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Marotta C, Cirri D, Kanavos I, Ronga L, Lobinski R, Funaioli T, Giacomelli C, Barresi E, Trincavelli ML, Marzo T, Pratesi A. Oxaliplatin(IV) Prodrugs Functionalized with Gemcitabine and Capecitabine Induce Blockage of Colorectal Cancer Cell Growth-An Investigation of the Activation Mechanism and Their Nanoformulation. Pharmaceutics 2024; 16:278. [PMID: 38399332 PMCID: PMC10892879 DOI: 10.3390/pharmaceutics16020278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs. The design, synthesis, and characterization of two novel Pt(IV) prodrugs based on oxaliplatin bearing the anticancer drugs gemcitabine or capecitabine in the axial positions have been reported. These complexes were able to dissociate into their constituents to promote cell death and induce apoptosis and cell cycle blockade in a representative colorectal cancer cell model. Specifically, the complex bearing gemcitabine resulted in being the most active on the HCT116 colorectal cancer cell line with an IC50 value of 0.49 ± 0.04. A pilot study on the encapsulation of these complexes in biocompatible PLGA-PEG nanoparticles is also included to confirm the retention of the pharmacological properties and cellular drug uptake, opening up to the possible delivery of the studied complexes through their nanoformulation.
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Affiliation(s)
- Carlo Marotta
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
| | - Damiano Cirri
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
| | - Ioannis Kanavos
- Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France; (I.K.); (L.R.); (R.L.)
| | - Luisa Ronga
- Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France; (I.K.); (L.R.); (R.L.)
| | - Ryszard Lobinski
- Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France; (I.K.); (L.R.); (R.L.)
| | - Tiziana Funaioli
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
| | - Chiara Giacomelli
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (E.B.); (M.L.T.); (T.M.)
| | - Elisabetta Barresi
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (E.B.); (M.L.T.); (T.M.)
| | | | - Tiziano Marzo
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (E.B.); (M.L.T.); (T.M.)
| | - Alessandro Pratesi
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
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Marotta C, Giorgi E, Binacchi F, Cirri D, Gabbiani C, Pratesi A. An overview of recent advancements in anticancer Pt(IV) prodrugs: New smart drug combinations, activation and delivery strategies. Inorganica Chim Acta 2023. [DOI: 10.1016/j.ica.2023.121388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Lupattelli M, Bellavita R, Natalini G, Giovenali P, Sidoni A, Castagnoli P, Corgna E, Draghini L, Trippolini R, Aristei C. Oxaliplatin with Raltitrexed and Preoperative Radiotherapy in T3-T4 Extraperitoneal Rectal Cancer. A Dose Finding Study. TUMORI JOURNAL 2019; 92:474-80. [PMID: 17260486 DOI: 10.1177/030089160609200602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and background The availability of new drugs offers the opportunity to improve the outcome of locally advanced rectal cancer. Raltitrexed and oxaliplatin are effective in advanced colorectal cancer with acceptable toxicity and can act as radiation enhancers as shown in phase 1-11 studies. The aim of the study was thus to determine the recommended dose of oxaliplatin concomitantly administered with raltitrexed and concurrent preoperative radiotherapy in patients with stage 11-111 extraperitoneal rectal cancer. Methods From September 2001 to September 2002, 18 consecutive patients with T3/T4 rectal cancer were treated at our Institution with preoperative chemoradiation followed by surgery after 6-8 weeks. Pelvic radiotherapy was delivered at a dose of 45 Gy in 25 fractions in 5 weeks followed by a 5.4 Gy boost at 1.8 Gy daily. Concomitant chemotherapy consisted of 3 mg/m2/iv of raltitrexed on days 1, 19, 38 of radiotherapy treatment with incremental doses of oxaliplatin according to dose finding rules (4 dose levels: 65, 85, 110, 130 mg/m2). Dose-limiting toxicity for oxaliplatin was defined as either grade 3-4 hematological or grade 3-4 gastrointestinal or neurological toxicity. We studied a minimum of 3 patients at each dose level. Results Three patients were treated at 65, 85, and 110 mg/m2/iv, respectively, while 9 patients were recruited at the last dose level. Neither grade 3-4 gastrointestinal nor neurological toxicity were documented. Dose-limiting toxicity was documented in 2/9 subjects at the 130 mg/m2 level consisting of grade 3 transient asymptomatic leukopenia. Thirteen patients developed transient increase of one or more liver enzymes (grade 3-4) and 2 patients developed grade 3 perineal dermatitis. All patients received the programmed dose of radiotherapy. The chemotherapy regimen was not completed in 4 cases due to grade 2 protracted leukopenia. Conclusions The maximum tolerated dose of oxaliplatin was not reached at the maximum dose level (IV); 130 mg/m2 can therefore be defined as the recommended dose. The combination of oxaliplatin with raltitrexed and radiotherapy can be considered feasible and well tolerated.
