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Third, the cellular targets of sunitinib in thymic carcinoma are unclear. Sunitinib attenuates the perfusion of thymic carcinoma;7 Thomas and colleagues showed that decreasing proportions of apoptotic circulating endothelial cells after administration of sunitinib correlate with a favourable outcome.5 However, whether sunitinib elicits its anti-angiogenic effect in thymic carcinoma by acting on tumour cells, endothelial cells, pericytes (which typically express PDGFRB), other stromal cells, or combinations thereof is unclear. Furthermore, sunitinib affects the functions of immune cells such as myeloid-derived suppressor cells and regulatory T cells (Tregs).8 It is currently unclear whether the immunogenetic background or somatic features of thymic carcinoma, or a combination of both of these, underlie the improved prognosis reported in sunitinib-treated patients with thymic carcinoma who showed better than average upregulation of PD-1 in circulating Tregs and CTLA4 in CD8+ T cells.5 To identify cellular biomarkers predicting the response of thymic carcinoma to sunitinib, future clinical trials should be complemented by studies of polymorphisms of immunoregulatory genes and by histological and molecular pathological investigations comparing features of neoplastic and non-neoplastic stromal components of pretherapeutic and, ideally, sequential thymic carcinoma biopsy samples from patients with a good and poor response to sunitinib. Thomas and colleagues highlight limitations of their study,5 including its single-group design, the heterogeneous treatment that patients received before enrolment, and the paucity of historical follow-up data in patients with stage IVb thymic carcinoma.4 These limitations impede comparison of the efficacy of sunitinib with that of non-targeted treatments3 and previous, disappointing findings in trials of other targeted agents in thymic carcinoma (Thomas and colleagues present a list of such trials in an appendix).5 Nevertheless, the finding that sunitinib

has high activity in a substantial subset of patients with thymic carcinoma and a satisfactory safety profile will certainly change current clinical management of refractory thymic carcinoma and, eventually, of thymic carcinoma in neoadjuvant settings if biomarkers become available. In view of Thomas and colleagues’ observation that immunoregulatory responses in blood lymphocytes of patients with thymic carcinoma treated with sunitinib have prognostic relevance, we agree that therapeutic protocols should be considered that combine sunitinib with immune checkpoint receptor inhibitors provided that the combinations have acceptable toxicity profiles.9 *Alexander Marx, Cleo-Aron Weis Institute of Pathology, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany (AM, C-AW) [email protected] We declare no competing interests. 1

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Travis WD, Brambilla E, Muller-Hermelink H, Harris C. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004. Petrini I, Meltzer PS, Kim IK, et al. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet 2014; 46: 844–49. Okuma Y, Saito M, Hosomi Y, Sakuyama T, Okamura T. Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2014; published online Aug 22. http://dx.doi. org/10.1007/s00432-014-1800-6. Litvak AM, Woo K, Hayes S, et al. Clinical characteristics and outcomes for patients with thymic carcinoma: evaluation of Masaoka staging. J Thorac Oncol 2014; 9: 1810–15. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol 2015; published online Jan 13. http://dx.doi. org/10.1016/S1470-2045(14)71181-7. Strobel P, Hartmann M, Jakob A, et al. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med 2004; 350: 2625–26. Strobel P, Bargou R, Wolff A, et al. Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience. Br J Cancer 2010; 103: 196–200. Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH. Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 2011; 77: 12–19. Rini BI, Stein M, Shannon P, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2011; 117: 758–67.

Dose escalation in lung cancer: have we gone full circle? In The Lancet Oncology, Jeffrey Bradley and colleagues1 report a randomised controlled trial of chemoradiotherapy for patients with stage III nonsmall-cell lung cancer. Patients were randomly assigned www.thelancet.com/oncology Vol 16 February 2015

to receive high-dose (74 Gy in 37 fractions) or standard dose (60 Gy in 30 fractions) radiotherapy concurrently with weekly paclitaxel and carboplatin with or without cetuximab, followed by consolidation chemotherapy

Published Online January 16, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70001-X See Articles page 187

