer cases and is characterised by its rapid doubling time, early dissemination and high response rate to both chemotherapy and radiotherapy treatments. About 30% of cases present as limited-stage disease (LD- SCLC), defined as disease that can be encompassed within a tolerable radiation treatment volume, and the remainder as extensive-stage (ED-SCLC), disease beyond the hemithorax of origin [1]. A number of randomised controlled trials have addressed the role of thoracic radiotherapy in addition to chemotherapy [2-6]. In LD-SCLC patients, combining thoracic radiotherapy with chemotherapy has been shown in two meta-analyses to improve local control by a factor of 50%, translating into an absolute survival advantage of 5% [7, 8]. Despite this, median survival rates remain poor at 16 to 24 months [9]. A number of questions remain unanswered regarding the optimal radiotherapy dose, fractionation schedule, sequencing and timing. The role of thoracic irradiation in ED-SCLC patients is less well defined; however, there is now a clear role for prophylactic cranial irradiation (PCI) in both groups of patients [10, 11]. Optimising dose SCLC in vitro studies have shown high intrinsic radiation sensitivity [12], although low-dose schedules have shown poor local control rates [13, 14]. Typically in the UK, doses of 45-55Gy over 4-5 weeks have been traditionally employed. There has been evidence from retrospective studies that doses 50Gy are associated with improved progression-free survival [13, 15, 16]. Several recent phase I and II studies have demonstrated the feasibility of dose-escalating to 70Gy in 35 fractions once daily with concurrent chemotherapy [17-19]. Dose-limiting toxicity has been grade 3 oesophagitis (about 20-30%) and pneumonitis (about 5-10%). Optimising fractionation Modified fractionation schedules employ either hyperfractionation (treating more than once-daily) or acceleration (reducing the overall treatment time by delivering >10Gy per week) or both. Hyperfractionation involves using an increased number of smaller RT fractions (<1.8Gy) and is

4 associated with less late normal tissue damage although it incurs increased acute toxicity, especially oesophagitis, and inconvenience. Acceleration overcomes the detrimental effect of repopulation of tumour clonogens, which typically begins at 28 days after the start of RT, although again acute toxicity is increased [20-22]. A landmark study by Turrisi et al demonstrated that 45Gy given twice a day over 3 weeks was superior to 45Gy delivered once a day over 5 weeks in terms of local control and overall survival [23]. It is unclear whether the superior results in the twice-daily arm are explained by the higher relative biological effective dose of this regimen or the effect of acceleration. Furthermore, there was a higher local thoracic relapse rate in the once-daily arm (56% versus 36%, p=0.06) suggesting that 45Gy in 5 weeks was a suboptimal dose. In contrast, the NCCTG phase III trial compared once-daily to twice-daily RT given concurrently with chemotherapy. There was no significant survival improvement in the twice-daily arm. This can be explained by the prolonged overall treatment time in the twice-daily arm (delivered as a split course treatment) which resulted in no acceleration of the RT in this arm of the trial [24]. A RTOG phase I study employed a concomitant boost strategy in which concurrent chemotherapy was given with a dose-escalated schedule of twice-daily fractions only during the last 9 days of treatment over a 5-week course, reaching a maximum tolerated dose of 61.2Gy [25]. The recently published phase II toxicity data revealed acceptable grade 3 oesophagitis of 17% [26] (compared to 27% in the Turrisi study [23]). Optimising sequencing and timing Chemotherapy and RT could be delivered sequentially or concurrently or as an alternating schedule. Early delivery of RT might reduce the emergence of chemoresistant tumour cells and could minimise the detrimental effects of accelerated repopulation of tumour clonogens. Furthermore, concomitant use of chemotherapy can have a radiosensitising effect, enhancing treatment response. On the other hand, delaying RT can allow full dose-intensity of chemotherapy up-front without the risk of dose reductions and/or reduction in number of chemotherapy cycles during more toxic concomitant treatment [27, 28]. It also allows a smaller target volume if post-chemotherapy volume is treated, resulting in less toxicity. The most favourable 5-year survival has been seen with early concurrent thoracic RT as shown in several meta-analyses [29-32]. Fried demonstrated a 2-year survival benefit for early thoracic RT compared to late RT of 5.2% (p=0.03) [30], similar to the benefit of adding thoracic RT or PCI to chemotherapy. This benefit was greater when cisplatin-based chemotherapy and hyperfractionated RT was used.

