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Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study

Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients... Background: Local control appears to be an important treatment aim in patients with limited metastases (oligometastases) of colorectal cancer (CRC). Those patients show a favourable prognosis, if - in addition to the local effective treatment - an occurrence of new metastases may also be postponed by effective systemic therapy. The purpose of this dose escalation phase I study was to establish the efficacy of local radiotherapy (RT) of oligometastatic CRC with a concurrent standard chemotherapy regimen. Methods: Patients with first-, second- or third-line therapy of oligometastatic CRC (1–3 metastases or local recurrence plus max. 2 metastases) received capecitabine (825 mg/m /d BID d 1–14; 22–35) and oxaliplatin (50 mg/ m d 1, 8, 22, 29). 3D-conformal RT of all metastatic lesions was delivered in 2.0 Gy up to 36 Gy to 50 Gy (3 dose levels). Primary endpoint was the maximal tolerable dose (MTD) of RT defined as the level at which two or more of six patients experienced dose-limiting toxicity (DLT). Results: Between 09/2004 and 08/2007, 9 patients (7 male, 2 female, 50–74 years) were enrolled, 6 patients treated at dose level 1 (36 Gy), 3 patients at dose level 2 (44 Gy). 1 patient from the first cohort experienced DLT (oxaliplatin-related hypersensitivity reaction). No radiation-induced DLT occurred. 6/9 patients achieved objective response (partial remission). One year after initiation, all patients were alive, 6 patients survived (16 to 54 months) patients died of tumor progression (14 to 23 months). The phase II part of the trial had to be closed due to recruitment failure. Conclusions: Local 3D-CRT to metastatic lesions in addition to standard chemotherapy was feasible, DLT was not documented. 3/9 patients survived for a period of 3.5 to 4.4 years (time at the last evaluation). Radiotherapy of metastatic lesions should be incorporated into subsequent trials. Keywords: Oligometastatic colorectal cancer, Chemoradiation, Capecitabine, Oxaliplatin, Phase I study Background develop metastatic disease after curative resection of the Colorectal cancer is one of the most common cancer primary tumor in the further course of disease, mainly diagnosis among both genders and with an estimated liver metastases. number of 207 400 (12.2%) of total deaths the second Patients with a single or few liver or lung metastases major cause of cancer death in Europe in 2006 [1]. At should undergo curative intended resection of their me- the time of diagnosis about 25% of patients present with tastases and have a chance of long-term cure in the metastases and more than one third of patients will range of 30 to 40% [2]. In irresectable metastases, pallia- tive chemotherapy aims to prolong survival while pre- serving or improving the quality of life. However, * Correspondence: kathrin.dellas@uksh.de definition of a potentially curative and a palliative ap- North European Radiooncological Center Kiel (NRoCK), Kiel, Germany Department of Radiooncology, University of Lübeck, Lübeck, Germany proach has therefore been mainly determined by Full list of author information is available at the end of the article © 2012 Dellas et al. 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. Dellas et al. Radiation Oncology 2012, 7:83 Page 2 of 7 http://www.ro-journal.com/content/7/1/83 resectability in the past. Recently, a variety of non- according to “Response Evaluation Criteria in Solid surgical local ablative therapies have been developed, Tumors” (RECIST). and the question was raised whether a subset of patients Key exclusion criteria included previously adminis- with a limited number of metastases (oligometastatic tered radiotherapy not allowing the required dose, sig- disease) might benefit from the addition of such local nificant cardiac disease (heart failure NYHA III-IV, therapy to systemic chemotherapy. myocardial infarction within the last three months or Local efficacy of radiotherapy has been well documen- symptomatic heart disease) and cerebrovascular disor- ted in mCRC and palliative radiotherapy can be used ef- ders thought to adverse-affects treatment compliance. fectively for controlling symptoms [3-8]. Though Patients with the following conditions were also ineli- improved diagnosis and therapy planning also multiple gible: serious, uncontrolled infections, malabsorption lesions can be localized exactly and irradiated in small syndrome, known sensitivity to fluoropyrimidines and volume, respectively. A requirement for this is also a dihydropyrimidine dehydrogenase deficiency, allergy to planning target definition adapted to the metastases. platin derivative, peripheral neuropathy, current treat- The combinations of oxaliplatin with capecitabine have ment with sorivudin or bivudin and treatment history of shown both, efficacy in mCRC as systemic treatment other cancer or participation in another clinical trial and radiosensitizing potential [9-15], and are therefore within 4 weeks of the start of treatment. Pregnant or lac- suitable from a radiobiological point of view particularly tating patients and women with childbearing potential for the combination with radiotherapy. The application who lacked a reliable contraceptive method were also can be used concurrently with radiotherapy, without in- excluded. creasing toxicity of the chemotherapy or radiotherapy considerly. Study design and treatment Therefore, the purpose of this dose escalation phase I We undertook a prospective, single center phase I study. study was to establish a regimen of local radiotherapy The primary endpoint was to determine the maximal with concurrent standard chemotherapy in oligometa- tolerable dose (MTD) and dose-limiting toxicity (DLT) static colorectal cancer. of chemoradiotherapy with concurrent 3D-radiotherapy to all (max. 3) metastatic lesions. Radiation dose levels Patients and methods of all metastatic leasions were the planned dose levels at The study was conducted according to the principles of 36 Gy, 44 Gy and 50 Gy in 2.0 Gy daily fractions (as the Declaration of Helsinki and to good clinical practice described later, the dose level at 50 Gy was not reached). guidelines. The Ethics Committee, University of Halle, The secondary endpoints included the evaluation of approved this study. Each patient gave written informed antitumor activity of the combined-modality treatment consent before being included. in objective response according to the Response Evalu- ation Criteria In Solid Tumors (RECIST) [16] (rate of Eligibility criteria complete or partial remission), time to progression, The eligibility criteria included histopathologically con- overall survival (one year survival rate) and toxicity. firmed oligometastatic colorectal cancer (1–3 metastases During radiotherapy, capecitabine was administered with largest diameter 5 cm or local recurrens of rectal with a fixed dose (825 mg/m /d orally BID on days 1–14 cancer plus 1–2 metastases of ≤ 5 cm in technically or and 22–35), and oxaliplatin (50 mg/m as 2 h infusion clinically irresectable disease, extention to the recruit- on days 1, 8, 22 and 29). After completion of chemora- ment of patients in a neoadjuvant situation (before diation, systemic treatment could be continued in stand- planned resection). Patients