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Ovarian transposition before radiotherapy in cervical cancer patients: functional outcome and the adequate dose constraint

Ovarian transposition before radiotherapy in cervical cancer patients: functional outcome and the... Background: The data regarding a transposed ovary in intensity-modulated radiotherapy (IMRT) are not sufficient. Here we aim to investigate the adequate dose constraint of ovarian transposition before radiotherapy in cervical cancer patients. Methods: This was a retrospective analysis of 118 patients with cervical cancer who received a radical hysterectomy and ovarian transposition before pelvic irradiation from April 2012 to July 2017. A total of 105 patients underwent IMRT with a limited radiation dose to the ovaries; 48 of these patients received unilateral ovary limitation, while 57 received bilateral ovary limitations. Patient follow up regarding sex hormone levels (estrogen [E2], follicle stimulating hormone [FSH]) and menopausal symptoms was completed one year after their radiation therapy. Results: A total of 41 out of 105 patients (39.0%) who underwent IMRT with a limited radiation dose to the ovaries preserved their normal ovarian function. The cutoff dose of comparatively lower side ovarian maximum dose was 9.985Gy and the cutoff of mean dose was 5.32Gy. The optimal dose–volume constrains to ovaries was V5.5 < 29.65%. Age ≤ 38 (P = 0.001) was an independent predictors of ovarian function, while limited ovarian side numbers were excluded. Conclusion: Using IMRT, preservation of ovarian function was possible when the limited dose was as low as possible to the ovaries regardless of bilateral or unilateral limitation to the ovaries. The ovarian maximum dose of less than 9.985Gy, the mean dose less than 5.32Gy and V5.5 < 29.65% could be better at preventing ovarian dysfunction. Patients younger than 38 years old were more likely to keep normal ovarian function while limited ovarian side numbers did not appear to exert an obvious effect. Keywords: Cervical cancer, Ovarian transposition, Radiotherapy, Ovarian function Background from 1993 to 2012 [3]. According to statistics from 2010, The number of cases of cervical cancer in young patients in China, nearly 15.7% of cervical cancer cases occurred in is growing. There were significant, increasing trends in women younger than 40 [4]. For patients diagnosed with cervical cancer mortality rates among young Japanese locally advanced cervical cancer, the standard treatment women below the age of 50 from 1975 to 2012 [1]. Cer- recommendation is concurrent pelvic radiation therapy vical cancer incidence among women 20–24 years old in- and chemotherapy [5]. In addition, postoperative adjuvant creased significantly for New Zealand women(1985–2013) radiotherapy for patients with high-risk pathological fac- [2]. In Korea, the incidence and mortality rates of cervical tors is recommended by the National Comprehensive cancer among young women (< 30 years old) increased Cancer Network (NCCN) Guidelines for Cervical Cancer Version 2017. Unfortunately, radiation may cause ovarian function failure. Reduction of radiation exposure is used * Correspondence: kegh5734@126.com to avoid radiation-induced ovarian failure that can occur Lina Yin and Saiquan Lu contributed equally to this work. Department of Gynecologic Oncology, Fudan University Shanghai Cancer at cumulative doses of 600 to 2000 cGy [6]. Decreased Center, Shanghai, China ovarian function may not only lead to menopausal symp- Department of Oncology, Shanghai Medical College, Fudan University, toms but may also cause osteoporosis, cardiovascular Shanghai, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yin et al. Radiation Oncology (2019) 14:100 Page 2 of 7 disease, and genitourinary atrophy. Because of these ad- ovarian maximum dose, ovarian mean dose and age upon verse events, some premenopausal patients with cervical transposed ovarian function was also evaluated. cancer are recommended to undergo ovarian transpos- All calculations were done using the SPSS 23.0 statistical ition [7–9]. software package (SPSS Inc. Chicago, IL). Receiver operator Ovarian transposition may decrease the likelihood of characteristic (ROC) analysis and 95% confidence interval ovarian dysfunction after treatment in young patients (CI) were used to analyze function of transposed ovaries scheduled to undergo chemotherapy and pelvic irradiation. and to determine the optimum cutoff point. Youden Typically, the ovaries are fixed in the paracolic gutters at index = sensitivity+specificity-1. Youden index were calcu- the level of pelvic brim with a sufficient angle to maintain lated based on ROC table and the dose corresponding to adequate blood supply [10]. In the era of 2D opposite-field the largest Youden index was defined as the cutoff point of radiotherapy, the standard recommended ovarian position dose constraints. during radiotherapy is 4 cm outside of the radiation field or Atwo-sided P value of < 0.05 was considered a significant more than 1.5 cm above the iliac crest [11]. calculation of the optimal limited radiation dose that would The ovaries are extremely sensitive to radiation. The esti- preserve ovarian function. Multivariate analysis was used to mated scatter dose to the ovaries was directly related to the analyze the relationship between covariates and normal preservation of ovarian function. If the dose to the ovaries ovarian function after lateral ovarian transposition. A two- is limited to 300 cGy or less, only 1 out of 9 patients (11%) sided P value of < 0.05 was considered significant. underwent menopause; however, 3 out of 5 patients (60%) became menopausal if the ovarian dose was more than 300 Results cGy [12]. A radiation dose of 250–300 cGy could inhibit Table 1 shows the characteristics of 118 patients. Accord- ovarian function, and 500–1500 cGy of radiation induced ing to the 2009 FIGO criteria, clinical staging of the tumors temporary sex hormone disorder and infertility. Further- identified 51 cases of Ib1, 18 cases of Ib2, 20 cases of IIa1, more, if the radiation dose went up to 2000–3000 cGy, irre- 15 cases of IIa2 and 14 cases of IIb. The median age of versible damage to the ovaries occurred [13]. These