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Background: Radically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers. Methods: In this explorative, retrospective, cohort analysis, we included all the consecutive patients with radically resected eULMS treated at two centers between 1997 and 2017. Results: A total of 109 consecutive patients were included. Sixty-six (60%) received an anthracycline-based regi- men, whereas 43 (40%) received a gemcitabine-based regimen. Median disease-free survival (DFS) was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30–0.80; P = 0.004). In the multivariable model, anthracycline-based regimens were independently associated with a better DFS. No difference in terms of overall survival was observed. Conclusions: DFS was not the same by using an anthracycline-based or a gemcitabine-based adjuvant chemother- apy for patients with radically resected eULMS. The results of our study are in line with recent prospective controlled evidence in limb and superficial trunk soft tissue sarcomas. The role of anthracycline-based adjuvant chemotherapy should still be viewed as a research issue in eULMS. Keywords: Uterine leiomyosarcoma, Adjuvant chemotherapy, Gemcitabine, Anthracycline Background treatment in uterine-confined ULMS (FIGO stage I) [2 ], Uterine leiomyosarcoma (ULMS) represents 1–2% of all avoiding procedures associated with a possible tumor uterine neoplasms. It is the most common type of uter- spillage (i.e. morcellation) that are discouraged by ine sarcomas, with an incidence of about 0.55/100,000 guidelines because of the negative impact on patients’ women per year . Surgery is considered the mainstay prognosis [3, 4]. Regrettably, ULMS is characterized by a poor prognosis even if diagnosed at an early stage . Until now, unfortunately, adjuvant strategies inves- *Correspondence: firstname.lastname@example.org 1 tigated failed to be demonstrated to improve overall Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy survival. Radiation therapy did not add any benefit to Full list of author information is available at the end of the article surgery alone in a large randomized trial , in spite of © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Fucà et al. Clin Sarcoma Res (2020) 10:17 Page 2 of 6 positive evidence provided by uncontrolled and retro- Statistical analyses spective studies, as far as the local regional relapse rate Disease-free survival (DFS) was defined as the time from is concerned. The efficacy of adjuvant chemotherapy is surgical resection of uterine leiomyosarcoma to radio- still an open issue in soft-tissue sarcomas, and there- logical evidence of recurrence or death from any cause. fore in uterine leiomyosarcomas as well, in the absence Overall survival (OS) was defined as the time from sur - of randomized study dedicated to uterine leiomyosar- gical resection of uterine leiomyosarcoma to death from coma but one, recently closed for low accrual. On the any cause. Chi-square test, Fisher exact test or Mann– other hand, interesting progression-free survival was Whitney U test were used, as appropriate, to assess the shown in patients treated with adjuvant chemother- association between clinico-pathological characteristics apy by uncontrolled clinical studies [7, 8]. Intriguingly, and type of adjuvant regimen and between relapse and in patients with localized somatic leiomyosarcoma type of adjuvant chemotherapy regimen. For survival (LMS), neoadjuvant anthracycline-based chemotherapy analysis, we used the Kaplan–Meier method and Cox showed a superiority in terms of overall survival com- proportional hazards regression model. In Cox propor- pared to gemcitabine-based chemotherapy in a ran- tional hazards regression models, covariates with P < 0.1 domized large study recently reported . Thus, the role of adjuvant chemotherapy for early stage ULMS is Table 1 Patients and disease characteristics in the entire population and according to adjuvant regimen still undefined . In this paper, we report on a retro - spective review of all the consecutive cases of uterine- Characteristic Total G based A based P* confined ULMS treated with adjuvant chemotherapy at (N = 109) (N = 43) (N = 66) two Italian reference cancer centers, highlighting two N (%) N (%) N (%) groups, one treated with anthracycline-based and the Center 0.16 other treated with gemcitabine-based regimens. INT 78 (72) 34 (79) 44 (67) IEO 31 (28) 9 (21) 22 (33) Age 0.59 Methods Median 50 49 52 Patients population IQR 43–57 43–56 44–59 This was an explorative, retrospective, cohort analysis. Stage 0.59 Institutional registries of two reference cancer centers in IA 20 (19) 7 (17) 13 (21) Italy (Fondazione IRCCS Istituto Nazionale dei Tumori, IB 83 (81) 35 (83) 48 (79) Milan; European Institute of Oncology, Milan) were NA 6 1 5 searched in order to identify all consecutive patients with Mitotic index 0.37 a histologic diagnosis of FIGO stage I uterine leiomyosar- Median 21 25 16 