Strahlentherapie und Onkologie

, Volume 190, Issue 2, pp 158–164 | Cite as

Oxaliplatin and capecitabine concomitant with neoadjuvant radiotherapy and extended to the resting period in high risk locally advanced rectal cancer

  • Y.-H. Gao
  • X. Zhang
  • X. An
  • M.-Y. Cai
  • Z.-F. Zeng
  • G. Chen
  • L.-H. Kong
  • J.-Z. Lin
  • D.-S. Wan
  • Z.-Z. Pan
  • P.-R. Ding
Original article

Abstract

Background

Conventional neoadjuvant chemoradiotherapy (CRT) is suboptimal for systemic control in locally advanced rectal cancer (LARC). To improve systemic control, we developed an alternative approach in which an intensified oxaliplatin and capecitabine (XELOX) chemotherapy regimen was administered concomitantly with radiation and extended to the resting period (consolidation chemotherapy) for high-risk LARC. The aim of the current study was to evaluate the short-term efficacy and toxicity of this strategy.

Methods

Patients with high-risk LARC were treated with CRT. Two cycles of XELOX were administered concomitantly with radiation. Thereafter, an additional cycle of the same regimen was administered during the resting period after completion of CRT. Tumor response, toxicities and surgical complications were recorded.

Results

This study includes 36 patients treated with the above strategy. All patients completed the planned concurrent CRT. Because of grade 3 toxicities, 2 patients were unable to complete the additional chemotherapy. Grade 3 toxicities were leucopenia (2.8 %), diarrhea (2.8 %) and radiodermatitis (2.8 %). All patients underwent optimal surgery with total mesorectal excision (TME) and a sphincter-saving procedure was performed in 27 patients (75 %). There was no perioperative mortality. Postoperative complications developed in 7 patients (19.4 %). Pathologic complete regression (pCR),“nearly pCR” (major regression), and moderate or minimal regression were achieved in 13 (36.1 %), 16 (44.4 %), and 7 patients (19.5 %), respectively.

Conclusion

The preliminary results suggest that a XELOX regimen initially administered concomitantly with radiotherapy and then extended to the resting period in high-risk LARC patients is well tolerated. The strategy is highly effective in terms of pCR and nearly pCR rates, and thus warrants further investigation.

Keywords

Chemoradiotherapy Consolidation chemotherapy Toxicity Survival Surgery 

Oxaliplatin und Capecitabin begleitend zur neoadjuvanten Radiotherapie und deren Ausweitung auf die Ruhephase beim lokal fortgeschrittenen High-Risk-Rektumkarzinom

Zusammenfassung

Hintergrund

Konventionell neoadjuvante Radiochemotherapie (CRT) ist suboptimal für die systemische Kontrolle des lokal fortgeschrittenen Rektumkarzinoms (LARC). Um die systemische Kontrolle zu verbessern, haben wir eine alternative Herangehensweise entwickelt, in welcher wir eine intensivierte Chemotherapie mit dem XELOX-Therapieschema (Oxaliplatin und Capecitabin) begleitend zur Bestrahlung kombiniert und auf die Ruhephase des High-Risk-LARC ausgeweitet haben (Konsolidierungschemotherapie). Das Ziel der Studie stellte die Evaluierung der Kurzzeit-Wirksamkeit und der Toxizität dieser Vorgehensweise dar.

Patienten und Methoden

Patienten mit High-Risk-LARC wurden mit einer CRT behandelt. Begleitend zur Bestrahlung wurden 2 Therapiezyklen XELOX verabreicht. Anschließend wurde ein zusätzlicher Therapiezyklus über die Ruhephase nach Abschluss der CRT verabreicht. Erfasst wurden Tumorantwort, Toxizität und Komplikationen beim Eingriff.

Ergebnisse

Es wurden 36 Patienten ermittelt, welche mit dieser Methode behandelt wurden. Alle Patienten komplettierten die begleitende CRT. Aufgrund von Grad-3-Toxizitäten konnten 2 Patienten die zusätzliche Chemotherapie nicht abschließen. Toxizitäten dritten Grades waren Leukozytopenie (2,8 %), Diarrhoe (2,8 %) und Radiodermatitis (2,8 %). Allen Patienten wurde eine optimale chirurgische Therapie durch totale mesorektale Exzision („total mesorectal excision“, TME) zuteil, unter ihnen befanden sich 27 Patienten (75 %), die spinktererhaltend operiert werden konnten. Es gab keine perioperative Mortalität in der Kohorte. Bei 7 Patienten (19,4 %) traten postoperative Komplikationen auf. Eine pathologisch vollständige Regression (pCR), überwiegende Regression (“nearly pCR“) und mäßige oder minimale Regression wurde bei je 13 (36,1 %), 16 (44,4 %) und 7 (19,5 %) Patienten erreicht.