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Affiliation(s)
- Marco Lupattelli
- Radiation Oncology Center, University and Hospital of Perugia, Perugia, Italy.
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Puri T, Greenhalgh TA, Wilson JM, Franklin J, Wang LM, Strauss V, Cunningham C, Partridge M, Maughan T. [ 18F]Fluoromisonidazole PET in rectal cancer. EJNMMI Res 2017; 7:78. [PMID: 28933018 PMCID: PMC5607050 DOI: 10.1186/s13550-017-0324-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 08/29/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND There is an increasing interest in developing predictive biomarkers of tissue hypoxia using functional imaging for personalised radiotherapy in patients with rectal cancer that are considered for neoadjuvant chemoradiotherapy (CRT). The study explores [18F]fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) scans for predicting clinical response in rectal cancer patients receiving neoadjuvant CRT. METHODS Patients with biopsy-proven rectal adenocarcinoma were imaged at 0-45 min, 2 and 4 h, at baseline and after 8-10 fractions of CRT (week 2). The first 6 patients did not receive an enema (the non-enema group) and the last 4 patients received an enema before PET-CT scan (the enema group). [18F]FMISO production failed on 2 occasions. Static PET images at 4 h were analysed using tumour-to-muscle (T:M) SUVmax and tumour-to-blood (T:B) SUVmax. The 0-45 min dynamic PET scans were analysed using Casciari model to report hypoxia and perfusion. Akaike information criteria (AIC) were used to compare data fittings for different pharmacokinetic models. Pathological tumour regression grade was scored using American Joint Committee on Cancer (AJCC) 7.0. Shapiro-Wilk test was used to evaluate the normality of the data. RESULTS Five out of eleven (5/11) patients were classed as good responders (AJCC 0/1 or good clinical response) and 6/11 as poor responders (AJCC 2/3 or poor clinical response). The median T:M SUVmax was 2.14 (IQR 0.58) at baseline and 1.30 (IQR 0.19) at week 2, and the corresponding median tumour hypoxia volume was 1.08 (IQR 1.31) cm3 and 0 (IQR 0.15) cm3, respectively. The median T:B SUVmax was 2.46 (IQR 1.50) at baseline and 1.61 (IQR 0.14) at week 2, and the corresponding median tumour hypoxia volume was 5.68 (IQR 5.86) cm3 and 0.76 (IQR 0.78) cm3, respectively. For 0-45 min tumour modelling, the median hypoxia was 0.92 (IQR 0.41) min-1 at baseline and 0.70 (IQR 0.10) min-1 at week 2. The median perfusion was 4.10 (IQR 1.71) ml g-1 min-1 at baseline and 2.48 (IQR 3.62) ml g-1 min-1 at week 2. In 9/11 patients with both PET scans, tumour perfusion decreased in non-responders and increased in responders except in one patient. None of the changes in other PET parameters showed any clear trend with clinical outcome. CONCLUSIONS This pilot study with small number of datasets revealed significant challenges in delivery and interpretation of [18F]FMISO PET scans of rectal cancer. There are two principal problems namely spill-in from non-tumour tracer activity from rectal and bladder contents. Emphasis should be made on reducing spill-in effects from the bladder to improve data quality. This preliminary study has shown fundamental difficulties in the interpretation of [18F]FMISO PET scans for rectal cancer, limiting its clinical applicability.
