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Kensen CM, Betgen A, Wiersema L, Peters FP, Kayembe MT, Marijnen CAM, van der Heide UA, Janssen TM. Online Adaptive MRI-Guided Radiotherapy for Primary Tumor and Lymph Node Boosting in Rectal Cancer. Cancers (Basel) 2023; 15:1009. [PMID: 36831354 PMCID: PMC9953931 DOI: 10.3390/cancers15041009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
The purpose of this study was to characterize the motion and define the required treatment margins of the pathological mesorectal lymph nodes (GTVln) for two online adaptive MRI-guided strategies for sequential boosting. Secondly, we determine the margins required for the primary gross tumor volume (GTVprim). Twenty-eight patients treated on a 1.5T MR-Linac were included in the study. On T2-weighted images for adaptation (MRIadapt) before and verification after irradiation (MRIpost) of five treatment fractions per patient, the GTVln and GTVprim were delineated. With online adaptive MRI-guided radiotherapy, daily plan adaptation can be performed through the use of two different strategies. In an adapt-to-shape (ATS) workflow the interfraction motion is effectively corrected by redelineation and the only relevant motion is intrafraction motion, while in an adapt-to-position (ATP) workflow the margin (for GTVln) is dominated by interfraction motion. The margin required for GTVprim will be identical to the ATS workflow, assuming each fraction would be perfectly matched on GTVprim. The intrafraction motion was calculated between MRIadapt and MRIpost for the GTVln and GTVprim separately. The interfraction motion of the GTVln was calculated with respect to the position of GTVprim, assuming each fraction would be perfectly matched on GTVprim. PTV margins were calculated for each strategy using the Van Herk recipe. For GTVln we randomly sampled the original dataset 20 times, with each subset containing a single randomly selected lymph node for each patient. The resulting margins for ATS ranged between 3 and 4 mm (LR), 3 and 5 mm (CC) and 5 and 6 mm (AP) based on the 20 randomly sampled datasets for GTVln. For ATP, the margins for GTVln were 10-12 mm in LR and AP and 16-19 mm in CC. The margins for ATS for GTVprim were 1.7 mm (LR), 4.7 mm (CC) and 3.2 mm anterior and 5.6 mm posterior. Daily delineation using ATS of both target volumes results in the smallest margins and is therefore recommended for safe dose escalation to the primary tumor and lymph nodes.
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Affiliation(s)
- Chavelli M. Kensen
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Anja Betgen
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Lisa Wiersema
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Femke P. Peters
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Mutamba T. Kayembe
- Department of Scientific Administration, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Corrie A. M. Marijnen
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Uulke A. van der Heide
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Tomas M. Janssen
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
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Delishaj D, Fumagalli IC, Ursino S, Cristaudo A, Colangelo F, Stefanelli A, Alghisi A, De Nobili G, D’Amico R, Cocchi A, Ardizzoia A, Soatti CP. Neoadjuvant radiotherapy dose escalation for locally advanced rectal cancers in the new era of radiotherapy: A review of literature. World J Clin Cases 2021; 9:9077-9089. [PMID: 34786390 PMCID: PMC8567526 DOI: 10.12998/wjcc.v9.i30.9077] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/27/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The standard treatment of locally advanced rectal cancers (LARC) consists on neoadjuvant chemoradiotherapy followed by total mesorectal excision. Different data in literature showed a benefit on tumor downstaging and pathological complete response (pCR) rate using radiotherapy dose escalation, however there is shortage of studies regarding dose escalation using the innovative techniques for LARC (T3-4 or N1-2).
AIM To analyze the role of neoadjuvant radiotherapy dose escalation for LARC using innovative radiotherapy techniques.
METHODS In December 2020, we conducted a comprehensive literature search of the following electronic databases: PubMed, Web of Science, Scopus and Cochrane library. The limit period of research included articles published from January 2009 to December 2020. Screening by title and abstract was carried out to identify only studies using radiation doses equivalent dose 2 Gy fraction (EQD2) ≥ 54 Gy and Volumetric Modulated Arc Therapy (VMAT), intensity-modulated radiotherapy or image-guided radiotherapy (IGRT) techniques. The authors’ searches generated a total of 2287 results and, according to PRISMA Group (2009) screening process, 21 publications fulfil selection criteria and were included for the review.
RESULTS The main radiotherapy technique used consisted in VMAT and IGRT modality. The mainly dose prescription was 55 Gy to high risk volume and 45 Gy as prophylactic volume in 25 fractions given with simultaneous integrated boosts technique (42.85%). The mean pCR was 28.2% with no correlation between dose prescribed and response rates (P value ≥ 0.5). The R0 margins and sphincter preservation rates were 98.88% and 76.03%, respectively. After a mean follow-up of 35 months local control was 92.29%. G3 or higher toxicity was 11.06% with no correlation between dose prescription and toxicities. Patients receiving EQD2 dose > 58.9 Gy and BED > 70.7 Gy had higher surgical complications rates compared to other group (P value = 0.047).
CONCLUSION Dose escalation neoadjuvant radiotherapy using innovative techniques is safe for LARC achieving higher rates of pCR. EQD2 doses > 58.9 Gy is associated with higher rate of surgical complications.
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Affiliation(s)
- Durim Delishaj
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | | | - Stefano Ursino
- Department of Radiation Oncology, Santa Chiara University Hospital, Pisa 56126, Italy
| | - Agostino Cristaudo
- Royal Preston Hospital, Lancashire Teaching Hospital- NHS Tust, Preston PR2 9HT, United Kingdom
| | - Francesco Colangelo
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | - Antonio Stefanelli
- Department of Radiation Oncology, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara 44124, Italy
| | - Alessandro Alghisi
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | - Giuseppe De Nobili
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | - Romerai D’Amico
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | - Alessandra Cocchi
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | - Antonio Ardizzoia
- Department of Clinical Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
| | - Carlo Pietro Soatti
- Department of Radiation Oncology, Alessandro Manzoni Hospital, Lecco 23900, Italy
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Roeder F, Meldolesi E, Gerum S, Valentini V, Rödel C. Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review. Radiat Oncol 2020; 15:262. [PMID: 33172475 PMCID: PMC7656724 DOI: 10.1186/s13014-020-01695-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/21/2020] [Indexed: 12/18/2022] Open
Abstract
The role of radiation therapy in the treatment of (colo)-rectal cancer has changed dramatically over the past decades. Introduced with the aim of reducing the high rates of local recurrences after conventional surgery, major developments in imaging, surgical technique, systemic therapy and radiation delivery have now created a much more complex environment leading to a more personalized approach. Functional aspects including reduction of acute or late treatment-related side effects, sphincter or even organ-preservation and the unsolved problem of still high distant failure rates have become more important while local recurrence rates can be kept low in the vast majority of patients. This review summarizes the actual role of radiation therapy in different subgroups of patients with rectal cancer, including the current standard approach in different subgroups as well as recent developments focusing on neoadjuvant treatment intensification and/or non-operative treatment approaches aiming at organ-preservation.
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Affiliation(s)
- F Roeder
- Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University, Landeskrankenhaus, Müllner Hautpstrasse 48, 5020, Salzburg, Austria.
| | - E Meldolesi
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - S Gerum
- Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University, Landeskrankenhaus, Müllner Hautpstrasse 48, 5020, Salzburg, Austria
| | - V Valentini
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - C Rödel
- Department of Radiotherapy, University of Frankfurt, Frankfurt, Germany
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Hearn N, Atwell D, Cahill K, Elks J, Vignarajah D, Lagopoulos J, Min M. Neoadjuvant Radiotherapy Dose Escalation in Locally Advanced Rectal Cancer: a Systematic Review and Meta-analysis of Modern Treatment Approaches and Outcomes. Clin Oncol (R Coll Radiol) 2020; 33:e1-e14. [PMID: 32669228 DOI: 10.1016/j.clon.2020.06.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 05/15/2020] [Accepted: 06/05/2020] [Indexed: 01/10/2023]
Abstract
AIMS Improving pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy for locally advanced rectal cancer may facilitate surgery-sparing treatment paradigms. Radiotherapy boost has been linked to higher rates of pCR; however, outcomes in moderately escalated inverse-planning studies have not been systematically evaluated. We therefore carried out a systematic review and meta-analysis of radiation dose-escalation studies in the context of neoadjuvant therapy for locally advanced rectal cancer. MATERIALS AND METHODS A systematic search of Pubmed, EMBASE and Cochrane databases for synonyms of 'rectal cancer', 'radiotherapy' and 'boost' was carried out. Studies were screened for radiotherapy prescription >54 Gy. Prespecified quality assessment was carried out for meta-analysis inclusion suitability. Pooled estimates of pCR, acute toxicity (grade ≥3) and R0 resection rates were determined with random-effects restricted maximum-likelihood estimation. Heterogeneity was assessed with Higgins I2 and Cochran Q statistic. Subset analysis examined outcomes in modern inverse-planning studies. Meta-regression with permutation correction was carried out for each outcome against radiation dose, radiotherapy technique, boost technique, chemotherapy intensification and other patient- and treatment-related cofactors. RESULTS Forty-nine primary and three follow-up publications were included in the systematic review. Pooled estimates of pCR, toxicity and R0 resection across 37 eligible publications (n = 1817 patients) were 24.1% (95% confidence interval 21.2-27.4%), 11.2% (95% confidence interval 7.2-17.0%) and 90.7% (95% confidence interval 87.9-93.8%). Within inverse-planning studies (17 publications, n = 959 patients), these rates were 25.7% (95% confidence interval 21.0-31.1%), 9.8% (95% confidence interval 4.6-19.7%) and 95.3% (95% confidence interval 91.6-97.4%). Regression analysis did not identify any significant predictor of pCR (P > 0.05). CONCLUSIONS Radiotherapy dose escalation above 54 Gy is associated with high rates of pCR and does not seem to increase the risk of acute grade ≥3 toxicity events. pCR rates approaching 25% may be achievable utilising moderate escalation (54-60 Gy) with modern inverse-planning techniques; however, a clear dose-response relationship was not identified in regression analysis and additional evidence is awaited given the prevalence of heterogenous single-arm studies to date.
