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1 Focused Issue of This Month Diagnosis and Treatment of Recurrent Cervical Cancer Sang Yoon Park, MD Department of Obstetrics and Gynecology, National Cancer Center parksang@ncc.re.kr J Korean Med Assoc 2007; 50(9): Abstract Despite recent advances in the early detection method and treatment modalities (surgery and/or radiation and/or chemotherapy), cervical cancer is still an important malignant disease in women. Almost half a million new cases occur every year in the world. The management of recurrent cervical cancers depends on primary treatment, the extent of disease, and performance status. Patients who received primary surgical treatment without radiotherapy (RT) may undergo curative RT. However, most recurrences occur in patients with advancedstage disease already treated by primary RT. For patients who failed primary RT or surgery plus adjuvant RT and had central relapse without pelvic sidewall recurrence, pelvic exenteration may be necessary. For patients who had pelvic sidewall recurrences, pelvic exenteration is usually not an option with curative intent. In such situation, combined operative and radiotherapeutic treatment (CORT), and laterally extended endopelvic resection (LEER), intraoperative radiotherapy (IORT) have been executed with some success. Simple or radical hysterectomy can be considered for patients who had small uterine and/or vaginal recurrences, but the high frequency of associated morbidities such as urinary and bowel tract injury or fistula is the problem. Patients with multiple or distant metastases are destined to receive cisplatinbased palliative chemotherapy. Recently there was a GOG 179 study that had firstly shown a statistically significant improvement on the overall response rate, median progressionfree survival, and median survival. Until now, however, the role of chemotherapy has been very limited. Keywords : Recurrent cervical cancer; Pelvic exenteration; Radiotherapy; Chemotherapy 796

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4 Recurrent Cervical Cancer A B C D E F Figure 1. Reconstuctive surgery after pelvic exenteration surgery. A) Formation of ileal conduit. B) After total pelvic exenteration. C~E) Formation of neovagina using vertical rectus abdominus myocutaneous flap. F) Followup of neovagina one year later. 799

5 Park SY A B C D Figure 2. Combined operative and radiotherapeutic treatment (CORT) was performed in case of clear but close resection margins to structures or residual disease after laterally extended endopelvic resection (LEER). A) Complete array of transabdominal guide tubes for postoperative brachytherapy fixed to the lesion by the brigde implant and additional sutures. B) Vertical rectus abdominus myocutaneous flap used as pelvic wall plasty for CORT. C) Completion of CORT procedure (open arrow; ileal conduit, closed arrow; colostomy). D) Postoperative computed tomogram. The lowermost three figures showed a CORT set including fixation bridges and guide tubes. 800

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8 Recurrent Cervical Cancer History & exam. Pap test+visit every 3~6months for 2yrs every 6months for 3yrs then annually Optional: Tumor markers a Lab. studies b Imaging studies c Suggest use of vaginal dilator after RT Persistent or recurrent disease Pelvic/abdominal /chest CT/PET Surgical exploration in selected cases Pelvic recurrence No prior RT or failure outside of previously treated field Prior RT Central disease Noncentral disease Definitive pelvic RT + platinumbased chemotherapy ± brachy therapy Pelvic exenteration ± RT Radical hysterectomy ± RT in carefully selected patients with small (<2cm) lesions See text Extrapelvic or paraaortic recurrence Multiple sites or unresectable Isolated site Platinum doublet based chemotherapy Best supportive care Resection ± RT RT+ Concurrent chemotherapy a Tumor markers; SCC Ag, CEA, CA125 if clinically indicated b Lab. studies; CBC with platelets, chemistry profile, chest Xray, ECG and urine analysis c Imaging studies; Abdominopelvic CT / MRI / PET if clinically indicated Chemotherapy RT: radiation therapy Figure 3. Practice guideline summary for cervical cancer. Table 1. Chemotherapy regimens for recurrent or metastatic cervical cancer Firstline therapy Possible firstline Secondline therapy combination therapy* Cisplatin Cisplatin/paclitaxel Docetaxel Carboplatin Cisplatin/topotecan Ifosfamide Paclitaxel Cisplatin/gemcitabine Vinorelbine Topotecan Carboplatin/paclitaxel Irinotecan Epirubicin Mitomycin 5FU * Preferred if cisplatin was previously used as a radiosensitizer. 803

