ORIGINAL STUDY
Management of Leimyosarcoma A Survey Among Members of the Korean Gynecologic Oncology Group Mi Kyoung Kim,* Taek Sang Lee,Þ Jae-Weon Kim,þ Jong-Min Lee,§ Beob Jong Kim,|| and Seok Ju Seong, MD, PhD*
Objective: This study aimed to investigate current clinical management of leiomyosarcoma (LMS) in Korea. Materials and Methods: We conducted a Web-based survey among members of the Korean Gynecologic Oncology Group regarding their treatment of LMS. Results: In total, 77 (27.8%) of 277 members responded to the survey. For surgical treatment of stage I LMS, 26.8% indicated total hysterectomy only and 16.9% indicated total hysterectomy with bilateral salpingo-oophorectomy. Also, lymph node dissection was indicated by 54.9% of respondents, whereas 46.5% stated that bilateral salpingo-oophorectomy could be omitted in young patients. More than half (57.7%) of the respondents recommended against adjuvant treatment. For stage I LMS diagnosed after morcellation, 79.2% of the respondents recommended lymph node dissection and 56.4% recommended adjuvant therapy. As for advanced-stage LMS, in cases of complete resection, adjuvant chemotherapy was preferred by 63.1%. For incomplete resection, combined radiotherapy/chemotherapy was the most preferred adjuvant therapy (63.1%). Conclusions: Among Korean Gynecologic Oncology Group members, there are many discrepancies in the clinical management of LMS. A large-scale prospective study to establish treatment guidelines is needed. Key Words: Uterine leiomyosarcoma, Survey, Treatment Received May 24, 2017, and in revised form July 4, 2017. Accepted for publication July 7, 2017. (Int J Gynecol Cancer 2017;27: 00Y00)
sarcomas account for 3% to 8% of uterine maligU terine nancy cases. The estimated annual incidence of the most
Treatment options include surgery, chemotherapy, radiotherapy, or a combination thereof, although surgery is the treatment of choice for initial therapy.3 The standard surgical treatment for patients with LMS grossly confined within the uterus is total hysterectomy (TH). In postmenopausal women,
*Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea; †Department of Obstetrics and Gynecology, SMG-SNU Boramae Medical Center, and ‡Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; §Department of Obstetrics and Gynecology, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Republic of Korea; and
||Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. Address correspondence and reprint requests to Seok Ju Seong, MD, PhD, Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 566, Nonhyeon-ro, Gangnam-gu, Seoul 135-081, Republic of Korea. E-mail: [email protected]. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).
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common uterine sarcoma, leiomyosarcoma (LMS), is 0.64 per 100,000 women.2 Although rare, it is significantly aggressive and has a poor prognosis.
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bilateral salpingo-oophorectomy (BSO) is recommended. In the absence of grossly enlarged lymph nodes or other extrauterine extension, lymph node metastasis in cases of LMS is rare, and there is no evidence of any therapeutic benefit of lymph node dissection (LND) in early-stage LMS. Therefore, LND is not routinely recommended.4Y7 For early-stage LMS, the data supporting adjuvant chemotherapy or radiation therapy are limited and conflicting. In patients with advanced or metastatic disease, treatment options mainly involve systemic chemotherapy. Recently, other targeted therapies such as pazopanib, an oral multikinase inhibitor, have been studied to determine their efficacy against LMS.8,9 Given the rarity of LMS and the lack of relevant clinical trials, consensus on its treatment remains elusive. In current clinical management of LMS, there are many discrepancies regarding the extent of surgery (need for BSO, omentectomy, and LND) and the use of adjuvant treatment (in cases where adjuvant treatment is used). Furthermore, the risk incurred in the morcellation of occult LMS during laparoscopic (LSC) surgery is another necessary point of consideration. For all of these reasons, we conducted a survey among members of the Korean Gynecologic Oncology Group (KGOG) to investigate the prevailing patterns in the treatment of LMS in Korea.
MATERIALS AND METHODS The survey questionnaire (Supplement 1, http://link. lww.com/IGC/A546) was sent via electronic mail to 277 KGOG members in 2015. All data were collected and stored by SurveyMonkey, an online survey distributor. All responses were anonymous. The questionnaire consisted of questions on demographic characteristics including age, sex, years of experience, type of work (clinic, general hospital, university hospital), and geographic location, as well as the number of new patients managed for gynecologic cancer per month. In addition, 13 questions, each referencing as hypothetical clinical scenario, were asked about surgical and adjuvant procedures used in the treatment of LMS.