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Affiliation(s)
- N Hearn
- Department of Radiation Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia; ICON Cancer Centre, Maroochydore, Queensland, Australia; University of the Sunshine Coast, Sippy Downs, Queensland, Australia.
| | - D Atwell
- Department of Radiation Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia; ICON Cancer Centre, Maroochydore, Queensland, Australia; University of the Sunshine Coast, Sippy Downs, Queensland, Australia
| | - K Cahill
- Department of Radiation Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia; University of the Sunshine Coast, Sippy Downs, Queensland, Australia
| | - J Elks
- University of the Sunshine Coast, Sippy Downs, Queensland, Australia
| | - D Vignarajah
- Department of Radiation Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia; ICON Cancer Centre, Maroochydore, Queensland, Australia
| | - J Lagopoulos
- University of the Sunshine Coast, Sippy Downs, Queensland, Australia; Sunshine Coast Mind and Neuroscience - Thompson Institute, University of the Sunshine Coast, Birtinya, Queensland, Australia
| | - M Min
- Department of Radiation Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia; ICON Cancer Centre, Maroochydore, Queensland, Australia; University of the Sunshine Coast, Sippy Downs, Queensland, Australia
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Ofshteyn A, Bingmer K, Dorth J, Dietz D, Steinhagen E, Stein SL. Disparities in neoadjuvant radiation dosing for treatment of rectal cancer. Am J Surg 2020; 220:987-992. [PMID: 31959352 DOI: 10.1016/j.amjsurg.2020.01.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Certain patients are less likely to undergo appropriate cancer treatment, worsening their overall cancer survival. The purpose of this investigation was to identify factors associated with inadequate neoadjuvant radiation for rectal cancer. METHODS The National Cancer Database was queried for patients with locally advanced rectal cancer who received neoadjuvant radiation 2006-2014. Adequate radiation was considered to be 4,500-5,040 cGy. Demographic, hospital and clinical variables were analyzed for association with inadequate radiation. RESULTS The study cohort was 34,391 patients; 1,842(5.4%) received inadequate radiation. On multivariate analysis, female gender, older age, other race, government-provided insurance, lower clinical stage and rural location correlated with inadequate radiation. CONCLUSIONS Women were 50% less likely than men to receive correct neoadjuvant radiation dosing. Other factors including age, race, insurance, clinical stage, geographic location and neoadjuvant chemotherapy were significantly associated with radiation dosing. These factors should be evaluated to determine if they can be modified to improve outcomes.
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Affiliation(s)
- Asya Ofshteyn
- Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Katherine Bingmer
- Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Jennifer Dorth
- Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - David Dietz
- Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Emily Steinhagen
- Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Sharon L Stein
- Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
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Current Views on the Interval Between Neoadjuvant Chemoradiation and Surgery for Rectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0370-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Burbach JPM, den Harder AM, Intven M, van Vulpen M, Verkooijen HM, Reerink O. Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: a systematic review and meta-analysis. Radiother Oncol 2014; 113:1-9. [PMID: 25281582 DOI: 10.1016/j.radonc.2014.08.035] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 08/25/2014] [Accepted: 08/31/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE We conducted a systematic review and meta-analysis to quantify the pathological complete response (pCR) rate after preoperative (chemo)radiation with doses of ⩾60Gy in patients with locally advanced rectal cancer. Complete response is relevant since this could select a proportion of patients for which organ-preserving strategies might be possible. Furthermore, we investigated correlations between EQD2 dose and pCR-rate, toxicity or resectability, and additionally between pCR-rate and chemotherapy, boost-approach or surgical-interval. METHODS AND MATERIALS PubMed, EMBASE and Cochrane libraries were searched with the terms 'radiotherapy', 'boost' and 'rectal cancer' and synonym terms. Studies delivering a preoperative dose of ⩾60 Gy were eligible for inclusion. Original English full texts that allowed intention-to-treat pCR-rate calculation were included. Study variables, including pCR, acute grade ⩾3 toxicity and resectability-rate, were extracted by two authors independently. Eligibility for meta-analysis was assessed by critical appraisal. Heterogeneity and pooled estimates were calculated for all three outcomes. Pearson correlation coefficients were calculated between the variables mentioned earlier. RESULTS The search identified 3377 original articles, of which 18 met our inclusion criteria (1106 patients). Fourteen studies were included for meta-analysis (487 patients treated with ⩾60 Gy). pCR-rate ranged between 0.0% and 44.4%. Toxicity ranged between 1.3% and 43.8% and resectability-rate between 34.0% and 100%. Pooled pCR-rate was 20.4% (95% CI 16.8-24.5%), with low heterogeneity (I2 0.0%, 95% CI 0.00-84.0%). Pooled acute grade ⩾3 toxicity was 10.3% (95% CI 5.4-18.6%) and pooled resectability-rate was 89.5% (95% CI 78.2-95.3%). CONCLUSION Dose escalation above 60 Gy for locally advanced rectal cancer results in high pCR-rates and acceptable early toxicity. This observation needs to be further investigated within larger randomized controlled phase 3 trials in the future.
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Affiliation(s)
| | | | - Martijn Intven
- Department of Radiation Oncology, University Medical Center, Utrecht, The Netherlands
| | - Marco van Vulpen
- Department of Radiation Oncology, University Medical Center, Utrecht, The Netherlands
| | | | - Onne Reerink
- Department of Radiation Oncology, University Medical Center, Utrecht, The Netherlands
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Park IJ, Kim JC. Adequate length of the distal resection margin in rectal cancer: from the oncological point of view. J Gastrointest Surg 2010; 14:1331-7. [PMID: 20143273 DOI: 10.1007/s11605-010-1165-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 01/11/2010] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The distal resection margin (DRM) has been considered an important factor for the oncological outcome of rectal cancer surgery. However, the optimal distal margins required to achieve safe oncological outcome remains to be controversial. MATERIAL AND METHODS More recently, as circumferential resection margin or mesorectal margin has been additionally reported to be more important factors predicting patient outcome than the distal mucosal margin, a re-evaluation of the impact of DRM on patient outcome is needed. RESULTS The extent of distal tumor spread is known to be influenced by a variety of factors such as tumor location, lymph node metastasis, and tumor size. DRM might affect survival more than a local recurrence. Because distal intramural tumor spread rarely exceeds 1 to 2 cm in most rectal cancers, and local control and survival do not seem to be compromised by shorter distal resection margins, the generally accepted practice is to aim for a 2-cm DRM. However, in the recent trend of curative resection after preoperative chemoradiotherapy, with an otherwise favorable tumor such as well-differentiated tumor and no lymph node metastasis, a DRM at < or =1 cm does not necessarily portend a poor prognosis. In cases with preoperative chemoradiotherapy, distal resection margins need to be evaluated individually. DISCUSSION It has been suggested that down-staging of low-lying rectal cancers after preoperative radiation might well include the pathological clearance of distal intramural microscopic spread. Moreover, the measurement of DRM varies with respective study, making it difficult to compare. CONCLUSION We need an applicable intraoperative method to accurately measure distal resection margin, enabling comparative outcome.
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Affiliation(s)
- In Ja Park
- Department of Surgery, Vievis Namuh Hospital, Seoul, South Korea
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de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Kalady MF, Geisler D, Dietz D, Lavery IC, Remzi FH, Fazio VW. Downstaging without complete pathologic response after neoadjuvant treatment improves cancer outcomes for cIII but not cII rectal cancers. Ann Surg Oncol 2010; 17:1758-66. [PMID: 20131015 DOI: 10.1245/s10434-010-0924-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of this study was to evaluate whether downstaging impacts prognosis in patients with cII versus cIII rectal cancer. MATERIALS AND METHODS We identified from our colorectal cancer database 295 patients with primary cII and cIII rectal cancer staged by CT and ERUS/MRI who received 5-FU-based chemoradiation followed by R0 surgery after a median interval of 7 weeks during 1997-2007. The median radiotherapy dose was 5040 cGy. We excluded 58 patients with pathologic complete response (pCR) and compared among the remaining 162 patients pathologic downstaging (cII to ypI, cIII to ypII or ypI) versus no pathologic downstaging (c stage < or = yp stage). Outcomes evaluated were 5-year overall survival, 3-year cancer-specific survival, disease-free survival, overall recurrence, local recurrence, and distant recurrence. RESULTS The median age was 58 years and median follow-up was 48 months. Patients with downstaging versus no downstaging were statistically comparable with respect to demographics, chemoradiation regimen, interval time between neoadjuvant chemoradiation and surgery, tumor distance from anal verge, surgical procedures performed, and follow-up time. With the exception of local recurrence rates, downstaging resulted in significantly improved cancer outcomes for cIII but not cII. CONCLUSIONS Downstaging without pCR is a significant prognostic factor for patients with stage cIII rectal cancer. Tumor response to neoadjuvant chemoradiation should be taken into account when defining the optimal adjuvant chemotherapy regimen for patients with cIII rectal cancer.