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Affiliation(s)
- Tanuj Puri
- CRUK/MRC Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ UK
| | - Tessa A. Greenhalgh
- CRUK/MRC Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ UK
| | - James M. Wilson
- CRUK/MRC Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ UK
| | - Jamie Franklin
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Lia Mun Wang
- Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Present address: Department of Laboratory Medicine, Changi General Hospital, 2 Simei Street 3, Singapore, Singapore
| | - Victoria Strauss
- Centre for Statistics in Medicine, Oxford Clinical Trial Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK
| | - Chris Cunningham
- Department of Colorectal Surgery, Cancer Centre, Churchill Hospital, Oxford, University Hospitals NHS Foundation Trust, Oxford, UK
| | - Mike Partridge
- CRUK/MRC Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ UK
| | - Tim Maughan
- CRUK/MRC Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ UK
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Jones RG, Tan D. How can we determine the best neoadjuvant chemoradiotherapy regimen for rectal cancer? COLORECTAL CANCER 2015. [DOI: 10.2217/crc.15.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY The current management of patients with clinically defined ‘locally advanced rectal cancer’ often involves fluoropyrimidine-based preoperative chemoradiotherapy (CRT) followed by total mesorectal excision. The focus remains primarily on reducing local recurrence, and improving survival, with organ preservation an increasing target. The best neoadjuvant CRT is the most effective regimen, balanced against the tolerability and late functional consequences, which should be selected for the individual according to their individual risk of local and distant recurrence. Hence, what makes the best neoadjuvant treatment depends on the activity and toxicity of the particular schedule, the aims of treatment, the individual disease characteristics and the individual patient pharmacogenomics. Current research efforts focus on enhancing the efficacy of CRT by integrating additional cytotoxics and biologically targeted agents.
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Affiliation(s)
- Rob Glynne Jones
- Consultant Radiation Oncologist, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, HA6 2RN, UK
| | - David Tan
- Radiation Oncologist, FRCR, Consultant Radiation Oncologist, National Cancer Centre, Singapore
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Verwer EE, Boellaard R, Veldt AAMVD. Positron emission tomography to assess hypoxia and perfusion in lung cancer. World J Clin Oncol 2014; 5:824-844. [PMID: 25493221 PMCID: PMC4259945 DOI: 10.5306/wjco.v5.i5.824] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 04/29/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed.
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Michael M, Chander S, McKendrick J, MacKay JR, Steel M, Hicks R, Heriot A, Leong T, Cooray P, Jefford M, Zalcberg J, Bressel M, McClure B, Ngan SY. Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer. Br J Cancer 2014; 111:1924-31. [PMID: 25211659 PMCID: PMC4229632 DOI: 10.1038/bjc.2014.487] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 07/29/2014] [Accepted: 08/13/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. METHODS Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. RESULTS Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. CONCLUSIONS Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.
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Affiliation(s)
- M Michael
- Division of Cancer Medicine, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Melbourne, Victoria, Australia
| | - S Chander
- Division of Radiation Oncology, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - J McKendrick
- Department of Medical Oncology, Box Hill Hospital, Melbourne, Victoria, Australia
| | - J R MacKay
- Division of Surgical Oncology, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - M Steel
- Department of Surgery, Box Hill Hospital, Melbourne, Victoria, Australia
| | - R Hicks
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Melbourne, Victoria, Australia
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A Heriot
- Division of Surgical Oncology, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - T Leong
- Division of Radiation Oncology, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - P Cooray
- Department of Medical Oncology, Box Hill Hospital, Melbourne, Victoria, Australia
| | - M Jefford
- Division of Cancer Medicine, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Melbourne, Victoria, Australia
| | - J Zalcberg
- Division of Cancer Medicine, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - M Bressel
- Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - B McClure
- Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - S Y Ngan
- Division of Radiation Oncology, Lower Gastrointestinal Tumour Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Retrospective comparative study of the effects of dendritic cell vaccine and cytokine-induced killer cell immunotherapy with that of chemotherapy alone and in combination for colorectal cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:214727. [PMID: 25210706 PMCID: PMC4151605 DOI: 10.1155/2014/214727] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 07/20/2014] [Accepted: 08/05/2014] [Indexed: 12/13/2022]
Abstract
Purpose. This retrospective study determined the delayed-type hypersensitivity (DTH) skin test and safety of dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell immunotherapy and the survival compared to chemotherapy in 239 colorectal cancer (CRC) patients. Methods. DTH and safety of the immunotherapy were recorded. The overall survival (OS) and disease free survival curves were compared according to the immunotherapy and/or chemotherapy received with Kaplan-Meier estimates. Results. Of the 70 patients who received immunotherapy, 62.86% had a positive DTH skin test, 38.57% developed fever, 47.14% developed insomnia, 38.57% developed anorexia, 4.29% developed joint soreness, and 11.43% developed skin rash. For 204 resectable CRC patients, median survival time (MST) (198.00 days) was significantly longer in patients with immunotherapy plus chemotherapy than with chemotherapy alone (106.00 days) (P = 0.02). For 35 patients with unresectable or postsurgery relapsed CRC and who were confirmed to be dead, no statistical difference was observed in the MST between the patients treated with immunotherapy and with chemotherapy (P = 0.41). MST in the patients treated with chemotherapy plus immunotherapy was 154 days longer than that of patients treated with chemotherapy alone (P = 0.41). Conclusions. DC vaccination and CIK immunotherapy did not cause severe adverse effects, induce immune response against CRC, and prolong OS.