with first-, second- or third- ard dosage (capecitabine 1000 mg/m /d orally BID on line therapy of oligometastatic colorectal cancer were days 1–14 and oxaliplatin 70 mg/m infusional on days eligible for this study in adequate renal, hepatic and 1 and 8). Staging was completed in the third week of the hematologic function. Additional inclusion criteria were third cycle (week 9), and therapy was considered to con- age ≥ 18 years, Karnofsky performance status ≥ 70%, tinue at the physician’s discretion. creatinin clearance> 30 mL/min calculated according to The following recommendations for dose reductions Cockroft and Gault, total bilirubin concentration less were applied: if one patient experienced grade 1 toxicity than 2.5 and transaminases less than 2.5 times the upper (according to National Cancer Institute Common Tox- normal limit with hepatic metastases after image-guided icity Criteria version 3.0) considered to be possibly exclusion of intra- or extrahepatic cholestasis and trans- related to radiation, treatment was continued, with ap- aminases less than 5.0 times the upper normal limit, propriate prophylactic treatment. In case of grade 2 tox- 9 9 neutrophils> 2.5 x 10 /L, platelet count> 125 x 10 /L, icity, radiation treatment was continued for one week at estimated life expectancy of more than 3 months, writ- maximum. If patient experienced any grade 2 toxicity ten informed consent and tumor assessment analyzed for more than one week or more severe intensity, Dellas et al. Radiation Oncology 2012, 7:83 Page 3 of 7 http://www.ro-journal.com/content/7/1/83 radiotherapy was halted for 3–7 days. When toxicity and during follow up every three months. Tumor assess- resolved to grade 1, treatment was resumed, if possible. ment was initiated on the basis of RECIST criteria 1.0 at Interruption or conduction of radiation may be related baseline, within 14 days before the start of treatment, to one or several planning target volumes. In case of re- and after the end of the combined treatment. currence of toxicity while continuing radiation, which would require further discontinuation of radiation ther- Statistical aspects apy (as defined above) radiation of this planning target A modified escalation design with three to six patients volume was permanently discontinued. Radiotherapy was chosen on empiric grounds, according to current was considered to be in accordance with the protocol if standards in phase I cancer trials. According to the ex- at least 80% of the planed dosage for the planning target ploratory nature of this pilot trial, only descriptive statis- volume was applied and therapy was no longer discon- tical methods are used, giving rates, means with SD, and tinued than for 7 days. quartiles and ranges. 3D-CRT technique Results A total irradiation dose of 36 Gy or 44 Gy was delivered A total of nine patients were enrolled (seven male and two in 2.0 Gy daily fractions, Monday through Friday. In this female patients between 50 and 74 years of age) into the protocol, high-energy photons (6 to 15 MeV) were used study at Halle University between September 2004 and Au- and three-dimensional planning with measurements of gust 2007 (Table 1). Before including into the study, six macroscopic tumor, planning target volume and organs patients had been previously treated with radiotherapy at at risk were mandatory. All lesions had to be defined by other sites, and all of the nine patients received previously computed tomography clearly. The clinical target vol- chemotherapy and surgery. In three patients, systemic pre- ume (CTV) was the GTV of each lesion. Planning target treatment was administered as capecitabine and oxaliplatin, volume contained all detectable metastases was derived one patient received capecitabine, oxaliplatin, 5-FU and leu- by adding a margin of 10 mm to account the CTV for covorin, one patient received 5-FU and leucovorin, one pa- the setup uncertainties. It was required that the 90%- tient received 5-FU and oxaliplatin, one patient was treated isodose line covered the planning target volume. Two with 5-FU, leucovorin, oxaliplatin and irinotecan, one pa- metastatic lesions could be integrated into one planning tient was treated with 5-FU, leucovorin, capecitabine, oxali- target volume if they were located close to each other. platin, irinotecan and cetuximab and one patient received 5-FU, leucovorin, irinotecan and bevacizumab. Issued by Evaluation of safety and efficacy the criteria for inclusion the metastatic lesions were not Adverse events were graded to National Cancer Institute of Canada (NCIC) Common Toxicity Criteria (CTC) Table 1 Characteristics of patients (revised in May 1991). Dose-limiting toxicity (DLT) was Dose level 1 Dose level 2 Total defined as the occurrence of any grade three and four n=6 n=3 n=9 toxicity, except alopecia, hematologic toxicity and transi- Sex ent elevation of transaminases. Within the three dose Male 4 3 7 levels, dose escalation of radiation was performed with Female 2 - 2 the same dose of chemotherapy. According to potentially Age, years different toxicity at different sites of metastatic lesions, modified rules for escalation were used: Three patients MW 63.2 65.3 63.9 had to be enrolled per predefined dose level. If there was SD 10.1 5.0 8.4 no DLT in the first three patients, the cohort was Karnofsky performance status (%) extended by another three patients at the same dose MW 93.3 96.7 94.4 level, to obtain sufficient safety profile associated with SD 8.2 5.8 7.3 different toxicity depending on multiple metastatic Pathologic staging (at the time of accrural) lesions. The safety analysis included all patients who received TT0 4 3 7 at least one dose (one day) of radiation and chemother- T4 2 - 2 apy. All adverse events were monitored continuously NN0 5 3 8 during treatment and observed until decreasing or N1 1 - 1 stabilization of symptoms. Hematology and clinical MM0 1 - 1 chemistry was performed weekly during treatment and M1 5 3 8 thereafter during chemotherapy weekly, respectively after every third cycle, after the end of chemotherapy MW: Mean, SD: Standard deviation. Dellas et al. Radiation Oncology 2012, 7:83 Page 4 of 7 http://www.ro-journal.com/content/7/1/83 Table 2 Incidence and maximum severity of toxicities Table 2 Incidence and maximum severity of toxicities (MedDRA classification) (MedDRA classification) (Continued) Dose level 1 Dose level 2 Investigations CTC grade 1/2 3 4 1/2 3 1/234 Blood amylase increased 1 0 0 0 0 1 00 MedDRA Code (n = 9 events) No. of Patients Blood bilirubin increased 2 0 0 3 0 5 00 Infections and infestations Blood pressure increased 0 0 0 2 0 2 00 Infection 0 2 0 0 0 0 20 Blood urea increased 1 0 0 0 0 1 00 Immune system disorders Blood urea decreased 0 0 0 2 0 2 00 Anaphylactic reaction 0 0 1 0 0 0 01 C-reactive protein increased 4 0 0 1 0 5 00 Nervous system disorders Blood fibrinogen increased 1 0 0 0 0 1 00 Peripheral sensory neuropathy 2 0 0 1 0 3 00 Gamma-glutamyltransferase increased 4 0 0 1 1 5 10 Eye disorders Blood glucose increased 0 0 0 1 0 1 00 Conjunctival haemorrhage 1 0 0 0 0 1 00 Haemoglobin decreased 4 0 0 2 0 6 00 Vision blurred 1 0 0 0 0 1 00 Blood uric acid increased 1 0 0 0 0 1 00 Disorder sight 1 0 0 0 0 1 00 Blood calcium decreased 3 0 0 2 0 5 00 Abnormal sensation in eye 1 0 0 0 0 1 00 Blood creatinine increased 3 0 0 1 0 4 00 Vascular disorders Blood lactate dehydrogenase