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Boller AM, Cima RR. Impact of pre- and postoperative multimodality therapy on rectal cancer. J Surg Oncol 2007; 96:665-70. [DOI: 10.1002/jso.20919] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Liszka L, Zielińska-Pajak E, Pajak J, Gołka D, Starzewski J, Lorenc Z. Usefulness of two independent histopathological classifications of tumor regression in patients with rectal cancer submitted to hyperfractionated pre-operative radiotherapy. World J Gastroenterol 2007; 13:515-24. [PMID: 17278216 PMCID: PMC4065972 DOI: 10.3748/wjg.v13.i4.524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the usefulness of two independent histopathological classifications of rectal cancer regression following neo-adjuvant therapy.
METHODS: Forty patients at the initial stage cT3NxM0 submitted to preoperative radiotherapy (42 Gy during 18 d) and then to radical surgical treatment. The relationship between “T-downstaging” versus regressive changes expressed by tumor regression grade (TRG 1-5) and Nasierowska-Guttmejer classification (NG 1-3) was studied as well as the relationship between TRG and NG versus local tumor stage ypT and lymph nodes status, ypN.
RESULTS: Complete regression (ypT0, TRG 1) was found in one patient. “T-downstaging” was observed in 11 (27.5%) patients. There was a weak statistical significance of the relationship between “T-downstaging” and TRG staging and NG stage. Patients with ypT1 were diagnosed as TRG 2-3 while those with ypT3 as TRG5. No lymph node metastases were found in patients with TRG 1-2. None of the patients without lymph node metastases were diagnosed as TRG 5. Patients in the ypT1 stage were NG 1-2. No lymph node metastases were found in NG 1. There was a significant correlation between TRG and NG.
CONCLUSION: Histopathological classifications may be useful in the monitoring of the effects of hyperfractionated preoperative radiotherapy in patients with rectal cancer at the stage of cT3NxM0. There is no unequivocal relationship between “T-downstaging” and TRG and NG. There is some concordance in the assessment of lymph node status with ypT, TRG and NG. TRG and NG are of limited value for the risk assessment of the lymph node involvement.
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Affiliation(s)
- Lukasz Liszka
- Department of Pathology, Medical University of Silesia, ul. Medykow 14, Katowice 40-754, Poland
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Kim NK, Baik SH, Seong JS, Kim H, Roh JK, Lee KY, Sohn SK, Cho CH. Oncologic outcomes after neoadjuvant chemoradiation followed by curative resection with tumor-specific mesorectal excision for fixed locally advanced rectal cancer: Impact of postirradiated pathologic downstaging on local recurrence and survival. Ann Surg 2007; 244:1024-30. [PMID: 17122629 PMCID: PMC1856621 DOI: 10.1097/01.sla.0000225360.99257.73] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The purpose of this study was to determine the oncologic outcomes and clinical factors affecting survival in patients who underwent neoadjuvant chemoradiotherapy following tumor specific mesorectal excision for locally advanced, fixed rectal cancer. SUMMARY BACKGROUND DATA Neoadjuvant chemoradiation therapy has resulted in significant tumor downstaging, which enhances curative resection and subsequently improves local disease control for rectal cancer. However, oncologic outcomes, according to clinical factors, have not yet been fully understood in locally advanced and fixed rectal cancer. METHODS A total of 114 patients who had undergone neoadjuvant chemoradiation for advanced rectal cancer (T3 or T4 and node positive) were investigated retrospectively. Chemotherapy was administered intravenously with 5-FU and leucovorin during weeks 1 and 5 of radiotherapy. The total radiation dose was 5040 cGY in 25 fractions delivered over 5 weeks. Tumor-specific mesorectal excision was done 4 to 6 weeks after the completion of neoadjuvant chemoradiation. Survival and recurrence rates, according to the pathologic stage, were evaluated. Moreover, factors affecting survival were investigated. RESULTS The 5-year survival rates according to pathologic stage were: 100% in pathologic complete remission (n = 10), 80% in stage I (n = 23), 56.8% in stage II (n = 34), and 42.3% in stage III (n = 47) (P = 0.0000). Local, systemic, and combined recurrence rates were 11.4%, 22.8%, and 3.5%, respectively. Multivariate analysis showed that the pathologic N stage and operation method were the independent factors affecting survival rate. CONCLUSION Pathologic complete remission showed excellent oncologic outcomes, and the pathologic N stage was the most important factor for oncologic outcomes.
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Affiliation(s)
- Nam Kyu Kim
- Colorectal Cancer Clinic, Severance Hospital, Yonsei University Medical Center, Yonsei University College of Medicine, Seoul, Korea.
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14
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Garces CA, McAuliffe PF, Hochwald SN, Cance WG. Neoadjuvant therapy in the treatment of solid tumors. Curr Probl Surg 2006; 43:457-551. [PMID: 16860653 DOI: 10.1067/j.cpsurg.2006.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Christopher A Garces
- General Surgery, University of Florida College of Medicine, Gainesville, FL, USA
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15
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Ceelen W, Pattyn P, Boterberg T, Peeters M. Pre-operative combined modality therapy in the management of locally advanced rectal cancer. Eur J Surg Oncol 2006; 32:259-68. [PMID: 16443345 DOI: 10.1016/j.ejso.2005.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2005] [Accepted: 12/07/2005] [Indexed: 12/19/2022] Open
Abstract
AIMS To review the use of pre-operative combined modality therapy (CMT, chemotherapy with radiotherapy) in the management of resectable rectal cancer. METHODS A systematic search was performed on pre-operative CMT and rectal cancer. Additional information was retrieved from hand searching the literature and from relevant congress proceedings. We addressed the following issues: Phase II studies of pre-operative CMT, pre-operative radiotherapy (RT) alone vs pre-operative CMT, pre-operative vs post-operative CMT, functional outcome and pathologic downstaging after CMT, prediction and importance of complete response to CMT. RESULTS Pre-operative CMT results in an average pathological complete response (pCR) rate of 18.5% in Phase II studies. Compared with pre-operative RT alone, the addition of CT significantly improves tumour response but not overall survival while acute toxicity increases and the effect on sphincter preservation is at present unclear. Pre-operative CMT has been proven to be superior to post-operative CMT in a German multicenter randomized trial. The scarce available data suggest that the addition of CT might worsen anorectal function compared to pre-operative RT alone. Although a significant pathological response is prognostically favourable, the clinical and imaging tools available at present do not allow to accurately predict pCR in clinical complete responders confirming the indication for surgery in this subgroup. CONCLUSIONS Pre-operative CMT enhances tumour response and could therefore, have a role in patients with possibly invaded resection margins or low lying cancers, although both acute toxicity and anorectal function are worse compared to RT alone. The final results of ongoing randomized trials will more accurately establish the role of pre-operative CMT in resectable rectal cancer patients.
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Affiliation(s)
- W Ceelen
- Department of Surgery, University Hospital, 2K12 IC, De Pintelaan 185, B-9000 Ghent, Belgium.
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16
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Starzewski JJ, Pajak JT, Pawełczyk I, Lange D, Gołka D, Brzezińska M, Lorenc Z. The radiation-induced changes in rectal mucosa: Hyperfractionated vs. hypofractionated preoperative radiation for rectal cancer. Int J Radiat Oncol Biol Phys 2006; 64:717-24. [PMID: 16242259 DOI: 10.1016/j.ijrobp.2005.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2005] [Revised: 07/26/2005] [Accepted: 08/09/2005] [Indexed: 02/07/2023]
Abstract
PURPOSE The purpose of the study was the qualitative and quantitative evaluation of acute radiation-induced rectal changes in patients who underwent preoperative radiotherapy according to two different irradiation protocols. PATIENTS AND METHODS Sixty-eight patients with rectal adenocarcinoma underwent preoperative radiotherapy; 44 and 24 patients underwent hyperfractionated and hypofractionated protocol, respectively. Fifteen patients treated with surgery alone served as a control group. Five basic histopathologic features (meganucleosis, inflammatory infiltrations, eosinophils, mucus secretion, and erosions) and two additional features (mitotic figures and architectural glandular abnormalities) of radiation-induced changes were qualified and quantified. RESULTS Acute radiation-induced reactions were found in 66 patients. The most common were eosinophilic and plasma-cell inflammatory infiltrations (65 patients), erosions, and decreased mucus secretion (54 patients). Meganucleosis and mitotic figures were more common in patients who underwent hyperfractionated radiotherapy. The least common were the glandular architectural distortions, especially in patients treated with hypofractionated radiotherapy. Statistically significant differences in morphologic parameters studied between groups treated with different irradiation protocols were found. CONCLUSION The system of assessment is a valuable tool in the evaluation of radiation-induced changes in the rectal mucosa. A greater intensity of regenerative changes was found in patients treated with hyperfractionated radiotherapy.