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Kelada OJ, Carlson DJ. Molecular imaging of tumor hypoxia with positron emission tomography. Radiat Res 2014; 181:335-49. [PMID: 24673257 DOI: 10.1667/rr13590.1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The problem of tumor hypoxia has been recognized and studied by the oncology community for over 60 years. From radiation and chemotherapy resistance to the increased risk of metastasis, low oxygen concentrations in tumors have caused patients with many types of tumors to respond poorly to conventional cancer therapies. It is clear that patients with high levels of tumor hypoxia have a poorer overall treatment response and that the magnitude of hypoxia is an important prognostic factor. As a result, the development of methods to measure tumor hypoxia using invasive and noninvasive techniques has become desirable to the clinical oncology community. A variety of imaging modalities have been established to visualize hypoxia in vivo. Positron emission tomography (PET) imaging, in particular, has played a key role for imaging tumor hypoxia because of the development of hypoxia-specific radiolabelled agents. Consequently, this technique is increasingly used in the clinic for a wide variety of cancer types. Following a broad overview of the complexity of tumor hypoxia and measurement techniques to date, this article will focus specifically on the accuracy and reproducibility of PET imaging to quantify tumor hypoxia. Despite numerous advances in the field of PET imaging for hypoxia, we continue to search for the ideal hypoxia tracer to both qualitatively and quantitatively define the tumor hypoxic volume in a clinical setting to optimize treatments and predict response in cancer patients.
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Affiliation(s)
- Olivia J Kelada
- a Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut; and
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Li YH, Li XF, Li JL, Zhu XG, Xu B, Cai Y. Therapeutic effect of postoperative radiotherapy in combination with oxaliplatin and 5-Fu in patients with stage II/III rectal cancer. Shijie Huaren Xiaohua Zazhi 2013; 21:729. [DOI: 10.11569/wcjd.v21.i8.729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Hypoxia-related proteins in patients with rectal cancer undergoing neoadjuvant combined modality therapy. Dis Colon Rectum 2012; 55:990-5. [PMID: 22874607 DOI: 10.1097/dcr.0b013e31825bd80c] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND We have previously demonstrated the prognostic significance of rectal cancer pathologic response to neoadjuvant chemoradiation. Recent studies in other cancers have reported that hypoxia influences response to neoadjuvant chemoradiation. OBJECTIVE This study aimed to 1) characterize hypoxia-related protein expression in locally advanced rectal cancer before neoadjuvant chemoradiation, 2) determine the comodulation of hypoxia-related protein expression, and 3) evaluate the relationship between hypoxia-related protein expression and overall survival, time to recurrence, and tumor regression grade. DESIGN Immunohistochemical analysis of 4 hypoxia-related proteins (HIF-1α, CA-IX, VEGF, and GLUT-1) was performed on archival pretreatment rectal cancer biopsies. PATIENTS : Eighty-five patients with locally advanced rectal cancer treated with neoadjuvant radiation and 5-fluorouracil-based chemotherapy were included. MAIN OUTCOME MEASURES The impact of hypoxia-related protein expression on outcome was evaluated by use of Cox proportional hazards model. Hypoxia-related protein expression was correlated with tumor regression grade by use of Spearman correlation coefficients. RESULTS Median follow-up was 54 months. CA-IX expression was associated with overall survival (p = 0.01). HIF-1α expression was weakly correlated with VEGF (r = 0.26, p = 0.02) and GLUT-1 (r = 0.35, p = 0.001). Hypoxia-related protein expression was not associated with time to recurrence or Mandard tumor regression grade. CONCLUSIONS Elevated CA-IX expression may be associated with poorer overall survival in locally advanced rectal cancer treated by neoadjuvant chemoradiation and resection. The expression of the hypoxia-related proteins HIF-1α, VEGF, and GLUT-1 may be comodulated in locally advanced rectal cancer. Further studies are needed to evaluate the mechanisms governing hypoxia regulation and the role of hypoxia in rectal cancer response to neoadjuvant chemoradiation.