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in all groups. The investigators concluded that neither high-dose radiation nor the addition of cetuximab improved survival. Before publication, RTOG 0617 was one of the most commented-on studies of this decade that could have a profound effect on future research in thoracic radiotherapy. When the study2 was presented at the ASTRO annual meeting in 2011 and subsequently at the ASCO annual meeting in 2013, it surprised the radiation oncology community because the delivery of high-dose radiotherapy had a detrimental effect on both survival and local control, which is counterintuitive in view of previous data suggesting a clear radiation dose–response curve in locally advanced non-small-cell lung cancer.3 In the ASCO presentation, Bradley and colleagues reported local failure rates at 18 months of 25·1% for the standard-dose group and 34·3% in the high-dose group (p=0·03). However, reporting local control in the context of chemoradiotherapy can be very challenging because of the development of radiation-induced fibrosis up to a year after treatment. This limitation might explain the omission of such data in the recent study.1 The study has major strengths and the investigators should be commended for the impressive recruitment of 544 patients from 185 institutions in 4 years. In particular, all radiotherapy plans were collected, and although the full analysis is not yet available, this should allow some important insights into causes of death in the high-dose group. Furthermore RTOG 0617 is undoubtedly the largest study providing outcome data for patients with stage III disease in the era of PET-CT staging and modern radiotherapy. Survival in the standard-dose group was substantially better than that in previous RTOG studies (28·7 months in RTOG 0617 vs 17·0 months in RTOG 9410), an improvement that might be largely attributable to improved staging with PET-CT (90·7% of patients staged with PET-CT in RTOG 0617, none in RTOG 9410).4 Likewise, stage migration might explain why the encouraging survival results of non-randomised phase 1/2 studies using 74 Gy in 37 fractions compared with historical control only did not fulfil their promise at phase 3.5 However, how can the finding that high doses of radiation therapy are potentially harmful be explained? Many oncologists have blamed the prolongation of overall radiotherapy treatment time, but a combination of factors is more likely to explain the results. Unreported 126

treatment-related deaths (cardiac and pulmonary) are probably one of the major causes for the worse survival in the high-dose group than in the standard-dose group, although the number of grade 5 events was not statistically different between the two groups (eight in the high-dose group vs three in standard-dose group). The accurate assessment of cause of death in the community is a major challenge and several studies have established inaccuracies in death certificates, showing that up to 47% of diagnoses on death certificates differed from those based on autopsy.6 This hypothesis is supported by the overall survival multivariate analysis that showed that the percentage of the heart receiving either 5 Gy or more or 30 Gy or more is associated with worse survival. Furthermore, local control in lung cancer is linked to survival, and the increased risk of local failure reported at ASCO in 2013 might have negatively affected survival. So, more than three decades after Perez and colleagues7 established 60 Gy in 2 Gy fractions as the control group for future RTOG studies, we have gone full circle without a better regimen established in the concurrent setting. What lessons can we learn from RTOG 0617? First, future studies and institutional protocols should enforce stricter heart and lung constraints and encourage the use of intensity-modulated radiotherapy for the treatment of large and complex volumes. In RTOG 0617, dose constraints to organs at risk were suggested but not mandatory and only about half of centres used intensity modulated radiotherapy. Second, stricter radiotherapy quality assurance programmes might be necessary in future multicentre trials, focusing on centres treating large numbers of patients.8 Third, it might be beneficial to reconsider traditional phase 1/2 non-randomised studies leading to phase 3 randomised studies, which might not be the best model for assessment of radiation treatment in lung cancer.9 Finally, dose escalation with conventional fractionation and concurrent chemotherapy is not the best way forward, but that does not mean that treatment intensification should be abandoned. This is an area of active research, made easier by the rapid development of advanced radiotherapy techniques such as four-dimensional radiotherapy planning, image guidance, intensity-modulated radiotherapy, and protons. Present strategies being used to improve local control and survival with radiotherapy include dose escalation with altered fractionation, individualised radiation dose escalation based on normal tissue dose www.thelancet.com/oncology Vol 16 February 2015

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constraints or functional imaging, stereotactic ablative radiotherapy boost, and the addition of targeted agents and immunotherapy to radiation.