increased3 0 0 1 0 4 00 Flushing 2 0 0 0 0 2 00 WBC count increased 1 0 0 0 0 1 00 Hypotension 1 0 0 1 0 2 00 WBC count decreased 1 1 0 2 0 3 10 Thrombophlebitis 1 0 0 0 0 1 00 Platelets decreased 3 0 0 2 0 5 00 Respiratory, thoracic and mediastinal disorders Transaminases increased 2 0 0 3 0 5 00 Dyspnoea 0 1 0 0 0 0 10 Gastrointestinal disorders Abdominal pain 0 0 0 1 0 1 00 restricted to the liver. The number of metastatic lesions Abdominal distension 1 0 0 0 0 1 00 was a single lesion in four patients, two lesions in two patients and three lesions in three patients (a total of 17 Vomiting 0 0 0 1 0 1 00 lesions in 9 patients). In seven patients the lesion was Obstipation 2 0 0 0 0 2 00 located in the liver and two patients had a non-liver-lesion Mucous stools 1 0 0 0 0 1 00 (vulva and local recurrence presacral). Nausea 3 0 0 2 0 5 00 Abdominal discomfort 1 0 0 0 0 1 00 Dose escalation and DLT Epigastric discomfort 0 0 0 1 0 1 00 Initially, three patients were treated at the lowest dose Skin and subcutaneous tissue disorders level of radiation (36 Gy), without dose-limiting toxicity. According to the study protocol, three additional patients Dermatitis 1 0 0 2 0 3 00 were included at this dose level. Therefore, six patients Musculoskeletal and connective tissue disorders were treated at the lowest dose level one and three Bone pain 1 0 0 0 0 1 00 patients at dose level two (44 Gy). The fourth patient Myalgia 1 0 0 0 0 1 00 from the first cohort experienced a non-radiotherapy Pain in extremity 1 0 0 0 0 1 00 related DLT (oxaliplatin-related hypersensitivity reac- Renal and urinary disorders tion). There was no DLT in the three patients treated in the second cohort until the premature termination. No Bladder discomfort 2 0 0 0 0 2 00 radiation-induced DLT occurred. The dosage finding General disorders and administration site conditions remained incomplete and MTD could not be deter- Injection site erythema 0 0 0 1 0 1 00 mined. The trial had to be closed due to recruitment fail- Pyrexia 1 0 0 1 0 2 00 ure. There were no safety-related concerns regarding the Injection site paraesthesia 0 0 0 1 0 1 00 premature trial termination. Mucosal inflammation 1 0 0 0 0 1 00 Pain 3 1 0 1 0 4 10 Hematologic and non-hematologic toxicity Adverse events according to MedDRA Code CTC sever- Chills 1 0 0 1 0 2 00 ity grade by body/organ system are presented for the Dellas et al. Radiation Oncology 2012, 7:83 Page 5 of 7 http://www.ro-journal.com/content/7/1/83 whole patients group (Table 2). The only grade 4 toxicity consisting of 3D-radiotherapy of all metastatic lesions was oxaliplatin-related hypersensitivity reaction (one pa- with a concurrently administered standard systemic tient in cohort one), consecutively classified as DLT. therapy with capecitabine and oxaliplatin (XELOX regi- Four patients experienced grade 3 toxicity, three patients men) [17,18]. The primary objective of this study was to from the first cohort and one patient from the second determine the maximal tolerable dose (MTD) of local dose level. In the three patients at dose level one, grade radiotherapy combined with standard chemotherapy. 3 toxicities occurred (infection, dyspnea, pain and leuco- The study used conventionally fractionated radiotherapy cytopenia). Grade 3 toxicity with increasead liver under the assumption that this treatment is widely avail- enzymes was documented in one patient at dose level able, safe and effective as known from preoperative two. No instance of radiation-induced liver disease radiotherapy in locally advanced rectal cancer. (RILD) has been observed. Most commonly, local disease control can be assessed Further hematologic and non-hematologic toxicity was by pathohistological response, which is likely correlated usually mild (grade 1 and 2). Five patients showed any with relapse free suvival after 5-FU based chemora- increased levels of blood bilirubin, transaminases and C- diotherapy. Pathological complete response (pCR) rates reactive protein, six patients an elevation of gamma- following fluoropyrimidine based chemoradiation have glutamyltransferase and four patients of lactate dehydro- been reported in 15-20% of patients. Many phase II trials genase. Low hemoglobin as well as low platelet counts indicate, that the rate of pathohistologic response (pCR) were seen in six and five patients, respectively. of the local tumor may be improved by adding highly ef- Gastrointestinal toxicities occurred in five patients con- fective substances like oxaliplatin, combined with 5-FU sisting primarily of nausea and in two patients with ab- or capecitabine - an emerging strategy in the multimod- dominal and epigastric discomfort. Furthermore, ality management of locally advanced rectal cancer [19]. dermatitis was recorded in three patients. In preoperative chemoradiation for localized rectal can- cer, phase II and III trials have shown that the combin- Antitumor activity ation of radiation with capecitabine and oxaliplatin Secondary endpoint was the objective tumor response, shows moderately high rates of histopathological eradi- defined as the rate of complete or partial remission. A cation of the tumor. Data of phase II trials suggests a total of seventeen lesions in nine patients were irra- pCR rate up to the above mentioned 20%, whereas rates diated. Six of nine patients achieved tumor response in phase III trials only showed “borderline” significant (partial remission), for two patients adequate data were improvement [12-15]. The arguments for a regimen of not assessable. Disease progression after one year oc- chemoradiation, based on capecitabine, oxaliplatin and curred in three patients (two patients from the first co- radiation, are the efficacy of the chemoradiation, radio- hort, one patient from the second cohort). The first sensitizing potential and the approved feasibility of the patient from the first cohort developed new liver metas- mentioned combined regimen in terms of systemic ac- tases and distant metastases (lung lesions). For the sec- tivity. However, the final prove of effectiveness of adding ond patient from the first cohort and the patient from oxaliplatin to the preoperative therapy is still under in- the second cohort with progressive disease adequate vestigation, but reported preliminary results from phase data were not available. One year after initiation, all III trials, the French ACCORD study [12], the Italian patients were still alive. Within the following year, three STAR-01 study [15] as well as the US NSABP R-04 trial patients died from tumor progression (14 to 23 months [14] did not show a significant increased rate of pCR´s, after initiation). At the time of last evaluation four and in the German phase III trial, only a small incre- patients had survived (16 to 54 months after initiation, ment was documented [13]. It has to be shown, whether Table 3). these results impact on lead to improved local failure or distant metastases. Discussions We aimed to evaluate the efficacy and feasibility of We conducted this phase I trial as a multimodal regimen adding capecitabine and oxaliplatin, administered at for patients with oligometastatic colorectal cancer, fixed doses according to a schedule previously developed Table 3 Parameters for survival Dosis 1 Dosis 2 Survived Lost to Follow up Survived Lost to Follow up Survived Lost to Follow up 1 year 6 0 3 0 9 0 3 years 3 0 0 3 3 3 One year after