Schlussfolgerung

Die vorläufigen Ergebnisse legen den Schluss nahe, dass ein Therapieschema mit XELOX begleitend zur Radiotherapie, ausgeweitet auf die Ruhephase bei High-Risk-LARC gut toleriert wird. Die Methode ist höchst effektiv in Bezug auf pCR- und überwiegende pCR-Raten. Somit sind weitere Untersuchungen gerechtfertigt.

Schlüsselwörter

Radiochemotherapie Konsolidierungschemotherapie Toxizität Überleben Operation 

Notes

Acknowledgments

The authors would like to acknowledge Andrea Schott and Senchao Lai for the German translation.

Financial disclosures

Grant support: This work was supported by funds from the Nature Science Foundation of China (No. 81101591); the Natural Science Foundation of Guangdong Province, China (No.S2011040005278; No. 9151008901000157) and the Science and Technology Planning Project of Guangdong Province, China (No.2010B060900043).

Compliance with ethical guidelines

Conflict of interests. Yuan-Hong Gao, Xu Zhang, Xin An, Mu-Yan Cai, Zhi-Fan Zeng, Gong Chen, Ling-Heng Kong, Jun-Zhong Lin, De-Sen Wan, Zhi-Zhong Pan and Pei-Rong Ding state that there are no conflicts of interest.

