Surgery and OncologySurgery and OncologyХирургия и онкология2949-5857Publishing House ABV Press18710.17650/2220-3478-2016-6-4-18-23ORIGINAL REPORTSОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯTHE USE OF PACLITAXEL IN CHEMORADIOTHERAPY OF PATIENTS WITH SQUAMOUS CELL CARCINOMA OF THE ANAL CANAL: A PILOT STUDYИСПОЛЬЗОВАНИЕ ПАКЛИТАКСЕЛА В ХИМИОЛУЧЕВОЙ ТЕРАПИИ БОЛЬНЫХ ПЛОСКОКЛЕТОЧНЫМ РАКОМ АНАЛЬНОГО КАНАЛА: ПИЛОТНОЕ ИССЛЕДОВАНИЕGordeevS. S.ГордеевС. С.
Russian Federation

23 Kashirskoe Shosse,Moscow115478,Russia

Контакты: Сергей Сергеевич Гордеев - ФГБУ РОНЦ им. Н.Н. Блохина Минздрава России, 115478 Москва, Каширское шоссе, 23 

ss.netoncology@gmail.comGorbunovaV. A.ГорбуноваВ. А.
Russian Federation
TkachevS. I.ТкачевС. И.
Russian Federation
GlebovskayaV. V.ГлебовскаяВ. В.
Russian Federation
BesovaN. S.БесоваН. С.
Russian Federation
SuraevaYu. E.СураеваЮ. Э.
Russian Federation
FedyaninM. Yu.ФедянинМ. Ю.
Russian Federation
IvanovV. A.ИвановВ. А.
Russian Federation
Anan’evV. S.АнаньевВ. С.
Russian Federation
MalikhovA. G.МалиховА. Г.
Russian Federation
RasulovA. O.РасуловА. О.
Russian Federation
N.N. Blokhin Russian Cancer Research CenterРоссийский онкологический научный центр им. Н.Н. Блохина Минздрава России040120176418230401201704012017Copyright ©; 2017, ABV-pressCopyright ©; 2017, АБВ-пресс2017ABV-pressАБВ-прессhttps://onco-surgery.info/jour/about/editorialPolicieshttps://onco-surgery.info/jour/article/view/187

Objectives: to assess the feasibility of a combination of the intensity-modulated radiation therapy (IMRT) with a triplet chemotherapy with paclitaxel, capecitabine, and mitomycin C in the treatment of patients with anal cancer, and to evaluate the toxicity of the proposed treatment regimen.

Materials and methods. All patients included in the study had stage I–IIIB anal cancer. All patients underwent IMRT radiotherapy 52–58 Gy (the dosage is calculated according T symbol) by 1.8 to 2.2 Gy fractions daily. The proposed chemotherapy scheme includes mitomycin C 10 mg/m2 on day 1, paclitaxel 45 mg/m2 on days 3, 10, 17, 24, 31, capecitabine 625 mg/m2 during radiotherapy. A complete response to treatment after 26 weeks, and the compliance to the study protocol were the primary end points of the study.

Results. The study included 38 patients. Among patients stage I anal cancer occurred in 1 (2.6 %) case, II – in 5 (13.2 %), IIIA – 15 (39.5 %) and IIIB – in 17 (44.7 %). A significant deviation from the protocol reported in 6 (15.8 %) patients, in 11 (28.9 %) patients a slight alteration from the treatment was documented, and 21 (55.3 %) patients completed the treatment of chemoradiotherapy with full compliance to the study protocol. The high profile of toxicity (grade III–IV) was recorded in 23 (60.5 %) patients. An incomplete clinical response at 26 weeks after treatment was reported in 5 (13.2 %) patients, one whom continued watchful waiting and achieved complete response at 9 months posttreatment. Median followup was 27 months. 1 patient developed a local recurrence 1 year posttreatment.

Conclusions. The proposed triplet chemotherapy regimen using IMRT is feasible and has acceptable toxicity. For further assess the continuous research is needed. 