data patients was 38 years, and the average was 37.93 years. are estimated based on data from the era of 2D opposite- Histological examination identified 104 cases of squamous field radiotherapy. The data regarding a transposed ovary in cell carcinoma, 7 cases of adenocarcinoma, and 7 cases of intensity-modulated radiotherapy (IMRT) are not sufficient. other cancers. The purpose of this study was to analyze transposed ovar- Table 2 shows the comparison of ovarian function in pa- ian dose limitation in IMRT. tients undergoing different limitations of radiation. Ovarian transpositionwas performedonone ovaryin11cases and Methods on both ovaries in 107 cases. Ovarian function was absent This was a retrospective analysis of 118 patients with cer- in 13 patients who received IMRT with no limitation on ra- vical cancer who received radical hysterectomy and ovarian diation dose to the ovaries. A total of 41 cases out of 105 transposition before pelvic irradiation from April 2012 to patients (39.0%) who underwent IMRT with a limited radi- December 2017 at the Fudan University Shanghai Cancer ation dose (as low as possible) to the ovaries had preserved, Center. The age of the patients ranged from 24 to 49. Ac- normal ovarian function. The percentage of patients with cording to 2009 FIGO criteria, the clinical staging of tu- normal ovarian function was 33.3 and 43.9% in unilateral mors was Ib1~IIb. Postoperative adjuvant IMRT with dose and bilateral ovaries limitation (P = 0.318), respectively. In of planning target volume (PTV) 4500–5000Gy/25–28f/5w Table 1 Patient characteristics was recommended for all 118 patients with high-risk Patient characteristics N = 118 pathological factors. In all cases, adjuvant, concurrent Age (Range) 38 (24–49) chemotherapy included 40 mg/m of cisplatin administered weekly for 4–6 weeks. A total of 13 patients received IMRT FIGO staging with no limitation on radiation dose to the ovaries. A total Ib1 51 of 105 patients underwent IMRT with a limited radiation Ib2 18 dose (as low as possible) to the ovaries, and 48 of these pa- IIa1 20 tients received unilateral ovary limitation while 57 received IIa2 15 bilateral ovaries limitation. During the follow up, ovarian IIb 14 function was evaluated by measuring levels of FSH and E2 serum one year after the completion of pelvic irradiation. Histological types Ovarian function was considered to be preserved when the Squamous cell carcinoma 104 last follow up level, without hormone replacement therapy, Adenocarcinoma 7 of FSH was<40 mIU/mL and E2 >50pg/mL, and patients Others 7 displayed no menopausal symptoms. The influence of Yin et al. Radiation Oncology (2019) 14:100 Page 3 of 7 Table 2 Comparison of ovarian function in patients undergoing different radiation limitations Limitation radiation to the ovary No. of patients with normal ovarian function/no. treated No 0/13 (0%) Yes 41/105 (39.0%) Unilateral limitation 16/48 (33.3%) Bilateral limitation 25/57 (43.9%) P = 0.318 unilateral ovaries limitation patients, the only unilateral dose distributions (max, mean) of patients with and without ovaries were took into statistics. While in bilateral ovaries ovarian functional preservation. limitation patients, we chose the compared lower dose side According to the cutoff of mean dose, by using area ovaries and took them into statistics. Below, the lower side under the ROC curve and 95% CI statistical analysis, we ovarian maximum/mean dose means the maximum/mean determined that the optimal dose–volume constrains to dose of only unilateral ovaries or compared lower dose side ovaries was V5.5 < 29.65% (Fig. 3). The area under the in bilateral ovaries. curve was 0.706, and the 95% CI was 0.611–0.800. Using the area under the ROC curve and Youden index, Among ovarian dose limited patients, the average age of we determined that the optimal limited radiation doses that normal and abnormal ovarian function was 35.44 years and are well tolerated by ovaries were Dmax< 9.985Gy and 39.09 years, respectively (P < 0.001). As shown in Table 3, Dmean< 5.32Gy (Fig. 1), and the area under the curve was patients were grouped by median age (38 years old), and 0.654 and 0.704, respectively, while the 95% CI was 0.556– we found that patients younger than 38 years old were 0.753 and 0.609–0.799, respectively. The lower side ovarian more likely to keep normal ovarian function (P < 0.01). maximum dose of less than 9.985Gy was better at prevent- To investigate the correlation in unilateral/bilateral limi- ing the disruption of ovarian function. The lower side ovar- tation, age and ovarian function, we used multivariate ana- ian mean dose of less than 5.32Gy was better at preventing lysis and found that age ≤ 38 (P = 0.001, OR 0.240, 95%CI the disruption of ovarian function. Figure 2 indicated the 0.100–0.578) was an independent predictors of ovarian Fig. 1 ROC curve statistics for determining the optimal ovarian limited dose. The blue color crossing dashed line denotes the cutoff value of mean dose and the green denotes the cutoff value of maximum dose Yin et al. Radiation Oncology (2019) 14:100 Page 4 of 7 Fig. 2 Maximum dose (a) and mean dose (b) distributions of patients with and without ovarian functional preservation function, while limited ovarian side numbers were excluded maintain ovarian function for premenopausal patients by (P = 0.128, OR 0.514, 95%CI 0.218–1.211). (Table 4). ovarian transposition possible and rationable. Ovarian transposition before radiation therapy has been a hot issue for several years. In 2000, Buekers et al. reported Discussion that for patients who underwent ovarian transposition Recently, the incidence of cervical cancer in younger pa- without radiation therapy, 98% of ovarian function was pre- tients has increased, and the rationale behind ovarian trans- served for as long as 126 months after the procedure, and position before radiotherapy is to maintain ovarian function the average menopause age was 45.8 years. When radiation for premenopausal patients. The incidence of cancer metas- therapy was added, nearly 41% of ovarian function was pre- tasis to the transposed ovaries could be thought of as rare served for an average period of 43 months, and the average and negligible [14, 15]. Morice P et al. found ovarian