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Affiliation(s)
- Jacek J Starzewski
- Department of General and Colorectal Surgery, Medical University of Silesia, Sosnowiec, Poland
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17
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François E, Ychou M, Ducreux M, Bertheault-Cvitkovic F, Giovannini M, Conroy T, Lemanski C, Thomas O, Magnin V. Combined radiotherapy, 5-fluorouracil continuous infusion and weekly oxaliplatin in advanced rectal cancer: A phase I study. Eur J Cancer 2005; 41:2861-7. [PMID: 16297614 DOI: 10.1016/j.ejca.2005.08.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2005] [Revised: 08/17/2005] [Accepted: 08/18/2005] [Indexed: 11/28/2022]
Abstract
The aim of this study was to determine the maximum-tolerated dose (MTD) of weekly oxaliplatin combined with 5-fluorouracil (5FU) continuous infusion administered concomitantly with fractionated radiotherapy in patients presenting advanced rectal cancer. Forty-three patients with rectal cancer (stage T3/T4 (n = 24), metastatic (n = 17) and 2 with local recurrence), were included. The radiotherapy dose delivered was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 days per week). The initial weekly oxaliplatin dosage was 30 mg/m2 and the 5FU dosage 150 mg/m2/d. The oxaliplatin and 5FU doses were escalated. Eight dose levels were tested. At dose level 8 (oxaliplatin 80 mg/m2, 5FU 225 mg/m2/d), 2 patients out of 4 presented dose-limiting toxicity (severe diarrhoea with dehydration and fatal shock, rectovesical fistula). At dose level 7, 2 further patients presented with grade 3 diarrhoea. The main toxicity of the combination was diarrhoea. The hematological and neurological toxicities were not severe and were not dose-limiting. Out of the 30 patients undergoing surgery, 4 (13.3%) presented with pathological complete response and 4 (13.3%) only presented with microscopic residual disease. The results from this study enabled determination of the recommended weekly oxaliplatin dose (60 mg/m2) combined with 5FU continuous infusion (225 mg/m2) and fractionated radiotherapy (45 Gy) in the pre-operative treatment of advanced rectal cancer. The good safety profile of the regimen, associated with promising results in terms of histological response, suggest that the regimen could be developed in future phase II/III studies.
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Affiliation(s)
- Eric François
- Department of Medical Oncology, Centre Antoine-Lacassagne, Avenue de Valombrose, 06189 Nice, Cedex 2, France.
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18
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Gavioli M, Luppi G, Losi L, Bertolini F, Santantonio M, Falchi AM, D'Amico R, Conte PF, Natalini G. Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer. Dis Colon Rectum 2005; 48:1851-7. [PMID: 16132481 DOI: 10.1007/s10350-005-0133-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE In advanced rectal cancer, chemoradiation can induce downstaging until complete disappearance of the tumor or its persistence in minimal form. The complete sterilized and the minimal residual disease often are considered similar. We evaluated the specific incidence of these two conditions and analyzed their impact in terms of local recurrence, distant metastasis, and survival. METHODS We studied 139 uT3/T4 N0/N+ rectal cancers, treated with preoperative chemoradiation and curative surgery after six to eight weeks. We evaluated ypTNM stage and tumoral regression, according to the five degrees proposed by Dworak, with special attention to 4 and 3 (sterilized and minimal residual disease). RESULTS Tumor downstaging occurred in 65 patients (46.7 percent), including 25 sterilized lesions (17.9 percent) and 24 minimal residual disease (17.2 percent). In median follow-up of 30 months, none of the patients with sterilized disease developed local or distant recurrence. Among patients with minimal residual disease, none developed local recurrence, whereas two (8.3 percent) developed distant metastasis, and one died from disease. In patients with gross residual disease (Grade 2, 1, 0) the percentage of local recurrence was 8.8 percent, distant recurrence 26.6 percent, and 13.3 percent died from disease. The difference between three groups is statistically significant as regards local and distant recurrence. CONCLUSIONS After preoperative therapy, the sterilized disease shows an excellent prognosis. The minimal residual disease has an important numeric incidence. Its outcome is different, with a not-negligible risk of distant recurrence. The minimal residual disease has a much better prognosis in comparison with the gross residual disease.
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19
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Ryan R, Gibbons D, Hyland JMP, Treanor D, White A, Mulcahy HE, O'Donoghue DP, Moriarty M, Fennelly D, Sheahan K. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 2005; 47:141-6. [PMID: 16045774 DOI: 10.1111/j.1365-2559.2005.02176.x] [Citation(s) in RCA: 490] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIMS To standardize the pathological analysis of total mesorectal excision specimens of rectal cancer following neoadjuvant chemoradiotherapy for locally advanced disease (T3/T4), including tumour regression. METHODS AND RESULTS Standardized dissection and reporting was used for 60 patients who underwent total mesorectal excision following long-course chemoradiotherapy. Tumour regression was scored by two pathologists (K.S., D.G.) using both an established 5-point tumour regression grade (TRG), and a novel 3-point grade. Both scores were evaluated for interobserver variability. A complete or near-complete pathological response (3-point TRG 1) was found in 10 patients (17%). Using the 5-point TRG, there was good agreement between both pathologists (kappa = 0.64). Using the 3-point grade, agreement was excellent (kappa = 0.84). No disease recurrence has been reported in patients with a complete, or near complete pathological response (3-point TRG 1), after a mean follow-up of 22 months. CONCLUSION Tumour regression grade is a useful method of scoring tumour response to chemoradiotherapy in rectal cancer. TRG 1 and 2 can be regarded as a complete pathological response (ypT0). A modified 3-point grade has the advantage of better reproducibility, with similar prognostic significance.
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Affiliation(s)
- R Ryan
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
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20
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Vironen J, Juhola M, Kairaluoma M, Jantunen I, Kellokumpu I. Tumour regression grading in the evaluation of tumour response after different preoperative radiotherapy treatments for rectal carcinoma. Int J Colorectal Dis 2005; 20:440-5. [PMID: 15856263 DOI: 10.1007/s00384-004-0733-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2004] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Preoperative radiotherapy (PRT) for rectal carcinoma has been shown to cause tumour regression and increase local control and patient survival. The aim of this study was to examine the usefulness of tumour regression grading (TRG) in quantifying the effect of PRT. METHODS Depending on the tumour stage (uT), as defined by preoperative endorectal ultrasound (ERUS), fixity and distance from the anal verge, 126 patients with rectal cancer underwent either surgery alone, or received short-course 25-Gy radiotherapy or long-course 50-Gy radiotherapy combined with 5-fluorouracil (5-FU) before surgery. TRG in each group was assessed and compared with the downstaging, defined as a change in preoperative uT stage and pathologic stage (pT). RESULTS Complete response (no residual tumour, TRG 1) was seen in 7% of the patients (3/44) and total or major regression (TRG 1-3) in 73% of the patients (32/44) treated with 50-Gy chemoradiation. Of those treated with 25-Gy PRT, 21% (9/42) showed major tumour regression. Of the patients who underwent ERUS and PRT, 32% (26/83) were downstaged when comparing uT with pT, but 53% (14/26) of the downstaged tumours showed no response by TRG. In comparison, 50% (28/57) of the tumours with no downstaging showed a marked response by TRG (p=0.05). CONCLUSIONS Tumour regression grading offers detailed information of the effect of PRT and shows that tumour regression is more marked after long-term chemoradiation than after short-course radiotherapy (p=0.02). In contrast, T-stage downstaging was similar in both groups and did not correlate with the TRG results (p=0.05).
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Affiliation(s)
- J Vironen
- Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland
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21
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Cook T, Wang Z, Alber S, Liu K, Watkins SC, Vodovotz Y, Billiar TR, Blumberg D. Nitric oxide and ionizing radiation synergistically promote apoptosis and growth inhibition of cancer by activating p53. Cancer Res 2004; 64:8015-21. [PMID: 15520210 DOI: 10.1158/0008-5472.can-04-2212] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nitric oxide (NO) is a potent tumor radiosensitizer; however, its clinical use is limited by systemic side effects. We have demonstrated previously that gene transfer of the human inducible NO synthase (iNOS) gene into tumor cells and tumors induces high-output NO production that significantly enhances tumor radioresponsiveness, with no observed side effects. Notably, iNOS gene transfer enhances tumor radioresponsiveness via apoptotic cell death. Because NO and ionizing radiation are both known to promote p53-dependent apoptosis, we hypothesized that p53 activation might be a primary mechanism for the synergy of these two genotoxic stresses. We report that NO and ionizing radiation synergistically activate p53 in colorectal cancers grown in athymic mice by augmenting phosphorylation of p53 at serine 15. The effect of NO and ionizing radiation on tumor cell apoptosis and tumor radioresponsiveness is significantly reduced in p53 knockout isogenic cancer cell lines. Furthermore, the transfer of both p53 and iNOS genes into tumor cells lacking functional p53 enhanced their radioresponsiveness more than transfer of either gene alone.