RESULTS Of the 277 KGOG members who received the survey questionnaire, 77 (27.8%) responded (Table 1). Most of the respondents were men (93.5%), aged 41 to 50 years (45.5%), and gynecologic oncologists affiliated with a university hospital or a general hospital (98.7%). The career length after obtaining board certification was, for most of the respondents (81.9%), more than 10 years. Almost half (44.2%) of the respondents answered that the number of new patients treated for gynecologic cancer was in the range of 5 to 10 per month. Scenario 1 (management for stage I LMS diagnosed after myomectomy in a young patient): A 35-year-old patient was diagnosed as having clinical stage I LMS after open myomectomy. Scenario 1-1 (surgical treatment): When asked about the preferred operative therapy in this scenario, 26.8% indicated total abdominal hysterectomy (TAH) only and 16.9% answered TAH with BSO. Meanwhile, 18.3% preferred the
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TABLE 1. Respondent’ sociodemographics (n = 77) No. (%) Age, y G30 30Y40 41Y50 51Y60 960 Sex Female Male Status of occupation Private clinic General hospital University hospital Province of occupation Seoul Gyeonggi Chungcheong Gangwon Jeolla Gyeongsang Jeju Others Years in specialty (years after obtaining board certification) G3 3Y5 6Y10 11Y20 920 No. new patients managed for gynecologic cancer (per month) G5 5Y10 11Y20 920
6 35 22 14
0 (7.8) (45.5) (28.6) (18.2)
5 (6.5) 72 (93.5) 1 (1.3) 13 (16.9) 63 (81.8) 33 16 4 2 4 15 1 2
(42.9) (20.8) (5.2) (2.6) (5.2) (19.5) (1.3) (2.6)
1 13 38 25
0 (1.3) (16.9) (49.4) (32.5)
19 34 12 12
(24.7) (44.2) (15.6) (15.6)
full surgical staging procedure: TAH, BSO, pelvic LND (PLND), para-aortic LND (PALND), and omentectomy. Overall, 54.9% recommended LND, of which 19.7% preferred PLND only and 35.2% preferred PLND and PALND. BSO was indicated by 53.5%, and ovarian preservation was preferred by 46.5% of the respondents (Fig. 1A). Scenario 1Y2 (adjuvant therapy): Finally, the patient was diagnosed as having stage I LMS. More than half (57.7%) of the respondents answered that they would not recommend adjuvant treatment. Among those who recommended adjuvant therapy, chemotherapy (33.8%) was the most preferred option (Fig. 1B). * 2017 IGCS and ESGO
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FIGURE 1. Management for stage I LMS diagnosed after open myomectomy in a young patient. CYVADIC, cyclophosphamide, vincristine, doxorubicin and dacarbazine; BS, bilateral salpingectomy; US, unilateral salpingectomy. Scenario 1Y3 (chemotherapy regimen): When those who had recommended chemotherapy were asked about their preferred regimens, the responses were relatively various. Docetaxel plus gemcitabine and adriamycin plus cisplatin were preferred by 29.2%, respectively, whereas doxorubicin plus ifosfamide was preferred by 25% (Fig. 1C). Scenario 2 (management for stage I LMS diagnosed after TAH in a young patient): A 40-year-old woman was diagnosed as having clinical stage I LMS after TAH. Scenario 2-1 (treatment plan): Faced with the treatment planning issue, 42% of respondents preferred close observation, 26.1% preferred chemotherapy, and 17.4% preferred additional surgical treatment (Fig. 2A). Scenario 2-2 (extent of surgery): Among those who recommended additional surgery, 50% preferred BSO with PLND, PALND, and omentectomy, whereas 16.7% chose BSO only. Overall, 83.3% recommended LND, and only 8.3% recommended preservation of the ovary (Fig. 2B). Scenario 3 (management for stage I LMS diagnosed after LSC myomectomy in a young patient): A 30-year-old patient underwent LSC myomectomy using morcellation and was diagnosed as having LMS on frozen section. Scenario 3-1 (treatment plan): When asked about their hypothetical treatment plan, more than half of the respondents preferred no further surgery and to determine the plan according to the final pathological report (58.8%; Fig. 3A). Scenario 3-2 (extent of surgery for fertility preservation): Given the question, ‘‘If you decide on fertility-preserving surgery in this setting, what is your preferred modality?’’ 22.6% answered ovarian wedge resection with PLND, PALND, and omentectomy, and 17.0% answered PLND, PALND, and omentectomy. Overall, 79.2% of the respondents preferred LND (Fig. 3B). Scenario 3-3 (additional surgical treatment including hysterectomy): The patient underwent surgical staging except
hysterectomy, and the final diagnosis was stage I LMS. When asked about additional hysterectomy, 52.7% of the respondents did not recommend it and 47.3% did (Fig. 3C). Scenarios 3Y4 and 3Y5 (adjuvant therapy): When asked about their preference for adjuvant therapy, among the respondents who recommended hysterectomy, 61.5% chose chemotherapy and 34.6% recommend only close observation (Fig. 3D). Among the respondents who would not perform hysterectomy, 51.7% preferred observation only and 41.4% preferred adjuvant chemotherapy (Fig. 3E). Scenario 4 (adjuvant therapy for advanced-stage LMS after complete resection): For advanced-stage LMS resected
FIGURE 2. Management for stage I LMS diagnosed after TAH in a young patient. A, Treatment plan. B, Extent of surgery.