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

References

  1. 1.
    Peeters KC, Marijnen CA, Nagtegaal ID et al (2007) The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693–701PubMedCrossRefGoogle Scholar
  2. 2.
    Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740PubMedCrossRefGoogle Scholar
  3. 3.
    Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123PubMedCrossRefGoogle Scholar
  4. 4.
    Gerard A, Buyse M, Nordlinger B et al (1998) Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 208:606–614CrossRefGoogle Scholar
  5. 5.
    o A (1984) The evaluation of low dose pre-operative X-ray therapy in the management of operable rectal cancer; results of a randomly controlled trial. Br J Surg 71:21–25CrossRefGoogle Scholar
  6. 6.
    Kapiteijn E, Marijnen CA, Nagtegaal ID et al (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646PubMedCrossRefGoogle Scholar
  7. 7.
    o A (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336:980–987CrossRefGoogle Scholar
  8. 8.
    Guckenberger M, Saur G, Wehner D et al (2012) Comparison of preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer. Strahlenther Onkol 188:551–557PubMedCrossRefGoogle Scholar
  9. 9.
    Fernandez-Martos C, Pericay C, Aparicio J et al (2010) 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 28:859–865PubMedCrossRefGoogle Scholar
  10. 10.
    Chau I, Brown G, Cunningham D et al (2006) Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 24:668–674PubMedCrossRefGoogle Scholar
  11. 11.
    Rodel C, Liersch T, Becker H et al (2012) Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13:679–687PubMedCrossRefGoogle Scholar
  12. 12.
    Bria E GR, Raftopoulos H et al (2007) Comparing two methods of meta-analysis in clinical research—individual patient data-based (IPD) and literature-based abstracted data (AD) methods: analyzing five oncology issues involving more than 10,000 patients in randomized clinical trials (RCTs). J Clin Oncol 25:abstr 6512CrossRefGoogle Scholar
  13. 13.
    Zampino MG, Magni E, Leonardi MC et al (2009) Capecitabine initially concomitant to radiotherapy then perioperatively administered in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 75:421–427PubMedCrossRefGoogle Scholar
  14. 14.
    Habr-Gama A, Perez RO, Sabbaga J et al (2009) Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period. Dis Colon Rectum 52:1927–1934PubMedCrossRefGoogle Scholar
  15. 15.
    Garcia-Aguilar J, Smith DD, Avila K et al (2011) Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 254:97–102PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    o A (2010) AJCC cancer staging manual, 7th edn. Springer, New YorkGoogle Scholar
  17. 17.
    Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23PubMedCrossRefGoogle Scholar
  18. 18.
    Ding P, Liska D, Tang P et al (2012) Pulmonary recurrence predominates after combined modality therapy for rectal cancer: an original retrospective study. Ann Surg 256:111–116PubMedCrossRefGoogle Scholar
  19. 19.
    Chua YJ, Barbachano Y, Cunningham D et al (2010) Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol 11:241–248PubMedCrossRefGoogle Scholar
  20. 20.
    Rodel C, Arnold D, Becker H et al (2010) Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer: is it time for a randomized phase III trial? Strahlenther Onkol 186:658–664PubMedCrossRefGoogle Scholar
  21. 21.
    An X, Lin X, Wang FH et al (2012) Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: a meta analysis. Eur J CancerGoogle Scholar
  22. 22.
    Nogue M, Salud A, Vicente P et al (2011) Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS study. Oncologist 16:614–620PubMedCrossRefGoogle Scholar
  23. 23.
    Kennecke H, Berry S, Wong R et al (2012) Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial. Eur J Cancer 48:37–45PubMedCrossRefGoogle Scholar
  24. 24.
    Grothey A (2009) A comparison of XELOX with FOLFOX-4 as first-line treatment for metastatic colorectal cancer. Nat Clin Pract Oncol 6:10–11PubMedCrossRefGoogle Scholar
  25. 25.
    Haller DG, Cassidy J, Clarke SJ et al (2008) Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 26:2118–2123PubMedCrossRefGoogle Scholar
  26. 26.
    Hochster HS, Hart LL, Ramanathan RK et al (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26:3523–3529PubMedCrossRefGoogle Scholar
  27. 27.
    Midgley R, Kerr DJ (2009) Capecitabine: have we got the dose right? Nat Clin Pract Oncol 6:17–24PubMedCrossRefGoogle Scholar
  28. 28.
    Gerard JP, Azria D, Gourgou-Bourgade S et al (2010) 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 28:1638–1644PubMedCrossRefGoogle Scholar
  29. 29.
    Aschele C, Cionini L, Lonardi S et al (2011) Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 29:2773–2780PubMedCrossRefGoogle Scholar
  30. 30.
    Campos-Lobato LF de, Stocchi L, Sousa JB de et al (2013) Less than 12 nodes in the surgical specimen after total mesorectal excision following neoadjuvant chemoradiation: it means more than you think! Ann Surg OncolGoogle Scholar
  31. 31.
    Miller ED, Robb BW, Cummings OW, Johnstone PA (2012) The effects of preoperative chemoradiotherapy on lymph node sampling in rectal cancer. Dis Colon Rectum 55:1002–1007PubMedCrossRefGoogle Scholar
  32. 32.
    Lee WS, Yun SH, Chun HK et al (2007) Clinical usefulness of chest radiography in detection of pulmonary metastases after curative resection for colorectal cancer. World J Surg 31:1502–1506PubMedCrossRefGoogle Scholar
  33. 33.
    Roh MS, Yothers GA, O’Connell MJ et al (2011) The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum. J Clin Oncol 29:abstr 3503Google Scholar
  34. 34.
    Eich HT, Stepien A, Zimmermann C et al (2011) Neoadjuvant radiochemotherapy and surgery for advanced rectal cancer: prognostic significance of tumor regression. Strahlenther Onkol 187:225–230PubMedCrossRefGoogle Scholar
  35. 35.
    MacMahon H, Austin JHM, Gamsu G et al (2005) Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 237:395–400PubMedCrossRefGoogle Scholar

Copyright information

© Springer Heidelberg Berlin 2014

Authors and Affiliations

  • Y.-H. Gao
    • 1
    • 2
  • X. Zhang
    • 1
    • 3
  • X. An
    • 1
    • 4
  • M.-Y. Cai
    • 1
    • 5
  • Z.-F. Zeng
    • 1
    • 2
  • G. Chen
    • 1
    • 6
  • L.-H. Kong
    • 1
    • 6
  • J.-Z. Lin
    • 1
    • 6
  • D.-S. Wan
    • 1
    • 6
  • Z.-Z. Pan
    • 1
    • 6
  • P.-R. Ding
    • 1
    • 6
  1. 1.State Key Laboratory of Oncology in South ChinaGuangzhouP.R. China
  2. 2.Departments of Radiation OncologySun Yat-sen University Cancer CenterGuangzhouP. R. China
  3. 3.Departments of Thoracic SurgerySun Yat-sen University Cancer CenterGuangzhouP. R. China
  4. 4.Departments of Medical OncologySun Yat-sen University Cancer CenterGuangzhouP. R. China
  5. 5.Departments of PathologySun Yat-sen University Cancer CenterGuangzhouP. R. China
  6. 6.Departments of Colorectal SurgerySun Yat-sen University Cancer CenterGuangzhouP. R. China

Personalised recommendations