9 Park SY Table 2. Surgical procedures Name of procedures Number of patients Vulvovaginectomy 1 Simple hysterectomy 1 Radical hysterectomy 2 Anterior pelvic exenteration 9 Posterior pelvic exenteration 1 Total pelvic exenteration 16 LEER 3 CORT 6 Total 39 LEER; laterally extended endopelvic resection, CORT; combined operative radiotherapeutic treatment Table 3. Bowel and Urinary Complications Complications (n) Fistula (6) Ureteroenteric (2) Enterocutaneous (2) Enterovaginal (1) Rectovaginal (1) Bowel perforation (3) Colorectum (2) Jejunum (1) Urostomy leakage (1) Stoma failure (6) Colostomy dehiscence (1) Colostomy obstruction (1) Urostomy necrosis (1) Urostomy retraction (1) Urostomy stricture (1) Urostomy obstruction (1) Cumulative Survival Cumulative Survival Disease Free Survival (n=39) 4 year discase free survival rate = 47% Follow-up Period (months) Overall Survival (n=39) 4 year overall free survival rate = Follow-up Period (months) Figure 4. The median disease free survival was 27 months, and the disease free survival probability at 51 months was 47.1%. The median overall survival time did not reach, and the overall survival probability at 51 months was 51.1%. 11. National Cancer information. Cancer, korea go.kr/ 12. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan Int J Cancer 2001; 94: Landoni F, Maneo A, Colombo A, Placa F, Milani R, Perego P, Favini G, Ferri L, Mangioni C. Randomised study of radical surgery versus radiotherapy for stage IbIIa cervical cancer. Lancet 1997; 350:

10 Recurrent Cervical Cancer Overall survival Overall survival Cumulative Survival Resection margin negative positive Cumulative Survival Lymph node metastasis No Yes 0.0 P= P= Follow-up Period (months) Follow-up Period (months) Figure 5. Overall survival by the resection margin status (left)(negative margin, n=37 vs. positive margin, n=7) and lymph node metastasis (right)(negative, n=40, vs. positive, n=4) after adjustment for tumor size, bladder wall invasion, status of resection margin, and lymph node metastasis (Cox regression model, P = and 0.012, respectively). 14. Maneo A, Landoni F, Cormio G, Colombo A, Mangioni C. Radical hysterectomy for recurrent or persistent cervical cancer following radiation therapy. Int J Gynecol Cancer 1999; 9: Coleman RL, Keeney ED, Freedman RS, Burke TW, Eifel PJ, Rutledge FN. Radical hysterectomy for recurrent carcinoma of the uterine cervix after radiotherapy. Gynecol Oncol 1994; 55: Shingleton HM, Soong SJ, Gelder MS, Hatch KD, Baker VV, Austin JM Jr. Clinical and histopathologic factors predicting recurrence and survival after pelvic exenteration for cancer of the cervix. Obstet Gynecol 1989; 73: Estape R, Angioli R.. Surgical management of advanced and recurrent cervical cancer. Semin Surg Oncol 1999; 16: Matthews CM, Morris M, Burke TW, Gershenson DM, Wharton JT, Rutledge FN. Pelvic exenteration in the elderly patient. Obstet Gynecol 1992; 79: Goldberg JM, Piver MS, Hempling RE, Aiduk C, Blumenson L, Recio FO. Improvements in pelvic exenteration: factors responsible for reducing morbidity and mortality. Ann Surg Oncol 1998; 5: Morley GW, Hopkins MP, Lindenauer SM, Roberts JA. Pelvic exenteration, University of Michigan: 100 patients at 5 years. Obstet Gynecol 1989; 74: Rutledge FN, Smith JP, Wharton JT, O Quinn AG. Pelvic exenteration: analysis of 296 patients. Am J Obstet Gynecol 1977; 129: Jain AK, DeFranzo AJ, Marks MW, Loggie BW, Lentz S. Reconstruction of pelvic exenterative wounds with transpelvic rectus abdominis flaps: a case series. Ann Plast Surg 1997; 38: ; discussion Soper JT, Berchuck A, Creasman WT, ClarkePearson DL. Pelvic exenteration: factors associated with major surgical morbidity. Gynecol Oncol 1989; 35: Copeland LJ, Hancock KC, Gershenson DM, Stringer CA, Atkinson EN, Edwards CL. Gracilis myocutaneous vaginal reconstruction concurrent with total pelvic exenteration. Am J Obstet Gynecol 1989; 160: Ratliff CR, Gershenson DM, Morris M, Burke TW, Levenback C, Schover LR, Mitchell MF, Atkinson EN, Wharton JT. Sexual adjustment of patients undergoing gracilis myocutaneous flap vaginal reconstruction in conjunction with pelvic exenteration. Cancer 1996; 78: Höckel M, Knapstein PG, Kutzner J. A novel combined operative and radiotherapeutic treatment approach for recurrent gynecologic malignant lesions infiltrating the pelvic wall. Surg Gynecol Obstet 1991; 173: Höckel M. Laterally extended endopelvic resection. Novel surgical treatment of locally recurrent cervical carcinoma involving the pelvic side wall. Gynecol Oncol 2003; 91: Höckel M. The transversus and rectus abdominis musculoperitoneal (TRAMP) composite flap for vulvovaginal recons truction. Plast Reconstr Surg 1996; 97: McCormack P. Surgical resection of pulmonary metastases. Semin Surg Oncol 1990; 6: Seki M, Nakagawa K, Tsuchiya S, Matsubara T, Kinoshita I, Weng SY, Tsuchiya E. Surgical treatment of pulmonary metastases from uterine cervical cancer. Operation method by lung 805