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FIGURE 3. Management for stage I LMS diagnosed after LSC myomectomy in a young patient. A, Treatment plan for LMS diagnosed with frozen section. B, Extent of surgery for fertility preservation. C, Additional surgical treatment including hysterectomy. D, Adjuvant therapy (after staging operation including hysterectomy). E, Adjuvant therapy (after staging operation except hysterectomy). completely, chemotherapy was the most preferred adjuvant therapy (63.1%; Fig. 4A). Scenario 5 (adjuvant therapy for advanced-stage LMS after incomplete resection): For advanced-stage LMS resected incompletely, radiotherapy with chemotherapy was the most preferred adjuvant therapy (63.1%). Chemotherapy alone was preferred by 33.8% (Fig. 4B). Scenario 6 (second-line chemotherapy regimen for recurrent LMS): When asked about a chemotherapy regimen for recurrent multiple LMS (the patient had undergone surgical treatment and first-line chemotherapy with gemcitabine plus docetaxel), doxorubicine plus ifosfamide was the most preferred (41.5%), followed by paclitaxel plus carboplatin (21.5%; Fig. 5).
DISCUSSION Although controversies remain with respect to the utilization of LND and BSO for premenopausal women, the
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standard surgical treatment of early-stage LMS is TH. In this survey, we tried to find the current preferred extent of surgery. Interestingly, there were some divergences between clinicians’ recommendations and their actual adopted practices. When asked about operative therapy for stage I LMS diagnosed after myomectomy in premenopausal patients, more than half of the respondents answered that they would perform LND (54.8%) and/or BSO (53.6%). In case of LMS diagnosed after TAH, only 17.4% of respondents preferred reoperation, whereas most recommended LND (83.3%) and/or BSO (91.7%). According to previous reports, LND and BSO have no proven therapeutic value in the treatment of LMS. In the absence of macroscopic extrauterine extension or enlarged lymph nodes, the incidence of nodal metastasis is relatively low. Furthermore, LND seems not to alter survival for early-stage LMS, and lymph node status has been found to be statistically insignificant to 5-year disease-specific survival.4Y7,10,11 * 2017 IGCS and ESGO
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Management of Leimyosarcoma
FIGURE 4. Adjuvant therapy for advanced-stage LMS. A, After complete surgical resection. B, After incomplete surgical resection. Also, with regard to the issue of ovarian preservation in young women, the benefit of oophorectomy remains unclear. On the basis of the reported data, the incidence of microscopic ovarian metastases in stage I LMS is low, and ovarian preservation seems not to adversely affect clinical outcomes.1,4,5,7,12 Therefore, LND is not routinely recommended unless suspicious node metastasis or extrauterine disease is present. Also, provided that ovaries show no macroscopic involvement, ovarian preservation in young women is possible. However, there are as yet an insufficient number of indisputable prospective randomized controlled trials (RCTs) demonstrating this; thus, discrepancies and disputes about the extent of surgery remain. In any case, certainly, further RCTs are needed. As for the use of adjuvant therapy for early-stage LMS, the supporting data have been limited and conflicting. The role of radiation therapy is controversial, and thus far, at least, no RCTs have shown any survival benefit. Several
retrospective analyses have demonstrated that adjuvant radiation therapy decreases the local recurrence rate (RR) but offers no survival benefit.13Y18 An RCT conducted by the European Organization for Research and Treatment of Cancer determined that among 103 patients with stages I or II LMS, neither the rate of local recurrence nor overall survival (OS) was improved.19 The role of adjuvant chemotherapy is even more poorly defined than radiation therapy, but has been considered nonetheless, especially given the high risk for distant relapse posed by LMS. A number of prospective and retrospective studies on adjuvant chemotherapy for stages I and II LMS have shown controversial results. Omura et al,20 having compared adjuvant-therapy doxorubicin with observation, found that although progression-free survival (PFS) and OS were not significantly improved, the RR was reduced from 61% to 44%. This result suggested a potential role for
FIGURE 5. Second-line chemotherapy regimen for recurrent LMS. * 2017 IGCS and ESGO
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chemotherapy, and since that study, other drugs have been assessed.21Y24 However, still, no compellingly supportive evidence for the routine use of adjuvant chemotherapy has been shown. Similarly, a recent meta-analysis and multicenter retrospective studies found no clinical benefit in terms of PFS or OS.25Y27 Recently, prospective phase II trial evaluating the combination of gemcitabine and docetaxel followed by doxorubicin reported promising results regarding activity (2-year PFS, 78%; 3-year PFS, 57%).28 However, the efficacy of these combinations could not be assessed because of the small sample size and the lack of a control arm. Thus, this regimen currently is under investigation in an RCT.29 These controversial findings notwithstanding, many Korean gynecologic oncologists indicated a preference for adjuvant therapy (42.3%) in our survey. This might reflect the fact that LMS has a poor prognosis and a high RR ranging from 30% to 80%, and that current staging systems fail to identify patients at higher risk