initiation all patients were alive, three patients had died of tumor progression within the following three years. Dellas et al. Radiation Oncology 2012, 7:83 Page 6 of 7 http://www.ro-journal.com/content/7/1/83 in rectal cancer [17,18], in addition to dose escalation of after resection of colorectal liver metastases defines cure. J Clin Oncol 2007, 25(29):4575–80. radiation of multiple metastatic lesions in patients with 3. Fokas E, Henzel M, Hamm K, Surber G, Kleinert G, Engenhart-Cabillic R: mCRC. Radiotherapy for brain metastases from renal cell cancer: should whole- There are several limitations of the study with respect brain radiotherapy be added to stereotactic radiosurgery?: analysis of 88 patients. Strahlenther Onkol 2010, 186(4):210–7. to the efficacy caused by the inhomogenous characteris- 4. Freundt K, Meyners T, Bajrovic A, Basic H, Karstens JH, Adamietz IA, Rudat V, tics of patients, the patients (pre)treatment with the Schild SE, Dunst J, Rades D: Radiotherapy for oligometastatic disease in first-, second- or third-line therapy and incomplete in- patients with spinal cord compression (MSCC) from relatively radioresistant tumors. Strahlenther Onkol 2010, 186(4):218–23. formation of local lesions and distant metastases of 5. Heisterkamp C, Haatanen T, Schild SE, Rades D: Dose escalation in patients patients with progressive disease. receiving whole-brain radiotherapy for brain metastases from colorectal Notwithstanding the trial had to be closed due to re- cancer. Strahlenther Onkol 2010, 186(2):70–5. 6. Rades D, Kueter JD, Hornung D, Veninga T, Hanssens P, Schild SE, Dunst J: cruitment failure, and the small sample size limits con- Comparison of stereotactic radiosurgery (SRS) alone and whole brain clusions. However, the data are promising with regard to radiotherapy (WBRT) plus a stereotactic boost (WBRT+SRS) for one to the results of the present trial and should stimulate more three brain metastases. Strahlenther Onkol 2008, 184(12):655–62. 7. Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg intense investigations to establish the best treatment SJ, Chidel MA, Pugh TJ, Franklin W, Kane M, Gaspar LE, Schefter TE: regimens to obtain better approaches in the therapy of Multi-institutional phase I/II trial of stereotactic body radiation therapy oligometastatic colorectal cancer. Moreover, more for liver metastases. J Clin Oncol 2009, 27(10):1572–8. 8. Rusthoven KE, Kavanagh BD, Burri SH, Rusthoven KE, Kavanagh BD, Burri SH, advanced radiotherapy techniques (e.g. IGRT, stereotac- Chen C, Cardenes H, Chidel MA, Pugh TJ, Kane M, Gaspar LE, Schefter TE: tic radiotherapy and radiosurgery) are now widely avail- Multi-institutional phase I/II trial of stereotactic body radiation therapy able and 3D-CRT is not considered as contemporary for lung metastases. J Clin Oncol 2009, 27(10):1579–84. 9. Gerard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, standard for radiotherapy to metastatic lesions in a po- Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz tentially curative setting. Nevertheless, our results might R, Ducreux M, Bedenne L: Preoperative radiotherapy with or without be helpful because they demonstrate the feasibility of a concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006, 24(28):4620–5. concurrent chemoradiotherapy approach in this subset 10. Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, of patients and there are so far few data on the question Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N: Preoperative of sequencing local and systemic therapy in metastatic multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009, 27(31):5124–30. patients. 11. Hofheinz R, Wenz FK, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler MH, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald Conclusions M, Kremers S, Constantin C, Hipp M, Gencer D, Burkholder I, Hochhaus A: Capecitabine (Cape) versus 5-fluorouracil (5-FU)–based (neo)adjuvant The results of this phase I study support the use of local chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): radiotherapy to metastatic lesions in addition to concur- Long-term results of a randomized, phase III trial. J Clin Oncol 2011, rent standard chemotherapy as an effective and feasible 29:3504. 12. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, therapeutic option in patients with oligometastatic colo- Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, rectal cancer. Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Montoto-Grillot C, Conroy T: Comparison of two neoadjuvant chemoradiotherapy regimens for locally Competing interests advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige The authors declare no conflicts of interest. 2. JClinOncol 2010, 28(10):1638–44. 13. Roedel C, Becker H, Fietkau R, Graeven U, Hohenberger W, Hothorn T, Lang- Author details Welzenbach M, Liersch T, Staib L, Christiansen H, Wittekind C, Sauer R: North European Radiooncological Center Kiel (NRoCK), Kiel, Germany. Preoperative chemoradiotherapy and postoperative chemotherapy with 5- Department of Radiooncology, University of Lübeck, Lübeck, Germany. fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced Department of Radiotherapy, Martin Luther University Halle-Wittenberg, rectal cancer: First results of the German CAO/ARO/AIO-04 randomized phase Halle (Saale), Germany. Coordination Center for Clinical Trials, Halle (Saale), III trial. JClinOncol 2011, 29:3505. Germany. Hubertus Wald Tumor Center, University Comprehensive Cancer 14. Roh MS, Yothers GA, O'Connell MJ, Beart RW, Pitot HC, Shields AF, Parda DS, Center Hamburg-Eppendorf (UCCH), Hamburg, Germany. Sharif S, Allegra CJ, Petrelli NJ, Landry JC, Ryan DP, Arora A, Evans TL, Soori GS, Chu L, Landes RV, Mohiuddin M, Lopa S, Wolmark N: The impact of Authors’ contribution capecitabine and oxaliplatin in the preoperative multimodality treatment in KD, MR, DA and JD designed and supervised the study. KD, TR, DA and JD patients with carcinoma of the rectum: NSABP R-04. JClin Oncol 2011, 29:3503. responsible for therapy and data collection. MR collected data and did 15. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, statistical analyses. KD drafted the manuscript and figures, and all authors Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, edited and/or approved the final version. Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L: Primary Tumor Response to Preoperative Chemoradiation With or Received: 24 January 2012 Accepted: 09 June 2012 Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Published: 09 June 2012 Results of the STAR-01 Randomized Phase III Trial. J Clin Oncol 2011, 29 (20):2773–80. References 16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 1. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P: Estimates of Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007, New guidelines to evaluate the response to treatment in solid tumors. 18(3):581–92. European Organization for Research and Treatment of Cancer, National 2. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Cancer Institute of the United States, National Cancer Institute of Kemeny N, Brennan MF, Blumgart LH, D'Angelica M: Actual 10-year survival Canada. J Natl Cancer Inst 2000, 92(3):205–16. Dellas et al. Radiation Oncology 2012, 7:83 Page 7 of 7 http://www.ro-journal.com/content/7/1/83 17. Rödel C, Grabenbauer GG, Papadopoulos T, Hohenberger W, Schmoll HJ, Sauer R: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003, 21(16):3098–104. 18. Rödel C, Liersch T, Hermann RM, Arnold D, Reese T, Hipp M, Fürst A, Schwella N, Bieker M, Hellmich G, Ewald H, Haier J, Lordick F, Flentje M, Sülberg H, Hohenberger W, Sauer R: Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 2007, 25 (1):110–7. 19. Rödel C, Sauer R: Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 2007, 183 (5):227–35. doi:10.1186/1748-717X-7-83 Cite this article as: Dellas et al.: Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study. Radiation Oncology 2012 7:83. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study