anal carcinomasquamous-cell cancerchemoradiotherapypaclitaxelрак анального каналаплоскоклеточный ракхимиолучевая терапияпаклитаксел1. Nigro N.D., Vaitkevicius V.K., Considine B.Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974;17(3):354–6.Nigro N.D., Vaitkevicius V.K., Considine B.Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974;17(3):354–6.2. 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 1996;348(9034):1049–54.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 1996;348(9034):1049–54.3. Bartelink H., Roelofsen F., Eschwege F. et al. 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 1997;15(5):2040–9.Bartelink H., Roelofsen F., Eschwege F. et al. 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 1997;15(5):2040–9.4. Flam M., John M., Pajak T.F. et al. 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 1996;14(9):2527–39.Flam M., John M., Pajak T.F. et al. 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 1996;14(9):2527–39.5. James R.D., Glynne-Jones R., Meadows H.M. et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 2013;14(6):516–24. DOI: 10.1016/S1470-2045(13)70086-X.James R.D., Glynne-Jones R., Meadows H.M. et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 2013;14(6):516–24. DOI: 10.1016/S1470-2045(13)70086-X.6. Gunderson L.L., Winter K.A., Ajani J.A. et al. Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/ cisplatin. J Clin Oncol 2012;30(35):4344–51. DOI: 10.1200/JCO.2012.43.8085.Gunderson L.L., Winter K.A., Ajani J.A. et al. Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/ cisplatin. J Clin Oncol 2012;30(35):4344–51. DOI: 10.1200/JCO.2012.43.8085.7. Thind G., Johal B., Follwell M., Kennecke H.F. Chemoradiation with capecitabine and mitomycin-C for stage I–III anal squamous cell carcinoma. Radiat Oncol 2014;9:124. DOI: 10.1186/1748-717X-9-124.Thind G., Johal B., Follwell M., Kennecke H.F. Chemoradiation with capecitabine and mitomycin-C for stage I–III anal squamous cell carcinoma. Radiat Oncol 2014;9:124. DOI: 10.1186/1748-717X-9-124.8. Meulendijks D., Dewit L., Tomasoa N. et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer 2014;111(9):1726–33. DOI: 10.1038/bjc.2014.467.Meulendijks D., Dewit L., Tomasoa N. et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer 2014;111(9):1726–33. DOI: 10.1038/bjc.2014.467.9. Glynne-Jones R., Meadows H., Wan S. et al. EXTRA – a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys 2008;72(1):119–26. DOI: 10.1016/j.ijrobp.2007.12.012.Glynne-Jones R., Meadows H., Wan S. et al. EXTRA – a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys 2008;72(1):119–26. DOI: 10.1016/j.ijrobp.2007.12.012.10. White E.C., Eriksson K., Aleshin A. et al. Chemoradiotherapy for squamous cell carcinoma of the anal canal: Comparison of one versus two cycles mitomycin-C. Radiother Oncol 2015;117(2):240–5. DOI: 10.1016/j.radonc.2015.08.015.White E.C., Eriksson K., Aleshin A. et al. Chemoradiotherapy for squamous cell carcinoma of the anal canal: Comparison of one versus two cycles mitomycin-C. Radiother Oncol 2015;117(2):240–5. DOI: 10.1016/j.radonc.2015.08.015.11. Saito Ramalho A., Dantas Lopes A., Talans A. et al. Molecular targets for therapeutic interventions in human papillomavirus-related cancers (review). Oncol Rep 2010;24(6):1419–26.Saito Ramalho A., Dantas Lopes A., Talans A. et al. Molecular targets for therapeutic interventions in human papillomavirus-related cancers (review). Oncol Rep 2010;24(6):1419–26.12. Clark J.I., Hofmeister C., Choudhury A. et al. Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma. Cancer 2001;92(9):2334–40.Clark J.I., Hofmeister C., Choudhury A. et al. Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma. Cancer 2001;92(9):2334–40.13. Forastiere A.A., Leong T., Rowinsky E. et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colonystimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 2001;19(4):1088–95.Forastiere A.A., Leong T., Rowinsky E. et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colonystimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 2001;19(4):1088–95.14. Moreno-Jimenez M., Valero J., Lopez-Picazo J.M. et al. Concomitant cisplatin, paclitaxel, and hyperfractionated radiotherapy in locally advanced head and neck cancer: comparison of two different schedules. Am J Clin Oncol 2010;33(2):137–43. DOI: 10.1097/COC.0b013e31819d369d.Moreno-Jimenez M., Valero J., Lopez-Picazo J.M. et al. Concomitant cisplatin, paclitaxel, and hyperfractionated radiotherapy in locally advanced head and neck cancer: comparison of two different schedules. Am J Clin Oncol 2010;33(2):137–43. DOI: 10.1097/COC.0b013e31819d369d.15. Hitt R., Paz-Ares L., Brandariz A. et al. Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Ann Oncol 2002;13(10):1665–73.Hitt R., Paz-Ares L., Brandariz A. et al. Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Ann Oncol 2002;13(10):1665–73.16. van Meerten E., Muller K., Tilanus H.W. et al. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer 2006;94(10):1389–94.van Meerten E., Muller K., Tilanus H.W. et al. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer 2006;94(10):1389–94.17. Meluch A.A., Greco F.A., Gray J.R. et al. Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J 2003;9(4):251–60.Meluch A.A., Greco F.A., Gray J.R. et al. Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J 2003;9(4):251–60.18. Higgins R., Bussey M., Naumann W. Concurrent carboplatin and paclitaxel with pelvic radiation therapy in the primary treatment of cervical cancer. Am J Obstet Gynecol 2007;197(2):205.e1–5; discussion 205.e5–7.Higgins R., Bussey M., Naumann W. Concurrent carboplatin and paclitaxel with pelvic radiation therapy in the primary treatment of cervical cancer. Am J Obstet Gynecol 2007;197(2):205.e1–5; discussion 205.e5–7.19. Abbas A., Nehme E., Fakih M. Singleagent paclitaxel in advanced anal cancer after failure of cisplatin and 5-fluorouracil chemotherapy. Anticancer Res 2011;31(12):4637–40.Abbas A., Nehme E., Fakih M. Singleagent paclitaxel in advanced anal cancer after failure of cisplatin and 5-fluorouracil chemotherapy. Anticancer Res 2011;31(12):4637–40.20. Alcindor T. Activity of paclitaxel in metastatic squamous anal carcinoma. Int J Colorectal Dis 2008;23(7):717. DOI: 10.1007/s00384-008-0467-3.Alcindor T. Activity of paclitaxel in metastatic squamous anal carcinoma. Int J Colorectal Dis 2008;23(7):717. DOI: 10.1007/s00384-008-0467-3.21. Byer J., Mahipal A., Dinwoodie W.R. Efficacy of carboplatin and paclitaxel therapy in patients with advanced squamous cell carcinoma (SCC) of the anal canal. J Clin Oncol 2012;30:(suppl 34; abstr 539).Byer J., Mahipal A., Dinwoodie W.R. Efficacy of carboplatin and paclitaxel therapy in patients with advanced squamous cell carcinoma (SCC) of the anal canal. J Clin Oncol 2012;30:(suppl 34; abstr 539).22. Sebag-Montefiore D., Meadows H.M., Cunningham D. et al. Three cytotoxic drugs combined with pelvic radiation and as maintenance chemotherapy for patients with squamous cell carcinoma of the anus (SCCA): long-term follow-up of a phase II pilot study using 5-fluorouracil, mitomycin C and cisplatin. Radiother Oncol 2012;104(2):155–60. DOI: 10.1016/j.radonc.2012.06.006.Sebag-Montefiore D., Meadows H.M., Cunningham D. et al. Three cytotoxic drugs combined with pelvic radiation and as maintenance chemotherapy for patients with squamous cell carcinoma of the anus (SCCA): long-term follow-up of a phase II pilot study using 5-fluorouracil, mitomycin C and cisplatin. Radiother Oncol 2012;104(2):155–60. DOI: 10.1016/j.radonc.2012.06.006.23. Mitchell M.P., Abboud M., Eng C. et al. Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Anal Cancer: Outcomes and Toxicity. Am J Clin Oncol 2014;37(5):461–6. DOI: 10.1097/COC.0b013e31827e52a3.Mitchell M.P., Abboud M., Eng C. et al. Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Anal Cancer: Outcomes and Toxicity. Am J Clin Oncol 2014;37(5):461–6. DOI: 10.1097/COC.0b013e31827e52a3.24. Chuong M.D., Freilich J.M., Hoffe S.E. et al. Intensity-Modulated Radiation Therapy vs. 3D Conformal Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal. Gastrointest Cancer Res 2013;6(2):39–45.Chuong M.D., Freilich J.M., Hoffe S.E. et al. Intensity-Modulated Radiation Therapy vs. 3D Conformal Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal. Gastrointest Cancer Res 2013;6(2):39–45.25. Sobin L.H., Gospodarowicz M.K., Wittekind C. TNM classification of malignant tumours. New York: John Wiley & Sons, 2011.Sobin L.H., Gospodarowicz M.K., Wittekind C. TNM classification of malignant tumours. New York: John Wiley & Sons, 2011.26. Myerson R.J., Garofalo M.C., El Naqa I. et al. Elective clinical target volumes for conformal therapy in anorectal cancer: an RTOG consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 2009;74(3):824. DOI: 10.1016/j.ijrobp.2008.08.070.Myerson R.J., Garofalo M.C., El Naqa I. et al. Elective clinical target volumes for conformal therapy in anorectal cancer: an RTOG consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 2009;74(3):824. DOI: 10.1016/j.ijrobp.2008.08.070.27. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Available at: http://evs.nci.nih.gov.sci-hub.org/ftp1/ CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_8.5x11.pdf.Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Available at: http://evs.nci.nih.gov.sci-hub.org/ftp1/ CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_8.5x11.pdf.28. Hryniuk W.M., Goodyear M. The calculation of received dose intensity. J Clin Oncol 1990;8(12):1935–7.Hryniuk W.M., Goodyear M. The calculation of received dose intensity. J Clin Oncol 1990;8(12):1935–7.29. Kachnic L.A., Winter K., Myerson R.J. et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86(1):27–33. DOI: 10.1016/j.ijrobp.2012.09.023.Kachnic L.A., Winter K., Myerson R.J. et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86(1):27–33. DOI: 10.1016/j.ijrobp.2012.09.023.30. Kachnic L.A., Tsai H.K., Coen J.J. et al. 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 2012;82(1):153–8. DOI: 10.1016/j.ijrobp.2010.09.030.Kachnic L.A., Tsai H.K., Coen J.J. et al. 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 2012;82(1):153–8. DOI: 10.1016/j.ijrobp.2010.09.030.31. Han K., Cummings B.J., Lindsay P. et al. 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 2014;90(3):587–94. DOI: 10.1016/j.ijrobp.2014.06.061.Han K., Cummings B.J., Lindsay P. et al. 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 2014;90(3):587–94. DOI: 10.1016/j.ijrobp.2014.06.061.