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Affiliation(s)
- Tracy Cook
- Department of Surgery and Center for Biologic Imaging, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15232, USA
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22
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Kauer WKH, Prantl L, Dittler HJ, Siewert JR. The value of endosonographic rectal carcinoma staging in routine diagnostics: a 10-year analysis. Surg Endosc 2004; 18:1075-8. [PMID: 15156388 DOI: 10.1007/s00464-003-9088-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2003] [Accepted: 01/14/2004] [Indexed: 12/20/2022]
Abstract
BACKGROUND Endosonography is currently the gold standard for the local staging of rectal carcinoma, but its accuracy varies from 62% to 91%. This study aimed to determine the accuracy of endosonography, to evaluate the interobserver variability, and to compare the performance of the 7.5-MHz and the 10-MHz ultrasound scanners. METHODS Between 1990 and 2000, 458 patients with rectal cancer were included in the study. All the patients had undergone rectal endosonography with a 7.5-MHz scan (period 1: 1990-1996) or a 10-MHz scan (period 2: 1997-2000). Endosonographic staging was compared with pathologic staging. RESULTS The overall rate for correctly classified patients was 69% with respect to the T category and 68% with respect to the N category. There was no difference between the two scanners. In terms of accuracy, the T3 category tumors were the most (86%) and the T4 tumors the least (36%) accurately classified. Overstaging of tumors (19%) was much more frequent than understaging (12%). A high interobserver variability of 61% to 77% was noted. For pT1 tumors, the 10-MHz scan was almost two times more accurate than the 7.5-MHz scan (71% vs 36%). CONCLUSIONS The accuracy of endosonographic staging of rectal carcinoma very much depends on the T category. A high-resolution scanner and an experienced examiner can help to ensure that endosonography remains an important tool in the staging process of patients with rectal carcinoma, especially early carcinoma.
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Affiliation(s)
- W K H Kauer
- Department Surgery, Chirurgische Klinik und Poliklinik, Klinikum rechts der lsar, Technische Universität München, Ismaningerstrasse 22, 81675, München, Germany.
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23
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Wang Z, Cook T, Alber S, Liu K, Kovesdi I, Watkins SK, Vodovotz Y, Billiar TR, Blumberg D. Adenoviral Gene Transfer of the Human Inducible Nitric Oxide Synthase Gene Enhances the Radiation Response of Human Colorectal Cancer Associated with Alterations in Tumor Vascularity. Cancer Res 2004; 64:1386-95. [PMID: 14973054 DOI: 10.1158/0008-5472.can-03-1307] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nitric oxide is a potent radiosensitizer of tumors, but its use clinically is limited by serious side effects when administered systemically. We have demonstrated previously that gene transfer of the inducible nitric oxide synthase gene (iNOS) into colorectal cancer cells enhances radiation-induced apoptosis in vitro. The objectives of this study were to further characterize the effects of iNOS gene transfer on the radiosensitivity of human colorectal cancer cells in vitro and tumors grown in athymic nude mice. Adenoviral gene transfer of iNOS (AdiNOS) into human colorectal cancer cell lines (HCT-116 and SNU-1040 cells) significantly enhanced the effects of radiation with sensitizing enhancement ratios (0.1) of 1.65 and 1.6, respectively. The radiation enhancement induced by iNOS was associated with increased iNOS expression and nitric oxide production and prevented by L-NIO, an enzymatic inhibitor of iNOS. AdiNOS treatment of HCT-116 tumors combined with radiation (2 Gy x three fractions) led to a 3.4-fold greater (P < 0.005) tumor growth delay compared with radiation (RT) alone. AdiNOS plus RT also caused significant (P < 0.01) tumor regression with 63% of tumors regressing compared with only 6% of tumors treated with RT. AdiNOS plus RT significantly (P < or = 0.001) increased the percentage of apoptotic cells (22 +/- 4%) compared with either tumors treated with control vector plus RT (9 +/- 1%), AdiNOS alone (9 +/- 3%), or no treatment (2 +/- 1%). These radiosensitizing effects of AdiNOS occurred at low infection efficiency (4% of tumor infected), indicating a significant bystander effect.
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Affiliation(s)
- Zifa Wang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
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24
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Magné N, Fischel JL, Formento P, Etienne MC, Dubreuil A, Marcié S, Lagrange JL, Milano G. Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status. Oncology 2003; 64:280-7. [PMID: 12697970 DOI: 10.1159/000069308] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVES AND METHODS The association oxaliplatin (OXA)-5-fluorouracil/folinic acid (FUFA) is currently a standard first-line treatment for advanced colorectal cancer. The main objective of this experimental study was to examine the cytotoxic effects resulting from the addition of ionizing radiation (Rgamma) to the combination OXA-FUFA on 2 human colon cancer cell lines (SW403, p53 wild type and WiDr, p53 mutated). A clinically relevant drug sequence was used consisting in OXA during 2 h followed by FUFA over 24 h. The impact of the position of radiation (1 and 4 Gy) was tested: radiation 2 h before drug application, in the middle of the drug application or 24 h after the drug application. RESULTS Both cell lines exhibited similar dose response curves to Rgamma alone, WiDr being more radio-sensitive than SW403 (IC50: 4.8 Gy and 7 Gy, respectively). The effects of Rgamma-drug combinations were assessed using a conventional isobolographic method and by computing a potentiation factor (F) defined as the ratio of IC50 drug combinations/IC50 drug combinations combined with Rgamma. The results from both calculation methods concurred: the combination of OXA-FUFA with Rgamma led to additive-antagonistic effects for the p53 mutated cell line (WiDr), whatever the sequence. In contrast, for the p53 wild type cell line (SW403), additive-synergistic effects were observed with, in this case, an optimal position for Rgamma occurring when applied before or at mid-drug application. CONCLUSIONS These results could be taken into consideration for an optimal design of clinical protocols associating Rgamma and OXA-FUFA.
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Affiliation(s)
- Nicolas Magné
- Oncopharmacology Laboratory, Centre Antoine Lacassagne, 33 Avenue de Valombrose, F-06189 Nice Cedex 2, France
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25
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Chung P, Cook T, Liu K, Vodovotz Y, Zamora R, Finkelstein S, Billiar T, Blumberg D. Overexpression of the human inducible nitric oxide synthase gene enhances radiation-induced apoptosis in colorectal cancer cells via a caspase-dependent mechanism. Nitric Oxide 2003; 8:119-26. [PMID: 12620375 DOI: 10.1016/s1089-8603(02)00147-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Nitric oxide (NO) has been reported to sensitize cancer cells to radiation. Since delivery of NO to tumors is limited in vivo by systemic toxicity of NO, we examined the potential of gene delivery of the human inducible nitric oxide synthase (iNOS) gene as a means of achieving high output NO production. We successfully transduced two colorectal cancer cell lines as evidenced by increased iNOS protein accumulation and nitrite production. We found that overexpression of iNOS enhanced the effects of radiation on apoptosis in both cell lines in a caspase-dependent fashion. Gene transfer of iNOS holds much promise as a potential radiosensitizer of cancer cells since it increases apoptosis in an additive manner with radiation.
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Affiliation(s)
- Peter Chung
- Department of Surgery, University of Pittsburgh School of Medicine, Cancer Pavillion, 5150 Centre Avenue, Rm 438, Pittsburgh, PA 15232, USA
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26
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Uzcudun AE, Batlle JF, Velasco JC, Sánchez Santos ME, Carpeño JDC, Grande AG, Juberías AM, Piñeiro EH, Olivar LM, García AG. Efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma when combined with oral tegafur-uracil modulated with leucovorin: results from a phase II study. Dis Colon Rectum 2002; 45:1349-58. [PMID: 12394434 DOI: 10.1007/s10350-004-6424-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The aim of this study was to evaluate the efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma (T3-T4) when delivered in combination with chemotherapy (oral tegafur-uracil modulated with leucovorin). METHODS Thirty-eight patients (23 males; mean age, 62 years.) with histologically proven rectal adenocarcinoma with primary tumor clinical classification T3-T4 (resectable) and N0 or N1-N2, according to TNM staging system, took part in the present clinical trial. After tumor and metastasis resectability confirmation, radiation therapy was administered by delivering a dose of 45 Gy in 25 fractions for 5 weeks. Chemotherapy treatment was initiated on the same day as radiotherapy and consisted of intravenous infusion of 6S-steroisomer of leucovorin 250 mg/m /day in 2 hours on Day 1, followed by oral 350 or 300 mg/m /day of tegafur (a 5-fluorouracil prodrug) plus uracil on Days 1 to 14 divided into 2 daily doses, and oral 6S-steroisomer of leucovorin 7.5 mg/12 hours on Days 2 to 14, with a total of 102 courses of neoadjuvant chemotherapy (, mean of 2.7 courses per patient). Six additional courses of tegafur-uracil were given postoperatively to all 38 patients but 1 who refused. RESULTS As a result of preoperative chemoradiation treatment, 4 (10.5 percent) complete responses, 20 (52.6 percent) partial responses, and 14 (36.8 percent) patients with disease stabilization were observed. No patients had preoperative disease progression. Histologically proven downstaging was observed in 23 (60 percent) patients. On initial evaluation, only 39 percent of patients were considered as being good candidates for sphincter-preserving surgery; however, on preoperative chemoradiation completion this figure increased up to 60 percent. For the 23 patients eventually undergoing sphincter-preserving surgery, postoperative sphincter function assessment showed excellent function in 15 (65 percent) patients, good in 5 (22 percent), fair in 2 (9 percent), and poor in 1(4 percent). With a median follow-up of 37 (range, 10-62) months, local failure was found in 3 (8 percent) patients and distant failure in 2 (5 percent). Three-year actuarial disease-free survival and 3-year overall survival rates were 83 and 90 percent, respectively. Local control rate was 92 percent. Toxicity and postoperative complication rates were reasonable. CONCLUSIONS Our neoadjuvant radiation therapy protocol is efficient for the preoperative treatment of resectable rectal adenocarcinoma when combined with chemotherapy (oral tegafur-uracil modulated with leucovorin). this protocol needs to be tested in a phase-III clinical trial with a larger sample size.
