Among women worldwide,cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death,accounting for 8% [275, 100] of total cancer deaths among women in 2008 (1). In China,cervical cancer is the seventh most commonly diagnosed cancer and the eighth leading cause of cancer death in women,accounting for 2.6% of total cancer deaths among women in 2010 (2). More than a decade ago,several randomized controlled trials (RCTs) reported significant survival advantages for patients who received concurrent chemoradiotherapy (CCRT) compared with those who received radiation therapy (RT) alone (3, 4, 5, 6). CCRT has also become a standard treatment for locally advanced cervical cancer (LACC) in Japan. However,CCRT was introduced differently in Japan than in Western countries. Because of the nationwide use of Okabayashi radical hysterectomy (corresponding to class Ⅳ hysterectomy in Piver’s classification),patients who present with International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰb disease rarely receive CCRT; surgery is the treatment of choice for stage Ⅱb disease in Japan (7). Whereas previous RCT populations mainly had stage Ⅰ-Ⅱ disease (3, 4, 5, 6, 8),Japanese patients who undergo CCRT often have stage Ⅲ-Ⅳa disease. Therefore,Japanese studies may offer useful findings regarding the therapeutic limit of CCRT. In this manuscript,there are two issues to be discussed: (Ⅰ) the therapeutic limit of CCRT; and (Ⅱ) a new treatment strategy for high-risk LACC.
Indications for CCRT according to the clinical guidelines
CCRT is the standard treatment for stage Ⅲ-Ⅳa cervical cancer in various guidelines including: the National Comprehensive Cancer Network (NCCN) (9); the National Cancer Institute (10); the European Society of Medical Oncology (11); the Arbeitsgemeinschaft fur Gynakologische Onkologie (12); and the Japan Society of Gynecologic Oncology (7). Among them,the description in the NCCN clinical guidelines is noteworthy; surgical staging,namely extraperitoneal or laparoscopic lymph node dissection is listed as an alternative for stage ⅠB2-ⅣA patients. Unless surgical staging is performed,the guideline instructs physicians to consider resection of radiologically enlarged lymph nodes. In a nutshell,the NCCN clinical guidelines imply that some LACC with lymph node metastasis cannot be cured by CCRT alone.
Pitfalls of clinical evidence regarding CCRT
Systematic reviews have reported that CCRT is therapeutically superior to RT alone in treating LACC (13, 14). However,most positive trials of CCRT had small percentages of patients with stage Ⅲ-Ⅳ disease. In contrast,fewer than 16% of Japanese institutions offer CCRT to patients with stage ⅠB2/ⅡA bulky disease (15). As for stage ⅡB disease,32% and 17% of Japanese institutions offer CCRT to patients with squamous and non-squamous cell carcinoma; respectively (15). Large percentages of patients in Japan with stage ⅠB2-ⅡB LACC had radical hysterectomies with regional lymphadenectomies. As a result,a higher percentage of patients treated with CCRT in Japan have stage Ⅲ-Ⅳ disease than in other countries.
In western countries,patients with involved para-aortic lymph nodes have been excluded from some relevant RCTs. On the other hand,surgical staging,namely resection of para-aortic lymph nodes before CCRT,is rarely performed in Japan. Some negative trials of CCRT did not require eligible patients to undergo surgical staging for para-aortic lymph nodes (8, 16). Therefore,both the smaller percentage of patients with stage Ⅲ-Ⅳ disease and elimination of those with para-aortic node involvement may have led to more positive results for CCRT in previous meta-analyses. No evidence has supported therapeutic superiority for CCRT over RT alone in Japanese women. One of the findings reported by systematic reviews is noteworthy; it implied that there was a smaller beneficial effect in trials involving a high proportion of stage Ⅲ/Ⅳ patients (13, 14). The relative effect of CCRT on survival has been suggested to decrease as stage increases,with estimated absolute 5-year survival benefits of 10% at stages Ⅰa-Ⅱa,7% at stage Ⅱb,and 3% at stages Ⅲ-Ⅳa (14). CCRT may have room for improvement as standard treatment for stage Ⅲ-Ⅳ patients.
Therapeutic limit of CCRT
Lymph node enlargement (17, 18, 19),tumor diameter (17, 19, 20, 21),pretreatment hemoglobin level (17, 18, 21) and clinical stage (20) have been confirmed as prognostic factors for patients with cervical cancer who are treated with CCRT (Table 1). Overall treatment period (22) was confirmed as a prognostic factor for patients who are treated with RT.
As described above,CCRT is therapeutically limited by high clinical stage,as is tumor size. Kim et al. showed that tumor size was a prognostic factor independent of clinical stage (20); and Kudaka et al. showed that tumor size was a prognostic factor in patients with stage Ⅲ/Ⅳ disease (21). Also,larger tumors usually destroy the normal structure of the cervical canal,which may complicate implementation of intracavitary brachytherapy (BRT). What is a reasonable cut-off value for tumor size as a therapeutic limit of CCRT? According to patients with mostly advanced disease,tumors of 5.5-6.0 cm in size are a plausible therapeutic limit for CCRT (19, 21).
Lymph node enlargement may also be a therapeutic limit of CCRT,as lymph node enlargement adversely affects prognosis independent of cervical tumor size because of differences in maximal radiation doses to lymph node areas and cervical tumor areas. In cases with enlarged lymph nodes,relevant areas will receive varying radiation doses,some of which will be considerably less than optimal.
LACC might be divided into two categories by prognosis: low-risk and high-risk. Novel tactics are needed to improve outcomes for high-risk disease.
Novel treatment strategies for high-risk locally advanced disease
What can be done besides CCRT for patients with large tumors and radiologically enlarged lymph nodes? Potential strategies include (Ⅰ) increased peak concentration of cisplatin (CDDP); (Ⅱ) surgery following CCRT; (Ⅲ) adjuvant chemotherapy (CT) following CCRT; and (Ⅳ) neoadjuvant CT before CCRT.
First,concomitant use of definitive RT and CDDP using a higher dose of one medication than standard might be a promising approach. Tumor response to CDDP has been shown to depend on its peak concentration up to 100 mg/m2 (23, 24). However,deterioration in prognosis was observed when treatment was temporarily suspended during CCRT. Side effects that lead to treatment delay are the greatest concern of this strategy. A RCT in which two CCRT regimens were compared in patients with stage ⅡB-ⅣA cervical cancer showed a significant survival advantage for patients who had received triweekly CDDP CT (75 mg/m2 in 3 cycles) concurrent with RT compared with those who received weekly CDDP CT (40 mg/m2 in 6 cycles) concurrent with RT (5-year overall survival: 89% vs. 67%; hazard ratio: 0.375; 95%CI,0.154-0.914) (25). Higher peak concentrations may be more critical in enhancing the synergy of CCRT than weekly CDDP exposure. The percentage of distant failure in the higher peak group was less than in the lower peak group (17% vs. 26%) (25). Higher peak concentrations may also be more effective in eliminating metastatic tumor cells. Compliance between the two groups did not significantly differ (higher peak group: 93%; lower peak group: 86%) (25). Grade 3/4 neutropenia was rather frequent in the lower peak group (39% vs. 23%,P=0.03) (25). CCRT with increased peak CDDP concentration might be useful and feasible in LACC,although further study is needed to validate its efficacy.
Second,surgery following CCRT has been evaluated with varying results (Table 2) (26, 27, 28, 29, 30, 31, 32, 33, 34, 35). Surgical morbidity is the greatest concern of this strategy. Acceptable morbidity was observed in extrafascial hysterectomy (33, 35),type Ⅱ radical hysterectomy (32, 33),and type ≥Ⅲ radical hysterectomy (28, 30, 34). However,further study is needed to confirm feasibility of type ≥Ⅲ radical hysterectomy following CCRT. Some studies failed to show a survival advantage for radical hysterectomy over extrafascial hysterectomy (33, 35). Sun et al. showed that survival in patients who underwent extrafascial hysterectomy was better than that in patients who underwent radical hysterectomy (35). They identified extrafascial hysterectomy with pelvic lymph node dissection as the most feasible surgical approach,even in a population consisting exclusively of stage Ⅲ/Ⅳ patients. Patient selection may also be critical to implement this strategy. Huguet et al. reported that type Ⅱ radical hysterectomy after CCRT for operable bulky stage Ⅰ/Ⅱ cervical cancer and negative lymph node metastasis on imaging can be used with acceptable toxicity and good tumor control (32). Residual tumor in resected specimen was seen in 14-100% of patients who underwent surgery after CCRT. Surgery following CCRT undoubtedly leads to improved local control rates. However,distant failure often occurs in LACC. A prospective randomized study should be conducted to assess the survival benefit of this strategy.
Third,adjuvant CT following CCRT appears to be the most promising treatment for advanced cervical cancer. A RCT in which CCRT,with and without adjuvant chemotherapy,was compared in patients with stage ⅡB-ⅣA cervical cancer showed a significant survival advantage for patients who underwent CCRT in combination with adjuvant chemotherapy (3-year progression-free survival rates,74% vs. 65%; P=0.029; Figure 1A) (36). A meta-analysis suggested a survival advantage for patients who received adjuvant chemotherapy following CCRT compared with those who were treated with CCRT alone (14). However,these data were based on only two trials,one of which investigated totally different CCRT regimens (intravenous mitomycin C and oral 5-fluorouracil) and different CT (oral 5-fluorouracil) from the standard at present. Therefore,the most recent systematic review concluded that no sufficient evidence supports use of adjuvant CT after CCRT (37). Taking these results into consideration,a RCT (the OUTBACK trial) in which CCRT with and without adjuvant CT is compared in LACC is now ongoing (Figure 1B).