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Hill EJ, Nicolay NH, Middleton MR, Sharma RA. Oxaliplatin as a radiosensitiser for upper and lower gastrointestinal tract malignancies: what have we learned from a decade of translational research? Crit Rev Oncol Hematol 2012; 83:353-87. [PMID: 22309673 DOI: 10.1016/j.critrevonc.2011.12.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Revised: 12/14/2011] [Accepted: 12/28/2011] [Indexed: 01/08/2023] Open
Abstract
Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies should be designed, the pre-clinical evidence for the use of oxaliplatin chemotherapy as a radiosensitising agent is appraised. Particular focus is placed on oxaliplatin's biological mechanisms of action, including cell cycle effects, the formation of DNA adducts and interstrand cross-links and the role of DNA repair proteins. At a clinical level, there is currently no evidence to suggest that oxaliplatin provides an additional benefit to concurrent chemo-radiation regimes that utilise fluoropyrimidines; we evaluate the reasons for this observation, the limitations of clinical trial design and the opportunities that currently exist to design clinical trials which are underpinned by an understanding of the basic biology.
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Affiliation(s)
- Esme J Hill
- Gray Institute of Radiation Oncology and Biology, Oncology Department, Old Road Campus Research Building, Oxford OX3 7DQ, UK
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Bellomi M, Travaini LL. Imaging as a surveillance tool in rectal cancer. Expert Rev Med Devices 2010; 7:99-112. [PMID: 20021242 DOI: 10.1586/erd.09.63] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Despite advances in diagnosis and treatment, half of patients with treated rectal cancer will die owing to recurrent disease. There is no evidence of benefit on survival from an intensive surveillance program, even if presymptomatic recurrent disease is detected. The aim of this article is to review the results described for the different imaging techniques in diagnosing rectal cancer recurrence in different sites and to discuss their relative clinical impact. The sensitivity of imaging techniques is related to the performance of the machines and the site being examined. Computed tomography is the most used technique owing to its availability, speed, panoramic images and ease of use, while MRI of the pelvis and the liver produces the highest resolution, sensitivity and specificity in these anatomical areas. Owing to its high cost, [(18)F] fluorodeoxyglucose-PET should be used as a third-level examination, a 'problem-solving' method when the site of recurrence is unknown or to rule out other possible sites of recurrence before a second surgery, and, finally, because it offers the possibility to investigate the whole body. The follow-up must be designed for individual patients, taking into account a number of factors. In the near future, whole-body imaging, probably by MRI, that is free from radiation will become the method of choice for screening for recurrent disease.
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Affiliation(s)
- Massimo Bellomi
- Department of Radiology and School of Medicine, University of Milano, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
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Affiliation(s)
- Rodney J Hicks
- Centre for Molecular Imaging, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
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Kapse N, Goh V. Functional imaging of colorectal cancer: positron emission tomography, magnetic resonance imaging, and computed tomography. Clin Colorectal Cancer 2009; 8:77-87. [PMID: 19423500 DOI: 10.3816/ccc.2009.n.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In the past 10 years, overall survival and disease-free survival of patients with colorectal cancer (CRC) has improved substantially because of a combination of factors: (1) more accurate staging as a result of advances in imaging technology; (2) refinements in surgical technique; (3) 'curative' metastasectomy for patients with limited metastatic disease; (4) improvements in radiation therapy planning and greater precision of radiation therapy delivery; and (5) increasing chemotherapeutic options, including antiangiogenic and vascular targeting drugs. In this era of 'personalized medicine,' the increasingly individualized treatment of patients with CRC has highlighted the need for functional imaging techniques in addition to conventional anatomic-based imaging. This review discusses the contribution of positron emission tomography to the clinical management of CRC. In addition, evolving techniques such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), DCE computed tomography (perfusion CT), diffusion-weighted MRI, and blood oxygenation level-dependent MRI that might have a future role will be covered.
