Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial

Abstract

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB–IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415–1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.

Keywords

chemotherapy / cervical cancer / lymph node metastasis / concurrent chemoradiotherapy / quality of life

References

[1] Li S, Hu T, Lv W, Zhou H, Li X, Yang R, Jia Y, Huang K, Chen Z, Wang S, Tang F, Zhang Q, Shen J, Zhou J, Xi L, Deng D, Wang H, Wang S, Xie X, Ma D. Changes in prevalence and clinical characteristics of cervical cancer in the People’s Republic of China: a study of 10,012 cases from a nationwide working group. Oncologist 2013; 18(10): 1101–1107

[2] Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr, Alberts DS. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18(8): 1606–1613

[3] Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, Eifel P, Bevers TB, Levenback CF, Gershenson DM, Bodurka DC. Quality of life and sexual functioning in cervical cancer survivors. J Clin Oncol 2005; 23(30): 7428–7436

[4] Curtin JP, Hoskins WJ, Venkatraman ES, Almadrones L, Podratz KC, Long H, Teneriello M, Averette HA, Sevin BU. Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): a randomized phase III trial. Gynecol Oncol 1996; 61(1): 3–10

[5] Lahousen M, Haas J, Pickel H, Hackl A, Kurz C, Ogris H, Stummvoll W, Winter R. Chemotherapy versus radiotherapy versus observation for high-risk cervical carcinoma after radical hysterectomy: a randomized, prospective, multicenter trial. Gynecol Oncol 1999; 73(2): 196–201

[6] Lee KB, Lee JM, Ki KD, Lee SK, Park CY, Ha SY. Comparison of adjuvant chemotherapy and radiation in patients with intermediate risk factors after radical surgery in FIGO stage IB–IIA cervical cancer. Int J Gynecol Cancer 2008; 18(5): 1027–1031

[7] Takeshima N, Umayahara K, Fujiwara K, Hirai Y, Takizawa K, Hasumi K. Treatment results of adjuvant chemotherapy after radical hysterectomy for intermediate- and high-risk stage IB–IIA cervical cancer. Gynecol Oncol 2006; 103(2): 618–622

[8] Hosaka M, Watari H, Kato T, Odagiri T, Konno Y, Endo D, Mitamura T, Kikawa S, Suzuki Y, Sakuragi N. Clinical efficacy of paclitaxel/cisplatin as an adjuvant chemotherapy for patients with cervical cancer who underwent radical hysterectomy and systematic lymphadenectomy. J Surg Oncol 2012; 105(6): 612–616

[9] Li S, Li X, Zhang Y, Zhou H, Tang F, Jia Y, Hu T, Sun H, Yang R, Chen Y, Cheng X, Lv W, Wu L, Zhou J, Wang S, Huang K, Wang L, Yao Y, Yang Q, Yang X, Zhang Q, Han X, Lin Z, Xing H, Qu P, Cai H, Song X, Tian X, Shen J, Xi L, Li K, Deng D, Wang H, Wang C, Wu M, Zhu T, Chen G, Gao Q, Wang S, Hu J, Kong B, Xie X, Ma D. Development and validation of a surgical-pathologic staging and scoring system for cervical cancer. Oncotarget 2016; 7(15): 21054–21063

[10] Monk BJ, Wang J, Im S, Stock RJ, Peters WA 3rd, Liu PY, Barrett RJ 2nd, Berek JS, Souhami L, Grigsby PW, Gordon W Jr, Alberts DS; Gynecologic Oncology Group; Southwest Oncology Group; Radiation Therapy Oncology Group. Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial. Gynecol Oncol 2005; 96(3): 721–728

[11] Ohno T, Kato S, Wakatsuki M, Noda SE, Murakami C, Nakamura M, Tsujii H. Incidence and temporal pattern of anorexia, diarrhea, weight loss, and leukopenia in patients with cervical cancer treated with concurrent radiation therapy and weekly cisplatin: comparison with radiation therapy alone. Gynecol Oncol 2006; 103(1): 94–99

[12] Chen MF, Tseng CJ, Tseng CC, Kuo YC, Yu CY, Chen WC. Clinical outcome in posthysterectomy cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys 2007; 67(5): 1438–1444