coma treated with adjuvant chemotherapy between 1997 IQR 12–34 14–34 12–33 and 2017. The choice of regimen (anthracycline-based NA 55 16 39 vs gemcitabine-based) was driven by the literature evi- Surgery 0.53 dences available at the time of treatment initiation, the LPT 90 (88) 34 (85) 56 (90) safety profile and patients’ preferences. Pathologic diag - LPS 12 (12) 6 (15) 6 (10) nosis was reviewed at each center by an expert patholo- NA 7 3 4 gist according to the Stanford Criteria . Data about Morcellation 0.04 demographics mitotic index, surgery, adjuvant chemo- No 52 (72) 15 (58) 37 (80) therapy, association with adjuvant radiotherapy and Yes 20 (28) 11 (42) 9 (20) clinical outcomes were retrieved. Patients were included NA 37 17 20 in two cohorts according to whether they received an Oophorectomy 0.19 anthracycline-based or a gemcitabine-based regimen. No 27 (27) 13 (34) 14 (22) The study was approved by the Institutional Review Yes 74 (73) 25 (66) 49 (78) Boards of Fondazione IRCCS Istituto Nazionale dei NA 8 5 3 Tumori di Milano and European Institute of Oncology RT 0.05 and was conducted according to the ethical principles No 98 (90) 42 (98) 56 (85) for medical research involving human subjects adopted Yes 11 (10) 1 (2) 10 (15) in the Declaration of Helsinki. All the patients signed an *Chi-square test, Fisher exact test or Mann-Whitney U test as appropriate informed consent for the use of their clinico-pathological INT Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, IEO European data for research purposes. Institute of Oncology, IQR interquartile range, G gemcitabine, A anthracycline, RT radiotherapy F ucà et al. Clin Sarcoma Res (2020) 10:17 Page 3 of 6 Fig. 1 Kaplan–Meier curves for disease-free survival according to the adjuvant chemotherapy regimen in the univariable model were included in the multivari- i.e. 90%) did not receive adjuvant radiotherapy. Clinico- able model. Statistical significance was set at a threshold pathological characteristics were well balanced between of P = 0.05. Statistical analyses were performed using R the two cohorts except for morcellation, that was more software (version 3.5.0) and RStudio software (version frequent in patients receiving gemcitabine-based adju- 1.1.453). vant chemotherapy as compared to patients receiving anthracycline-based adjuvant chemotherapy (42 vs 20%, respectively). Results Patients characteristics Between 1997 and 2017, a total of 109 consecutive Clinical outcomes according to the adjuvant chemotherapy patients with resected stage I ULMS were treated with regimen adjuvant chemotherapy at two Italian reference cancer After a median follow up time of 87.8 months (IQR: centers. Sixty-six patients (60%) received an anthracy- 58.9–122.9), we observed a total of 38 relapses and 24 cline-based regimen, whereas 43 (40%) received a gem- deaths. Specifically, we observed a relapse of disease in citabine-based regimen. Additional file 1: Table S1 shows 38 patients treated with anthracycline-based adjuvant the details about adjuvant chemotherapy regimens used. chemotherapy and 31 treated with gemcitabine-based Patient and disease characteristics are summarized in adjuvant chemotherapy. Median DFS was 41.3 months Table 1. Median age was 50 years (interquartile range (95% CI: 28.2-NA) for patients treated with anthracy- [IQR]: 43–57) and 83 out of 109 patients (81%) had a cline-based adjuvant chemotherapy (3-years DFS rate: stage IB ULMS. Data about morcellation and bilateral 53.6%) compared to 20.9 months (95% CI: 13.4–37.2) oophorectomy at the time of surgery were available for 72 for patients treated with gemcitabine-based adjuvant and 101 patients, respectively. Overall, 20 patients (28%) chemotherapy (3-years DFS rate: 33.1%) (HR: 0.49; 95% received morcellation and 74 (73%) underwent bilat- CI: 0.30–0.80; P = 0.004) (Fig. 1). In the multivariable eral oophorectomy. Most of the patients (98 out of 109, model, including other covariates associated with DFS Fucà et al. Clin Sarcoma Res (2020) 10:17 Page 4 of 6 Table 2 Cox proportional hazard regression models a different benefit, especially in terms of DFS, for patients for disease-free survival treated with anthracycline-based chemotherapy com- pared to patients treated with gemcitabine-based chemo- Characteristic Univariable model Multivariable model therapy, even after adjusting for other relevant variables HR (95% CI) P HR (95% CI) P (i.e. FIGO stage and mitotic index). Today, the standard of care of localized early stage Age (years) 1.07 (0.84–1.35) 0.59 – – ULMS is radical surgery alone [3, 4, 12]. Unfortunately, Stage after the failure for low accrual of the first large rand - IB vs IA 1.99 (0.98–4.03) 0.06 4.27 (1.28–14.20) 0.02 omized study of adjuvant chemotherapy versus observa- Mitotic index tion, it is very unlikely that a new controlled international 34 vs 12 1.02 (1.00–1.03) 0.07 1.01 (0.99–1.03) 0.22 study will be proposed to establish a definitive role of the Surgery adjuvant