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27
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Iyer RB, Silverman PM, DuBrow RA, Charnsangavej C. Imaging in the diagnosis, staging, and follow-up of colorectal cancer. AJR Am J Roentgenol 2002; 179:3-13. [PMID: 12076894 DOI: 10.2214/ajr.179.1.1790003] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Revathy B Iyer
- Department of Diagnostic Radiology, Box 57, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
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28
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Morgan MJ, Koorey DJ, Painter D, Findlay M, Tran K, Stevens G, Solomon MJ. Histological tumour response to pre-operative combined modality therapy in locally advanced rectal cancer. Colorectal Dis 2002; 4:177-183. [PMID: 12780612 DOI: 10.1046/j.1463-1318.2002.00330.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND: Pre-operative combined modality therapy (CMT) is used in locally advanced rectal cancer. Its use affects the clinicopathological staging based on the resected specimen. Assessment of the tumour response in the resected specimen may provide prognostic information. This study was undertaken to determine the histological response to pre-operative chemoradiation and to assess the interobserver reliability of a newly developed tumour response grading system for rectal cancer. METHODS: Pre-operative biopsy specimens and the resected specimens of 21 patients with low rectal cancer were assessed. The patients underwent pre-operative CMT consisting of radiotherapy (45 Gy) with 5-FU either as a continuous infusion or as a bolus intravenous infusion with leucovorin. After four to six weeks tumour response was assessed by comparing pre-operative transrectal ultrasound (TRUS) findings (uT1-4, uN0-1) with postoperative histopathological assessment (pT1-4, pN0-1) using UICC TNM characteristics. Tumour response was defined as a decrease in T status. The histological response to CMT was based on the tumour regression grade (TRG) and ranged from fibrosis extending through the rectal wall with no residual cancer (TRG 1), to no evidence of tumour response (TRG 5). Inter-observer reliability was assessed using weighted and unweighted kappa statistics. RESULTS: Local downstaging was demonstrated in 11/21 (52%) of patients. Three of 21 patients had a TRG 1 response. Thirteen of 21 (62%) patients had TRG 1-3 responses to CMT. There was no significant correlation between local downstaging and TRG. The interobserver correlation coefficient for assessment of TRG was 0.88 (unweighted kappa). CONCLUSIONS: Local downstaging by pre-operative CMT can be demonstrated if pre-operative TRUS staging is compared to standard pathology staging in patients with rectal cancer. Local downstaging is not directly related to histologic response as assessed by TRG. Inter-observer reporting of tumour regression grade (TRG) is reliable.
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Affiliation(s)
- M. J Morgan
- University of Sydney, Royal Prince Alfred Hospital, Sydney NSW Australia, Department of Surgery, Royal Prince Alfred Hospital, Sydney NSW Australia, Department of Gastroenterology, Royal Prince Alfred Hospital, Sydney NSW Australia, Department of Pathology, Royal Prince Alfred Hospital, Sydney NSW Australia, Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney NSW Australia, Wellington Cancer Centre, Wellington Hospital, New Zealand
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Feliu J, Calvilio J, Escribano A, de Castro J, Sánchez ME, Mata A, Espinosa E, García Grande A, Mateo A, González Barón M. Neoadjuvant therapy of rectal carcinoma with UFT-leucovorin plus radiotherapy. Ann Oncol 2002; 13:730-6. [PMID: 12075741 DOI: 10.1093/annonc/mdf116] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The object of this phase II study was to assess the impact of preoperative external radiation therapy combined with UFT and leucovorin on tumor response, sphincter preservation and tumor control in patients with rectal carcinoma. PATIENTS AND METHODS Forty-one patients with resectable extraperitoneal rectal adenocarcinoma received radiation therapy and two courses of chemotherapy. Chemotherapy consisted of a 2-h infusion of 6S-steroisomer of leucovorin (6SLV) 250 mg/m2 on day 1, oral 6SLV 7.5 mg every 12 h on days 2-14, and UFT either 350 or 300 mg/m2 on days 1 to 14 every 28 days. Six additional courses of chemotherapy were given after surgery. RESULTS Seven of 16 patients (43%) who received 350 mg/m2/day of UFT had grade 3-4 diarrhea and two other patients (12%) had grade 3-4 dermatitis. The next 25 patients received 300 mg/m2/day of UFT and only 14% of them had grade 3-4 diarrhea. Surgery consisted of low-anterior resection in 26 patients (63%) and abdominal-perineal amputation in 15 (37%). There were six histological complete responses (15%). Downstaging occurred in 25 patients (63%). The overall survival at 3 years was 90% and the pelvic disease-free survival 92%. CONCLUSIONS Preoperative therapy with radiotherapy and UFT-6SLV downstaged 63% of tumors and allowed a sphincter-preserving procedure in some patients. Toxicity was moderate. This scheme is convenient because of the oral administration of chemotherapy.
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Affiliation(s)
- J Feliu
- Department of Medical Oncology, Hospital La Paz, Madrid, Spain.
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Esposito G, Pucciarelli S, Alaggio R, Giacomelli L, Marchiori E, Iaderosa GA, Friso ML, Toppan P, Chieco-Bianchi L, Lise M. P27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer. Ann Surg Oncol 2001; 8:311-8. [PMID: 11352304 DOI: 10.1007/s10434-001-0311-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Our aim was to ascertain whether or not the response to preoperative chemoradiotherapy for rectal cancer is associated with p27kip1 and p53 protein expression. METHODS Thirty-eight patients (27 male, 11 female) with a mean age of 59 years (age range 33-87) and stage II-III rectal cancer received preoperative chemoradiotherapy (45-50.4 Gy; 5-FU 350 mg/m2/day and leucovorin 10 mg/m2/day). Thirty-one underwent low anterior resection; seven underwent abdominoperineal excision. Endoscopic tumor biopsies, performed before adjuvant therapy, were evaluated for: histologic type, tumor differentiation, mitotic index, and p27kip1 and p53 protein expression which were immunohistochemically determined. p53 expression was graded as: a) absent or present in < or =10% of tumor cells; b) present in 11-25%; c) present in 26-75%; and d) present in >75% of tumor cells. p27kip1 expression was assessed using both light microscopy (percent of stained cells x10 HPF) and cytometry with an image analysis workstation. Tumor response, ascertained with histology, was classified using a scale from 0 (no response) to 6 (complete pathologic response). RESULTS The mitotic index for the endoscopic biopsies was low in 14 cases, moderate in 17 cases, and high in 7 cases. p53 protein expression was found in 21 (a), 3 (b), 3 (c), and 11 (d) cases. The mean percentage of cells expressing the p27kip1 protein was 34 (range 0-77.14%). A close correlation was found between cytometric and light microscopy findings for p27kip1 (r2 = 0.92, P = .0001). Tumor differentiation was good in 5 cases, poor in 2 cases, and moderate in the remaining 31 cases. While the response to adjuvant therapy was good/complete in 25 (65.78%) cases, it was absent/poor in 13 (34.21%) cases. Univariate analysis associated type of adjuvant therapy (chemoradiotherapy, P = .0428) and p27kip1 protein lower expression (P = .0148) with a poor response to adjuvant treatment. Stepwise linear regression found overexpression of p53 and p27kip1 and young age to be independent variables that were linked to a good response to adjuvant therapy. CONCLUSIONS Lack of p27kip1 and p53 protein expression in rectal cancer is associated with a poor response to preoperative adjuvant therapy.
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Affiliation(s)
- G Esposito
- Section of Oncology, Department of Oncology and Surgery of the University of Padova, Italy.
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Affiliation(s)
- V E Pricolo
- Division of Colon and Rectal Surgery, Department of Surgery, Brown University, Providence, RI, USA.
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Kuvshinoff B, Maghfoor I, Miedema B, Bryer M, Westgate S, Wilkes J, Ota D. Distal margin requirements after preoperative chemoradiotherapy for distal rectal carcinomas: are < or = 1 cm distal margins sufficient? Ann Surg Oncol 2001; 8:163-9. [PMID: 11258782 DOI: 10.1007/s10434-001-0163-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Sphincter-sparing alternatives to abdominoperineal resection (APR) in the treatment of rectal cancer often are underused out of concern for inadequate distal margins and local failure. The present study addresses whether sphincter-sparing techniques with distal margins < or = 1 cm adversely influence oncological outcome in patients given preoperative chemoradiotherapy. METHODS Thirty-seven patients with rectal cancer < or = 8 cm from the anal verge were enrolled in the study. Preoperative external beam radiotherapy (5400 Gy) was administered together with continuous infusion of 5-fluorouracil (300 mg/m2/day). Surgical resection was performed in 36 patients with pathological assessment of tumor response and margins. Patients with sphincter-sparing resection and distal margins > 1 cm or < or = 1 cm and those who underwent APR were compared. RESULTS Thirty-six patients completed preoperative chemoradiotherapy, with successful sphincter-preservation in 28 patients. At a median follow-up of 33 months, there were 12 recurrences overall, which included 11 distant failures and four pelvic failures. Disease-free survival (DFS) was not different between those who had an APR compared with sphincter-sparing resection with distal margins < or = 1 cm. DFS was worse (P < .02) when radial margins were < or = 3 mm compared with > 3 mm. CONCLUSIONS Sphincter preservation is feasible in more than 75% of patients with tumors < or = 8 cm from the anal verge after preoperative chemoradiotherapy. Sphincter-sparing surgery with distal margins < or = 1 cm can be used without adversely influencing local recurrence or DFS. Limited radial margins (< or = 3 mm), however, are associated with increased disease recurrence.
