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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 references 21

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          Preoperative versus postoperative chemoradiotherapy for rectal cancer.

          Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer. We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival. Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01). Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival. Copyright 2004 Massachusetts Medical Society.
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            Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.

            Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable rectal cancer. We conducted a multicenter, randomized trial to determine whether the addition of preoperative radiotherapy increases the benefit of total mesorectal excision. We randomly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy (5 Gy on each of five days) followed by total mesorectal excision (924 patients) or to total mesorectal excision alone (937 patients). The trial was conducted with the use of standardization and quality-control measures to ensure the consistency of the radiotherapy, surgery, and pathological techniques. Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate. The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent. The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P<0.001). Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision.
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              Optimal two-stage designs for phase II clinical trials.

              The primary objective of a phase II clinical trial of a new drug or regimen is to determine whether it has sufficient biological activity against the disease under study to warrant more extensive development. Such trials are often conducted in a multi-institution setting where designs of more than two stages are difficult to manage. This paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the regimen has low activity subject to constraints upon the size of the type 1 and type 2 errors. Two-stage designs which minimize the maximum sample size are also determined. Optimum and "minimax" designs for a range of design parameters are tabulated. These designs can also be used for pilot studies of new regimens where toxicity is the endpoint of interest.
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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
                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.

                Categories
                Study Protocol

                Oncology & Radiotherapy

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