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      Phase I/II trial evaluating carbon ion radiotherapy for the treatment of recurrent rectal cancer: the PANDORA-01 trial

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          Abstract

          Background

          Treatment standard for patients with rectal cancer depends on the initial staging and includes surgical resection, radiotherapy as well as chemotherapy. For stage II and III tumors, radiochemotherapy should be performed in addition to surgery, preferentially as preoperative radiochemotherapy or as short-course hypofractionated radiation. Advances in surgical approaches, especially the establishment of the total mesorectal excision (TME) in combination with sophisticated radiation and chemotherapy have reduced local recurrence rates to only few percent. However, due to the high incidence of rectal cancer, still a high absolute number of patients present with recurrent rectal carcinomas, and effective treatment is therefore needed.

          Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the cell line as well as the endpoint analyzed.

          Japanese data on the treatment of patients with recurrent rectal cancer previously not treated with radiation therapy have shown local control rates of carbon ion treatment superior to those of surgery. Therefore, this treatment concept should also be evaluated for recurrences after radiotherapy, when dose application using conventional photons is limited. Moreover, these patients are likely to benefit from the enhanced biological efficacy of carbon ions.

          Methods and design

          In the current Phase I/II-PANDORA-01-Study the recommended dose of carbon ion radiotherapy for recurrent rectal cancer will be determined in the Phase I part, and feasibilty and progression-free survival will be assessed in the Phase II part of the study.

          Within the Phase I part, increasing doses from 12 × 3 Gy E to 18 × 3 Gy E will be applied.

          The primary endpoint in the Phase I part is toxicity, the primary endpoint in the Phase II part is progression-free survival.

          Discussion

          With conventional photon irradiation treatment of recurrent rectal cancer is limited, and the clinical effect is only moderate. With carbon ions, an improved outcome can be expected due to the physical and biological characteristics of the carbon ion beam. However, the optimal dose applicable in this clincial situation as re-irradiation still has to be determined. This, as well as efficacy, is to be evaluated in the present Phase I/II trial.

          Trial registration

          NCT01528683

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          Most cited references15

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          Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial

          Summary Background Preoperative or postoperative radiotherapy reduces the risk of local recurrence in patients with operable rectal cancer. However, improvements in surgery and histopathological assessment mean that the role of radiotherapy needs to be reassessed. We compared short-course preoperative radiotherapy versus initial surgery with selective postoperative chemoradiotherapy. Methods We undertook a randomised trial in 80 centres in four countries. 1350 patients with operable adenocarcinoma of the rectum were randomly assigned, by a minimisation procedure, to short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or to initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). The primary outcome measure was local recurrence. Analysis was by intention to treat. This study is registered, number ISRCTN 28785842. Findings At the time of analysis, which included all participants, 330 patients had died (157 preoperative radiotherapy group vs 173 selective postoperative chemoradiotherapy), and median follow-up of surviving patients was 4 years. 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). We noted a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (hazard ratio [HR] 0·39, 95% CI 0·27–0·58, p<0·0001), and an absolute difference at 3 years of 6·2% (95% CI 5·3–7·1) (4·4% preoperative radiotherapy vs 10·6% selective postoperative chemoradiotherapy). We recorded a relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy (HR 0·76, 95% CI 0·62–0·94, p=0·013), and an absolute difference at 3 years of 6·0% (95% CI 5·3–6·8) (77·5% vs 71·5%). Overall survival did not differ between the groups (HR 0·91, 95% CI 0·73–1·13, p=0·40). Interpretation Taken with results from other randomised trials, our findings provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer. Funding Medical Research Council (UK) and the National Cancer Institute of Canada.
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            Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial

            Summary Background Local recurrence rates in operable rectal cancer are improved by radiotherapy (with or without chemotherapy) and surgical techniques such as total mesorectal excision. However, the contributions of surgery and radiotherapy to outcomes are unclear. We assessed the effect of the involvement of the circumferential resection margin and the plane of surgery achieved. Methods In this prospective study, the plane of surgery achieved and the involvement of the circumferential resection margin were assessed by local pathologists, using a standard pathological protocol in 1156 patients with operable rectal cancer from the CR07 and NCIC-CTG CO16 trial, which compared short-course (5 days) preoperative radiotherapy and selective postoperative chemoradiotherapy, between March, 1998, and August, 2005. All analyses were by intention to treat. This trial is registered, number ISRCTN 28785842. Findings 128 patients (11%) had involvement of the circumferential resection margin, and the plane of surgery achieved was classified as good (mesorectal) in 604 (52%), intermediate (intramesorectal) in 398 (34%), and poor (muscularis propria plane) in 154 (13%). We found that both a negative circumferential resection margin and a superior plane of surgery achieved were associated with low local recurrence rates. Hazard ratio (HR) was 0·32 (95% CI 0·16–0·63, p=0·0011) with 3-year local recurrence rates of 6% (5–8%) and 17% (10–26%) for patients who were negative and positive for circumferential resection margin, respectively. For plane of surgery achieved, HRs for mesorectal and intramesorectal groups compared with the muscularis propria group were 0·32 (0·16–0·64) and 0·48 (0·25–0·93), respectively. At 3 years, the estimated local recurrence rates were 4% (3–6%) for mesorectal, 7% (5–11%) for intramesorectal, and 13% (8–21%) for muscularis propria groups. The benefit of short-course preoperative radiotherapy did not differ in the three plane of surgery groups (p=0·30 for trend). Patients in the short-course preoperative radiotherapy group who had a resection in the mesorectal plane had a 3-year local recurrence rate of only 1%. Interpretation In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence. Short-course preoperative radiotherapy reduced the rate of local recurrence for all three plane of surgery groups, almost abolishing local recurrence in short-course preoperative radiotherapy patients who had a resection in the mesorectal plane. The plane of surgery achieved should therefore be assessed and reported routinely. Funding Medical Research Council (UK) and the National Cancer Institute of Canada.
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              The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.

              To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery. Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years. One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 x 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins. With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.
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                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2012
                3 April 2012
                : 12
                : 137
                Affiliations
                [1 ]Deparment of Radiation Oncology, Im Neuenheimer Feld 400, University Hospital of Heidelberg, Heidelberg 69120, Germany
                [2 ]Department of Biostatistics, Im Neuenheimer Feld 305, University Hospital of Heidelberg, Heidelberg 69120, Germany
                [3 ]Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany
                [4 ]Nationales Centrum für Tumorerkrankungen (NCT), Medizinische Onkologie, Im Neuenheimer Feld 360, Heidelberg 69120, Germany
                [5 ]Fondazione CNAO - Centro Nazionale di Adroterapia Oncologica, Via Caminadella, 16, Milano 20123, Italy
                [6 ]Department of Radiation Oncology, Baldingerstraße, University Hospital of Marburg, Marburg 35043, Germany
                [7 ]Department of Radiation Oncology, University of Vienna, Währinger Gürtel 18-20, Wien 1090, Austria
                [8 ]CERN, Geneva 23 1211, Switzerland
                [9 ]Heidelberger Ionenstrahl Therapiezentrum (HIT), Im Neuenheimer Feld 450, Heidelberg 69120, Germany
                Article
                1471-2407-12-137
                10.1186/1471-2407-12-137
                3342902
                22472035
                f18e099c-3e03-4c38-8023-91cb0dcc955b
                Copyright ©2012 Combs et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 7 February 2012
                : 3 April 2012
                Categories
                Study Protocol

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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