for relapse and death. Moreover, reliable data from RCTs comparing adjuvant therapy with no immediate treatment are lacking. Definitely, such trials are necessary. In this survey, we asked about treatment plan when a young patient was diagnosed as having unexpected LMS on frozen section. There could be 2 main concerns in this case. One is that reliability of intraoperative frozen section analysis to ascertain myometrial disease is still controversial, and the other is whether the surgeon could determine definitive treatment without preoperative full discussions with the patient about potential risk and treatment strategy for LMS. As expected, respondents took a more prudent attitude to determine definitive treatment according to frozen-section diagnosis. More than half of the respondents preferred no further surgery and to determine the plan according to the final pathological report. Only 16.2% choose immediate hysterectomy. Another important issue is risk incurred in the morcellation of occult LMS. Because laparoscopy came to replace open abdominal procedures, the use of tissue morcellation increased. Recently, the Food and Drug Administration warned against the use of power morcellation for tissue retrieval during laparoscopy, because, in the process, there is a risk of potentially malignant debris dissemination.30 From the publication of the Food and Drug Administration’s cautionary notice, the debates surrounding the use of morcellation have intensified.31Y33 The growing concerns about the use of uterine morcellation aside, data on the incidence of unsuspected LMS with apparent leiomyoma remains scant. Also, there is an ongoing debate about the effect of morcellation on the survival outcomes of patients with LMS. In the current survey, for management of occult LMS diagnosed after the use of morcellation, 79.2% recommended LND and 56.4% recommended adjuvant therapy more, in fact, than those in the case of laparotomy. This trend might be a reflection of concerns about the risk of malignant debris dissemination consequent upon the use of morcellation. Several retrospective studies and meta-analyses have suggested that in certain cases, morcellation increased the overall risk of recurrence and worsened prognosis.34Y38 However, those reports were highly biased and of low quality;
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thus, whether power morcellation up-stages occult LMS and affects survival is still an open question.39,40 Therefore, large prospective studies focusing on the effects of morcellation in LMS are warranted. Furthermore, to make decisions on appropriate types of surgery, it will be necessary to identify the most accurate and reliable preoperative diagnostic tools. The present study has limitations such as respondent selection bias and relatively low participation rate (27.8%). Notwithstanding, to our best knowledge, this is the first survey and analysis of LMS management to have been conducted in Korea. Through this survey, we could document the actual clinical management of LMS among Korean gynecologic oncologists. It is clear that there are many discrepancies among KGOG members in their management of LMS, and moreover, there is a certain discrepancy between evidence-based data and actual practices adopted by clinicians. This result reflects the lack of evidence-based clinical trials for establishment of an LMS treatment consensus. In this light, more RCTs are needed to answer the important questions surrounding the treatment of LMS.
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and adjuvant hormonal treatment in endometrial stromal sarcoma. Br J Cancer. 2007;97:1194Y1199. Le T. Adjuvant pelvic radiotherapy for uterine carcinosarcoma in a high risk population. Eur J Surg Oncol. 2001;27:282Y285. Chi DS, Mychalczak B, Saigo PE, et al. The role of whole-pelvic irradiation in the treatment of early-stage uterine carcinosarcoma. Gynecol Oncol. 1997;65:493Y498. Dusenbery KE, Potish RA, Agenta PA, et al. On the apparent failure of adjuvant pelvic radiotherapy to improve survival for women with uterine sarcomas confined to the uterus. Am J Clin Oncol. 2005;28:295Y300. Mahdavi A, Monk BJ, Ragazzo J, et al. Pelvic radiation improves local control after hysterectomy for uterine leiomyosarcoma: a 20-year experience. Int J Gynecol Cancer. 2009;19:1080Y1084. Wright JD, Seshan VE, Shah M, et al. The role of radiation in improving survival for early-stage carcinosarcoma and leiomyosarcoma. Am J Obstet Gynecol. 2008;199: 536.e1Y536.e8. Sampath S, Schultheiss TE, Ryu JK, et al. The role of adjuvant radiation in uterine sarcomas. Int J Radiat Oncol Biol Phys. 2010;76:728Y734. Reed NS, Mangioni C, Malmstro¨m H, et al. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: a European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur J Cancer. 2008;44:808Y818. Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol. 1985;3:1240Y1245. Muss H, Omura GA, Blessing JA, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J ClinOncol. 1985;3:1240Y1245. van Nagell JR Jr, Hanson MB, Donaldson ES, et al. Adjuvant vincristine, dactinomycin, and cyclophosphamide therapy in stage I uterine sarcomas. A pilot study. Cancer. 1986;57:1451Y1454. Sutton GP, Blessing JA, Barrett RJ, et al. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1992;166:556Y559. Odunsi K, Moneke V, Tammela J, et al. Efficacy of adjuvant CYVADIC chemotherapy in early stage uterine sarcomas: results of long-term follow-up. Int J Gynecol Cancer. 2004;14: 659Y664. Bramwell VH. Adjuvant chemotherapy for adult soft tissue sarcoma: is there a standard of care? J Clin Oncol. 2001;19: 1238Y1247.
