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Reduced radiation dose for elective nodal irradiation in node-negative anal cancer: back to the roots?

Dosisreduzierte elektive Lymphknotenbestrahlung beim nodalnegativen Analkarzinom: Zurück zu den Wurzeln?

Strahlentherapie und Onkologie volume 191, pages 845–854 (2015)Cite this article

Abstract

Background

Chemoradiation (CRT) is the standard of care in patients with node-positive (cN+) and node-negative (cN0) anal cancer. Depending on the tumor size (T-stage), total doses of 50–60 Gray (Gy) in daily fractions of 1.8–2.0 Gy are usually applied to the tumor site. Inguinal and iliac lymph nodes usually receive a dose of ≥ 45 Gy. Since 2010, our policy has been to apply a reduced total dose of 39.6 Gy to uninvolved nodal regions. This paper provides preliminary results of the efficacy and safety of this protocol.

Patients and methods

Overall, 30 patients with histologically confirmed and node-negative anal cancer were treated in our department from 2009–2014 with definitive CRT. Histology all cases showed squamous cell carcinoma. A total dose of 39.6 Gy [single dose (SD) 1.8 Gy] was delivered to the iliac/inguinal lymph nodes. The area of the primary tumor received 50–59.4 Gy, depending on the T-stage. In parallel with the irradiation, 5-fluorouracil (5-FU) at a dose of 1000 mg/m2 was administered by continuous intravenous infusion over 24 h on days 1–4 and 29–32, and mitomycin C (MMC) at a dose of 10 mg/m2 (maximum absolute dose 14 mg) was administered on days 1 and 29. The distribution of the tumor stages was as follows: T1, n = 8; T2, n = 17; T3 n = 3. Overall survival (OS), local control (LC) of the lymph nodes, colostomy-free survival (CFS), and acute and chronic toxicities were assessed.

Results

The median follow-up was 27.3 months (range 2.7–57.4 months). Three patients (10.0 %) died, 2 of cardiopulmonary diseases and one of liver failure, yielding a 3-year OS of 90.0 %. Two patients (6.7 %) relapsed early and received salvage colostomies, yielding a 3-year CFS of 93.3 %. No lymph node relapses were observed, giving a lymph node LC of 100 %. According to the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V. 4.0), there were no grade IV gastrointestinal or genitourinary acute toxicities. Seven patients showed acute grade III perineal skin toxicity. Acute grade III groin skin toxicity was not observed.

Conclusion

Reducing the total irradiation dose to uninvolved nodal regions to 39.6 Gy in chemoradiation protocols for anal carcinoma was safe and effective, and a prospective evaluation in future clinical trials is warranted.

Zusammenfassung

Hintergrund

Die primäre Radio(chemo)therapie (RCT) ist die Therapie der Wahl beim nodalpositiven (cN+) und nodalnegativen (cN0) Analkarzinom. Abhängig von der Tumorgröße (T-Stadium) werden in der Primärtumorregion Gesamtdosen (GD) von 50–60 Gy mit täglichen Fraktionen zwischen 1,8–2,0 Gy eingestrahlt. Die elektive Bestrahlung des inguinalen/pelvinen Lymphabflusses (LAG) erfolgt in der Regel mit einer GD von ≥ 45 Gy. Seit 2010 erhielten Patienten mit einem cN0-Analkarzinom in unserer Klinik eine reduzierte GD im Bereich des inguinalen/iliakalen LAG mit 39,6 Gy [Einzeldosis (ED) 1,8 Gy]. Diese Publikation zeigt Sicherheit und Wirksamkeit dieses Protokolls.

Patienten und Methoden

Insgesamt wurden 30 Patienten mit einem nodalnegativen, histologisch gesicherten Analkarzinom untersucht, welche zwischen 2009 und 2014 eine primäre RCT in unserer Klinik erhielten. In allen Fällen handelte es sich histologisch um ein Plattenepithelkarzinom. Iliakal/inguinal wurde eine GD von 39,6 Gy (ED 1,8 Gy) eingestrahlt. Im Bereich der Primärtumorregion wurde T-Stadien-abhängig eine GD von 50–59,4 Gy eingestrahlt. Simultan zur Bestrahlung wurde 5- Fluorouracil (5-FU) als intravenöse Dauerinfusion mit einer Dosis von 1000 mg/m2 über 24 h an Tag 1–4 und Tag 29–32 sowie Mitomycin C (MMC) als Bolusgabe mit einer Dosis von 10 mg/m2 (Maximum 14 mg absolut) an Tag 1 und 29 gegeben. Die retrospektive Verteilung der Tumorstadien war wie folgt: 8-mal T1, 17-mal T2, 3-mal T3. Es wurden das Gesamtüberleben (OS), die lokale Kontrollrate (LC) der Lymphknoten, das kolostomiefreie Überleben (CFS) sowie Akut- und Spättoxizitäten analysiert.