Fourth,another novel strategy involving the metachronous CT at a sufficient level to control distant metastasis has recently attracted attention. In 2013,a group from the UK published results of a phase Ⅱ study of neoadjuvant CT before CCRT for LACC (CxⅡ trial) (38). In this trial,46 patients received dose-dense carboplatin (CBDCA) (AUC2) and paclitaxel (PTX) (80 mg/m2) weekly for 6 cycles before standard CCRT and achieved good response rates (70% at the end of neoadjuvant CT and 85%,12 weeks after completing CCRT). In view of the CxⅡ trial results,a RCT (the INTERLACE trial) that compares CCRT in LACC with and without prior neoadjuvant CT is now ongoing (Figure 2). Neoadjuvant CT before CCRT is a novel strategy for potentially systemic (i.e.,high-risk) LACC. However,patients with FIGO stage ⅠB2-ⅡA disease are eligible for the INTERLACE trial,although those with radiologically enlarged lymph nodes above the aortic bifurcation are ineligible. We are concerned that so few patients with high-risk systemic disease are represented in the INTERLACE trial. If most INTERLACE patients are low-risk,the results will mainly reflect the responses of low-risk patients and may imply that less invasive treatments should be the standard of treatment. Therefore,RCTs carried out in Western countries may reach conclusions disadvantageous to high-risk patients,although high-risk patients require more effective treatments,regardless of invasiveness. For example,we present a case of high-risk LACC: our patient had a large tumor that involved the lower third of her vagina,with pelvic and para-aortic lymph node metastasis (Figure 3A-C). It responded remarkably well to neoadjuvant CT (Figure 3D,E). The patient then received modified CCRT with extended-field irradiation and achieved a long-term disease-free survival period. Such a case cannot be entered in the INTERLACE trial,although chemo-sensitive cervical cancer is not unusual. Neoadjuvant CT before CCRT for high-risk cases of LACC certainly merits wider testing.
The authors gratefully acknowledge the assistance of Michiko Ichii.
Conflicts of Interest: The authors declare no conflict of interest.
- Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. [PubMed]
- Chen W, Zheng R, Zhang S, et al. Annual report on status of cancer in China, 2010. Chin J Cancer Res 2014;26:48-58. [PubMed]
- Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage ⅡB-ⅣA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339-48. [PubMed]
- Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144-53. [PubMed]
- Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-43. [PubMed]
- Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004;22:872-80. [PubMed]
- Nagase S, Inoue Y, Umesaki N, et al. Evidence-based guidelines for treatment of cervical cancer in Japan: Japan Society of Gynecologic Oncology (JSGO) 2007 edition. Int J Clin Oncol 2010;15:117-24. [PubMed]
- Pearcey R, Brundage M, Drouin P, et al. Phase Ⅲ trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 2002;20:966-72. [PubMed]
- NCCN Clinical Guideline in Oncology. Cervical Cancer Version 2. 2015. Available online: http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf [PubMed]
- Cervical Cancer Treatment(PDQ®). Available online: http://www.cancer.gov/cancertopics/pdq/treatment/cervical/Patient/page5 [PubMed]
- Colombo N, Carinelli S, Colombo A, et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23:vii27-32. [PubMed]
- Cervical carcinoma. Available online: http://www.ago-online.de/de/infothek-fuer-aerzte/leitlinienempfehlungen/uterus/ [PubMed]
- Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001;358:781-6. [PubMed]
- Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008;26:5802-12. [PubMed]
- Mikami M, Aoki Y, Sakamoto M, et al. Surgical principles for managing stage ⅠB2, ⅡA2, and ⅡB uterine cervical cancer (Bulky Tumors) in Japan: a survey of the Japanese Gynecologic Oncology Group. Int J Gynecol Cancer 2014;24:1333-40. [PubMed]
- Cikaric S, Petrovic-Stupar S, Marjanov Ⅰ, et al. Radiotherapy vs. radiotherapy + chemotherapy of advanced cervical cancer: regression of tumour, early and late sequalaes, relapses of disease and 3 years survival (the third phase). European Journal of Cancer Supplements 2005;3:266.