11 Park SY tumor size. J Thorac Cardiovasc Surg 1992; 104: Anraku M, Yokoi K, Nakagawa K, Fujisawa T, Nakajima J, Akiyama H, Nishimura Y, Kobayashi K; Metastatic Lung Tumor Study Group of Japan. Pulmonary metastases from uterine malignancies: results of surgical resection in 133 patients. J Thorac Cardio vasc Surg : Ijaz T, Eifel PJ, Burke T, Oswald MJ. Radiation therapy of pelvic recurrence after radical hysterectomy for cervical carcinoma. Gynecol Oncol 1998; 70: Averette HE, Lichtinger M, Sevin BU, Girtanner RE. Pelvic exenteration: a 15year experience in a general metropolitan hospital. Am J Obstet Gynecol 1984; 150: Mahe MA, Gerard JP, Dubois JB, Roussel A, Bussieres E, Delannes M, Guillemin F, Schmitt T, Dargent D, Guillard Y, Martel P, Richaud P, Cuilliere JC, De Ranieri J, Malissard L. Intraoperative radiation therapy in recurrent carcinoma of the uterine cervix: report of the French intraoperative group on 70 patients. Int J Radiat Oncol Biol Phys 1996; 34: MartinezMonge R, Jurado M, Aristu JJ, Moreno M, Cambeiro M, PerezOchoa A, LopezGarcia G, Alcazar JL. Intraoperative electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer. Gynecol Oncol 2001; 82: Garton GR, Gunderson LL, Webb MJ, Wilson TO, Cha SS, Podratz KC. Intraoperative radiation therapy in gynecologic cancer: update of the experience at a single institution. Int J Radiat Oncol Biol Phys 1997; 37: The Korea Society of Gynecologc Oncology and Colposcopy; Practice guideline for gynecologic cancer version 1, 17, Park JY, Choi HJ, Jeong SY, Chung JS, Park JK, Park SY, The role of pelive exenteration and reconstruction for treatment of advanced or recurrent gynecologic malignancies; analysis of risk factors predicting recurrence and survival. J Sung Oncal 2007; 20 epublication. Peer Reviewer Commentary 806

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy