You are here

  • Home
  • Archive
  • Volume 9, Issue 10
  • Multicentre, randomised controlled trial of adjuvant chemotherapy in cervical cancer with residual human papilloma virus DNA following primary radiotherapy or chemoradiotherapy: a study protocol

Article Text

Article menu

Download PDFPDF

XML
Oncology
Protocol
Multicentre, randomised controlled trial of adjuvant chemotherapy in cervical cancer with residual human papilloma virus DNA following primary radiotherapy or chemoradiotherapy: a study protocol
  1. Yanhong Wang1,
  2. Yi Ouyang2,
  3. Jingjing Su1,
  4. Jing Liu3,
  5. Qunrong Cai1,
  6. Qin Xu3,
  7. Zhigang Bai1,
  8. Xinping Cao2
  1. 1 Radiotherapy Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
  2. 2 Radiotherapy Department, Sun Yat-sen University Cancer Center, Guangzhou, China
  3. 3 Gynecology Department, Fujian Provincial Tumor Hospital, Fuzhou, China
  1. Correspondence to Dr Xinping Cao; caoxp{at}sysucc.org.cn

Abstract

Introduction The role of adjuvant chemotherapy after radical radiotherapy (RT) or chemoradiotherapy (CRT) in cervical cancer awaits further confirmation. Evidences have shown that persistent human papilloma virus (HPV) DNA in exfoliated cell post-RT is a potential biomarker of subclinical residual disease and thus increases the risk of recurrence. In this prospective, multicentre, randomised controlled trial, we will use HPV DNA in exfoliated cell to identify patients with cervical cancer who received definitive RT or CRT with higher risk of relapse for adjuvant chemotherapy.

Methods and analysis Eligible patients with histologically confirmed cervical cancer stage IIA2 to IVA of the International Federation of Gynaecology and Obstetrics, adequate organ function and no locoregional disease or distant metastasis after completion of primary treatment will be screened for HPV DNA in exfoliated cell at 1 month post-RT. Patients with undetectable HPV DNA will undergo standard surveillance. Patients with detectable HPV DNA will be randomly assigned to either adjuvant chemotherapy with docetaxel and nedaplatin for four cycles (arm 1) or observation (arm 2). Patients will be stratified for primary treatment (RT vs CRT). The primary endpoint is relapse-free survival.

Ethics and dissemination This protocol received a favourable ethical opinion from the Ethics Committee of the Second Affiliated Hospital of Fujian Medical University on 6 February, 2018, (No. 28). The trial results will be published in peer-reviewed journals and presented in conferences. A summary of the findings will be made available to participants.

Trial registration number ChiCTR-IIR-17012655; Pre-results.

  • cervical cancer
  • HPV persistence
  • adjuvant chemotherapy
  • survival
  • clinical trial

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2018-028171

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Strengths and limitations of this study

    • This is the first study to investigate the efficacy of adjuvant chemotherapy for patients with cervical cancer who have residual humanpapilloma virus (HPV) DNA at 1 month post-radical radiotherapy (RT) or chemoradiotherapy (CRT).

    • Previous studies have reported that patients with cervical cancer with persistent HPV after radical RT or CRT would have a higher recurrence rate and worse survival than patients with cleared HPV DNA; thus, we propose to include post-RT HPV DNA as a non-anatomical determinant of risk classification and treatment selection for adjuvant therapy in cervical cancer.

    • A study showed that prognostic accuracy of HPV test was highest at 3 months (82%), but, considering prognostic accuracy and impact of overall treatment time on survival, this study focuses on patients with persistent HPV DNA at 1 month, which may lead to false-positive results.

    • If relapse-free survival is greater in patients treated with adjuvant chemotherapy, this study will provide a new standard of care for patients with cervical cancer with residual HPV DNA, and HPV DNA persistence will be identified as one of the indications of adjuvant chemotherapy for patients with cervical cancer treated with curative RT or CRT.

    Introduction

    Cervical cancer remains to be one of the most common tumours affecting women worldwide, ranking third for cancer incidence and fourth for mortality.1 In China, approximately 98 900 women developed this disease, and 30 500 women died in 2015.2

    Adjuvant chemotherapy following radiotherapy or chemoradiotherapy

    For locally advanced cervical cancer, curative-intent chemoradiotherapy (CRT) is the mainstay of treatment, and most patients will achieve complete clinical remission. However, the disease will subsequently recur in 30% to 40% of patients either at the locoregional site or through distant metastasis, which prevents long-term cure.3 4 Thus, adjuvant chemotherapy has been studied to improve the efficacy. In 2011, Dueñas-González et al published a Consolidated Standards of Reporting Trials study in which 259 patients were submitted to concurrent CRT (cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 weekly for 6 weeks), followed by two cycles of adjuvant chemotherapy (cisplatin 50 mg/m2 on day 1, plus gemcitabine 1000 mg/m2 on days 1 and 8) and 255 patients were assigned to concurrent cisplatin (40 mg/m2) treatment and radiotherapy (RT). This study showed that adjuvant chemotherapy after concurrent CRT conferred superior progression-free survival over CRT (74.4% vs 65% at 3 years).5 Dr. Wang also reported that, for locally advanced cervical cancer, concurrent cisplatin (40 mg/m2 weekly) treatment and RT plus adjuvant chemotherapy (docetaxel 60 mg/m2 was used on day 1, cisplatin 40 mg on days 1 to 3, three cycles) could improve short-term and long-term survival and local control rate with tolerated toxicities compared with RT alone.6 Although the addition of adjuvant chemotherapy plus concurrent CRT rendered better survival than CRT or RT alone, the relative contribution of concurrent and adjuvant components of chemotherapy has not been adequately evaluated, and the extent to which adjuvant chemotherapy can affect survival in cervical cancer awaits further study. Adjuvant chemotherapy after RT alone or CRT did not improve disease-free survival and overall survival (OS) in another randomised controlled trial. In this trial, mitomycin C and oral 5-fluorouracil (5-FU) was administered concurrently with RT, and maintenance oral 5-FU was administered as adjuvant chemotherapy.7 Not all patients will likely gain from adjuvant chemotherapy after CRT or RT alone, so the key point is in patient selection to maximise the magnitude of benefit.

    Relationship of human papillomavirus with prognosis of cervical cancer after RT

    The involvement of humanpapilloma virus (HPV) in the development of cervical cancer has been firmly established, and >90% of patients harbour HPV in their tumour cells.8 9 Furthermore, for patients with cervical cancer treated with radical RT or CRT, pretreatment HPV infection is associated with better survival and lesser recurrence compared with HPV-negative tumour, which may be interpreted by the fact that irradiation interferes the E6/E7 inactivation p53/pRb and renders HPV-positive cancer cells more responsive to therapy.10–13

    It also has been reported that residual HPV DNA is clinically useful as a new marker to predict local recurrence after conization for cervical intraepithelial neoplasia14–18 and after RT for invasive cervical carcinoma.19–28 In the study conducted by the University of the Ryukyus in Japan, local recurrence rate was significantly higher in patients with persistent HPV than in patients cleared for HPV who were treated with RT (34% vs 7.1%). Multivariate analysis showed that persistence of HPV infection exhibited the largest HR values and smallest p values, which suggested that HPV persistence was the most powerful independent predictor for local disease-free survival and OS.21 Datta et al have reconfirmed that patients with reduction ≥99.5% in HPV titers at baseline had better survival outcome than those with reduction <99.5%.20

    Another study analysed the correlation of HPV prevalence in the exfoliated cell with recurrence in post-RT cervical carcinoma. It indicated that HPV persistence in exfoliated cell had high sensitivity (100%) in detecting recurrence after RT and further suggested that the presence of latent tumour cells with residual HPV infection, which were resistant to therapy, maybe the origin of recurrence.22 This conclusion was further strengthened by Italian researchers: 16 patients with locally advanced cervical cancer were treated with CRT followed by radical surgery, and majority of the women cleared of HPV had pathologically complete response (pCR), 6/6), while only 40% of patients with persistent HPV achieved pCR. It suggested that residual HPV DNA may exist in silent tumour cells, which maybe the source of high local relapse rate.19 Moreover, they demonstrated that the HPV type, physical status and point mutation after RT were exactly similar to those at the onset of therapy, which indicated that viral persistence rather than re-infection occurs in these patients.

    As stated above, a detectable HPV DNA after RT represents a biomarker of subclinical residual disease and is a valid tool for assessing the risk of recurrence. Because of the generally poor salvage rate of the central recurrences of locally advanced cervical cancer and grave symptoms of patients with uncontrolled recurrent pelvic disease, the value of adjuvant therapy to eradicate the subclinical disease could be tremendous.

    Timing of HPV test after RT or CRT

    HPV DNA may be persistently detected after RT in tumours because HPV DNA fragments may be present in degraded tumour cells even after all cancer cells have been eradicated.29 Song et al performed the HPV test on every patient visit and evaluated the association of HPV results with prognosis. They suggested that prognostic accuracy of HPV test was highest at 3 months (82%).30 To our knowledge, worse treatment outcomes can be expected with prolonged overall treatment time (OTT) during definitive or adjuvant CRT for cervical cancer.31–34 If adjuvant chemotherapy was administered to patients with persistent HPV at 3 months, it would be too late to effectively eradicate subclinical residual tumour cells and reduce the recurrence rate. Considering the adverse effect of OTT, an HPV test at 1 month is adopted in our study, as it has secondary sensitivity and specificity only to that of 3 months.

    We presume that patients with cervical cancer with detectable post-RT HPV have a significant likelihood of developing local recurrence, and administration of adjuvant chemotherapy can significantly improve local control and, therefore, relapse-free survival (RFS) by eradicating silent tumour cells. Correlation of post-RT HPV DNA and clinical outcome is a secondary endpoint of the study.

    Methods and analysis

    Study design and treatment

    This is a multicentre, randomised controlled trial which will investigate whether adjuvant chemotherapy can reduce recurrence rate and improve RFS compared with observation in patients with cervical cancer with persistent HPV after RT. RT alone or concurrent CRT will be stratified in both treatment arms. rThis study is funded by Science and Technology Planning Project of Quanzhou Science and Technology Bureau and Fujian Provincial Health and Family Planning Commission Research Talent Training Project.

    Sample-size calculation

    As the role of adjuvant chemotherapy after radical RT is uncertain, a meta-analysis of 3-year RFS for adjuvant chemotherapy after RT was conducted. Data of RFS was extracted from three prospective studies, and the HR of the 3-year RFS is 0.74 (95% CI 0.63 to 0.84).5 7 35 We presume that patients with cervical cancer with persistent HPV at 1 month post-RT will gain more advantage from adjuvant chemotherapy than all patients with cervical cancer. Therefore, with an estimated HR of 0.74 (observation arm as reference), approximately 295 patients will be required with a power of 0.8, α of 0.05 and a dropout rate of 10%.

    Study setting

    The study will be conducted at the Second Affiliated Hospital of Fujian Medical University, Sun Yat-sen University Cancer Center (SYSUCC) and Fujian Provincial Tumor Hospital. The study will run for 7 years between 1 March, 2018, and 28 February, 2025. All sites have existing personnel experienced in the treatment of cervical cancer and HPV test.

    Study endpoints

    The primary endpoint is RFS, with secondary endpoints including OS, local relapse-free survival, distant failure-free survival, incidence of adverse events and correlation of HPV DNA and clinical outcome.

    Eligibility criteria

    Patients with locally advanced cervical cancer diagnosed as stage IIA2 to IVA according to the International Federation of Gynaecology and Obstetrics (FIGO) who meet the inclusion criteria and dissatisfy the exclusion criteria described below will be considered eligible.

    Inclusion criteria

    1. Newly diagnosed and histologically confirmed cervical cancer.

    2. Age ≥18 and ≤70 years at the time of consent.

    3. Positive HPV DNA at diagnosis.

    4. FIGO stage IIA2 to IVA.

    5. No clinical evidence of distant metastasis at diagnosis.

    6. Achievement of clinical complete remission at 1 month after completion of primary RT or CRT.

    7. Persistence of the same type HPV DNA in the exfoliated cell at 1 month post-RT.

    8. Good general health condition (Eastern Cooperative Oncology Group score 0 or 1).

    9. Laboratory findings within the following ranges (at ≤14 days prior to enrolment): leucocyte count ≥3.0×109/L, neutrophil count ≥1.5×109/L, platelet count ≥100×109/L, total bilirubin level ≤1.5 ×upper limit of normal (ULN), aspartate aminotransferase/alanine aminotransferase level <2.5 × ULN and creatinine clearance >50 mL/min.

    10. Signed informed consent and appropriate compliance to ensure follow-up visit.

    Exclusion criteria

    1. Pregnancy or lactation.

    2. Previous (<5 years) malignancy (except cured skin cancer).

    3. >12 weeks after completion of primary RT.

    4. Receipt of prior neoadjuvant chemotherapy.

    5. Serious complication that affects tolerance to treatment.

    Informed consent

    Eligibility to participate will be confirmed by a clinician prior to obtaining consent. Patients will be given at least 24 hours to consider the patient information sheet and time to ask questions prior to obtaining written informed consent by a trial doctor. Before each HPV test, informed consent will have to been signed (online supplementary appendix 1).

    Supplemental material

    Randomisation

    Randomisation will be administered centrally by the SYSUCC. Eligible patients will be randomly allocated using the random number table. Randomisation will be conducted 1:1, with stratification for the type of primary treatment (RT or CRT), to either adjuvant chemotherapy (arm 1) or surveillance only (arm 2).

    Blinding

    There will be no blinding in this study.

    Workflow

    HPV DNA will be tested prior to the start of RT and also at 1 and 3 months post-RT. Cervical cells for the HPV DNA test will be collected using the cervical cell capture kit (Hybribio Limited Corp, Chaozhou, China). This consists of a cervical brush and one tube with 3 mL of specimen transport medium. The brush will be rotated clockwise three to five times in full turns in the endocervical os and swabbed on the ectocervical epithelium and then placed in the specimen transport media. The specimens will be stored at 4°C before HPV DNA testing. The presence of HPV will be examined by using flow-through hybridisation and gene-chip technology, which can detect 15 high-risk (16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66 and 68) and 6 low-risk HPV types (6, 11, 42, 43, 44 and C-CP8304).

    All pretreatment screening procedures have to be completed within 4 weeks before randomisation, which consist of demographic data, medical history, disease history (including date of initial diagnosis, histology and status of regional lymph nodes, FIGO stage), complete physical examination (including performance status (PS), body weight, height and vital sign of vagino-recto-abdominal examination), baseline laboratory tests (haematology, biochemistry and hepatitis B surface antigen), electrocardiography, tumour biomarker (squamous cell carcinoma antigen, cancer antigen-125 and carcinoembryonic antigen), colour Doppler of surpraclavicular and inguinal lymph nodes, chest CT, MRI of the abdomen and pelvis and bone scan. In arm 1, patients will receive docetaxel 75 mg/m2 and nedaplatin 75 mg/m2 intravenously, both administrated on day 1 every 3 weeks for a total of four cycles. Cisplatin or carboplatin administered on day 1 will be used to replace nedaplatin when significant (grade ≥3) thrombocytopenia or allergy exists (figure 1).

    Figure 1
    Figure 1

    Trial flowchart. CRT, chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynaecologyand Obstetrics; HPV, human papilloma virus; RT, radiotherapy.

    During adjuvant chemotherapy, laboratory haematology, biochemistry and adverse events will be assessed weekly of each cycle. Adverse events will be graded according to Common Terminology Criteria for Adverse Events (V.3). When the absolute neutrophil count is ＜1.5×109/L or platelet count is ＜75×109/L, chemotherapy will be interrupted until recovery. When patients have grade 4 haematological toxicity, impaired renal function and other non-haematological toxicities, the dose of docetaxel and nedaplatin will be reduced. If adjuvant chemotherapy is postponed for >4 weeks, the patient will be suspended from subsequent chemotherapy but will continue to complete the follow-up schedule.

    For all patients on both arms, an assessment will be conducted by the treating physician every 3 months for the first 2 years, then 6 monthly until 5 years, then yearly thereafter. During each scheduled visit, physical examination (including body weight and PS, vagino-recto-abdominal examination), tumour biomarker tests, HPV DNA test and documentation of the status of inguinal and supraclavicular lymph nodes will be performed. Thin-cytologic test, colour Doppler of surpraclavicular and inguinal lymph nodes, chest CT, abdominal and pelvic MRI and bone scan will be required at 6, 12, 18 and 24 months and then yearly post-chemotherapy. Evaluation of late toxicity (defined as toxicity that occurs at least 3 months after the last day of RT) of the gastrointestinal tract, rectum, kidneys and bladder and lymphoedema will be performed at each visit using the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer late radiation morbidity scoring criteria.36

    Data collection and management

    Every participant will be assigned a unique trial number on consenting to the study and identified in all study-related documentation by the trial number and initials.

    Participating centres’ completed case report forms (CRFs) consist of the following:

    1. Eligibility checklist before or at the time of randomisation.

    2. Pretreatment and tumour assessment at baseline prior to RT or CRT. The collected data included histology, FIGO stage, tumour size, lymph status, HPV type, tumour biomarker and RT sheet (including the total dose and fraction of RT and brachytherapy, regimen and cycle of concurrent chemotherapy).

    3. Treatment forms on day 1 of each chemotherapy cycle. The collected data included PS, baseline laboratory tests, protocol treatments received, toxicity and reasons for reduction/delay/omission of treatment.

    4. Toxicity forms that will be completed weekly of each cycle of chemotherapy.

    5. Follow-up forms at each follow-up visit. The collected data included late toxicities, serious adverse events and patient’s status (progression/relapse/death).

    Copies of all CRFs will be returned to the trial centre for statistical analysis. Paper copies of the CRFs will be retained at sites for at least 15 years following the last patient entered. All data will be uploaded to a study-defined database.

    The trial centre sponsors will be in regular contact with local centre personnel to check on the progress and help with any question that may arise. Incoming forms will be checked for completeness, consistency, timeliness and compliance with the protocol.

    Planned statistical analyses

    Intention-to-treat analyses will be performed for survival, and a Kaplan-Meier survival curve will be used to analyse all time-to-event data. A log-rank test will be used to estimate the difference in survival between the two patient groups. The HR and 95% CI will be assessed using Cox proportional hazards model. Missing data will be censored at the date they are last known to be alive. Adverse events (grades 3 to 5) will be compared between groups using χ² of Fisher’s exact test for the safety population (defined as patients who received at least one dose of chemotherapy). All tests will be two-sided, and a p value of 0.05 will be considered statistically significant.

    Patient and public involvement statement

    The patients and public are not involved in the design and conduct of the study.

    Ethics and dissemination

    All investigators shall comply with the protocol, unless a protocol amendment needs to eliminate immediate hazard to a participant. Data from all centres will be analysed together and reported as soon as possible. Individual participants cannot publish data about their patients that are directly related to questions proposed by the trial until the Trial Management Group (TMG) has published its report. The TMG will have access to the final data set, form the basis of the Writing Committee and advise on the nature of publications. With regard to dissemination, the results of this study will be published in an academic journal and presented at national and international conferences.

    Discussion and conclusion

    There is growing evidence supporting that patients with cervical cancer with persistent HPV DNA post-RT have increased recurrence than those without. There are also no definitive data on the group that will benefit from adjuvant chemotherapy. This presented randomised trial evaluated for the first time whether adjuvant chemotherapy post-RT in cervical cancer with residual HPV DNA can result in higher tumour control rates compared with clinical surveillance only. The study is currently recruiting participants. The study opened the recruitment in China on 1 March, 2018, the first patient was enrolled on 19 August, 2018, and 10 eligible patients have been enrolled.

    References

    1. ↵
      2. Torre LA ,
      3. Bray F ,
      4. Siegel RL , et al
      . Global cancer statistics, 2012. CA: A Cancer J Clin 2015;65:87–108.doi:10.3322/caac.21262
      OpenUrlCrossRef
    2. ↵
      2. Chen W ,
      3. Zheng R ,
      4. Baade PD , et al
      . Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115–32.doi:10.3322/caac.21338
      OpenUrlCrossRefPubMed
    3. ↵
      2. Kobayashi R ,
      3. Yamashita H ,
      4. Okuma K , et al
      . Details of recurrence sites after definitive radiation therapy for cervical cancer. J Gynecol Oncol 2016;27:e16.doi:10.3802/jgo.2016.27.e16
    4. ↵
      2. Schwarz JK ,
      3. Siegel BA ,
      4. Dehdashti F , et al
      . Metabolic response on post-therapy FDG-PET predicts patterns of failure after radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2012;83:185–90.doi:10.1016/j.ijrobp.2011.05.053
      OpenUrlPubMed
    5. ↵
      2. Dueñas-González A ,
      3. Zarbá JJ ,
      4. Patel F , 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.doi:10.1200/JCO.2009.25.9663
      OpenUrlAbstract/FREE Full Text
    6. ↵
      2. Wang S ,
      3. Zhang D-S ,
      4. Pan T , et al
      . Efficacy of concurrent chemoradiotherapy plus adjuvant chemotherapy on advanced cervical cancer. Chin J Cancer 2010;29:959–63.doi:10.5732/cjc.010.10186
      OpenUrlPubMed
    7. ↵
      2. Lorvidhaya V ,
      3. Chitapanarux I ,
      4. Sangruchi S , et al
      . Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 2003;55:1226–32.doi:10.1016/S0360-3016(02)04405-X
      OpenUrlCrossRefPubMed
    8. ↵
      2. Bosch FX ,
      3. Manos MM ,
      4. Muñoz N , et al
      . Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87:796–802.doi:10.1093/jnci/87.11.796
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      2. Walboomers JM ,
      3. Jacobs MV ,
      4. Manos MM , et al
      . Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–19.doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Harima Y ,
      3. Sawada S ,
      4. Nagata K , et al
      . Chromosome 6p21.2, 18q21.2 and human papilloma virus (HPV) DNA can predict prognosis of cervical cancer after radiotherapy. Int J Cancer 2001;96:286–96.doi:10.1002/ijc.1027
      OpenUrlCrossRefPubMed
    11. ↵
      2. Harima Y ,
      3. Sawada S ,
      4. Nagata K , et al
      . Human papilloma virus (HPV) DNA associated with prognosis of cervical cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2002;52:1345–51.doi:10.1016/S0360-3016(01)02796-1
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      2. Ikenberg H ,
      3. Sauerbrei W ,
      4. Schottmüller U , et al
      . Human papillomavirus DNA in cervical carcinoma–correlation with clinical data and influence on prognosis. Int J Cancer 1994;59:322–6.doi:10.1002/ijc.2910590306
      OpenUrlPubMed
    13. ↵
      2. Riou G ,
      3. Favre M ,
      4. Jeannel D , et al
      . Association between poor prognosis in early-stage invasive cervical carcinomas and non-detection of HPV DNA. Lancet 1990;335:1171–4.doi:10.1016/0140-6736(90)92693-C