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Institute of Cancer Sciences, The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK corinne.fi[email protected]

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I declare no competing interests. 1

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Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; published online Jan 16. http:// dx.doi.org/10.1016/S1470-2045(14)71207-0 Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab forstage III non-small cell lung cancer: results on radiation dose in RTOG 0617. Proc Am Soc Clin Oncol 2013; 31 (suppl): abstr 750.

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Martel MK, Ten Haken RK, Hazuka MB, et al. Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer 1999; 24: 31–37. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011; 103: 1452–60. Chang AJ, Bradley JD. Clinical perspectives on dose escalation for non-small-cell lung cancer. Clin Lung Cancer 2010; 11: 299–302. Modelmog D, Rahlenbeck S, Trichopoulos D. Accuracy of death certificates: a population-based, complete-coverage, one-year autopsy study in East Germany. Cancer Causes Control 1992; 3: 541–46. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat cell carcinoma of the lung: preliminary report by the Radiation Therapy Oncology Group. Cancer 1980; 45: 2744–53. Eaton BR, Pugh SL, Bradley JD, et al. The effect of institutional clinical trial enrollment volume on survival of patients with stage III non-small cell lung cancer treated with chemoradiation: a report of the Radiation Therapy Oncology Group (RTOG) 0617. Proc Am Soc J Clin Oncol 2014; 32 (suppl): abstr 5s. Faivre-Finn C, Snee M. Traditional phase 1 and 2 studies in thoracic radiation oncology should be abandoned. Int J Radiat Oncol Biol Phys 2014; 90: 487–89.

Clinicians in many countries, as well as international guidelines (NCCN, ASCO, ESMO) recommend adjuvant chemotherapy for stage II–III rectal cancer after preoperative (chemo)radiotherapy, assuming the same benefit in distant recurrences as in colon cancer, but the available data do not unequivocally support this approach.1 This debate will be further fostered by an individual patient data meta-analysis by Anne Breugom and colleagues2 in The Lancet Oncology. In this analysis, there is no evidence of a benefit of adjuvant chemotherapy with fluorouracil for patients with rectal cancer treated with preoperative (chemo)radiotherapy. With a median follow-up of 7 years, the cumulative incidence of distant recurrences at 5 years was 36·5% (95% CI 32·6–40·8) in patients in the observation group and 35·5% (31·7–39·8) for patients who received adjuvant chemotherapy (hazard ratio 0·94, 95% CI 0·78–1·14; p=0·523). Further, overall survival did not differ significantly between groups. Why were distant recurrences not reduced significantly? One possibility is weaknesses in the available data. Breugom and colleagues pointed out very clearly the limitations of their analysis: the lack of enough statistical power in some of the included studies; differences in the timing of randomisation; www.thelancet.com/oncology Vol 16 February 2015

poor compliance to adjuvant chemotherapy; and long accrual time, with consequent heterogeneity in surgical and radiation treatments. These shortcomings aside, Breugom and colleagues’ state—very correctly—that most clinicians justify the use of adjuvant chemotherapy in this setting on the basis of a borderline significant improvement in overall survival in the QUASAR study,3 in which, 21% of patients with rectal cancer received preoperative radiotherapy and the relative efficacy of postoperative chemotherapy was similar in patients with rectal cancer and those with colon cancer, irrespective of whether radiotherapy was received or not. The benefit of adjuvant chemotherapy noted for patients with colon cancer seems to be lost for patients with rectal cancer. Breugom and colleagues2 suggest that this difference is a result of biological and genetic differences between the two diseases. The finding that adjuvant chemotherapy might affect tumours 10–15 cm from the anal verge in terms of disease-free survival and distant recurrences (although still not for overall survival) lends some support to the idea of an important difference between cancer of rectum and of the colon. Results of a Cochrane review by Petersen and colleagues4 showed an HR of 0·83 (95% CI 0·76–0·91)

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The paradox of preoperative (chemo)radiotherapy for rectal cancer

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Dose escalation in lung cancer: have we gone full circle?

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