Ergebnisse

Die mediane Nachbeobachtungszeit betrug 27,3 Monate (Spanne 2,7–57,4 Monate). Insgesamt 3 Patienten (10 %) verstarben nichttumorbedingt, (zwei kardiale Ereignisse, ein Leberversagen), so dass sich ein 3-Jahres-OS von 90,0 % ergab. Ein lokales Frührezidiv mit nachfolgender Kolostomie wurde bei 2 Patienten beobachtet (6,7 %). Ein Lymphknotenrezidiv trat im Beobachtungszeitraum nicht auf, so dass sich ein 3-Jahres-CFS von 93,3 % und eine LC der Lymphknoten von 100 % ergab. Akuttoxizitäten vom Grad 4 gemäß der Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V. 4.0) wurden nicht beobachtet. Eine akute perineale Hautreaktion vom Grad 3 zeigten 7 Patienten. Akute Grad-3-Hautreaktionen im Leistenbereich traten nicht auf.

Schlussfolgerung

Eine reduzierte Strahlendosis von 39,6 Gy im Bereich klinisch nichtbefallener Lymphknoten war im Rahmen der durchgeführten Radiochemotherapie onkologisch sicher, gut verträglich und rechtfertig eine Evaluation in prospektiven Studien.

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References

  1. Johnson LG, Madeleine MM, Newcomer LM et al (2004) Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 101:281–288

    Article  PubMed  Google Scholar 

  2. Frisch M (2002) On the etiology of anal squamous carcinoma. Dan Med Bull 49:194–209

    PubMed  Google Scholar 

  3. Daling JR, Madeleine MM, Johnson LG et al (2004) Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer 101:270–280

    Article  PubMed  Google Scholar 

  4. o A (1996) Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348:1049–1054. (No authors listed)

  5. Flam M, John M, Pajak TF et al (1996) Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 14:2527–2539

    CAS  PubMed  Google Scholar 

  6. Glynne-Jones R, Lim F (2011) Anal cancer: an examination of radiotherapy strategies. Int J Radiat Oncol Biol Phys 79:1290–1301

    Article  PubMed  Google Scholar 

  7. Kachnic LA, Winter K, Myerson RJ et al (2013) RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluoroucil and mitomycin-C for the reduction of acute morbidity in carcinoma oft he anal canal. Int J Radiat Oncol Biol Phys 86:27–33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Bartelink H, Roelofsen F, Eschwege F et al (1997) Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040–2049

    CAS  PubMed  Google Scholar 

  9. Nigro ND, Seydel HG, Considine B et al (1983) Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 51:1826–1829

    Article  CAS  PubMed  Google Scholar 

  10. James RD, Glynne-Jones R, Meadows HM et al (2013) Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous cell carcinoma of the anus (ACT II): a randomized, phase 3, open label, 2 × 2 factorial trial. Lancet Oncol 14:516–524

    Article  CAS  PubMed  Google Scholar 

  11. Blinde SE, Schasfoort R, Mens JW et al (2014) Inguinal lymph node recurrence in the untreated groin of patients with anal carcinoma. Dis Colon Rectum 57:578–584

    Article  PubMed  Google Scholar 

  12. Call JA, Haddock MG, Quevedo JF et al (2011) Intensity-modulated radiotherapy for squamous cell carcinoma of the anal cacnal: Efficacyof a low daily dose to clinically negative regions. Radiat Oncol 6:134. doi:10.1186/1748-717X-6-134

    Article  PubMed Central  PubMed  Google Scholar 

  13. Kachnic LA, Tsai HK, Coen JJ et al (2012) Dose-painted intensity-modulated radiation therapy for anal cancer: a multi-institutional report of acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys 82:153–158

    Article  PubMed  Google Scholar 

  14. Mai SK, Welzel G, Hermann B et al (2009) Can the radiation dose to CT enlarged but FDG-PET negative inguinal lymph nodes in anal cacner be reduced? Strahlenther Onkol 185:254–259

    Article  PubMed  Google Scholar 

  15. Janssen S, Glanzmann C, Bauerfeind P et al (2014) Clinical experience of SIB-IMRT in anal cancer and selective literature review. Radiat Oncol 9:199. doi:10.1186/1748-717X-9-199

    Article  PubMed Central  PubMed  Google Scholar 

  16. Provencher S, Oehler S, Lavertu S, Jolicoeur M et al (2010) Quality of life after split-course chemoradiation for anal canal carcinoma. Radiat Oncol 5:41. doi:10.1186/1748-717X-5-41

    Article  PubMed Central  PubMed  Google Scholar 

  17. Serup-Hansen E, Linnemann D, Skovrinder-Ruminski W et al (2014) Human papillovirus genotyping and p16 expression as prognostic factors for patients with americanJoint Committee on Cancer stages I to III carcinoma of the anal canal. J Clin Oncol 32:1812–1817

    Article  PubMed  Google Scholar 

  18. International Commission on Radiation Units and Measurements (icru) ICRU Report 62. Bethesda: ICRU; 1999. Prescribing, Recording and Reporting Photon Beam Therapy [supplement to ICRU Report 50]

  19. International Commission on Radiation Units and Measurements (2010) ICRU Report 83. prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT). J ICRU 10:1 doi: 10.1093/jicru/ndq002

  20. http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed on 16/03/2015

  21. Pavy JJ, Denekamp J, Letschert J et al (1995) EORTC Late Effects Working Group. Late effects toxicity scoring: the SOMA scale. Int J Radiat Oncol Biol Phys 31:1043–1091

    Article  CAS  PubMed  Google Scholar 

  22. Northover J, Glynne-Jones R, Sebaq-Montefiore D et al (2010) Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCR Anal Cancer Trial (ACT I). Br J Cancer 102:1123–1128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Zilli T, Betz M, Bieri S et al (2013) Elective inguinal node irradiation in early-stage T2N0 anal cancer: prognostic impact on locoregional control. Int J Radiat Oncol Biol Phys 87:60–66

    Article  PubMed  Google Scholar 

  24. De Bari B, Lestrade L, Pommier P et al (2015) Could concomitant Radio-Chemotherapy improve the outcomes of early-stage node negative anal cancer patients? A retrospective analysis of 122 patients. Cancer Invest 33:114–120

    Article  CAS  PubMed  Google Scholar 

  25. National Cancer Comprehensive Network (2015) Guideline anal carcinoma version 2. http://www.nccn.org/professionals/physician_gls/pdf/anal.pdf. Accessed 16 March 2015

  26. Ajani JA, Winter KA, Gunderson LL et al (2008) Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 299:1914–1921

    Article  CAS  PubMed  Google Scholar 

  27. Gerard JP, Chapet O, Samjei F et al (2001) Management of inguinal lymph node metastases in patients with carcinoma of the anal canal: experience in a series of 270 patients treated in Lyon and review of literature. Cancer 92:77–84

    Article  CAS  PubMed  Google Scholar 

  28. Grabenbauer GG, Kessler H, Matzel KE et al (2005) Tumor site predicts outcome after radiochemotherapy in squamous-cell carcinoma of the anal region: long-term results of 101 patients. Dis Colon Rectum 48:1742–1751

    Article  PubMed  Google Scholar 

  29. Matthews JH, Burmeister BH, Borg M et al (2011) T1–2 anal carcinoma requires elective inguinal radiation treatment-the results of Trans-Tasman Radiation Oncology Group study TROG 99.02. Radiother Oncol 98:93–98

    Article  PubMed  Google Scholar 

  30. Peiffert D, Tournier-Rangeard L, Gérard JP et al (2012) Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal carcinoma: final analysis of the radomizes UNICANCER ACCORD 03 trial. J Clin Oncol 30:1941–1948

    Article  CAS  PubMed  Google Scholar 

  31. Wright JL, Patil SM, Temple LK et al (2010) Squamous cell carcinoma of the anal canal: patterns and predictors of failure and implications for intensity-modulated radiation treatment planning. J Radiat Oncol Biol Phys 78:1064–1072

    Article  Google Scholar 

  32. Glynne-Jones R, Kadalayil L, Meadows HM et al (2014) Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial. Ann Oncol 25:1616–1622

    Article  PubMed  Google Scholar 

  33. Fakhrian K, Sauer T, Dinkel A et al (2013) Chronic adverse events and quality of life after radiochemotherapy in anal cancer patients. A single institution experience and review of the literature. Strahlenther Onkol 189:486–494

    Article  CAS  PubMed  Google Scholar 

  34. Han K, Cummings BJ, Lindsay P et al (2014) Prospective evaluation of acute toxicity and quality of life after IMRT and concurrent chemotherapy for anal canal and perianal cancer. Int J Radiat Oncol Biol Phys 90:587–594

    Article  PubMed  Google Scholar 

  35. Frenzel T, Krüll A (2015) The use of IMRT in Germany. Strahlenther Onkol. (in press). DOI: 10.1007/s00066-015-0832-4

  36. Hernando-Requejo O, López M, Cubillo A et al (2014) Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation. Strahlenther Onkol 190:515–520

    Article  PubMed  Google Scholar 

  37. Devisetty K, Salama JK, Schomas DA et al (2009) A multi-institutional acute gastrointestinal toxcicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. Radiother Oncol 93:298–301

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Radiation Oncology, Klinik für Strahlentherapie und Spezielle Onkologie, Medizinische Hochschule Hannover, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Christoph Henkenberens,  Daniela Meinecke,  Michael Bremer &  Hans Christiansen

  2. End- und Dickdarmzentrum Hannover, Hannover, Germany

    Stoll Michael

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Correspondence to Christoph Henkenberens.

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C. Henkenberens, D. Meinecke, M. Stoll, M. Bremer, and H. Christiansen state that there are no conflicts of interest.

The accompanying manuscript does not include studies on humans or animals.

Additional information

C. Henkenberens and D. Meinecke contributed equally to this work.

The data were presented at the 2014 DEGRO (German Society for Radiation Oncology) Annual Meeting in Düsseldorf, Germany.

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Henkenberens, C., Meinecke, D., Michael, S. et al. Reduced radiation dose for elective nodal irradiation in node-negative anal cancer: back to the roots?. Strahlenther Onkol 191, 845–854 (2015). https://doi.org/10.1007/s00066-015-0885-4

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