5 A recent Cochrane review that included seven randomised trials defined early RT as starting within 30 days of initiation of chemotherapy and late RT as starting 30 days or more after initiation of chemotherapy [32, 33]. There was a 5-year survival benefit in favour of early thoracic radiotherapy and cisplatin-based chemotherapy (OR 0.64, 95% CI 0.44 to 0.92). Optimising concurrent chemotherapy So far, new chemotherapy and targeted agents have failed to demonstrate their superiority compared to cisplatin-etoposide and are therefore not routinely used with thoracic RT [34-36]. Cisplatin-etoposide remains the standard of care. Both agents can be delivered at full doses when given concurrently with radiation. Unanswered questions in LD-SCLC Is twice-daily radiotherapy given concurrently with platinum-etoposide chemotherapy the gold standard treatment? What is the importance of the radiotherapy dose? What is the importance of the overall treatment time? Can conformal radiotherapy decrease toxicity? Can we identify patients who are likely to benefit from CT-RT and/or accelerated hyperfractionated RT and who are at a high risk of developing toxicity? CONVERT trial summary CONVERT is a multicentre, international, randomised phase III trial, sponsored by The Christie NHS Foundation Trust. The trial protocol was developed with the input of several collaborating groups, including the European Organisation for Research & Treatment of Cancer, Spanish Lung Cancer Group, Groupe Français de Pneumo-Cancérologie, and the National Cancer Institute of Canada. CONVERT is a phase III trial looking at the optimisation of chemo-radiotherapy in LD-SCLC. There are no other competing trials in this group of patients in Europe or Canada. This trial has the potential to define a new standard chemoradiotherapy regimen for patients with LD-SCLC and good performance status. There are two treatment arms: All patients receive either 4 or 6 cycles of IV cisplatin plus etoposide All patients receive concurrent radiotherapy commencing day 22 of cycle 1 with either: o Once-daily arm: 66Gy in 33 daily fractions over 6.5 weeks, 5 days per week

6 o Twice-daily arm: 45Gy in 30 twice-daily fractions over 3 weeks, 5 days per week Radiotherapy is delivered using modern 3 Dimensional conformal techniques (use of IMRT is permitted) without elective nodal irradiation. Aims of the trial To establish a standard regimen in this group of patients To test whether we could improve on the results of the Turrisi twice-daily regimen by increasing the total radiotherapy dose, using conventional fractionation. To provide us with toxicity and outcome data for the Turrisi regimen using modern radiotherapy techniques To increase our understanding of the biology of this disease with the translational research addon study 532 patients are to be recruited over a period of four years. The CONVERT trial will also have a significant translational research component, with correlative studies to give improved insight into the molecular biology of SCLC and to identify markers of resistance or toxicity to chemoradiotherpay in this disease. Current trial status A total of 92 sites have expressed an interest in participating in the trial to date, including: UK - 36 sites France - 28 sites Spain - 8 sites EORTC 8 sites (3 Netherlands, 3 Belgium, 1 Poland, 1 Slovenia) Canada 12 sites Estimates of recruitment from sites who have returned feasibility information indicate that there is a good chance of completing the recruitment of 532 patients in 4-5 years. Recruitment for CONVERT began in April 2008 Recruitment target = 532 Estimated date of recruitment close = 2012 Contacts for further information

7 Chief Investigator Dr Corinne Faivre-Finn +44 (0) Translational Research Lead Dr Fiona Blackhall +44 (0) Trial Manager Sally Falk +44 (0) References [1] M Zelen. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep ;4: [2] C Faivre-Finn, LW Lee, P Lorigan, C West, N Thatcher. Thoracic radiotherapy for limitedstage small-cell lung cancer: controversies and future developments. Clin Oncol (R Coll Radiol) 2005;17: [3] C Faivre-Finn, P Lorigan, C West, N Thatcher. Thoracic radiation therapy for limited-stage small-cell lung cancer: unanswered questions. Clin Lung Cancer 2005;7:23-9. [4] MA Socinski, JA Bogart. Limited-stage small-cell lung cancer: the current status of combinedmodality therapy. J Clin Oncol 2007;25: [5] WJ Curran, Jr. Therapy of limited stage small cell lung cancer. Cancer Treat Res 2001;105: [6] D De Ruysscher, J Vansteenkiste. Chest radiotherapy in limited-stage small cell lung cancer: facts, questions, prospects. Radiother Oncol 2000;55:1-9. [7] JP Pignon, R Arriagada, DC Ihde, DH Johnson, MC Perry, RL Souhami, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327: [8] P Warde, D Payne. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10: [9] J.F. Lester, E. Hudson, M. Flubacher, F. Macbeth, J. Baker, R. Wade, D. Morrey, L. Hanna, A. Brewster, S.J. Linnane. Small Cell Lung Cancer Treated in Southeast Wales. Clin Oncol 2006; 18 (5); [10] A Auperin, R Arriagada, JP Pignon, C Le Pechoux, A Gregor, RJ Stephens, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341: [11] B Slotman, C Faivre-Finn, G Kramer, E Rankin, M Snee, M Hatton, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:

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