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      2. Chua KL ,
      3. Hjerpe A
      . Human papillomavirus analysis as a prognostic marker following conization of the cervix uteri. Gynecol Oncol 1997;66:108–13.doi:10.1006/gyno.1997.4753
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      2. Elfgren K ,
      3. Jacobs M ,
      4. Walboomers JMM , et al
      . Rate of human papillomavirus clearance after treatment of cervical intraepithelial neoplasia. Obstet Gynecol 2002;100:965–71.doi:10.1016/s0029-7844(02)02280-9
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      2. Kudoh A ,
      3. Sato S ,
      4. Itamochi H , et al
      . Human papillomavirus type-specific persistence and reappearance after successful conization in patients with cervical intraepithelial neoplasia. Int J Clin Oncol 2016;21:580–7.doi:10.1007/s10147-015-0929-x
      OpenUrl
    17. ↵
      2. Park J-Y ,
      3. Bae J ,
      4. Lim MC , et al
      . Role of high risk-human papilloma virus test in the follow-up of patients who underwent conization of the cervix for cervical intraepithelial neoplasia. J Gynecol Oncol 2009;20:86–90.doi:10.3802/jgo.2009.20.2.86
      OpenUrlPubMed
    18. ↵
      2. Park J-Y ,
      3. Kim D-Y ,
      4. Kim J-H , et al
      . Human papillomavirus test after conization in predicting residual disease in subsequent hysterectomy specimens. Obstet Gynecol 2009;114:87–92.doi:10.1097/AOG.0b013e3181ab6dca
      OpenUrlCrossRefPubMed
    19. ↵
      2. Badaracco G ,
      3. Savarese A ,
      4. Micheli A , et al
      . Persistence of HPV after radio-chemotherapy in locally advanced cervical cancer. Oncol Rep 2010;23:1093–9.doi:10.3892/or_00000737
      OpenUrlPubMed
    20. ↵
      2. Datta NR ,
      3. Kumar P ,
      4. Singh S , et al
      . Does pretreatment human papillomavirus (HPV) titers predict radiation response and survival outcomes in cancer cervix?–a pilot study. Gynecol Oncol 2006;103:100–5.doi:10.1016/j.ygyno.2006.01.058
      OpenUrlPubMed
    21. ↵
      2. Nagai Y ,
      3. Toma T ,
      4. Moromizato H , et al
      . Persistence of human papillomavirus infection as a predictor for recurrence in carcinoma of the cervix after radiotherapy. Am J Obstet Gynecol 2004;191:1907–13.doi:10.1016/j.ajog.2004.06.088
      OpenUrlPubMed
    22. ↵
      2. Singh RK ,
      3. Maulik S ,
      4. Mitra S , et al
      . Human papillomavirus prevalence in postradiotherapy uterine cervical carcinoma patients: correlation with recurrence of the disease. Int J Gynecol Cancer 2006;16:1048–54.doi:10.1136/ijgc-00009577-200605000-00016
      OpenUrlAbstract/FREE Full Text
    23. ↵
      2. Lin G ,
      3. Yang L-Y ,
      4. Lin Y-C , et al
      . Prognostic model based on magnetic resonance imaging, whole-tumour apparent diffusion coefficient values and HPV genotyping for stage IB-IV cervical cancer patients following chemoradiotherapy. Eur Radiol 2019;29:556–65.doi:10.1007/s00330-018-5651-4
      OpenUrlCrossRefPubMed
    24. ↵
      2. Huang Y ,
      3. He Q ,
      4. Xu K , et al
      . A new marker based on risk stratification of human papillomavirus DNA and tumor size to predict survival of locally advanced cervical cancer. Int J Gynecol Cancer 2019;29:459–65.doi:10.1136/ijgc-2018-000095
      OpenUrlAbstract/FREE Full Text
    25. ↵
      2. Okonogi N ,
      3. Kobayashi D ,
      4. Suga T , et al
      . Human papillomavirus genotype affects metastatic rate following radiotherapy in patients with uterine cervical cancer. Oncol Lett 2018;15:459–66.doi:10.3892/ol.2017.7327
      OpenUrl
    26. ↵
      2. Mahantshetty U ,
      3. Teni T ,
      4. Naga P , et al
      . Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study. Gynecol Oncol 2018;148:299–304.doi:10.1016/j.ygyno.2017.11.034
      OpenUrl
    27. ↵
      2. Kaliff M ,
      3. Sorbe B ,
      4. Mordhorst LB , et al
      . Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy. Oncotarget 2018;9:18786–96.doi:10.18632/oncotarget.24666
      OpenUrl
    28. ↵
      2. Joo J ,
      3. Shin H-J ,
      4. Park B , et al
      . Integration pattern of human papillomavirus is a strong prognostic factor for disease-free survival after radiation therapy in cervical cancer patients. Int J Radiat Oncol Biol Phys 2017;98:654–61.doi:10.1016/j.ijrobp.2017.02.226
      OpenUrl
    29. ↵
      2. Czeglédy J ,
      3. Iosif C ,
      4. Hansson BG , et al
      . Can a test for E6/E7 transcripts of human papillomavirus type 16 serve as a diagnostic tool for the detection of micrometastasis in cervical cancer? Int J Cancer 1995;64:211–5.doi:10.1002/ijc.2910640312
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      2. Song YJ ,
      3. Kim J-Y ,
      4. Lee S-K , et al
      . Persistent human papillomavirus DNA is associated with local recurrence after radiotherapy of uterine cervical cancer. Int J Cancer 2011;129:896–902.
      OpenUrlPubMed
    31. ↵
      2. Chen SW ,
      3. Liang JA ,
      4. Yang SN , et al
      . The adverse effect of treatment prolongation in cervical cancer by high-dose-rate intracavitary brachytherapy. Radiother Oncol 2003;67:69–76.doi:10.1016/S0167-8140(02)00439-5
      OpenUrlCrossRefPubMed
    32. ↵
      2. Jhawar S ,
      3. Hathout L ,
      4. Elshaikh MA , et al
      . Adjuvant chemoradiation therapy for cervical cancer and effect of timing and duration on treatment outcome. Int J Radiat Oncol Biol Phys 2017;98:1132–41.doi:10.1016/j.ijrobp.2017.03.045
      OpenUrl
    33. ↵
      2. Petereit DG ,
      3. Sarkaria JN ,
      4. Chappell R , et al
      . The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301–7.doi:10.1016/0360-3016(94)00635-X
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      2. Shaverdian N ,
      3. Gondi V ,
      4. Sklenar KL , et al
      . Effects of treatment duration during concomitant chemoradiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys 2013;86:562–8.doi:10.1016/j.ijrobp.2013.01.037
      OpenUrl
    35. ↵
      2. Tang J ,
      3. Tang Y ,
      4. Yang J , et al
      . Chemoradiation and adjuvant chemotherapy in advanced cervical adenocarcinoma. Gynecol Oncol 2012;125:297–302.doi:10.1016/j.ygyno.2012.01.033
      OpenUrlPubMed
    36. ↵
      2. Cox JD ,
      3. Stetz J ,
      4. Pajak TF
      . Toxicity criteria of the radiation therapy Oncology Group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–6.doi:10.1016/0360-3016(95)00060-C
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • YW and YO contributed equally.

    • ZB and XC contributed equally.

    • Contributors YHW and YOY drafted the main manuscript. JJS and JL did the literature search. QRC played a chief role in statistical part. YHW, QX, ZGB and XPC participated in the design of the study. All authors have read and approved the final manuscript.

    • Funding This work was supported by Science and Technology Planning Project of Quanzhou Science and Technology Bureau grant number [2018N001S] and Fujian Provincial Health and Family planning Commission Research Talent training project grant number [2018-1-60].

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval Ethics approval for this trial has been granted by the Ethics Committee of the Second Affiliated Hospital of Fujian Medical University on 6 February, 2018, (No.28).

    • Provenance and peer review Not commissioned; externally peer reviewed.