- Parker K, Gallop-Evans E, Hanna L, et al. Five years' experience treating locally advanced cervical cancer with concurrent chemoradiotherapy and high-dose-rate brachytherapy: results from a single institution. Int J Radiat Oncol Biol Phys 2009;74:140-6. [PubMed]
- Lim A, Sia S. Outcomes of chemoradiotherapy in cervical cancer--the Western Australian experience. Int J Radiat Oncol Biol Phys 2012;82:1431-8. [PubMed]
- Endo D, Todo Y, Okamoto K, et al. Prognostic factors for patients with cervical cancer treated with concurrent chemoradiotherapy: a retrospective analysis in a Japanese cohort. J Gynecol Oncol 2015;26:12-8. [PubMed]
- Kim TE, Park BJ, Kwack HS, et al. Outcomes and prognostic factors of cervical cancer after concurrent chemoradiation. J Obstet Gynaecol Res 2012;38:1315-20. [PubMed]
- Kudaka W, Nagai Y, Toita T, et al. Long-term results and prognostic factors in patients with stage Ⅲ-ⅣA squamous cell carcinoma of the cervix treated with concurrent chemoradiotherapy from a single institution study. Int J Clin Oncol 2013;18:916-21. [PubMed]
- Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix. Ⅰ. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275-88. [PubMed]
- Bonomi P, Blessing JA, Stehman FB, et al. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 1985;3:1079-85. [PubMed]
- Thigpen T, Shingleton H, Homesley H, et al. cis-Dichlorodiammineplatinum(Ⅱ) in the treatment of gynecologic malignancies: phase Ⅱ trials by the Gynecologic Oncology Group. Cancer Treat Rep 1979;63:1549-55. [PubMed]
- Ryu SY, Lee WM, Kim K, et al. Randomized clinical trial of weekly vs. triweekly cisplatin-based chemotherapy concurrent with radiotherapy in the treatment of locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2011;81:e577-81. [PubMed]
- Azria E, Morice P, Haie-Meder C, et al. Results of hysterectomy in patients with bulky residual disease at the end of chemoradiotherapy for stage ⅠB2/Ⅱ cervical carcinoma. Ann Surg Oncol 2005;12:332-7. [PubMed]
- Houvenaeghel G, Lelievre L, Gonzague-Casabianca L, et al. Long-term survival after concomitant chemoradiotherapy prior to surgery in advanced cervical carcinoma. Gynecol Oncol 2006;100:338-43. [PubMed]
- Mariagrazia D, Anna F, Gabriella F, et al. Preoperative chemoradiotherapy in locally advanced cervical cancer: long-term outcome and complications. Gynecol Oncol 2005;99:S166-70. [PubMed]
- Classe JM, Rauch P, Rodier JF, et al. Surgery after concurrent chemoradiotherapy and brachytherapy for the treatment of advanced cervical cancer: morbidity and outcome: results of a multicenter study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer). Gynecol Oncol 2006;102:523-9. [PubMed]
- Ferrandina G, Legge F, Fagotti A, et al. Preoperative concomitant chemoradiotherapy in locally advanced cervical cancer: safety, outcome, and prognostic measures. Gynecol Oncol 2007;107:S127-32. [PubMed]
- Delpech Y, Haie-Meder C, Rey A, et al. Para-aortic involvement and interest of para-aortic lymphadenectomy after chemoradiation therapy in patients with stage ⅠB2 and Ⅱ cervical carcinoma radiologically confined to the pelvic cavity. Ann Surg Oncol 2007;14:3223-31. [PubMed]
- Huguet F, Cojocariu OM, Levy P, et al. Preoperative concurrent radiation therapy and chemotherapy for bulky stage ⅠB2, ⅡA, and ⅡB carcinoma of the uterine cervix with proximal parametrial invasion. Int J Radiat Oncol Biol Phys 2008;72:1508-15. [PubMed]
- Motton S, Houvenaeghel G, Delannes M, et al. Results of surgery after concurrent chemoradiotherapy in advanced cervical cancer: comparison of extended hysterectomy and extrafascial hysterectomy. Int J Gynecol Cancer 2010;20:268-75. [PubMed]
- Legge F, Margariti PA, Lucidi A, et al. Completion surgery after concomitant chemoradiation in obese women with locally advanced cervical cancer: Evaluation of toxicity and outcome measures. Acta Oncol 2013;52:166-73. [PubMed]
- Sun L, Sheng X, Jiang J, et al. Surgical morbidity and oncologic results after concurrent chemoradiation therapy for advanced cervical cancer. Int J Gynaecol Obstet 2014;125:111-5. [PubMed]
- Dueñas-González A, Zarbá JJ, et al. Phase Ⅲ, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage ⅡB to ⅣA carcinoma of the cervix. J Clin Oncol 2011;29:1678-85. [PubMed]
- Tangjitgamol S, Katanyoo K, Laopaiboon M, et al. Adjuvant chemotherapy after concurrent chemoradiation for locally advanced cervical cancer. Cochrane Database Syst Rev 2014;12:CD010401. [PubMed]
- McCormack M, Kadalayil L, Hackshaw A, et al. A phase Ⅱ study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer. Br J Cancer 2013;108:2464-9. [PubMed]