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Springer Journals
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Copyright © 2012 by Dellas et al.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-7-83
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22681700
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Abstract

Background: Local control appears to be an important treatment aim in patients with limited metastases (oligometastases) of colorectal cancer (CRC). Those patients show a favourable prognosis, if - in addition to the local effective treatment - an occurrence of new metastases may also be postponed by effective systemic therapy. The purpose of this dose escalation phase I study was to establish the efficacy of local radiotherapy (RT) of oligometastatic CRC with a concurrent standard chemotherapy regimen. Methods: Patients with first-, second- or third-line therapy of oligometastatic CRC (1–3 metastases or local recurrence plus max. 2 metastases) received capecitabine (825 mg/m /d BID d 1–14; 22–35) and oxaliplatin (50 mg/ m d 1, 8, 22, 29). 3D-conformal RT of all metastatic lesions was delivered in 2.0 Gy up to 36 Gy to 50 Gy (3 dose levels). Primary endpoint was the maximal tolerable dose (MTD) of RT defined as the level at which two or more of six patients experienced dose-limiting toxicity (DLT). Results: Between 09/2004 and 08/2007, 9 patients (7 male, 2 female, 50–74 years) were enrolled, 6 patients treated at dose level 1 (36 Gy), 3 patients at dose level 2 (44 Gy). 1 patient from the first cohort experienced DLT (oxaliplatin-related hypersensitivity reaction). No radiation-induced DLT occurred. 6/9 patients achieved objective response (partial remission). One year after initiation, all patients were alive, 6 patients survived (16 to 54 months) patients died of tumor progression (14 to 23 months). The phase II part of the trial had to be closed due to recruitment failure. Conclusions: Local 3D-CRT to metastatic lesions in addition to standard chemotherapy was feasible, DLT was not documented. 3/9 patients survived for a period of 3.5 to 4.4 years (time at the last evaluation). Radiotherapy of metastatic lesions should be incorporated into subsequent trials. Keywords: Oligometastatic colorectal cancer, Chemoradiation, Capecitabine, Oxaliplatin, Phase I study Background develop metastatic disease after curative resection of the Colorectal cancer is one of the most common cancer primary tumor in the further course of disease, mainly diagnosis among both genders and with an estimated liver metastases. number of 207 400 (12.2%) of total deaths the second Patients with a single or few liver or lung metastases major cause of cancer death in Europe in 2006 [1]. At should undergo curative intended resection of their me- the time of diagnosis about 25% of patients present with tastases and have a chance of long-term cure in the metastases and more than one third of patients will range of 30 to 40% [2]. In irresectable metastases, pallia- tive chemotherapy aims to prolong survival while pre- serving or improving the quality of life. However, * Correspondence: kathrin.dellas@uksh.de definition of a potentially curative and a palliative ap- North European Radiooncological Center Kiel (NRoCK), Kiel, Germany Department of Radiooncology, University of Lübeck, Lübeck, Germany proach has therefore been mainly determined by Full list of author information is available at the end of the article © 2012 Dellas et al. 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. Dellas et al. Radiation Oncology 2012, 7:83 Page 2 of 7 http://www.ro-journal.com/content/7/1/83 resectability in the past. Recently, a variety of non- according to “Response Evaluation Criteria in Solid surgical local ablative therapies have been developed, Tumors” (RECIST). and the question was raised whether a subset of patients Key exclusion criteria included previously adminis- with a limited number of metastases (oligometastatic tered radiotherapy not allowing the required dose, sig- disease) might benefit from the addition of such local nificant cardiac disease (heart failure NYHA III-IV, therapy to systemic chemotherapy. myocardial infarction within the last three months or Local efficacy of radiotherapy has been well documen- symptomatic heart disease) and cerebrovascular disor- ted in mCRC and palliative radiotherapy can be used ef- ders thought to adverse-affects treatment compliance. fectively for controlling symptoms [3-8]. Though Patients with the following conditions were also ineli- improved diagnosis and therapy planning also multiple gible: serious, uncontrolled infections, malabsorption lesions can be localized exactly and irradiated in small syndrome, known sensitivity to fluoropyrimidines and volume, respectively. A requirement for this is also a dihydropyrimidine dehydrogenase deficiency, allergy to planning target definition adapted to the metastases. platin derivative, peripheral neuropathy, current treat- The combinations of oxaliplatin with capecitabine have ment with sorivudin or bivudin and treatment history of shown both, efficacy in mCRC as systemic treatment other cancer or participation in another clinical trial and radiosensitizing potential [9-15], and are therefore within 4 weeks of the start of treatment. Pregnant or lac- suitable from a radiobiological point of view particularly tating patients and women with childbearing potential for the combination with radiotherapy. The application who lacked a reliable contraceptive method were also can be used concurrently with radiotherapy, without in- excluded. creasing toxicity of the chemotherapy or radiotherapy considerly. Study design and treatment Therefore, the purpose of this dose escalation phase I We undertook a prospective, single center phase I study. study was to establish a regimen of local radiotherapy The primary endpoint was to determine the maximal with concurrent standard chemotherapy in oligometa- tolerable dose (MTD) and dose-limiting toxicity (DLT) static colorectal cancer. of chemoradiotherapy with concurrent 3D-radiotherapy to all (max. 3) metastatic lesions. Radiation dose levels Patients and methods of all metastatic leasions were the planned dose levels at The study was conducted according to the principles of 36 Gy, 44 Gy and 50 Gy in 2.0 Gy daily fractions (as the Declaration of Helsinki and to good clinical practice described later, the dose level at 50 Gy was not reached). guidelines. The Ethics Committee, University of Halle, The secondary endpoints included the evaluation of approved this study. Each patient gave written informed antitumor activity of the combined-modality treatment consent before being included. in objective response according to the Response Evalu- ation