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Affiliation(s)
- B Kuvshinoff
- Department of Surgery, University of Missouri Ellis Fischel Cancer Center, Columbia 65203, USA.
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Tamada K, Wada S, Ohashi A, Tomiyama T, Satoh Y, Miyata T, Ido K, Nakazawa M, Sugano K. Intraductal US in assessing the effects of radiation therapy and prediction of patency of metallic stents in extrahepatic bile duct carcinoma. Gastrointest Endosc 2000; 51:405-11. [PMID: 10744810 DOI: 10.1016/s0016-5107(00)70439-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND We assessed the local effects of radiation therapy using intraductal ultrasonography (US) to predict the subsequent patency of metallic stents in bile duct carcinoma. METHODS Data from 16 patients with extrahepatic-suprapancreatic bile duct carcinoma were prospectively analyzed. Thin-caliber US probes (2.0 mm diameter/20 MHz frequency and 2.8 mm diameter/10 MHz frequency) were inserted into the bile duct via a percutaneous transhepatic approach pre- and postradiation therapy to evaluate the effects of treatment. When intraductal US showed a reduction in bile duct wall thickness of 30% or greater or showed a lessening of vessel (portal vein or right hepatic artery) invasion, radiation therapy was judged to be effective. Noncovered metallic stents were then inserted, and their patency was evaluated over time. RESULTS When radiation therapy was effective (n = 7), the metallic stent was patent for 522 +/- 571 days. When radiation was ineffective (n = 9), the metallic stent was patent for only 188 +/- 159 days. When radiation therapy was ineffective, stent obstruction occurred in 6 of 9 (66.7%) patients during this period, significantly more frequently than when radiation therapy was effective (14.3%, p < 0.05). CONCLUSIONS Assessment of local radiation effects by intraductal US is useful for predicting patency of metallic stents in bile duct cancer.
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Affiliation(s)
- K Tamada
- Departments of Gastroenterology and Radiology, Jichi Medical School, Yakushiji, Tochigi, Japan
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Abstract
A review of the history, indications, basic technique, end results, and complications of exenterative surgery for pelvic neoplasms is provided. The authors discuss their broad personal experience with the operation. Much of this experience evolved from work at Barnes Hospital and the Ellis Fischel State Cancer Hospital. The techniques are applicable to advanced neoplasms of the cervix uteri, scrotum, urinary bladder, and other, less frequent neoplasms still confined to the pelvis.
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Affiliation(s)
- M J Lopez
- Tufts University School of Medicine, St. Elizabeth Medical Center, Boston, Massachusetts, USA
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Wheeler JM, Warren BF, Jones AC, Mortensen NJ. Preoperative radiotherapy for rectal cancer: implications for surgeons, pathologists and radiologists. Br J Surg 1999; 86:1108-20. [PMID: 10504363 DOI: 10.1046/j.1365-2168.1999.01209.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Over 10,000 new cases of rectal cancer are reported in the UK each year and adjuvant treatments, such as preoperative radiotherapy, are now being used almost routinely. METHODS A literature review was performed on the Medline database for English language publications on preoperative radiotherapy and rectal cancer. The radioresponsiveness of rectal cancer, tumour downstaging, radiological staging of irradiated rectal cancer, effects of radiotherapy on anastomotic integrity, anorectal and genitourinary function, the role of preoperative radiotherapy in local excision of rectal cancer, and the histological changes peculiar to radiotherapy were evaluated. RESULTS AND CONCLUSION Following preoperative radiotherapy, rectal cancer may be downstaged or, occasionally, eradicated histologically. Rectal cancer can now be staged accurately before operation, but this is significantly less reliable following irradiation. The pathological specimen must be examined thoroughly before a tumour can be reported to have been eradicated, especially as unique histological changes are produced by radiotherapy. There is no evidence to suggest that preoperative radiotherapy adversely affects anastomotic integrity. It appears that preoperative radiotherapy has some adverse affects on long-term anorectal dysfunction, but this must not distract from its main objectives in rectal cancer, namely reduced local recurrence rates and improved overall survival.
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Affiliation(s)
- J M Wheeler
- Department of Colorectal Surgery, John radcliffe Hospital, Oxford, UK
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Minsky BD. Adjuvant combined modality therapy for rectal cancer. Cancer Treat Res 1999; 98:153-71. [PMID: 10326668 DOI: 10.1007/978-1-4615-4977-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Affiliation(s)
- B D Minsky
- Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
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Adams DR, Blatchford GJ, Lin KM, Ternent CA, Thorson AG, Christensen MA. Use of preoperative ultrasound staging for treatment of rectal cancer. Dis Colon Rectum 1999; 42:159-66. [PMID: 10211490 DOI: 10.1007/bf02237121] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Transrectal ultrasound is the standard method for preoperative staging of rectal cancer. This study reviews the accuracy of transrectal ultrasound staging for T3 disease and its use in the selection of patients for neoadjuvant chemoradiation. METHODS One hundred seventeen patients underwent preoperative transrectal ultrasound evaluation for rectal cancer. Accuracy of transrectal ultrasound was evaluated among 70 patients not receiving preoperative chemoradiation. Forty-seven patients received neoadjuvant chemoradiation based on transrectal ultrasound results. Tumor downstaging and early recurrence were evaluated among 45 of 47 patients receiving neoadjuvant chemoradiation. RESULTS Among 70 nonirradiated patients, 19 were pathologic Stage pT3. Transrectal ultrasound correctly identified 18 of 19 patients with Stage pT3 (sensitivity, 94.7 percent). Transrectal ultrasound correctly identified 44 of 51 patients with less than pT3 disease (specificity, 86.3 percent). After preoperative chemoradiation in 45 patients with ultrasound Stage uT3 or uT4 tumors, 56 percent of them experienced a reduction in T stage. Residual nodal disease was found in 31 percent of patients. A complete pathologic response with no residual disease at operation was observed in 22 percent of patients. During a median follow-up period of 21 months after diagnosis, seven patients experienced a recurrence of their disease at a median of 12 months after diagnosis. Five of seven patients with recurrence were among a subgroup of ten patients who both failed to downstage T and had residual nodal disease at operation. CONCLUSION Transrectal ultrasound is an accurate modality for selecting patients for neoadjuvant treatment. Preoperative chemoradiation produced downstaging in 56 percent of patients. Factors related to early recurrence included residual nodal disease and failure to downstage T after neoadjuvant chemoradiation.
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Affiliation(s)
- D R Adams
- Department of Surgery, Creighton University, Omaha, Nebraska 38131, USA
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Rossi BM, Nakagawa WT, Borges AY, Bechara Júnior W, Vieira RADC, Lopes A, Kowalski LP. Radioterapia e cirurgia na abordagem do câncer do reto: revisão de literatura, fatores prognósticos e resultados de tratamento. Rev Col Bras Cir 1998. [DOI: 10.1590/s0100-69911998000200003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
O objetivo principal deste estudo foi avaliar os resultados da cirurgia isolada ou associada a radioterapia pré-operatória em pacientes portadores de adenocarcinoma do reto. Foram analisados retrospectivamente 96 pacientes submetidos a cirurgias curativas entre 1972 e 1993. A análise visou, principalmente, comparar as taxas de sobrevida global em cinco anos e de recidiva local. Quarenta e seis pacientes tratados por cirurgias isoladas tiveram taxas de sobrevida em cinco anos e de recidiva local de 51,7% e 26,9%, respectivamente, nos estádios II e III. Cinqüenta pacientes submeteram-se a radioterapia pré-operatória na dosagem de 4.500 cGy, em 25 sessões de 180 cGy, com taxas de sobrevi da em cinco anos e de recidiva local de 60,8% e 18,2%, respectivamente, nos estádios II e III. As diferenças entre os dois grupos terapêuticos não foram estatisticamente significativas. A análise multivariada demonstrou que o estadiamento da neoplasia, principalmente com relação à presença ou não de linfonodos regionais metastáticos, foi o fator prognóstico mais importante, independentemente do grupo terapêutico analisado. Baseados nos resultados apresentados, discutimos que a indicação da radioterapia em câncer do reto deve ser mais seletiva, com realização de cirurgia imediata em pacientes portadores de tumores retais móveis, mesmo infiltrativos na parede, irradiando no pós-operatório apenas os casos com maior risco de recidiva, de acordo com o resultado do exame anatomopatológico da peça cirúrgica. Pacientes portadores de tumores com mobilidade reduzida em relação às paredes pélvicas devem ser irradiados no pré-operatório com a finalidade de facilitação do ato cirúrgico e diminuição do risco de disseminação de células tumorais no intra-operatório e conseqüente diminuição das taxas de recidiva local.