metas- menopause age was 36.6 years [18]. Hwang et al. reported tasisinjust1 outof103 patients [16]. Only 3% of patients that all eight patients who did not receive adjuvant radi- who had adnexal disease in transposed ovaries required ation displayed normal ovarian function for more than one analgesics or further surgery [17]. These results made year when at least one of the ovaries was saved [11]. Feeney, Yin et al. Radiation Oncology (2019) 14:100 Page 5 of 7 Fig. 3 ROC curve statistics for determining the optimal dose–volume constrains. Area under the curve (AUC) is 0.706 (95% CI = 0.611–0.800). The blue crossing dashed line denotes the cutoff value of dose–volume D. D et al. found that without postoperative pelvic radio- to protect ovaries from radiation as ovaries are very sensi- therapy only 3/104(2.9%) patients who underwent lateral tive to radiation-induced damage. ovarian transposition experienced menopausal symptoms; The international commission on radiation units and however, only 14/28 (50%) of patients had preserved ovar- measurements (ICRU) recommends that planning organ ian function when undergoing pelvic radiotherapy [17]. at risk volume (PRV) margins should be used, because un- According to a review by Pahisa J, at a mean follow up of certainties and variations in the positioning of the organ 44 months, 63.6% of patients who received radiotherapy at risk (OAR) during treatment must be considered to and 93% of those patients without irradiation maintained avoid serious complications [20]. A recent study proposed normal ovarian function [19]. that the PRV margin for transposed ovaries is ~ 2 cm in During the follow up period in the current study, we did all directions [21]; however, 2 cm margins would be exces- not find ovarian metastasis in any of the 118 cases. Ovar- sively large in many cases. When the patient is younger, ian function was absent in 13 patients who received IMRT and the preservation of ovarian function is required, with no limitation on radiation dose to ovaries. Approxi- should the dose constraint of the ovarian PRV be consid- mately 39.0% of patients who underwent IMRT with a ered as a priority, and what is the adequate dose con- limited radiation dose (as low as possible) to the ovaries straint to transported ovaries? had preserved normal ovarian function. According to In 2016, Zhenhua Du et al. reported on 21 patients who these results, when postoperative radiotherapy is consid- underwent IMRT with limited radiation dose (V10 < 20%) ered, ovarian transposition and dose limitation are needed to the ovaries and sex hormone levels were measured. Table 3 Comparison of ovarian function in patients of different Table 4 Multivariate analysis of factor associated with ovarian age groups function after lateral ovarian transposition Age No. of patients with normal ovarian function/no. limitation treated Charateristics OR 95% CI P value ≤38 30/57 (52.6%) Age (≤38/>38) 0.240 0.100–0.578 0.001 >38 11/48 (22.9%) P < 0.01 Unilateral/bilateral limitation 0.514 0.218–1.211 0.128 Yin et al. Radiation Oncology (2019) 14:100 Page 6 of 7 They found that limiting the ovarian radiation dose to to irradiation. Only 2 patients older than 40 years were ob- V7.5 < 26% in IMRT can prevent the disruption of ovarian served menopause among the 14 patients [14]. In our function, with the area under the curve being 0.740 and a study, the average age of normal and abnormal ovarian 95% CI = 0.606–0.874 [22]. The samples used in this re- endocrine function was 35.44 years and 39.09 years, re- search were not enough, so we attempted to find the opti- spectively (P < 0.001). Multivariate analysis was used and mal radiation dose constraint to preserve ovarian function age ≤ 38 years was one independent predictor of ovarian in IMRT. function (P = 0.001, OR 0.240, 95%CI 0.100–0.578) while It has been shown that without radiation treatment, limited ovarian side numbers were excluded, which means ovarian endocrine function could be well preserved. In that transported ovaries in relatively younger patients may this study, ovarian function of 13 patients who received be more likely to be preserved in IMRT while unilateral/ IMRT with no particular limitation on radiation dose to bilateral ovaries limitation did not appear to exert an ovaries was absent, suggesting that ovarian function was obvious effect. significantly affected. Using IMRT, preservation of ovarian After all, the ROC curve method applied for further ana- function should be possible when the limited dose was as lysis indicated that the comparatively lower side ovarian low as possible to the ovaries. maximum dose less than 9.985Gy, the mean dose of less There has been many discussions about ovarian preserva- than 5.32Gy, may be better at preserving ovarian function. tion in the era of 2D opposite-field radiotherapy. In previ- These data suggest a new, optimal dose limit in IMRT to ous studies, the effectiveness of lateral ovarian transposition preserve ovarian function. The mean dose showed more for ovarian preservation after adjuvant 2D radiation has area under the curve than the maximum dose. Limiting ra- been reported. The rate of ovarian failure varied widely diation dose to V5.5 < 29.65% in IMRT was the new option from 17.0–88.6% after adjuvant radiation in patients after for the preservation of ovarian function. While the area lateral ovarian transposition [15, 23, 24]. The widely varied under the ROC curve were not very good, only showed result may be caused by many different influences such as limited predictive value (around 0.70), which may be caused the distance from iliac crest, uni- versus bilateral transpos- by sample-size restriction and the lack of stratification ana- ition, the age and so on. lysis that could affect the ovarian function. Jong Ha Hwang et al. reported that 32.3% patients who received adjuvant radiotherapy had normal ovarian func- Conclusion tion regardless of the distance of translocated ovaries and In summary, lateral ovarian transposition is an available the iliac crest [21]. Other research also reported that method to preserve ovarian function in IMRT that still 63.6–71% of patients had preserved ovarian function after needs sufficient distance between ovaries and the radiation transposition