chemotherapy in ULMS. On the other hand, LPS vs LPT 0.82 (0.35–1.89) 0.64 – – two phase 2 studies of adjuvant chemotherapy, with gem- Morcellation citabine and docetaxel and with gemcitabine and doc- Yes vs No 1.01 (0.51–2.01) 0.98 – – etaxel followed by anthracycline, respectively, showed Oophorectomy an interesting DFS for adjuvant chemotherapy compared Yes vs No 0.92 (0.53–81.60) 0.78 – – with historical control [7, 8]. In particular, the addition RT of four cycles of anthracycline to gemcitabine and doc- Yes vs No 0.68 (0.29–1.58) 0.37 – – etaxel demonstrated an improvement in DFS in respect Regimen of the use of gemcitabine and docetaxel alone previously A based vs G based 0.49 (0.30–0.80) 0.004 0.37 (0.17–0.80) 0.01 reported . At the same time, a recent controlled study The reported values are the third and first quartiles of the variable distribution of neo-adjuvant tailored chemotherapy versus anthra- Hazard ratio for a 10 years increase in age cycline-based chemotherapy in high-risk soft tissue sar- HR hazard ratio, CI confidence interval, G gemcitabine, A anthracycline, RT coma of limbs and superficial trunk, including somatic radiotherapy leiomyosarcomas, showed better results for patients treated with an anthracycline-based regimen compared (i.e. stage and mitotic index), the use of anthracycline- to a histology-driven one (which was based on gemcit- based adjuvant chemotherapy independently correlated abine for leiomyosarcomas). with a better DFS (HR: 0.37; 95% CI: 0.17–0.80; P = 0.01) This case series analysis is retrospective in nature and (Table 2). No difference in terms of overall survival was included patients treated in a long-time span (20 years) found between patients treated with anthracycline-based with different schedules, although they were all managed adjuvant chemotherapy and patients treated with gem- at two reference centers for gynecological sarcomas. citabine-based adjuvant chemotherapy (5-years OS rate: 71.6% vs 65.8%, respectively; HR: 0.67; 95% CI: 0.33–1.37; Conclusion P = 0.27) (Fig. 2). When we analyzed the effect of the two In conclusion, there is still a lack of unequivocal evi- different adjuvant regimens according to FIGO stage, dence on the survival advantage in using adjuvant we observed a significant advantage in terms of DFS for chemotherapy for high-risk soft tissue sarcoma (includ- anthracycline-based regimens in patients with stage IB ing ULMS), despite the meta-analysis by the Sarcoma (HR: 0.62; 95% CI: 0.17–2.32) ULMS, but not in patients Meta-analysis Collaboration showed a possible small with stage IA (HR: 0.42; 95% CI: 0.24–0.72) even if the benefit . Histotype-tailored chemotherapy is not interaction test was not statistically significant (P = 0.77) the answer, as has been clearly previously demonstrated (Additional file 2: Figure S1). Accordingly, a non-signifi - in the neoadjuvant setting  and corroborated by the cant trend toward a better OS with anthracycline-based present adjuvant data. Indeed, our results provide fur- adjuvant chemotherapy was observed in patients with ther evidence, in addition to the ISG-STS 1001 trial, stage IB ULMS (Additional file 2: Figure S1). on the value of anthracycline-based chemotherapy in ULMS. Given the heterogeneity of sarcomas, we probably need focused prospective trials powered for the individual tumor types (such as ULMS), which is Discussion impossible to achieve without international collabora- In this explorative, retrospective cohort analysis of 109 tions. Based on the results of the present analysis and consecutive patients with completely resected stage I literature data, we believe that an optimal design for a ULMS treated with adjuvant chemotherapy, we observed F ucà et al. Clin Sarcoma Res (2020) 10:17 Page 5 of 6 Fig. 2 Kaplan–Meier curves for overall survival according to the adjuvant chemotherapy regimen Authors’ contributions prospective trial should include a stage I ULMS cohort Study conception and design: RS, PGC. Acquisition of data: GF, CF, SM, GB, CM, using anthracycline-based adjuvant chemotherapy and PC, RM, FR. Analysis and interpretation of data: RS, GF, CF, PGC, NC, FR. Drafting should be powered for separate subgroup analyses of of manuscript: RS, GF, CF. Critical revision: RS, EF, RB, PGC, NC, FR, PC. All authors read and approved the final manuscript. IA and IB disease. Funding Supplementary information The present study was funded by institutional funds from Fondazione IRCCS Istituto Nazionale dei Tumori di Milano. Supplementary information accompanies this paper at https ://doi. org/10.1186/s1356 9-020-00139 -3. Availability of data and materials The datasets generated during and/or analyzed during the current study are Additional file 1: Table S1. Specific adjuvant chemotherapy regimens. available from the corresponding author on reasonable request. Additional file 2: Figure S2. Kaplan–Meier curves for disease-free survival Ethics approval and consent to participate and overall survival