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Affiliation(s)
- Nikhil Kapse
- The Paul Strickland Scanner Centre, The Cancer Centre, Mount Vernon Hospital, Northwood, UK
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Roels S, Slagmolen P, Nuyts J, Lee JA, Loeckx D, Maes F, Stroobants S, Penninckx F, Haustermans K. Biological image-guided radiotherapy in rectal cancer: is there a role for FMISO or FLT, next to FDG? Acta Oncol 2008; 47:1237-48. [PMID: 18654902 DOI: 10.1080/02841860802256434] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The purpose of this study is to investigate the use of PET/CT with fluorodeoxyglucose (FDG), fluorothymidine (FLT) and fluoromisonidazole (FMISO) for radiotherapy (RT) target definition and evolution in rectal cancer. MATERIALS AND METHODS PET/CT was performed before and during preoperative chemoradiotherapy (CRT) in 15 patients with resectable rectal cancer. PET signals were delineated and CT images on the different time points were non-rigidly registered. Mismatch analyses were carried out to quantify the overlap between FDG and FLT or FMISO tumour volumes (TV) and between PET TVs over time. RESULTS Ninety sequential PET/CT images were analyzed. The mean FDG, FLT and FMISO-PET TVs showed a tendency to shrink during preoperative CRT. On each time point, the mean FDG-PET TV was significantly larger than the FMISO-PET TV but not significantly larger than the mean FLT-PET TV. There was a mean 65% mismatch between the FMISO and FDG TVs obtained before and during CRT. FLT TVs corresponded better with the FDG TVs (25% mismatch before and 56% during CRT). During CRT, on average 61% of the mean FDG TV (7 cc) overlapped with the baseline mean TV (15.5 cc) (n=15). For FLT, the TV overlap was 49% (n=5) and for FMISO only 20% of the TV during CRT remained inside the contour at baseline (n=10). CONCLUSION FDG, FLT and FMISO-PET reflect different functional characteristics that change during CRT in rectal cancer. FLT and FDG show good spatial correspondence, while FMISO seems less reliable due to the non-specific FMISO uptake in normoxic tissue and tracer diffusion through the bowel wall. FDG and FLT-PET/CT imaging seem most appropriate to integrate in preoperative RT for rectal cancer.
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Phase I study of preoperative radiation therapy with concurrent infusional 5-fluorouracil and oxaliplatin followed by surgery and postoperative 5-fluorouracil plus leucovorin for T3/T4 rectal adenocarcinoma: ECOG E1297. Int J Radiat Oncol Biol Phys 2008; 72:108-13. [PMID: 18722265 DOI: 10.1016/j.ijrobp.2008.05.054] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Revised: 05/29/2008] [Accepted: 05/29/2008] [Indexed: 11/23/2022]
Abstract
PURPOSE Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. METHODS AND MATERIALS Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. RESULTS Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). CONCLUSIONS Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.
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Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a phase I/II study. Br J Cancer 2008; 98:1210-6. [PMID: 18349840 PMCID: PMC2359647 DOI: 10.1038/sj.bjc.6604292] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m−2 to 60 mg m−2 to 70 mg m−2 to identify the maximum tolerated dose (60 mg m−2). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m−2 per day) for 5 weeks. Irinotecan (60 mg m−2) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity.
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Folkvord S, Flatmark K, Seierstad T, Røe K, Rasmussen H, Ree AH. Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity? Radiother Oncol 2008; 86:428-34. [DOI: 10.1016/j.radonc.2007.10.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Accepted: 10/11/2007] [Indexed: 11/29/2022]
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Dolinsky CM, Mahmoud NN, Mick R, Sun W, Whittington RW, Solin LJ, Haller DG, Giantonio BJ, O'Dwyer PJ, Rosato EF, Fry RD, Metz JM. Effect of time interval between surgery and preoperative chemoradiotherapy with 5-fluorouracil or 5-fluorouracil and oxaliplatin on outcomes in rectal cancer. J Surg Oncol 2007; 96:207-12. [PMID: 17443718 DOI: 10.1002/jso.20815] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Preoperative chemoradiotherapy for locally advanced rectal cancer is now considered "standard of care." However, the optimal time interval for resection after neoadjuvant therapy is unknown. METHODS Between 11/90 and 11/04, 107 patients with rectal adenocarcinoma underwent preoperative chemo/RT at the University of Pennsylvania. Fifty-six percent had LAR and 40% had APR. Chemotherapy consisted of 5-FU/oxaliplatin in 28% and 5-FU in 72% of patients. All patients received preoperative RT. RESULTS A longer time interval between chemo/RT and surgery was associated with tumor downstaging (OR 1.24, P = 0.02). A longer time interval was not associated with: nodal downstaging (OR 1.00, P = 0.98); pathologic complete response (PCR) (OR 0.97, P = 0.80); likelihood of performing an LAR (OR 0.90, P = 0.47); improved disease free survival (DFS), local control, or distant control (HR 1.05, P = 0.49; HR 1.14, P = 0.22; HR 1.06, P = 0.52, respectively). The PCR rate was 34.5% in the 5-FU/oxaliplatin/radiation group, and 13.7% in the 5-FU/radiation group. If patients with microscopic CR were excluded, then the PCR rate for 5FU/OX was 21.4% and for 5-FU was 12.2%. CONCLUSIONS Time interval between surgery and chemo/RT appeared to have little effect on PCR or LAR rates. Patients receiving 5 FU/oxaliplatin/RT had a high PCR rate. A prospective randomized trial to test superiority of 5 FU/oxaliplatin is warranted.