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26. Ricci S, Giuntoli RL 2nd, Eisenhauer E, et al. Does adjuvant chemotherapy improve survival for women with early-stage uterine leiomyosarcoma? Gynecol Oncol. 2013;131:629Y633. 27. Mancari R, Signorelli M, Gadducci A, et al. Adjuvant chemotherapy in stage IYII uterine leiomyosarcoma: a multicentric retrospective study of 140 patients. Gynecol Oncol. 2014;133:531Y536. 28. Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005). Cancer. 2013;119:1555Y1561. 29. Gynecologic Oncology Group. Gemcitabine hydrochloride and docetaxel followed by doxorubicin hydrochloride or observation in treating patients with high-risk uterine leiomyosarcoma previously removed by surgery. Status: recruiting. Available at: http://www.ClinicalTrials.gov. Identifier: NCT01533207. 30. Hampton T. Use of morcellation to remove fibroids scrutinized at FDA hearings. JAMA. 2014;312:588. 31. Goff BA. SGO not soft on morcellation: risks and benefits must be weighed. Lancet Oncol. 2014;15:e148. 32. Kho KA, Nezhat CH. Evaluating the risks of electric uterine morcellation. JAMA. 2014;311:905Y906. 33. AAGL Advancing Minimally Invasive Gynecology Worldwide. AAGL practice report: morcellation during uterine tissue extraction. J Minim Invasive Gynecol. 2014;21:517Y530. 34. Anupama R, Ahmad SZ, Kuriakose S, et al. Disseminated peritoneal leiomyosarcomas after laparoscopic ‘‘myomectomy’’ and morcellation. J Minim Invasive Gynecol. 2011;18: 386Y389. 35. Della BC, Karini H. Endometrial stromal sarcoma diagnosed after uterine morcellation in laparoscopic supracervical hysterectomy. J Minim Invasive Gynecol. 2010;17:791Y793. 36. Oduyebo T, Rauh-Hain AJ, Meserve EE, et al. The value of re-exploration in patients with inadvertently morcellated uterine sarcoma. Gynecol Oncol. 2014;132:360Y365. 37. Einstein MH, Barakat RR, Chi DS, et al. Management of uterine malignancy found incidentally after supracervical hysterectomy or uterine morcellation for presumed benign disease. Int J Gynecol Cancer. 2008;18:1065Y1070. 38. Graebe K, Garcia-Soto A, Aziz M, et al. Incidental power morcellation of malignancy: a retrospective cohort study. Gynecol Oncol. 2015;136:274Y277. 39. Bogani G, Cliby WA, Aletti GD, et al. Impact of morcellation on survival outcomes of patients with unexpected uterine leiomyosarcoma: a systematic review and meta-analysis. Gynecol Oncol. 2015;137:167Y172. 40. Liu FW, Galvan-Turner VB, Pfaendler KS, et al. A critical assessment of morcellation and its impact on gynecologic surgery and the limitations of the existing literature. Am J Obstet Gynecol. 2015;212:717Y724.
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Management of Leimyosarcoma A Survey Among Members of the Korean Gynecologic Oncology Group Mi Kyoung Kim,* Taek Sang Lee,Þ Jae-Weon Kim,þ Jong-Min Lee,§ Beob Jong Kim,|| and Seok Ju Seong, MD, PhD*
Objective: This study aimed to investigate current clinical management of leiomyosarcoma (LMS) in Korea. Materials and Methods: We conducted a Web-based survey among members of the Korean Gynecologic Oncology Group regarding their treatment of LMS. Results: In total, 77 (27.8%) of 277 members responded to the survey. For surgical treatment of stage I LMS, 26.8% indicated total hysterectomy only and 16.9% indicated total hysterectomy with bilateral salpingo-oophorectomy. Also, lymph node dissection was indicated by 54.9% of respondents, whereas 46.5% stated that bilateral salpingo-oophorectomy could be omitted in young patients. More than half (57.7%) of the respondents recommended against adjuvant treatment. For stage I LMS diagnosed after morcellation, 79.2% of the respondents recommended lymph node dissection and 56.4% recommended adjuvant therapy. As for advanced-stage LMS, in cases of complete resection, adjuvant chemotherapy was preferred by 63.1%. For incomplete resection, combined radiotherapy/chemotherapy was the most preferred adjuvant therapy (63.1%). Conclusions: Among Korean Gynecologic Oncology Group members, there are many discrepancies in the clinical management of LMS. A large-scale prospective study to establish treatment guidelines is needed. Key Words: Uterine leiomyosarcoma, Survey, Treatment Received May 24, 2017, and in revised form July 4, 2017. Accepted for publication July 7, 2017. (Int J Gynecol Cancer 2017;27: 00Y00)
sarcomas account for 3% to 8% of uterine maligU terine nancy cases. The estimated annual incidence of the most
Treatment options include surgery, chemotherapy, radiotherapy, or a combination thereof, although surgery is the treatment of choice for initial therapy.3 The standard surgical treatment for patients with LMS grossly confined within the uterus is total hysterectomy (TH). In postmenopausal women,
*Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea; †Department of Obstetrics and Gynecology, SMG-SNU Boramae Medical Center, and ‡Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; §Department of Obstetrics and Gynecology, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Republic of Korea; and
||Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. Address correspondence and reprint requests to Seok Ju Seong, MD, PhD, Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 566, Nonhyeon-ro, Gangnam-gu, Seoul 135-081, Republic of Korea. E-mail: [email protected]. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).
1
common uterine sarcoma, leiomyosarcoma (LMS), is 0.64 per 100,000 women.2 Although rare, it is significantly aggressive and has a poor prognosis.
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bilateral salpingo-oophorectomy (BSO) is recommended. In the absence of grossly enlarged lymph nodes or other extrauterine extension, lymph node metastasis in cases of LMS is rare, and there is no evidence of any therapeutic benefit of lymph node dissection (LND) in early-stage LMS. Therefore, LND is not routinely recommended.4Y7 For early-stage LMS, the data supporting adjuvant chemotherapy or radiation therapy are limited and conflicting. In patients with advanced or metastatic disease, treatment options mainly involve systemic chemotherapy. Recently, other targeted therapies such as pazopanib, an oral multikinase inhibitor, have been studied to determine their efficacy against LMS.8,9 Given the rarity of LMS and the lack of relevant clinical trials, consensus on its treatment remains elusive. In current clinical management of LMS, there are many discrepancies regarding the extent of surgery (need for BSO, omentectomy, and LND) and the use of adjuvant treatment (in cases where adjuvant treatment is used). Furthermore, the risk incurred in the morcellation of occult LMS during laparoscopic (LSC) surgery is another necessary point of consideration. For all of these reasons, we conducted a survey among members of the Korean Gynecologic Oncology Group (KGOG) to investigate the prevailing patterns in the treatment of LMS in Korea.
MATERIALS AND METHODS The survey questionnaire (Supplement 1, http://link. lww.com/IGC/A546) was sent via electronic mail to 277 KGOG members in 2015. All data were collected and stored by SurveyMonkey, an online survey distributor. All responses were anonymous. The questionnaire consisted of questions on demographic characteristics including age, sex, years of experience, type of work (clinic, general hospital, university hospital), and geographic location, as well as the number of new patients managed for gynecologic cancer per month. In addition, 13 questions, each referencing as hypothetical clinical scenario, were asked about surgical and adjuvant procedures used in the treatment of LMS.
RESULTS Of the 277 KGOG members who received the survey questionnaire, 77 (27.8%) responded (Table 1). Most of the respondents were men (93.5%), aged 41 to 50 years (45.5%), and gynecologic oncologists affiliated with a university hospital or a general hospital (98.7%). The career length after obtaining board certification was, for most of the respondents (81.9%), more than 10 years. Almost half (44.2%) of the respondents answered that the number of new patients treated for gynecologic cancer was in the range of 5 to 10 per month. Scenario 1 (management for stage I LMS diagnosed after myomectomy in a young patient): A 35-year-old patient was diagnosed as having clinical stage I LMS after open myomectomy. Scenario 1-1 (surgical treatment): When asked about the preferred operative therapy in this scenario, 26.8% indicated total abdominal hysterectomy (TAH) only and 16.9% answered TAH with BSO. Meanwhile, 18.3% preferred the
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TABLE 1. Respondent’ sociodemographics (n = 77) No. (%) Age, y G30 30Y40 41Y50 51Y60 960 Sex Female Male Status of occupation Private clinic General hospital University hospital Province of occupation Seoul Gyeonggi Chungcheong Gangwon Jeolla Gyeongsang Jeju Others Years in specialty (years after obtaining board certification) G3 3Y5 6Y10 11Y20 920 No. new patients managed for gynecologic cancer (per month) G5 5Y10 11Y20 920
6 35 22 14
0 (7.8) (45.5) (28.6) (18.2)
5 (6.5) 72 (93.5) 1 (1.3) 13 (16.9) 63 (81.8) 33 16 4 2 4 15 1 2
(42.9) (20.8) (5.2) (2.6) (5.2) (19.5) (1.3) (2.6)
1 13 38 25
0 (1.3) (16.9) (49.4) (32.5)
19 34 12 12
(24.7) (44.2) (15.6) (15.6)
full surgical staging procedure: TAH, BSO, pelvic LND (PLND), para-aortic LND (PALND), and omentectomy. Overall, 54.9% recommended LND, of which 19.7% preferred PLND only and 35.2% preferred PLND and PALND. BSO was indicated by 53.5%, and ovarian preservation was preferred by 46.5% of the respondents (Fig. 1A). Scenario 1Y2 (adjuvant therapy): Finally, the patient was diagnosed as having stage I LMS. More than half (57.7%) of the respondents answered that they would not recommend adjuvant treatment. Among those who recommended adjuvant therapy, chemotherapy (33.8%) was the most preferred option (Fig. 1B). * 2017 IGCS and ESGO
