Background:
In the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity.
Material and Methods:
This review article focuses on phase II–III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings.
Results:
After preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients’ refusal, or investigator’s discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease.
Conclusion:
Whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.
Hintergrund:
Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann.
Material und Methoden:
Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts von ASCO/ASTRO/ESTRO-Konferenzen.
Ergebnisse:
Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen, patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter Phase- II-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit (histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde, könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken.
Schlussfolgerung:
Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie das krankheitsfreie Überleben verbessern kann.
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References
Aschele C, Pinto C, Cordio S, et al. Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol (Meeting Abstracts) 2009;27:CRA4008.
Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23.
Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 2010, epub ahead of print.
Burton S, Brown G, Daniels IR, et al. MRI directed multidisciplinary team preoperative treatment strategy: the way to eliminate positive circumferential margins? Br J Cancer 2006;94:351–7.
Calvo FA, Serrano FJ, Diaz-Gonzalez JA, et al. Improved incidence of pTO downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol 2006;17:1103–10.
Chau I, Allen M, Cunningham D, et al. Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer. Br J Cancer 2003;88:1017–24.
Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006;24:668–74.
Chua YJ, Barbachano Y, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRIdefined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol 2010;11:241–8.
Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3–4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007;25:4379–86.
Fernandez-Martos C, Pericay C, Aparicio J, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol 2010;28:859–65.
Fernandez-Martos C, Safont M, Feliu J, et al. Induction chemotherapy with or without chemoradiation in intermediate-risk rectal cancer patients defined by magnetic resonance imaging (MRI): A GEMCAD study. J Clin Oncol (Meeting Abstracts) 2010;28:TPS196.
Garcia-Aguilar J, Shi Q, Thomas CR, Jr., et al. Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) of uT2uN0 rectal cancer (RC) treated by local excision (LE): Results of the ACOSOG Z6041 trial. J Clin Oncol (Meeting Abstracts) 2010;28:3510.
Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010;28:1638–44.
Ghadimi BM, Grade M, Difilippantonio MJ, et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 2005;23:1826–38.
Glynne-Jones R, Grainger J, Harrison M, et al. Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious? Br J Cancer 2006;94:363–71.
Gunnlaugsson A, Anderson H, Fernebro E, et al. Multicentre phase II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable colorectal cancer: the CORGI-L Study. Eur J Cancer 2009;45:807– 13.
Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004;240:711–7; discussion 7–8.
Koeberle D, Burkhard R, von Moos R, et al. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer. Br J Cancer 2008;98:1204–9.
Liersch T, Grade M, Gaedcke J, et al. Preoperative chemoradiotherapy in locally advanced rectal cancer: correlation of a gene expression-based response signature with recurrence. Cancer Genet Cytogenet 2009;190:57– 65.
Marechal R, Vos B, Polus M, et al. Chemotherapy induction followed by preoperative chemoradiation versus preoperative chemoradiation alone in locally advanced rectal cancer (LARC): A randomized controlled phase II study. J Clin Oncol (Meeting Abstracts) 2010;28:3637.
Marquardt F, Rodel F, Capalbo G, et al. Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol 2009;185:371–8.
Minsky BD, Roedel C, Valentini V. Combined modality therapy for rectal cancer. Cancer J 2010;16:253–61.
Ngan S, Fisher R, Goldstein D, et al. A randomized trial comparing local recurrence (LR) rates between short-course (SC) and long-course (LC) preoperative radiotherapy (RT) for clinical T3 rectal cancer: An intergroup trial (TROG, AGITG, CSSANZ, RACS). J Clin Oncol (Meeting Abstracts) 2010;28:3509.
Påhlman L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma. Report from a randomized multicenter trial. Ann Surg 1990;211:187–95.
Paskeviciute B, Bolling T, Brinkmann M, et al. Impact of (18)F-FDG-PET/CT on staging and irradiation of patients with locally advanced rectal cancer. Strahlenther Onkol 2009;185:260–5.
Quasar Collaborative G, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007;370:2020–9.
Rödel C, Liersch T, Hermann RM, et al. Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 2007;25:110–7.
Rödel C, Sauer R. Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 2007;183:227–35.
Rödel C, Sauer R, Fietkau R. The role of magnetic resonance imaging to select patients for preoperative treatment in rectal cancer. Strahlenther Onkol 2009;185:488–92.
Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124–30.
Rutten H, Sebag-Montefiori D, Glynne-Jones R, et al. Capecitabine, oxaliplatin, radiotherapy, and excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma: Results of an international multicenter phase II study. J Clin Oncol (Meeting abstracts) 2006;24:153s.
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40.
Schmiegel W, Pox C, Reinacher-Schick A, et al. S3 guidelines for colorectal carcinoma: results of an evidence-based consensus conference on February 6/7, 2004 and June 8/9, 2007 (for the topics IV, VI and VII). Z Gastroenterol 2010;48:65–136.
Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin Oncol (Meeting Abstracts) 2010;28:3511.
Valentini V, Aristei C, Glimelius B, et al. Multidisciplinary Rectal Cancer Management: 2nd European Rectal Cancer Consensus Conference (EURECACC2). Radiother Oncol 2009;92:148–63.
van Dijk TH, Havenga K, Beukema J, et al. Short-course radiation therapy, neoadjuvant bevacizumab, capecitabine and oxaliplatin, and radical resection of primary tumor and metastases in primary stage IV rectal cancer: A phase II multicenter study of the Dutch Colorectal Cancer Group. J Clin Oncol (Meeting abstracts) 2010;28:3638.
Vliegen RF, Beets-Tan RG, Vanhauten B, et al. Can an FDG-PET/CT predict tumor clearance of the mesorectal fascia after preoperative chemoradiation of locally advanced rectal cancer? Strahlenther Onkol 2008;184:457–64.
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Rödel, C., Arnold, D., Becker, H. et al. Induction Chemotherapy before Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer. Strahlenther Onkol 186, 658–664 (2010). https://doi.org/10.1007/s00066-010-2194-2
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DOI: https://doi.org/10.1007/s00066-010-2194-2