according to stage (panels A and B, respectively). The study was approved by the Institutional Review Boards of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano and European Institute of Oncology and was conducted according to the ethical principles for medical Abbreviations research involving human subjects adopted in the Declaration of Helsinki. All ULMS: Uterine leiomyosarcoma; eULMS: Early uterine leiomyosarcoma; IQR: the patients signed an informed consent for the use of their clinico-pathologi- Interquartile range; DFS: Disease-free survival; OS: Overall survival. cal data for research purposes. Acknowledgements Consent for publication Not applicable. The present manuscript does not contain any individual person’s data in any form. Fucà et al. Clin Sarcoma Res (2020) 10:17 Page 6 of 6 Competing interests survey of a total population from 1970 to 2000 including 419 patients. PGC received honoraria for speaker, consultancy or advisory role from: Bayer, Histopathology. 2009;54:355–64. Deciphera, Eisai, Eli Lilly, Nektar Therapeutics, Pfizer. His Unit received research 6. Reed NS, Mangioni C, Malmström H, Scarfone G, Poveda A, Pecorelli S, funds from: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, et al. Phase III randomised study to evaluate the role of adjuvant pelvic Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme radiotherapy in the treatment of uterine sarcomas stages I and II: an Euro- Inc, Glaxo, Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar. All the pean Organisation for Research and Treatment of Cancer Gynaecological other authors declare no competing interests. Cancer Group Study (protocol 55874). Eur J Cancer. 2008;44:808–18. 7. Hensley ML, Ishill N, Soslow R, Larkin J, Abu-Rustum N, Sabbatini P, et al. Author details Adjuvant gemcitabine plus docetaxel for completely resected stages Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS I-IV high grade uterine leiomyosarcoma: results of a prospective study. Istituto Nazionale Dei Tumori Di Milano, Milan, Italy. Program of Gynecologic Gynecol Oncol. 2009;112:563–7. Oncology, IEO, Istituto Europeo Di Oncologia, IRCCS, Milan, Italy. Department 8. Hensley ML, Wathen JK, Maki RG, Araujo DM, Sutton G, Priebat DA, et al. of Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results Di Milano, Milan, Italy. Department of Radiology, Fondazione IRCCS Istituto of a phase 2 trial (SARC 005). Cancer. 2013;119:1555–611. Nazionale Dei Tumori Di Milano, Milan, Italy. Department of Pathology, Fon- 9. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, et al. dazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy. University Histotype-tailored neoadjuvant chemotherapy versus standard chemo- of Milan-Bicocca, Milan, Italy. Oncology and Haemato-Oncology Depart- therapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an ment, University of Milan, Milan, Italy. international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18:812–22. Received: 13 March 2020 Accepted: 17 August 2020 10. Bogani G, Fucà G, Maltese G, Ditto A, Martinelli F, Signorelli M, et al. Effi- cacy of adjuvant chemotherapy in early stage uterine leiomyosarcoma: a systematic review and meta-analysis. Gynecol Oncol. 2016;143:443–7. 11. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth mus- cle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol. 1994;18:535–58. References 12. Raspagliesi F, Maltese G, Bogani G, Fucà G, Lepori S, De Iaco P, et al. 1. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence pat- Morcellation worsens survival outcomes in patients with undiagnosed terns of soft tissue sarcomas, regardless of primary site, in the surveil- uterine leiomyosarcomas: a Retrospective MITO Group Study. Gynecol lance, epidemiology and end results program, 1978–2001: an analysis of Oncol. 2017;144:90–5. 26,758 cases. Int J Cancer. 2006;119:2922–30. 13. Sarcoma Meta-analysis Collaboration (SMAC). Adjuvant chemotherapy 2. Roberts ME, Aynardi JT, Chu CS. Uterine leiomyosarcoma: a review of for localised resectable soft tissue sarcoma in adults. Cochrane Database the literature and update on management options. Gynecol Oncol. Syst Rev. 2000;(4):CD001419. 2018;151:562–72. 3. Prat J. FIGO staging for uterine sarcomas. Int J Gynaecol Obstet. 2009;104:177–8. Publisher’s Note 4. Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft Springer Nature remains neutral with regard to jurisdictional claims in pub- tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines lished maps and institutional affiliations. for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv51–iv67. 5. Abeler VM, Røyne O, Thoresen S, Danielsen HE, Nesland JM, Kristensen GB. Uterine sarcomas in Norway. A histopathological and prognostic Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your ﬁeld rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions
Clinical Sarcoma Research – Springer Journals
Published: Aug 28, 2020
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