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FIGURE 1. Management for stage I LMS diagnosed after open myomectomy in a young patient. CYVADIC, cyclophosphamide, vincristine, doxorubicin and dacarbazine; BS, bilateral salpingectomy; US, unilateral salpingectomy. Scenario 1Y3 (chemotherapy regimen): When those who had recommended chemotherapy were asked about their preferred regimens, the responses were relatively various. Docetaxel plus gemcitabine and adriamycin plus cisplatin were preferred by 29.2%, respectively, whereas doxorubicin plus ifosfamide was preferred by 25% (Fig. 1C). Scenario 2 (management for stage I LMS diagnosed after TAH in a young patient): A 40-year-old woman was diagnosed as having clinical stage I LMS after TAH. Scenario 2-1 (treatment plan): Faced with the treatment planning issue, 42% of respondents preferred close observation, 26.1% preferred chemotherapy, and 17.4% preferred additional surgical treatment (Fig. 2A). Scenario 2-2 (extent of surgery): Among those who recommended additional surgery, 50% preferred BSO with PLND, PALND, and omentectomy, whereas 16.7% chose BSO only. Overall, 83.3% recommended LND, and only 8.3% recommended preservation of the ovary (Fig. 2B). Scenario 3 (management for stage I LMS diagnosed after LSC myomectomy in a young patient): A 30-year-old patient underwent LSC myomectomy using morcellation and was diagnosed as having LMS on frozen section. Scenario 3-1 (treatment plan): When asked about their hypothetical treatment plan, more than half of the respondents preferred no further surgery and to determine the plan according to the final pathological report (58.8%; Fig. 3A). Scenario 3-2 (extent of surgery for fertility preservation): Given the question, ‘‘If you decide on fertility-preserving surgery in this setting, what is your preferred modality?’’ 22.6% answered ovarian wedge resection with PLND, PALND, and omentectomy, and 17.0% answered PLND, PALND, and omentectomy. Overall, 79.2% of the respondents preferred LND (Fig. 3B). Scenario 3-3 (additional surgical treatment including hysterectomy): The patient underwent surgical staging except
hysterectomy, and the final diagnosis was stage I LMS. When asked about additional hysterectomy, 52.7% of the respondents did not recommend it and 47.3% did (Fig. 3C). Scenarios 3Y4 and 3Y5 (adjuvant therapy): When asked about their preference for adjuvant therapy, among the respondents who recommended hysterectomy, 61.5% chose chemotherapy and 34.6% recommend only close observation (Fig. 3D). Among the respondents who would not perform hysterectomy, 51.7% preferred observation only and 41.4% preferred adjuvant chemotherapy (Fig. 3E). Scenario 4 (adjuvant therapy for advanced-stage LMS after complete resection): For advanced-stage LMS resected
FIGURE 2. Management for stage I LMS diagnosed after TAH in a young patient. A, Treatment plan. B, Extent of surgery.
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FIGURE 3. Management for stage I LMS diagnosed after LSC myomectomy in a young patient. A, Treatment plan for LMS diagnosed with frozen section. B, Extent of surgery for fertility preservation. C, Additional surgical treatment including hysterectomy. D, Adjuvant therapy (after staging operation including hysterectomy). E, Adjuvant therapy (after staging operation except hysterectomy). completely, chemotherapy was the most preferred adjuvant therapy (63.1%; Fig. 4A). Scenario 5 (adjuvant therapy for advanced-stage LMS after incomplete resection): For advanced-stage LMS resected incompletely, radiotherapy with chemotherapy was the most preferred adjuvant therapy (63.1%). Chemotherapy alone was preferred by 33.8% (Fig. 4B). Scenario 6 (second-line chemotherapy regimen for recurrent LMS): When asked about a chemotherapy regimen for recurrent multiple LMS (the patient had undergone surgical treatment and first-line chemotherapy with gemcitabine plus docetaxel), doxorubicine plus ifosfamide was the most preferred (41.5%), followed by paclitaxel plus carboplatin (21.5%; Fig. 5).