of the ovary of more than 4~5 cm above the field. The selection of younger patients and adequate dose iliac crest [25]. In these cases in our study, translocated limitation of the transposed ovary during is required to ovaries did not provide a satisfactory outcome, which may maintain ovarian function effectively. Limiting the be aslo caused by the insufficient distance between ovaries radiation dose to Dmax< 9.985Gy, Dmean< 5.32Gy and and the radiation field. V5.5 < 29.65% in translocated ovaries in IMRT might be In addition, bilateral ovary limitation may provide a bet- the new optimal option for the preservation of ovarian ter outcome compared to unilateral limitation. A total of function, and there is no significant statistical difference 39.0% of patients in our study who underwent IMRT with between bilateral and unilateral limitations. However, a limited radiation dose (as low as possible) to the ovaries there are still some limitations in our study, such as the had preserved, normal ovarian function. The percentage lack of comparison between hormone levels before and of patients with normal ovarian function was 33.3 and after radiotherapy or at different follow up times. The re- 43.9% in unilateral and bilateral ovaries limitation (P = sults of our study may provide information for the design 0.318, Table 2), respectively. Bilateral ovary limitation of future studies. Larger studies with a longer follow up seemed better than unilateral, but there was not statistical time are needed to confirm the predictors for increased significance. ovarian function preservation. In addition, the relationship between age, limited ovarian side numbers and the success of ovarian transposition was observed. It had been reported previously that age was sig- Abbreviations nificantly correlated with ovarian function failure [16, 26]. CI: Confidence interval; Dmax: Maximum dose; Dmean: Mean dose; Jong Ha Hwang et al. recommended bilateral ovarian E2: Estrogen; FIGO: Federation of Gynecology and Obstetrics; FSH: Follicle transposition in patients who are< 32 years of age based on stimulating hormone; ICRU: International commission on radiation units and measurements; IMRT: Intensity-modulated radiotherapy; NCCN: National the ROC curve [11]. Clough KB. observed that the success Comprehensive Cancer Network; OAR: Organ at risk; PRV: Planning organ at rate was 100% for patients younger than age 40 years risk volume; PTV: Planning target volume; ROC: Receiver operator though laparoscopic unilateral ovarian transposition prior characteristic; V5.5: Percentage of volume with irradiated dose of 5.5 Gy Yin et al. Radiation Oncology (2019) 14:100 Page 7 of 7 Acknowledgements with uterine cervical cancer treated with (postoperative or primary) pelvic We would like to thank all the patients involved in this study for sharing their radiotherapy. Fertil Steril. 2012;97(6):1387–93 e1-2. information during the follow-up period. We are also very grateful to all the 12. Chambers SK, Chambers JT, Holm C, Peschel RE, Schwartz PE. Sequelae of members of our department for helpful discussions. lateral ovarian transposition in unirradiated cervical cancer patients. Gynecol Oncol. 1990;39(2):155–9. 13. Chambers SK, Chambers JT, Kier R, Peschel RE. Sequelae of lateral ovarian Authors’ contributions transposition in irradiated cervical cancer patients. Int J Radiat Oncol Biol GK and LY designed the research; SL, LY and WZ extracted data; LY and JZ Phys. 1991;20(6):1305–8. analyzed the data; all the authors attended the follow-up visits and wrote and 14. Clough KB, Goffinet F, Labib A, Renolleau C, Campana F, de la Rochefordiere approved the final manuscript. A, et al. Laparoscopic unilateral ovarian transposition prior to irradiation: prospective study of 20 cases. Cancer. 1996;77(12):2638–45. Funding 15. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an Not applicable. underused procedure. Am J Obstet Gynecol. 2003;188(2):367–70. 16. Morice P, Juncker L, Rey A, El-Hassan J, Haie-Meder C, Castaigne D. Ovarian Availability of data and materials transposition for patients with cervical carcinoma treated by radiosurgical The datasets used and/or analyzed during the current study are available combination. Fertil Steril. 2000;74(4):743–8. upon reasonable request. 17. Feeney DD, Moore DH, Look KY, Stehman FB, Sutton GP. The fate of the ovaries after radical hysterectomy and ovarian transposition. Gynecol Oncol. Ethics approval and consent to participate 1995;56(1):3–7. This was a retrospective study and all data were collected according to the 18. Buekers TE, Anderson B, Sorosky JI, Buller RE. Ovarian function after surgical guidelines of the Ethics Committee in Cancer Hospital of Fudan University. treatment for cervical cancer. Gynecol Oncol. 2001;80(1):85–8. 19. Pahisa J, Martinez-Roman S, Martinez-Zamora MA, Torne A, Caparros X, Consent for publication Sanjuan A, et al. Laparoscopic ovarian transposition in patients with early Not applicable. cervical cancer. Int J Gynecol Cancer. 2008;18(3):584–9. 20. Bentzen SM, Constine LS, Deasy JO, Eisbruch A, Jackson A, Marks LB, et al. Competing interests Quantitative analyses of Normal tissue effects in the clinic (QUANTEC): an The authors declare that they have no competing interests. introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S3–9. Author details 21. Soda I, Ishiyama H, Ono S, Takenaka K, Arai M, Arai T, et al. Assessment of Department of Gynecologic Oncology, Fudan University Shanghai Cancer transposed ovarian movement: how much of a safety margin should be Center, Shanghai, China. Department of Oncology, Shanghai Medical added during pelvic radiotherapy? J Radiat Res. 2015;56(2):354–9. College, Fudan University, Shanghai, China. Department of Radiation 22. Du Z, Qu H. The relationship between ovarian function and ovarian limited Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. dose in radiotherapy postoperation of ovarian transposition in young Department of Gynecologic Oncology, Nantong Tumor Hospital, Nantong patients with cervical cancer. Cancer Med. 2017;6(3):508–15. University, Nantong, China. 23. Anderson B, LaPolla J, Turner D, Chapman G, Buller R. Ovarian transposition in cervical cancer. Gynecol Oncol. 