Criteria In Solid Tumors (RECIST) [16] (rate of Eligibility criteria complete or partial remission), time to progression, The eligibility criteria included histopathologically con- overall survival (one year survival rate) and toxicity. firmed oligometastatic colorectal cancer (1–3 metastases During radiotherapy, capecitabine was administered with largest diameter 5 cm or local recurrens of rectal with a fixed dose (825 mg/m /d orally BID on days 1–14 cancer plus 1–2 metastases of ≤ 5 cm in technically or and 22–35), and oxaliplatin (50 mg/m as 2 h infusion clinically irresectable disease, extention to the recruit- on days 1, 8, 22 and 29). After completion of chemora- ment of patients in a neoadjuvant situation (before diation, systemic treatment could be continued in stand- planned resection). Patients with first-, second- or third- ard dosage (capecitabine 1000 mg/m /d orally BID on line therapy of oligometastatic colorectal cancer were days 1–14 and oxaliplatin 70 mg/m infusional on days eligible for this study in adequate renal, hepatic and 1 and 8). Staging was completed in the third week of the hematologic function. Additional inclusion criteria were third cycle (week 9), and therapy was considered to con- age ≥ 18 years, Karnofsky performance status ≥ 70%, tinue at the physician’s discretion. creatinin clearance> 30 mL/min calculated according to The following recommendations for dose reductions Cockroft and Gault, total bilirubin concentration less were applied: if one patient experienced grade 1 toxicity than 2.5 and transaminases less than 2.5 times the upper (according to National Cancer Institute Common Tox- normal limit with hepatic metastases after image-guided icity Criteria version 3.0) considered to be possibly exclusion of intra- or extrahepatic cholestasis and trans- related to radiation, treatment was continued, with ap- aminases less than 5.0 times the upper normal limit, propriate prophylactic treatment. In case of grade 2 tox- 9 9 neutrophils> 2.5 x 10 /L, platelet count> 125 x 10 /L, icity, radiation treatment was continued for one week at estimated life expectancy of more than 3 months, writ- maximum. If patient experienced any grade 2 toxicity ten informed consent and tumor assessment analyzed for more than one week or more severe intensity, Dellas et al. Radiation Oncology 2012, 7:83 Page 3 of 7 http://www.ro-journal.com/content/7/1/83 radiotherapy was halted for 3–7 days. When toxicity and during follow up every three months. Tumor assess- resolved to grade 1, treatment was resumed, if possible. ment was initiated on the basis of RECIST criteria 1.0 at Interruption or conduction of radiation may be related baseline, within 14 days before the start of treatment, to one or several planning target volumes. In case of re- and after the end of the combined treatment. currence of toxicity while continuing radiation, which would require further discontinuation of radiation ther- Statistical aspects apy (as defined above) radiation of this planning target A modified escalation design with three to six patients volume was permanently discontinued. Radiotherapy was chosen on empiric grounds, according to current was considered to be in accordance with the protocol if standards in phase I cancer trials. According to the ex- at least 80% of the planed dosage for the planning target ploratory nature of this pilot trial, only descriptive statis- volume was applied and therapy was no longer discon- tical methods are used, giving rates, means with SD, and tinued than for 7 days. quartiles and ranges. 3D-CRT technique Results A total irradiation dose of 36 Gy or 44 Gy was delivered A total of nine patients were enrolled (seven male and two in 2.0 Gy daily fractions, Monday through Friday. In this female patients between 50 and 74 years of age) into the protocol, high-energy photons (6 to 15 MeV) were used study at Halle University between September 2004 and Au- and three-dimensional planning with measurements of gust 2007 (Table 1). Before including into the study, six macroscopic tumor, planning target volume and organs patients had been previously treated with radiotherapy at at risk were mandatory. All lesions had to be defined by other sites, and all of the nine patients received previously computed tomography clearly. The clinical target vol- chemotherapy and surgery. In three patients, systemic pre- ume (CTV) was the GTV of each lesion. Planning target treatment was administered as capecitabine and oxaliplatin, volume contained all detectable metastases was derived one patient received capecitabine, oxaliplatin, 5-FU and leu- by adding a margin of 10 mm to account the CTV for covorin, one patient received 5-FU and leucovorin, one pa- the setup uncertainties. It was required that the 90%- tient received 5-FU and oxaliplatin, one patient was treated isodose line covered the planning target volume. Two with 5-FU, leucovorin, oxaliplatin and irinotecan, one pa- metastatic lesions could be integrated into one planning tient was treated with 5-FU, leucovorin, capecitabine, oxali- target volume if they were located close to each other. platin, irinotecan and cetuximab and one patient received 5-FU, leucovorin, irinotecan and bevacizumab. Issued by Evaluation of safety and efficacy the criteria for inclusion the metastatic lesions were not Adverse events were graded to National Cancer Institute of Canada (NCIC) Common Toxicity Criteria (CTC) Table 1 Characteristics of patients (revised in May 1991). Dose-limiting toxicity (DLT) was Dose level 1 Dose level 2 Total defined as the occurrence of any grade three and four n=6 n=3 n=9 toxicity, except alopecia, hematologic toxicity and transi- Sex ent elevation of transaminases. Within the three dose Male 4 3 7 levels, dose escalation of radiation was performed with Female 2 - 2 the same dose of chemotherapy. According to potentially Age, years different toxicity at different sites of metastatic lesions, modified rules for escalation were used: Three patients MW 63.2 65.3 63.9 had to be enrolled per predefined dose level. If there was SD 10.1 5.0 8.4 no DLT in the first three patients, the cohort was Karnofsky performance status (%) extended by another three patients at the same dose MW 93.3 96.7 94.4 level, to obtain sufficient safety profile associated with SD 8.2 5.8 7.3 different toxicity depending on multiple metastatic Pathologic staging (at the time of accrural) lesions. The safety analysis included all patients who received TT0 4 3 7 at least one dose (one day) of radiation and chemother- T4 2 - 2 apy. All adverse events were monitored continuously NN0 5 3 8 during treatment and observed until decreasing or N1 1 - 1 stabilization of symptoms. Hematology and clinical MM0 1 - 1 chemistry was performed weekly during treatment and M1 5 3 8 thereafter during chemotherapy weekly, respectively after every third cycle, after the end of chemotherapy MW: Mean, SD: Standard deviation. Dellas et al. Radiation Oncology 2012, 7:83 Page 4 of 7 http://www.ro-journal.com/content/7/1/83 Table 2 Incidence and maximum severity of toxicities Table 2 Incidence and maximum severity of toxicities (MedDRA classification) (MedDRA classification) (Continued) Dose level 1 Dose level 2 Investigations CTC grade 1/2 3 4 1/2 3 1/234 Blood amylase increased 1 0 0 0 0 1 00 MedDRA Code (n = 9 events) No. of Patients Blood bilirubin increased 2 0 0 3 0 5 00 Infections and