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Affiliation(s)
- C M Dolinsky
- Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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Abstract
The purpose of this review is to provide an overview of the methods available for imaging tissue oxygenation. The following imaging methods are reviewed: phosphorescence, near-infrared (NIR), positron emission tomography (PET), magnetic resonance imaging ((19)F MRI and BOLD MRI), and electron paramagnetic resonance (EPR). The methods are based on different principles and differ in their ability to accurately quantify tissue oxygenation, either the absolute value of a particular measure of oxygenation (partial pressure of oxygen, concentration), or a parameter related to it (oxygen saturation). Methods that can provide images of relative changes in oxygenation or visualization of hypoxia in a specific tissue of interest are also considered valuable tools for biomedical research and clinical applications.
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Affiliation(s)
- Deepti S Vikram
- Center for Biomedical EPR Spectroscopy and Imaging, Comprehensive Cancer Center, Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA
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Klautke G, Fietkau R. Intensified neoadjuvant radiochemotherapy for locally advanced rectal cancer: a review. Int J Colorectal Dis 2007; 22:457-65. [PMID: 17072624 DOI: 10.1007/s00384-006-0204-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND The rate of local recurrence of locally advanced rectal cancer (stage III and IV according to the criteria of Union Internationale Contre Le Cancer) is still high, and also the rate of distant metastases. There are a lot of phase I/II trails of intensified neoadjuvant radiochemotherapy with different chemotherapeutic agents and current protocols to radiotherapy. AIM The objective of this review of literature was to evaluate the necessity, the results, and comparability of the different regimes and to evaluate a potential impact on later adjuvant chemotherapy.
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Affiliation(s)
- Gunther Klautke
- Klinik und Poliklinik für Strahlentherapie der Universität Rostock, Rostock, Germany.
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Yasui M, Ikeda M, Sekimoto M, Yamamoto H, Takemasa I, Ueda T, Shimizu J, Fukunaga M, Suzuki O, Inoue T, Monden M. Preliminary results of phase I trial of oral uracil/tegafur (UFT), leucovorin plus irinotecan and radiation therapy for patients with locally recurrent rectal cancer. World J Surg Oncol 2006; 4:83. [PMID: 17118210 PMCID: PMC1664567 DOI: 10.1186/1477-7819-4-83] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2006] [Accepted: 11/22/2006] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Surgical attempts for locally recurrent rectal cancer often fail due to local re-recurrence and distant metastasis. Preoperative chemoradiation may enhance better local control and survival. The aim of this study was to assess the safety of oral uracil and tegafur (UFT) plus leucovorin (LV), and irinotecan combined with radiation and determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of the triple drug regimen. PATIENTS AND METHODS Patients with locally recurrent rectal cancer received escalating doses of irinotecan on days 1, 8, 15, and 22 (starting at 30 mg/m2, with 10 mg increments between consecutive cohorts) and fixed doses of UFT (300 mg/m2) plus LV (75 mg/day) on days 3 to 7, 10 to 14, 17 to 21, and 24 to 28. Radiation was given 5 days per week totaling 40 to 50 Gy (2Gy/day). RESULTS Six patients were treated at the starting dose, and 2 received the full scheduled chemoradiotherapy. The other 4 patients had grade 3 diarrhea and diarrhea was the DLT. One patient had partial response and he had subsequently radical surgical resection. Median progression free survival for local recurrence was 320 days. CONCLUSION Irinotecan plus UFT/LV with concomitant radiotherapy in patients with locally recurrent rectal cancer was not feasible due to diarrhea in this setting. Modification of the treatment is needed.
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Affiliation(s)
- Masayoshi Yasui
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masataka Ikeda
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Mitsugu Sekimoto
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hirofumi Yamamoto
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ichiro Takemasa
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takafumi Ueda
- Department of Orthopeadics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Junzo Shimizu
- Department of Surgery, Sakai Municipal Hospital, Osaka, Japan
| | | | - Osamu Suzuki
- Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiro Inoue
- Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Morito Monden
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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Klautke G, Küchenmeister U, Foitzik T, Ludwig K, Prall F, Klar E, Fietkau R. Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study. Br J Cancer 2006; 94:976-81. [PMID: 16552435 PMCID: PMC2361227 DOI: 10.1038/sj.bjc.6603053] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer. Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 (50.4+5.4) Gy. Concurrently, irinotecan 40 mg m−2 once weekly and capecitabine continuously at dose levels of 500, 650, 750 and 825 mg m−2 twice daily were administered. Surgery was performed 4–6 weeks following completion of chemoradiation. A total of 28 patients (3 UICC II, 25 UICC III) were enrolled and all received treatment. Dose-limiting toxicity was diarrhoea grade IV and hand–foot syndrome at the 825 mg m−2 dose level. The maximum tolerated dose of capecitabine was 750 mg m−2. Diarrhoea was the most common toxicity: grade III in nine patients. Two patients died, one due to pneumonia and one due to sudden cardiac death. A complete response and only microfocal residual tumour disease was achieved in four and three patients (27%). In all, 25 of 28 patients undergoing surgery, 24 (96%) had R0 resection. Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer.
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Affiliation(s)
- G Klautke
- Department of Radiotherapy, University of Rostock, University Hospital, Südring 75, 18059 Rostock, Germany.
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Calvo FA, Serrano FJ, Diaz-González JA, Gomez-Espi M, Lozano E, Garcia R, de la Mata D, Arranz JA, García-Alfonso P, Pérez-Manga G, Alvarez E. Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol 2006; 17:1103-10. [PMID: 16670204 DOI: 10.1093/annonc/mdl085] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
PURPOSE To compare efficacy in terms of pathologic response in LARC patients treated with preoperative chemoradiation, with or without a short-intense course of induction oxaliplatin. PATIENTS AND METHODS From 05/98 to 10/02, 114 patients were treated with preoperative chemoradiation (4500-5040 cGy + oral Tegafur 1200 mg/day) for cT(3)-(4)N(+/x)M(0) rectal cancer. Starting 05/01, 52 consecutive patients additionally received induction FOLFOX-4, oxaliplatin (85 mg/m(2) iv d1), 5-FU (400 mg/m(2) iv bolus d1) and 600 mg/m(2) iv continuous infusion in 22 h with leucovorin (200 mg iv) d1 and d2, every 15 days (2 cycles), followed by the previously described Tegafur chemoradiation regime. Surgery was performed in 5-6 weeks. Pathological assessment investigated post-treatment T and N status in the rectal wall and peri-rectal tissues. RESULTS Patients, tumor and treatment characteristics were comparable between groups. Incidence of pT(0) specimens was significantly increased by induction FOLFOX-4 (P = 0.006). Total T and N downstaging were 58% versus 75% and 42% versus 40%, respectively (P = ns). T downstaging of > or =2 categories was significantly superior in FOLFOX-4 group (P = 0.029). CONCLUSIONS Short-intense induction FOLFOX-4 significantly improves pathologic complete response in LARC patients treated with tegafur-sensitized preoperative chemoradiation. The 44% rate of pT(0)-(1) specimens observed in the oxaliplatin group should impulse innovative surgical approaches to promote ano-rectal sphincter conserving protocols.
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Affiliation(s)
- F A Calvo
- Department of Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
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Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A, Norman AR, Tebbutt N, Hill M, Ross PJ, Massey A, Oates J. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006; 24:668-74. [PMID: 16446339 DOI: 10.1200/jco.2005.04.4875] [Citation(s) in RCA: 348] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) -defined poor-risk rectal cancer. PATIENTS AND METHODS MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending > or = 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine. RESULTS Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis. CONCLUSION Capecitabine/oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection.
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Affiliation(s)
- Ian Chau
- Department of Medicine, Royal Marsden Hospital, London, United Kingdom
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