1993;49(2):206–14. Received: 22 November 2018 Accepted: 29 May 2019 24. Owens S, Roberts WS, Fiorica JV, Hoffman MS, LaPolla JP, Cavanagh D. Ovarian management at the time of radical hysterectomy for cancer of the cervix. Gynecol Oncol. 1989;35(3):349–51. References 25. An Y, Qiao Z, Zou M, Yu J. Dynamic monitoring on ovarian function among 1. Motoki Y, Mizushima S, Taguri M, Takahashi K, Asano R, Kato H, et al. Increasing patients having had cervical squamous cell carcinoma transposition surgery. trends in cervical cancer mortality among young Japanese women below the Zhonghua Liu Xing Bing Xue Za Zhi. 2014;35(1):85–7. age of 50 years: an analysis using the Kanagawa population-based Cancer 26. Huang KG, Lee CL, Tsai CS, Han CM, Hwang LL. A new approach for registry, 1975-2012. Cancer Epidemiol. 2015;39(5):700–6. laparoscopic ovarian transposition before pelvic irradiation. Gynecol Oncol. 2. Smith MA, Edwards S, Canfell K. Impact of the National Cervical Screening 2007;105(1):234–7. Programme in New Zealand by age: analysis of cervical cancer trends 1985- 2013 in all women and in Maori women. Cancer Causes Control. 2017; 28(12):1393–404. Publisher’sNote 3. Moon EK, Oh CM, Won YJ, Lee JK, Jung KW, Cho H, et al. Trends and age- Springer Nature remains neutral with regard to jurisdictional claims in period-cohort effects on the incidence and mortality rate of cervical Cancer published maps and institutional affiliations. in Korea. Cancer Res Treat. 2017;49(2):526–33. 4. Cai HB, Liu XM, Huang Y, Li XN, Lie DM, Zhou Q, et al. Trends in cervical cancer in young women in Hubei, China. Int J Gynecol Cancer. 2010;20(7):1240–3. 5. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, 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(15):1137–43. 6. Lushbaugh CC, Casarett GW. The effects of gonadal irradiation in clinical radiation therapy: a review. Cancer. 1976;37(2 Suppl):1111–25. 7. Martin KA, Manson JE. Approach to the patient with menopausal symptoms. J Clin Endocrinol Metab. 2008;93(12):4567–75. 8. Dursun P, Ayhan A, Yanik FB, Kuscu E. Ovarian transposition for the preservation of ovarian function in young patients with cervical carcinoma. Eur J Gynaecol Oncol. 2009;30(1):13–5. 9. Mascarenhas-Melo F, Sereno J, Teixeira-Lemos E, Ribeiro S, Rocha-Pereira P, Cotterill E, et al. Markers of increased cardiovascular risk in postmenopausal women: focus on oxidized-LDL and HDL subpopulations. Dis Markers. 2013; 35(2):85–96. 10. Farber LA, Ames JW, Rush S, Gal D. Laparoscopic ovarian transposition to preserve ovarian function before pelvic radiation and chemotherapy in a young patient with rectal cancer. MedGenMed. 2005;7(1):66. 11. Hwang JH, Yoo HJ, Park SH, Lim MC, Seo SS, Kang S, et al. Association between the location of transposed ovary and ovarian function in patients http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Ovarian transposition before radiotherapy in cervical cancer patients: functional outcome and the adequate dose constraint

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Springer Journals
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Copyright © 2019 by The Author(s).
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Biomedicine; Cancer Research; Oncology; Radiotherapy; Imaging / Radiology
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Abstract

Background: The data regarding a transposed ovary in intensity-modulated radiotherapy (IMRT) are not sufficient. Here we aim to investigate the adequate dose constraint of ovarian transposition before radiotherapy in cervical cancer patients. Methods: This was a retrospective analysis of 118 patients with cervical cancer who received a radical hysterectomy and ovarian transposition before pelvic irradiation from April 2012 to July 2017. A total of 105 patients underwent IMRT with a limited radiation dose to the ovaries; 48 of these patients received unilateral ovary limitation, while 57 received bilateral ovary limitations. Patient follow up regarding sex hormone levels (estrogen [E2], follicle stimulating hormone [FSH]) and menopausal symptoms was completed one year after their radiation therapy. Results: A total of 41 out of 105 patients (39.0%) who underwent IMRT with a limited radiation dose to the ovaries preserved their normal ovarian function. The cutoff dose of comparatively lower side ovarian maximum dose was 9.985Gy and the cutoff of mean dose was 5.32Gy. The optimal dose–volume constrains to ovaries was V5.5 < 29.65%. Age ≤ 38 (P = 0.001) was an independent predictors of ovarian function, while limited ovarian side numbers were excluded. Conclusion: Using IMRT, preservation of ovarian function was possible when the limited dose was as low as possible to the ovaries regardless of bilateral or unilateral limitation to the ovaries. The ovarian maximum dose of less than 9.985Gy, the mean dose less than 5.32Gy and V5.5 < 29.65% could be better at preventing ovarian dysfunction. Patients younger than 38 years old were more likely to keep normal ovarian function while limited ovarian side numbers did not appear to exert an obvious effect. Keywords: Cervical cancer, Ovarian transposition, Radiotherapy, Ovarian function Background from 1993 to 2012 [3]. According to statistics from 2010, The number of cases of cervical cancer in young patients in China, nearly 15.7% of cervical cancer cases occurred in is growing. There were significant, increasing trends in women younger than 40 [4]. For patients diagnosed with cervical cancer mortality rates among young Japanese locally advanced cervical cancer, the standard treatment women below the age of 50 from 1975 to 2012 [1]. Cer- recommendation is concurrent pelvic radiation therapy vical cancer incidence among women 20–24 years old in- and chemotherapy [5]. In addition, postoperative adjuvant creased significantly for New Zealand women(1985–2013) radiotherapy for patients with high-risk pathological fac- [2]. In Korea, the incidence and mortality rates of cervical tors is recommended by the National Comprehensive cancer among young women (< 30 years old) increased Cancer Network (NCCN) Guidelines for Cervical Cancer Version 2017. Unfortunately, radiation may cause ovarian function failure. Reduction of radiation exposure is used * Correspondence: kegh5734@126.com to avoid radiation-induced ovarian failure that can occur Lina Yin and Saiquan Lu contributed equally to this work. Department of Gynecologic Oncology, Fudan University Shanghai Cancer at cumulative doses of 600 to 2000 cGy [6]. Decreased Center, Shanghai, China ovarian function may not only lead to menopausal symp- Department of Oncology, Shanghai Medical College, Fudan University, toms but may also cause osteoporosis, cardiovascular Shanghai, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yin et al. Radiation Oncology (2019) 14:100 Page 2 of 7 disease, and genitourinary atrophy. Because of these ad- ovarian maximum dose, ovarian mean dose and age upon verse events, some premenopausal patients with cervical transposed ovarian function was also evaluated. cancer are recommended to undergo ovarian transpos- All calculations were done using the SPSS 23.0 statistical ition [7–9]. software package (SPSS Inc. Chicago, IL). Receiver operator Ovarian transposition may decrease the likelihood of characteristic (ROC) analysis and 95% confidence interval ovarian dysfunction after treatment in young patients (CI) were used to analyze function of transposed ovaries scheduled to undergo chemotherapy and pelvic irradiation. and to determine the optimum cutoff point. Youden Typically, the ovaries are fixed in the paracolic gutters at index = sensitivity+specificity-1. Youden index were calcu- the level of pelvic brim with a sufficient angle to maintain lated based on ROC table and the dose corresponding to adequate blood supply [10]. In the era of 2D opposite-field the largest Youden index was defined as the cutoff point of radiotherapy, the standard recommended ovarian position dose constraints. during radiotherapy is 4 cm outside of the radiation field or Atwo-sided P value of < 0.05 was considered a significant more than 1.5 cm above the iliac crest [11]. calculation of the optimal limited radiation dose that would The ovaries are extremely sensitive to radiation. The esti- preserve ovarian function. Multivariate analysis was used to mated scatter dose to the ovaries was directly related to the analyze the relationship between covariates and normal preservation of ovarian function. If the dose to the ovaries ovarian function after lateral ovarian transposition. A two- is limited to 300 cGy or less, only 1 out of 9 patients (11%) sided P value of < 0.05 was considered significant. underwent menopause; however, 3 out of 5 patients (60%) became menopausal if the ovarian dose was more than 300 Results cGy [12]. A radiation dose of 250–300 cGy could inhibit Table 1 shows the characteristics of 118 patients. Accord- ovarian function, and 500–1500 cGy of radiation induced ing to the 2009 FIGO criteria, clinical staging of the tumors temporary sex hormone disorder and infertility. Further- identified 51 cases of Ib1, 18 cases of Ib2, 20 cases of IIa1, more, if the radiation dose went up to 2000–3000 cGy, irre- 15 cases of IIa2 and 14 cases of IIb. The median age of versible damage to the ovaries occurred [13]. These data patients was 38 years, and the average was 37.93 years. are estimated based on data from the era of 2D opposite- Histological examination identified 104 cases of squamous field radiotherapy. The data regarding a transposed ovary in cell carcinoma, 7 cases of adenocarcinoma, and 7 cases of intensity-modulated radiotherapy (IMRT) are not sufficient. other cancers. The purpose of this study was to analyze transposed ovar- Table 2 shows the comparison of ovarian function in pa- ian dose limitation in IMRT. tients undergoing different limitations of radiation. Ovarian transpositionwas performedonone ovaryin11cases and Methods on both ovaries in 107 cases. Ovarian function was absent This was a retrospective analysis of 118 patients with cer- in 13 patients who received IMRT with no limitation on ra- vical cancer who received radical hysterectomy and ovarian diation dose to the ovaries. A total of 41 cases out of 105 transposition before pelvic irradiation from April 2012 to patients (39.0%) who underwent IMRT with a limited radi- December 2017 at the Fudan University Shanghai Cancer ation dose (as low as possible) to the ovaries had preserved, Center. The age of the patients ranged from 24 to 49. Ac- normal ovarian function. The percentage of patients with cording to 2009 FIGO criteria, the clinical staging of tu- normal ovarian function was 33.3 and 43.9% in unilateral mors was Ib1~IIb. Postoperative adjuvant IMRT with dose and bilateral ovaries limitation (P = 0.318), respectively. In of planning target volume (PTV) 4500–5000Gy/25–28f/5w Table 1 Patient characteristics was recommended for all 118 patients with high-risk Patient characteristics N = 118 pathological factors. In all cases, adjuvant, concurrent Age (Range) 38 (24–49) chemotherapy included 40 mg/m of cisplatin administered weekly for 4–6 weeks. A total of 13 patients received IMRT FIGO staging with no limitation on radiation dose to the ovaries. A total Ib1 51 of 105 patients underwent IMRT with a limited radiation Ib2 18 dose (as low as possible) to the ovaries, and 48 of these pa- IIa1 20 tients received unilateral ovary limitation while 57 received IIa2 15 bilateral ovaries limitation. During the follow up, ovarian IIb 14 function was evaluated by measuring levels of FSH and E2 serum one year after the completion of pelvic irradiation. Histological types Ovarian function was considered to be preserved when the Squamous cell carcinoma 104 last follow up level, without hormone replacement therapy, Adenocarcinoma 7 of FSH was<40 mIU/mL and E2 >50pg/mL, and patients Others 7 displayed no menopausal symptoms. The influence of Yin et al. Radiation Oncology (2019) 14:100 Page 3 of 7 Table 2 Comparison of ovarian function in patients undergoing different radiation limitations Limitation radiation to the ovary No. of patients with normal ovarian function/no. treated No 0/13 (0%) Yes 41/105 (39.0%) Unilateral limitation 16/48 (33.3%) Bilateral limitation 25/57 (43.9%) P = 0.318 unilateral ovaries limitation patients, the only unilateral dose distributions (max, mean) of patients with and without ovaries were took into statistics. While in bilateral ovaries ovarian functional preservation. limitation patients, we chose the compared lower dose side According to