DISCUSSION Although controversies remain with respect to the utilization of LND and BSO for premenopausal women, the
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standard surgical treatment of early-stage LMS is TH. In this survey, we tried to find the current preferred extent of surgery. Interestingly, there were some divergences between clinicians’ recommendations and their actual adopted practices. When asked about operative therapy for stage I LMS diagnosed after myomectomy in premenopausal patients, more than half of the respondents answered that they would perform LND (54.8%) and/or BSO (53.6%). In case of LMS diagnosed after TAH, only 17.4% of respondents preferred reoperation, whereas most recommended LND (83.3%) and/or BSO (91.7%). According to previous reports, LND and BSO have no proven therapeutic value in the treatment of LMS. In the absence of macroscopic extrauterine extension or enlarged lymph nodes, the incidence of nodal metastasis is relatively low. Furthermore, LND seems not to alter survival for early-stage LMS, and lymph node status has been found to be statistically insignificant to 5-year disease-specific survival.4Y7,10,11 * 2017 IGCS and ESGO
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FIGURE 4. Adjuvant therapy for advanced-stage LMS. A, After complete surgical resection. B, After incomplete surgical resection. Also, with regard to the issue of ovarian preservation in young women, the benefit of oophorectomy remains unclear. On the basis of the reported data, the incidence of microscopic ovarian metastases in stage I LMS is low, and ovarian preservation seems not to adversely affect clinical outcomes.1,4,5,7,12 Therefore, LND is not routinely recommended unless suspicious node metastasis or extrauterine disease is present. Also, provided that ovaries show no macroscopic involvement, ovarian preservation in young women is possible. However, there are as yet an insufficient number of indisputable prospective randomized controlled trials (RCTs) demonstrating this; thus, discrepancies and disputes about the extent of surgery remain. In any case, certainly, further RCTs are needed. As for the use of adjuvant therapy for early-stage LMS, the supporting data have been limited and conflicting. The role of radiation therapy is controversial, and thus far, at least, no RCTs have shown any survival benefit. Several
retrospective analyses have demonstrated that adjuvant radiation therapy decreases the local recurrence rate (RR) but offers no survival benefit.13Y18 An RCT conducted by the European Organization for Research and Treatment of Cancer determined that among 103 patients with stages I or II LMS, neither the rate of local recurrence nor overall survival (OS) was improved.19 The role of adjuvant chemotherapy is even more poorly defined than radiation therapy, but has been considered nonetheless, especially given the high risk for distant relapse posed by LMS. A number of prospective and retrospective studies on adjuvant chemotherapy for stages I and II LMS have shown controversial results. Omura et al,20 having compared adjuvant-therapy doxorubicin with observation, found that although progression-free survival (PFS) and OS were not significantly improved, the RR was reduced from 61% to 44%. This result suggested a potential role for
FIGURE 5. Second-line chemotherapy regimen for recurrent LMS. * 2017 IGCS and ESGO
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chemotherapy, and since that study, other drugs have been assessed.21Y24 However, still, no compellingly supportive evidence for the routine use of adjuvant chemotherapy has been shown. Similarly, a recent meta-analysis and multicenter retrospective studies found no clinical benefit in terms of PFS or OS.25Y27 Recently, prospective phase II trial evaluating the combination of gemcitabine and docetaxel followed by doxorubicin reported promising results regarding activity (2-year PFS, 78%; 3-year PFS, 57%).28 However, the efficacy of these combinations could not be assessed because of the small sample size and the lack of a control arm. Thus, this regimen currently is under investigation in an RCT.29 These controversial findings notwithstanding, many Korean gynecologic oncologists indicated a preference for adjuvant therapy (42.3%) in our survey. This might reflect the fact that LMS has a poor prognosis and a high RR ranging from 30% to 80%, and that current staging systems fail to identify patients at higher risk for relapse and death. Moreover, reliable data from RCTs comparing adjuvant therapy with no immediate treatment are lacking. Definitely, such trials are necessary. In this survey, we asked about treatment plan when a young patient was diagnosed as having unexpected LMS on frozen section. There could be 2 main concerns in this case. One is that reliability of intraoperative frozen section analysis to ascertain myometrial disease is still controversial, and the other is whether the surgeon could determine definitive treatment without preoperative full discussions with the patient about potential risk and treatment strategy for LMS. As expected, respondents took a more prudent attitude to determine definitive treatment according to frozen-section diagnosis. More than half of the respondents preferred no further surgery and to determine the plan according to the final pathological report. Only 16.2% choose immediate hysterectomy. Another important issue is risk incurred in the morcellation of occult LMS. Because laparoscopy came to replace open abdominal procedures, the use of tissue morcellation increased. Recently, the Food and Drug Administration warned against the use of power morcellation for tissue retrieval during laparoscopy, because, in the process, there is a risk of potentially malignant debris dissemination.30 From the publication of the Food and Drug Administration’s cautionary notice, the debates surrounding the use of morcellation have intensified.31Y33 The growing concerns about the use of uterine morcellation aside, data on the incidence of unsuspected LMS with apparent leiomyoma remains scant. Also, there is an ongoing debate about the effect of morcellation on the survival outcomes of patients with LMS. In the current survey, for management of occult LMS diagnosed after the use of morcellation, 79.2% recommended LND and 56.4% recommended adjuvant therapy more, in fact, than those in the case of laparotomy. This trend might be a reflection of concerns about the risk of malignant debris dissemination consequent upon the use of morcellation. Several retrospective studies and meta-analyses have suggested that in certain cases, morcellation increased the overall risk of recurrence and worsened prognosis.34Y38 However, those reports were highly biased and of low quality;
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thus, whether power morcellation up-stages occult LMS and affects survival is still an open question.39,40 Therefore, large prospective studies focusing on the effects of morcellation in LMS are warranted. Furthermore, to make decisions on appropriate types of surgery, it will be necessary to identify the most accurate and reliable preoperative diagnostic tools. The present study has limitations such as respondent selection bias and relatively low participation rate (27.8%). Notwithstanding, to our best knowledge, this is the first survey and analysis of LMS management to have been conducted in Korea. Through this survey, we could document the actual clinical management of LMS among Korean gynecologic oncologists. It is clear that there are many discrepancies among KGOG members in their management of LMS, and moreover, there is a certain discrepancy between evidence-based data and actual practices adopted by clinicians. This result reflects the lack of evidence-based clinical trials for establishment of an LMS treatment consensus. In this light, more RCTs are needed to answer the important questions surrounding the treatment of LMS.
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