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40
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Edney JA. 50 years of breast, endocrine, and oncologic surgery at the Southwestern Surgical Congress: earlier diagnosis and improved outcomes. Am J Surg 1998; 175:92S-98S. [PMID: 9558057 DOI: 10.1016/s0002-9610(98)00065-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- J A Edney
- Department of Surgery, University of Nebraska Medical Center, Omaha 68198-3280, USA
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41
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Rossi BM, Nakagawa WT, Novaes PE, Filho WD, Lopes A. Radiation and chemotherapy instead of surgery for low infiltrative rectal adenocarcinoma: a prospective trial. Ann Surg Oncol 1998; 5:113-8. [PMID: 9527263 DOI: 10.1007/bf02303843] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The objective of this prospective study was to determine the possibility of treatment based exclusively on chemotherapy and radiotherapy for patients with low infiltrative rectal tumors in an attempt to preserve sphincter function. METHODS Sixteen patients with rectal adenocarcinoma up to 3 cm above the pectineal line with initial indications for abdominoperineal resection (APR) were submitted to a 5040-cGy (28 x 180 cGy) radiotherapy dose and chemotherapy during the first 3 and last 3 days of radiotherapy, using 425 mg/m2/day of 5-fluorouracil (5FU) and 20 mg/m2/day of folinic acid. Levamisole was used at 150 mg/day for 3 consecutive days at 2-week intervals throughout the period of therapy. Patients with a complete response were not submitted to APR, but received additional brachytherapy for curative purposes with doses from 2000 to 3000 cGy. Patients with recurrence after a complete response, with partial response, or with no response were submitted to APR. RESULTS Six patients (37.5%) presented a complete response, five (31.25%) presented a partial response, and five (31.35%) did not respond. The disease-free interval ranged from 1 to 34 months (mean = 11 months) among the six patients with complete response, and only one patient not submitted to APR is currently asymptomatic. Among the 15 patients with an indication for APR, three refused surgery because of full improvement of clinical symptoms and currently have tumor activity in the rectum. Mean patient follow-up was 23.8 months (8 to 43 months), and ten patients (62.5%) showed no evidence of active disease at last follow-up. CONCLUSIONS The therapeutic schedule used was not effective in preserving sphincter function in patients with low infiltrative rectal adenocarcinoma, because responses, although very frequent, were only temporary.
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Affiliation(s)
- B M Rossi
- Department of Pelvic Surgery, A.C. Camargo Hospital, Antonio Prudente Foundation, São Paulo, Brazil
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42
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Pokorny RM, Wrightson WR, Lewis RK, Paris KJ, Hofmeister A, LaRocca R, Myers SR, Ackerman D, Galandiuk S. Suppository administration of chemotherapeutic drugs with concomitant radiation for rectal cancer. Dis Colon Rectum 1997; 40:1414-20. [PMID: 9407977 DOI: 10.1007/bf02070704] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Preoperative radiation with combined chemotherapy is effective in shrinking advanced rectal cancer locally and facilitating subsequent surgery. Suppository delivery of 5-fluorouracil is associated with less toxicity and higher rectal tissue concentrations than intravenous administration. This prompted us to evaluate suppository and intravenous administration of 5-fluorouracil and mitomycin C with concomitant radiation to determine associated toxicity. METHODS Rectal, liver, lymph node, and lung tissue and systemic and portal blood were collected serially from male Sprague Dawley rats to determine drug concentrations following suppository or intravenous delivery of 5-fluorouracil or mitomycin C. Thirty-six animals were randomly assigned to treatment groups and received 5-fluorouracil suppositories, mitomycin C suppositories, or an equivalent intravenous dose of 5-fluorouracil or mitomycin C 30 minutes before radiation therapy. Before and 3, 6, 10, and 15 days following this treatment, blood was collected, colonoscopy was performed, and rectal tissue was harvested for histologic examination. RESULTS Mitomycin C suppository was significantly less toxic compared with intravenous delivery, and higher rectal tissue concentrations were observed from 10 to 30 minutes (P < 0.05). Compared with intravenous 5-fluorouracil administration and radiation, 5-fluorouracil suppository and radiation resulted in additive myelosuppression at day 6 (P < 0.05) with rapid recovery. CONCLUSIONS 5-Fluorouracil and mitomycin C suppository delivery combined with radiation causes less systemic toxicity and is more effective than intravenous administration.
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Affiliation(s)
- R M Pokorny
- Price Institute of Surgical Research and Department of Surgery, University of Louisville School of Medicine, Kentucky 40292, USA
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Stotland BR, Siegelman ES, Morris JB, Kochman ML. Preoperative and postoperative imaging for colorectal cancer. Hematol Oncol Clin North Am 1997; 11:635-54. [PMID: 9257149 DOI: 10.1016/s0889-8588(05)70454-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Management and survival in colorectal cancer are dictated by the extent of the disease at the initial diagnosis. Technological advances over the past 25 years have improved the ability to accurately preoperatively stage these lesions and detect recurrence. This article reviews the focus on the utility of computerized tomography, magnetic resonance, endoscopic ultrasound, and newer imaging methods including PET scan and monoclonal antibodies in the management of colorectal carcinoma.
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Affiliation(s)
- B R Stotland
- Department of Medicine, University of Pennsylvania Health System, Philadelphia, USA
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45
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Minsky BD. The role of adjuvant radiation therapy in the treatment of colorectal cancer. Hematol Oncol Clin North Am 1997; 11:679-97. [PMID: 9257151 DOI: 10.1016/s0889-8588(05)70456-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Radiation therapy in conjunction with 5-FU chemotherapy is an effective method in the adjuvant treatment of both colon and rectal cancer.
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Affiliation(s)
- B D Minsky
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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46
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Cohen AM, Kelsen D, Saltz L, Minsky BD, Nelson H, Farouk R, Gunderson LL, Michelassi F, Arenas RB, Schilsky RL, Willet CG. Adjuvant therapy for colorectal cancer. Curr Probl Surg 1997; 34:601-76. [PMID: 9251585 DOI: 10.1016/s0011-3840(97)80013-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- A M Cohen
- Department of Surgery, Cornell University Medical College, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
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Grann A, Minsky BD, Cohen AM, Saltz L, Guillem JG, Paty PB, Kelsen DP, Kemeny N, Ilson D, Bass-Loeb J. Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer. Dis Colon Rectum 1997; 40:515-22. [PMID: 9152176 DOI: 10.1007/bf02055370] [Citation(s) in RCA: 186] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE We report the downstaging, sphincter preservation, acute toxicity, and preliminary local control and survival results of preoperative 5-fluorouracil (5-FU), low-dose leucovorin (LV), and concurrent radiation therapy followed by postoperative LV/5-FU for treatment of patients with clinically resectable T3 rectal cancer. MATERIALS AND METHODS A total of 32 patients received two monthly cycles of preoperative LV/5-FU (bolus daily X 5). Radiation therapy (5,040 cGy) began concurrently on day 1. Postoperatively, patients received a median of two monthly cycles of LV/5-FU (range, 0-10). RESULTS The complete response rate was 9 percent pathologic and 13 percent clinical, for a total of 22 percent. Total Grade 3+ acute toxicity during the preoperative combined modality segment was 25 percent (8/32). Of the 20 patients who were thought to initially require an abdominoperineal resection and for whom the intent of treatment was sphincter preservation, 17 (85 percent) were able to undergo sphincter-preserving surgery. With a median follow-up of 22 (3-59) months, none have developed local failure, and the three-year actuarial disease-free survival rate was 60 percent. CONCLUSION Our data reveal encouraging downstaging, sphincter preservation and acute toxicity with this regimen. Additional follow-up is needed to assess the long-term local control and survival rates.
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Affiliation(s)
- A Grann
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
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48
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Gore RM. COLORECTAL CANCER. Radiol Clin North Am 1997. [DOI: 10.1016/s0033-8389(22)00715-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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Kahn H, Alexander A, Rakinic J, Nagle D, Fry R. Preoperative staging of irradiated rectal cancers using digital rectal examination, computed tomography, endorectal ultrasound, and magnetic resonance imaging does not accurately predict T0,N0 pathology. Dis Colon Rectum 1997; 40:140-4. [PMID: 9075746 DOI: 10.1007/bf02054977] [Citation(s) in RCA: 77] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The postradiation preoperative staging results of 25 patients with rectal cancer who were found to have Stage T0,N0 lesions after surgery were examined. Our aim was to assess the ability of preoperative staging following radiation therapy to predict the absence of disease. METHODS From 1983 to 1994, 25 patients treated with preoperative radiation therapy for biopsy-proven rectal cancer were found to have no pathologic evidence of disease in the resected specimen (T0,N0). The preoperative postradiation disease staging results of these patients were compared with the postoperative pathologic findings. Each patient received 4,500 to 5,580 cGy during a five-week to six-week period, and four patients had preoperative chemotherapy. Surgical resection was performed six to eight weeks after completion of radiation therapy. All 25 patients were staged by digital rectal examination before surgery. In addition, 13 patients were assessed using computed tomography, 6 by endorectal ultrasound, and 1 by magnetic resonance imaging. RESULTS Most irradiated lesions were overstaged by radiologic assessment and physical examination. No technique could reliably distinguish between postradiation fibrosis and residual cancer. The negative predictive value for digital rectal examination was 24 percent. Computed tomography accurately staged 23 percent of lesions, and endorectal ultrasound predicted 17 percent of lesions correctly. The single patient evaluated by magnetic resonance imaging was overstaged and thought to have a T2 lesion. CONCLUSIONS Our ability to assess local eradication of rectal cancer following radiation therapy remains poor. Conventional imaging and clinical examination techniques are unable to safely predict which patients do not require surgical excision following curative radiation therapy for rectal cancer.
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Affiliation(s)
- H Kahn
- Division of Colon and Rectal Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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Affiliation(s)
- S Galandiuk
- Department of Surgery, University of Louisville School of Medicine, Kentucky 40292, USA
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