the cutoff of mean dose, by using area ovaries and took them into statistics. Below, the lower side under the ROC curve and 95% CI statistical analysis, we ovarian maximum/mean dose means the maximum/mean determined that the optimal dose–volume constrains to dose of only unilateral ovaries or compared lower dose side ovaries was V5.5 < 29.65% (Fig. 3). The area under the in bilateral ovaries. curve was 0.706, and the 95% CI was 0.611–0.800. Using the area under the ROC curve and Youden index, Among ovarian dose limited patients, the average age of we determined that the optimal limited radiation doses that normal and abnormal ovarian function was 35.44 years and are well tolerated by ovaries were Dmax< 9.985Gy and 39.09 years, respectively (P < 0.001). As shown in Table 3, Dmean< 5.32Gy (Fig. 1), and the area under the curve was patients were grouped by median age (38 years old), and 0.654 and 0.704, respectively, while the 95% CI was 0.556– we found that patients younger than 38 years old were 0.753 and 0.609–0.799, respectively. The lower side ovarian more likely to keep normal ovarian function (P < 0.01). maximum dose of less than 9.985Gy was better at prevent- To investigate the correlation in unilateral/bilateral limi- ing the disruption of ovarian function. The lower side ovar- tation, age and ovarian function, we used multivariate ana- ian mean dose of less than 5.32Gy was better at preventing lysis and found that age ≤ 38 (P = 0.001, OR 0.240, 95%CI the disruption of ovarian function. Figure 2 indicated the 0.100–0.578) was an independent predictors of ovarian Fig. 1 ROC curve statistics for determining the optimal ovarian limited dose. The blue color crossing dashed line denotes the cutoff value of mean dose and the green denotes the cutoff value of maximum dose Yin et al. Radiation Oncology (2019) 14:100 Page 4 of 7 Fig. 2 Maximum dose (a) and mean dose (b) distributions of patients with and without ovarian functional preservation function, while limited ovarian side numbers were excluded maintain ovarian function for premenopausal patients by (P = 0.128, OR 0.514, 95%CI 0.218–1.211). (Table 4). ovarian transposition possible and rationable. Ovarian transposition before radiation therapy has been a hot issue for several years. In 2000, Buekers et al. reported Discussion that for patients who underwent ovarian transposition Recently, the incidence of cervical cancer in younger pa- without radiation therapy, 98% of ovarian function was pre- tients has increased, and the rationale behind ovarian trans- served for as long as 126 months after the procedure, and position before radiotherapy is to maintain ovarian function the average menopause age was 45.8 years. When radiation for premenopausal patients. The incidence of cancer metas- therapy was added, nearly 41% of ovarian function was pre- tasis to the transposed ovaries could be thought of as rare served for an average period of 43 months, and the average and negligible [14, 15]. Morice P et al. found ovarian metas- menopause age was 36.6 years [18]. Hwang et al. reported tasisinjust1 outof103 patients [16]. Only 3% of patients that all eight patients who did not receive adjuvant radi- who had adnexal disease in transposed ovaries required ation displayed normal ovarian function for more than one analgesics or further surgery [17]. These results made year when at least one of the ovaries was saved [11]. Feeney, Yin et al. Radiation Oncology (2019) 14:100 Page 5 of 7 Fig. 3 ROC curve statistics for determining the optimal dose–volume constrains. Area under the curve (AUC) is 0.706 (95% CI = 0.611–0.800). The blue crossing dashed line denotes the cutoff value of dose–volume D. D et al. found that without postoperative pelvic radio- to protect ovaries from radiation as ovaries are very sensi- therapy only 3/104(2.9%) patients who underwent lateral tive to radiation-induced damage. ovarian transposition experienced menopausal symptoms; The international commission on radiation units and however, only 14/28 (50%) of patients had preserved ovar- measurements (ICRU) recommends that planning organ ian function when undergoing pelvic radiotherapy [17]. at risk volume (PRV) margins should be used, because un- According to a review by Pahisa J, at a mean follow up of certainties and variations in the positioning of the organ 44 months, 63.6% of patients who received radiotherapy at risk (OAR) during treatment must be considered to and 93% of those patients without irradiation maintained avoid serious complications [20]. A recent study proposed normal ovarian function [19]. that the PRV margin for transposed ovaries is ~ 2 cm in During the follow up period in the current study, we did all directions [21]; however, 2 cm margins would be exces- not find ovarian metastasis in any of the 118 cases. Ovar- sively large in many cases. When the patient is younger, ian function was absent in 13 patients who received IMRT and the preservation of ovarian function is required, with no limitation on radiation dose to ovaries. Approxi- should the dose constraint of the ovarian PRV be consid- mately 39.0% of patients who underwent IMRT with a ered as a priority, and what is the adequate dose con- limited radiation dose (as low as possible) to the ovaries straint to transported ovaries? had preserved normal ovarian function. According to In 2016, Zhenhua Du et al. reported on 21 patients who these results, when postoperative radiotherapy is consid- underwent IMRT with limited radiation dose (V10 < 20%) ered, ovarian transposition and dose limitation are needed to the ovaries and sex hormone levels were measured. Table 3 Comparison of ovarian function in patients of different Table 4 Multivariate analysis of factor associated with ovarian age groups function after lateral ovarian transposition Age No. of patients with normal ovarian function/no. limitation treated Charateristics OR 95% CI P value ≤38 30/57 (52.6%) Age (≤38/>38) 0.240 0.100–0.578 0.001 >38 11/48 (22.9%) P < 0.01 Unilateral/bilateral limitation 0.514 0.218–1.211 0.128 Yin et al. Radiation Oncology (2019) 14:100 Page 6 of 7 They found that limiting the ovarian radiation dose to to irradiation. Only 2 patients older than 40 years were ob- V7.5 < 26% in IMRT can prevent the disruption of