[13] Kobayashi Y, Ohara T, Wada Y, Okuda Y, Kondo H, Okuma Y, Suzuki N, Gomi H, Kiguchi K, Ishizuka B. Concurrent chemoradiotherapy with nedaplatin after radical hysterectomy in patients with stage IB and II cervical cancer. J Obstet Gynaecol Res 2009; 35(3): 490–494

[14] Ryu SY, Park SI, Nam BH, Cho CK, Kim K, Kim BJ, Kim MH, Choi SC, Lee ED, Lee KH. Is adjuvant chemoradiotherapy overtreatment in cervical cancer patients with intermediate risk factors?. Int J Radiat Oncol Biol Phys 2011; 79(3): 794–799

[15] Li S, Hu T, Chen Y, Zhou H, Li X, Cheng X, Yang R, Wang S, Xie X, Ma D. Adjuvant chemotherapy, a valuable alternative option in selected patients with cervical cancer. PLoS One 2013; 8(9): e73837

[16] Nakanishi T, Wakai K, Ishikawa H, Nawa A, Suzuki Y, Nakamura S, Kuzuya K. A comparison of ovarian metastasis between squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecol Oncol 2001; 82(3): 504–509

[17] Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R; Gynecologic Oncology Group. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003; 21(17): 3194–3200

[18] Matsuo K, Shimada M, Yokota H, Satoh T, Katabuchi H, Kodama S, Sasaki H, Matsumura N, Mikami M, Sugiyama T. Effectiveness of adjuvant systemic chemotherapy for intermediate-risk stage IB cervical cancer. Oncotarget 2017; 8(63): 106866–106875

[19] Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group Study. Gynecol Oncol 1999; 73(2): 177–183

[20] Song S, Song C, Kim HJ, Wu HG, Kim JH, Park NH, Song YS, Kim JW, Kang SB, Ha SW. 20 year experience of postoperative radiotherapy in IB–IIA cervical cancer patients with intermediate risk factors: impact of treatment period and concurrent chemotherapy. Gynecol Oncol 2012; 124(1): 63–67

[21] Stroud JS, Mutch D, Rader J, Powell M, Thaker PH, Grigsby PW. Effects of cancer treatment on ovarian function. Fertil Steril 2009; 92(2): 417–427

[22] Kim MK, Sim JA, Yun YH, Bae DS, Nam JH, Park CT, Cho CH, Lee JM, Park SY. Health-related quality of life and sociodemographic characteristics as prognostic indicators of long-term survival in disease-free cervical cancer survivors. Int J Gynecol Cancer 2016; 26(4): 743–749

[23] Pasek M, Suchocka L, Urbański K. Quality of life in cervical cancer patients treated with radiation therapy. J Clin Nurs 2013; 22(5–6): 690–697

[24] Guthrie D. Chemotherapy of cervical cancer. Clin Obstet Gynaecol 1985; 12(1): 229–246

[25] Jung PS, Kim DY, Lee SW, Park JY, Suh DS, Kim JH, Kim YM, Kim YT, Nam JH. Clinical role of adjuvant chemotherapy after radical hysterectomy for FIGO stage IB–IIA cervical cancer: comparison with adjuvant RT/CCRT using inverse-probability-of-treatment weighting. PLoS One 2015; 10(7): e0132298

[26] Matsuo K, Shimada M, Yokota H, Satoh T, Katabuchi H, Kodama S, Sasaki H, Matsumura N, Mikami M, Sugiyama T. Effectiveness of adjuvant systemic chemotherapy for intermediate-risk stage IB cervical cancer. Oncotarget 2017; 8(63): 106866–106875

[27] Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990; 38(3): 352–357

[28] Hu T, Wu L, Xing H, Yang R, Li X, Huang K, Jia Y, Zhang Q, Chen Z, Wang S, Liu D, Han X, Lin Z, Qu P, Cai H, Song X, Tian X, Wang H, Wang S, Xie X, Li S, Ma D. Development of criteria for ovarian preservation in cervical cancer patients treated with radical surgery with or without neoadjuvant chemotherapy: a multicenter retrospective study and meta-analysis. Ann Surg Oncol 2013; 20(3): 881–890

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