infestations Blood pressure increased 0 0 0 2 0 2 00 Infection 0 2 0 0 0 0 20 Blood urea increased 1 0 0 0 0 1 00 Immune system disorders Blood urea decreased 0 0 0 2 0 2 00 Anaphylactic reaction 0 0 1 0 0 0 01 C-reactive protein increased 4 0 0 1 0 5 00 Nervous system disorders Blood fibrinogen increased 1 0 0 0 0 1 00 Peripheral sensory neuropathy 2 0 0 1 0 3 00 Gamma-glutamyltransferase increased 4 0 0 1 1 5 10 Eye disorders Blood glucose increased 0 0 0 1 0 1 00 Conjunctival haemorrhage 1 0 0 0 0 1 00 Haemoglobin decreased 4 0 0 2 0 6 00 Vision blurred 1 0 0 0 0 1 00 Blood uric acid increased 1 0 0 0 0 1 00 Disorder sight 1 0 0 0 0 1 00 Blood calcium decreased 3 0 0 2 0 5 00 Abnormal sensation in eye 1 0 0 0 0 1 00 Blood creatinine increased 3 0 0 1 0 4 00 Vascular disorders Blood lactate dehydrogenase increased3 0 0 1 0 4 00 Flushing 2 0 0 0 0 2 00 WBC count increased 1 0 0 0 0 1 00 Hypotension 1 0 0 1 0 2 00 WBC count decreased 1 1 0 2 0 3 10 Thrombophlebitis 1 0 0 0 0 1 00 Platelets decreased 3 0 0 2 0 5 00 Respiratory, thoracic and mediastinal disorders Transaminases increased 2 0 0 3 0 5 00 Dyspnoea 0 1 0 0 0 0 10 Gastrointestinal disorders Abdominal pain 0 0 0 1 0 1 00 restricted to the liver. The number of metastatic lesions Abdominal distension 1 0 0 0 0 1 00 was a single lesion in four patients, two lesions in two patients and three lesions in three patients (a total of 17 Vomiting 0 0 0 1 0 1 00 lesions in 9 patients). In seven patients the lesion was Obstipation 2 0 0 0 0 2 00 located in the liver and two patients had a non-liver-lesion Mucous stools 1 0 0 0 0 1 00 (vulva and local recurrence presacral). Nausea 3 0 0 2 0 5 00 Abdominal discomfort 1 0 0 0 0 1 00 Dose escalation and DLT Epigastric discomfort 0 0 0 1 0 1 00 Initially, three patients were treated at the lowest dose Skin and subcutaneous tissue disorders level of radiation (36 Gy), without dose-limiting toxicity. According to the study protocol, three additional patients Dermatitis 1 0 0 2 0 3 00 were included at this dose level. Therefore, six patients Musculoskeletal and connective tissue disorders were treated at the lowest dose level one and three Bone pain 1 0 0 0 0 1 00 patients at dose level two (44 Gy). The fourth patient Myalgia 1 0 0 0 0 1 00 from the first cohort experienced a non-radiotherapy Pain in extremity 1 0 0 0 0 1 00 related DLT (oxaliplatin-related hypersensitivity reac- Renal and urinary disorders tion). There was no DLT in the three patients treated in the second cohort until the premature termination. No Bladder discomfort 2 0 0 0 0 2 00 radiation-induced DLT occurred. The dosage finding General disorders and administration site conditions remained incomplete and MTD could not be deter- Injection site erythema 0 0 0 1 0 1 00 mined. The trial had to be closed due to recruitment fail- Pyrexia 1 0 0 1 0 2 00 ure. There were no safety-related concerns regarding the Injection site paraesthesia 0 0 0 1 0 1 00 premature trial termination. Mucosal inflammation 1 0 0 0 0 1 00 Pain 3 1 0 1 0 4 10 Hematologic and non-hematologic toxicity Adverse events according to MedDRA Code CTC sever- Chills 1 0 0 1 0 2 00 ity grade by body/organ system are presented for the Dellas et al. Radiation Oncology 2012, 7:83 Page 5 of 7 http://www.ro-journal.com/content/7/1/83 whole patients group (Table 2). The only grade 4 toxicity consisting of 3D-radiotherapy of all metastatic lesions was oxaliplatin-related hypersensitivity reaction (one pa- with a concurrently administered standard systemic tient in cohort one), consecutively classified as DLT. therapy with capecitabine and oxaliplatin (XELOX regi- Four patients experienced grade 3 toxicity, three patients men) [17,18]. The primary objective of this study was to from the first cohort and one patient from the second determine the maximal tolerable dose (MTD) of local dose level. In the three patients at dose level one, grade radiotherapy combined with standard chemotherapy. 3 toxicities occurred (infection, dyspnea, pain and leuco- The study used conventionally fractionated radiotherapy cytopenia). Grade 3 toxicity with increasead liver under the assumption that this treatment is widely avail- enzymes was documented in one patient at dose level able, safe and effective as known from preoperative two. No instance of radiation-induced liver disease radiotherapy in locally advanced rectal cancer. (RILD) has been observed. Most commonly, local disease control can be assessed Further hematologic and non-hematologic toxicity was by pathohistological response, which is likely correlated usually mild (grade 1 and 2). Five patients showed any with relapse free suvival after 5-FU based chemora- increased levels of blood bilirubin, transaminases and C- diotherapy. Pathological complete response (pCR) rates reactive protein, six patients an elevation of gamma- following fluoropyrimidine based chemoradiation have glutamyltransferase and four patients of lactate dehydro- been reported in 15-20% of patients. Many phase II trials genase. Low hemoglobin as well as low platelet counts indicate, that the rate of pathohistologic response (pCR) were seen in six and five patients, respectively. of the local tumor may be improved by adding highly ef- Gastrointestinal toxicities occurred in five patients con- fective substances like oxaliplatin, combined with 5-FU sisting primarily of nausea and in two patients with ab- or capecitabine - an emerging strategy in the multimod- dominal and epigastric discomfort. Furthermore, ality management of locally advanced rectal cancer [19]. dermatitis was recorded in three patients. In preoperative chemoradiation for localized rectal can- cer, phase II and III trials have shown that the combin- Antitumor activity ation of radiation with capecitabine and oxaliplatin Secondary endpoint was the objective tumor response, shows moderately high rates of histopathological eradi- defined as the rate of complete or partial remission. A cation of the tumor. Data of phase II trials suggests a total of seventeen lesions in nine patients were irra- pCR rate up to the above mentioned 20%, whereas rates diated. Six of nine patients achieved tumor response in phase III trials only showed “borderline” significant (partial remission), for two patients adequate data were improvement [12-15]. The arguments for a regimen of not assessable. Disease progression after one year oc- chemoradiation, based on capecitabine, oxaliplatin and curred in three patients (two patients from the first co- radiation, are the efficacy of the chemoradiation, radio- hort, one patient from the second cohort). The first sensitizing potential and the approved feasibility of the patient from the first cohort developed new liver metas- mentioned combined regimen in terms of systemic ac- tases and distant metastases (lung lesions). For the sec- tivity. However, the final prove of effectiveness of adding ond patient from the first cohort and the patient from oxaliplatin to the preoperative therapy is still under in- the second cohort with progressive disease adequate vestigation, but reported preliminary results from phase data were not available. One year after initiation, all III trials, the French ACCORD study [12], the Italian patients were still alive. Within the following year, three STAR-01 study [15] as well as the US NSABP R-04 trial patients died from tumor progression (14 to 23 months [14] did not show a significant increased rate of pCR´s, after initiation). At the time of last evaluation four and in the German phase III trial, only a small incre- patients had survived (16 to 54 months after initiation, ment was documented [13]. It has to be shown, whether Table 3). these results impact on lead to improved local failure or distant metastases. Discussions We aimed to evaluate the efficacy and feasibility of We conducted this phase I trial as a multimodal regimen adding capecitabine and oxaliplatin, administered at for patients with oligometastatic colorectal cancer, fixed doses according to a schedule previously developed Table 3 Parameters for survival Dosis 1 Dosis 2 Survived Lost to Follow up Survived Lost to Follow up Survived Lost to Follow up 1 year 6 0 3 0 9 0 3 years 3 0 0 3 3 3 One year after initiation all patients were alive, three patients had died of tumor progression within the following three years. Dellas et al. Radiation Oncology 2012, 7:83 Page 6 of 7 http://www.ro-journal.com/content/7/1/83 in rectal cancer [17,18], in addition to dose escalation of after resection of colorectal liver metastases defines cure. J Clin Oncol 2007, 25(29):4575–80. radiation of multiple metastatic lesions in patients with 3. Fokas E, Henzel M, Hamm K, Surber G, Kleinert G, Engenhart-Cabillic R: mCRC. Radiotherapy for brain metastases from renal cell cancer: should whole- There are several limitations of the study with respect brain radiotherapy be added to stereotactic radiosurgery?: analysis of 88 patients. Strahlenther Onkol 2010, 186(4):210–7. to the efficacy caused by the inhomogenous characteris- 4. Freundt K, Meyners T, Bajrovic A, Basic H, Karstens JH, Adamietz IA, Rudat V, tics of patients, the patients (pre)treatment with the Schild SE, Dunst J, Rades D: Radiotherapy for oligometastatic disease in first-, second- or third-line therapy and incomplete in- patients with spinal cord compression (MSCC) from relatively radioresistant tumors. Strahlenther Onkol 2010, 186(4):218–23. formation of local lesions and distant metastases of 5. Heisterkamp C, Haatanen T, Schild SE, Rades D: Dose escalation in patients patients with progressive disease. receiving whole-brain radiotherapy for brain metastases from colorectal Notwithstanding the trial had to be closed due to re- cancer. Strahlenther Onkol 2010, 186(2):70–5. 6. Rades D, Kueter JD, Hornung D, Veninga T, Hanssens P, Schild SE, Dunst J: cruitment failure, and the small sample size limits con- Comparison of stereotactic radiosurgery (SRS) alone and whole brain clusions. However, the data are promising with regard to radiotherapy (WBRT) plus a stereotactic boost (WBRT+SRS) for one to the results of the present trial and should stimulate more three brain metastases. Strahlenther Onkol 2008, 184(12):655–62. 7. Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg intense investigations to establish the best treatment SJ, Chidel MA, Pugh TJ, Franklin W, Kane M, Gaspar LE, Schefter TE: regimens to obtain better approaches in the therapy of Multi-institutional phase I/II trial of stereotactic body radiation therapy oligometastatic colorectal cancer. Moreover, more for liver metastases. J Clin Oncol 2009, 27(10):1572–8. 8. Rusthoven KE, Kavanagh BD, Burri SH, Rusthoven KE, Kavanagh BD, Burri SH, advanced radiotherapy techniques (e.g. IGRT, stereotac- Chen C, Cardenes H, Chidel MA, Pugh TJ, Kane M, Gaspar LE, Schefter TE: tic radiotherapy and radiosurgery) are now widely avail- Multi-institutional phase I/II trial of stereotactic body radiation therapy able and 3D-CRT is not considered as contemporary for lung metastases. J Clin Oncol 2009, 27(10):1579–84. 9. Gerard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, standard for radiotherapy to metastatic lesions in a po- Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz tentially curative setting. Nevertheless, our results might R, Ducreux M, Bedenne L: Preoperative radiotherapy with or without be helpful because they demonstrate the feasibility of a concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006, 24(28):4620–5. concurrent chemoradiotherapy approach in this subset 10. Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, of patients and there are so far few data on the question Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N: Preoperative of sequencing local and systemic therapy in metastatic multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009, 27(31):5124–30. patients. 11. Hofheinz R, Wenz FK, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler MH, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald Conclusions M, Kremers S, Constantin C, Hipp M, Gencer D, Burkholder I, Hochhaus A: Capecitabine (Cape) versus 5-fluorouracil (5-FU)–based (neo)adjuvant The results of this phase I study support the use of local chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): radiotherapy to metastatic lesions in addition to concur- Long-term results of a randomized, phase III trial. J Clin Oncol 2011, rent standard chemotherapy as an effective and feasible 29:3504. 12. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, therapeutic option in patients with oligometastatic colo- Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, rectal cancer. Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Montoto-Grillot C, Conroy T: Comparison of two neoadjuvant chemoradiotherapy regimens for locally Competing interests advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige The authors declare no conflicts of interest. 2. JClinOncol 2010, 28(10):1638–44. 13. Roedel C, Becker H, Fietkau R, Graeven U, Hohenberger W, Hothorn T, Lang- Author details Welzenbach M, Liersch T, Staib L, Christiansen H, Wittekind C, Sauer R: North European Radiooncological Center Kiel (NRoCK), Kiel, Germany. Preoperative chemoradiotherapy and postoperative chemotherapy with 5- Department of Radiooncology, University of Lübeck, Lübeck, Germany. fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced Department of Radiotherapy, Martin Luther University Halle-Wittenberg, rectal cancer: First results of the German CAO/ARO/AIO-04 randomized phase Halle (Saale), Germany. Coordination Center for Clinical Trials, Halle (Saale), III trial. JClinOncol 2011, 29:3505. Germany. Hubertus Wald Tumor Center, University Comprehensive Cancer 14. Roh MS, Yothers GA, O'Connell MJ, Beart RW, Pitot HC, Shields AF, Parda DS, Center Hamburg-Eppendorf (UCCH), Hamburg, Germany. Sharif S, Allegra CJ, Petrelli NJ, Landry JC, Ryan DP, Arora A, Evans TL, Soori GS, Chu L, Landes RV, Mohiuddin M, Lopa S, Wolmark N: The impact of Authors’ contribution capecitabine and oxaliplatin in the preoperative multimodality treatment in KD, MR, DA and JD designed and supervised the study. KD, TR, DA and JD patients with carcinoma of the rectum: NSABP R-04. JClin Oncol 2011, 29:3503. responsible for therapy and data collection. MR collected data and did 15. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, statistical analyses. 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Strahlenther Onkol 2007, 183 (5):227–35. doi:10.1186/1748-717X-7-83 Cite this article as: Dellas et al.: Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study. Radiation Oncology 2012 7:83. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

Journal

Radiation OncologySpringer Journals

Published: Jun 9, 2012

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