ovarian served menopause among the 14 patients [14]. In our function, with the area under the curve being 0.740 and a study, the average age of normal and abnormal ovarian 95% CI = 0.606–0.874 [22]. The samples used in this re- endocrine function was 35.44 years and 39.09 years, re- search were not enough, so we attempted to find the opti- spectively (P < 0.001). Multivariate analysis was used and mal radiation dose constraint to preserve ovarian function age ≤ 38 years was one independent predictor of ovarian in IMRT. function (P = 0.001, OR 0.240, 95%CI 0.100–0.578) while It has been shown that without radiation treatment, limited ovarian side numbers were excluded, which means ovarian endocrine function could be well preserved. In that transported ovaries in relatively younger patients may this study, ovarian function of 13 patients who received be more likely to be preserved in IMRT while unilateral/ IMRT with no particular limitation on radiation dose to bilateral ovaries limitation did not appear to exert an ovaries was absent, suggesting that ovarian function was obvious effect. significantly affected. Using IMRT, preservation of ovarian After all, the ROC curve method applied for further ana- function should be possible when the limited dose was as lysis indicated that the comparatively lower side ovarian low as possible to the ovaries. maximum dose less than 9.985Gy, the mean dose of less There has been many discussions about ovarian preserva- than 5.32Gy, may be better at preserving ovarian function. tion in the era of 2D opposite-field radiotherapy. In previ- These data suggest a new, optimal dose limit in IMRT to ous studies, the effectiveness of lateral ovarian transposition preserve ovarian function. The mean dose showed more for ovarian preservation after adjuvant 2D radiation has area under the curve than the maximum dose. Limiting ra- been reported. The rate of ovarian failure varied widely diation dose to V5.5 < 29.65% in IMRT was the new option from 17.0–88.6% after adjuvant radiation in patients after for the preservation of ovarian function. While the area lateral ovarian transposition [15, 23, 24]. The widely varied under the ROC curve were not very good, only showed result may be caused by many different influences such as limited predictive value (around 0.70), which may be caused the distance from iliac crest, uni- versus bilateral transpos- by sample-size restriction and the lack of stratification ana- ition, the age and so on. lysis that could affect the ovarian function. Jong Ha Hwang et al. reported that 32.3% patients who received adjuvant radiotherapy had normal ovarian func- Conclusion tion regardless of the distance of translocated ovaries and In summary, lateral ovarian transposition is an available the iliac crest [21]. Other research also reported that method to preserve ovarian function in IMRT that still 63.6–71% of patients had preserved ovarian function after needs sufficient distance between ovaries and the radiation transposition of the ovary of more than 4~5 cm above the field. The selection of younger patients and adequate dose iliac crest [25]. In these cases in our study, translocated limitation of the transposed ovary during is required to ovaries did not provide a satisfactory outcome, which may maintain ovarian function effectively. Limiting the be aslo caused by the insufficient distance between ovaries radiation dose to Dmax< 9.985Gy, Dmean< 5.32Gy and and the radiation field. V5.5 < 29.65% in translocated ovaries in IMRT might be In addition, bilateral ovary limitation may provide a bet- the new optimal option for the preservation of ovarian ter outcome compared to unilateral limitation. A total of function, and there is no significant statistical difference 39.0% of patients in our study who underwent IMRT with between bilateral and unilateral limitations. However, a limited radiation dose (as low as possible) to the ovaries there are still some limitations in our study, such as the had preserved, normal ovarian function. The percentage lack of comparison between hormone levels before and of patients with normal ovarian function was 33.3 and after radiotherapy or at different follow up times. The re- 43.9% in unilateral and bilateral ovaries limitation (P = sults of our study may provide information for the design 0.318, Table 2), respectively. Bilateral ovary limitation of future studies. Larger studies with a longer follow up seemed better than unilateral, but there was not statistical time are needed to confirm the predictors for increased significance. ovarian function preservation. In addition, the relationship between age, limited ovarian side numbers and the success of ovarian transposition was observed. It had been reported previously that age was sig- Abbreviations nificantly correlated with ovarian function failure [16, 26]. CI: Confidence interval; Dmax: Maximum dose; Dmean: Mean dose; Jong Ha Hwang et al. recommended bilateral ovarian E2: Estrogen; FIGO: Federation of Gynecology and Obstetrics; FSH: Follicle transposition in patients who are< 32 years of age based on stimulating hormone; ICRU: International commission on radiation units and measurements; IMRT: Intensity-modulated radiotherapy; NCCN: National the ROC curve [11]. Clough KB. observed that the success Comprehensive Cancer Network; OAR: Organ at risk; PRV: Planning organ at rate was 100% for patients younger than age 40 years risk volume; PTV: Planning target volume; ROC: Receiver operator though laparoscopic unilateral ovarian transposition prior characteristic; V5.5: Percentage of volume with irradiated dose of 5.5 Gy Yin et al. Radiation Oncology (2019) 14:100 Page 7 of 7 Acknowledgements with uterine cervical cancer treated with (postoperative or primary) pelvic We would like to thank all the patients involved in this study for sharing their radiotherapy. Fertil Steril. 2012;97(6):1387–93 e1-2. information during the follow-up period. We are also very grateful to all the 12. Chambers SK, Chambers JT, Holm C, Peschel RE, Schwartz PE. Sequelae of members of our department for helpful discussions. lateral ovarian transposition in unirradiated cervical cancer patients. Gynecol Oncol. 1990;39(2):155–9. 13. 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