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The Impact of Addition of Consolidation Chemotherapy to Standard Cisplatin-Based Chemoradiotherapy in Uterine Cervical Cancer: Matter of Distant Relapse

The Impact of Addition of Consolidation Chemotherapy to Standard Cisplatin-Based... Hindawi Journal of Oncology Volume 2019, Article ID 1217838, 9 pages https://doi.org/10.1155/2019/1217838 Research Article The Impact of Addition of Consolidation Chemotherapy to Standard Cisplatin-Based Chemoradiotherapy in Uterine Cervical Cancer: Matter of Distant Relapse 1 1 2 1 Vanessa A. Fabri, Ana C.M.Queiroz , Henrique Mantoan, Solange M. Sanches, 1 1 1 1 Andrea P. G. Guimarães, AdrianaR.G.Ribeiro, Ronaldo P. Souza, Joyce M. L. Maya, 1 1 1 3 Elizabeth S. Santos , Fabr-cio S. Castro, João P. N. S. Lima, Michael J. Chen , 2 1 Glauco Baiocchi, and Alexandre A. B. A. da Costa Medical Oncology Department, A.C.Camargo Cancer Center, Sao Paulo, 211 Professor Antonio Prudente Street, 01509-900 Liberdade, Brazil Gynecology Oncology Department, A.C.Camargo Cancer Center, Sao Paulo, 211 Professor Antonio Prudente Street, 01509-900 Liberdade, Brazil Radiotherapy Department, A.C.Camargo Cancer Center, Sao Paulo, 211 Professor Antonio Prudente Street, 01509-900 Liberdade, Brazil Correspondence should be addressed to Alexandre A. B. A. da Costa; alexandreandredacosta@gmail.com Received 5 December 2018; Accepted 17 February 2019; Published 11 March 2019 Academic Editor: Ozkan Kanat Copyright © 2019 Vanessa A. Fabri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Treatment of advanced uterine cervical cancer has advanced little in the last 15 years. Although two phase III trials showed survival benefit with the addition of consolidation chemotherapy (CT) aeft r cisplatin-based chemoradiotherapy (RTCT), it is not considered standard of care. We aimed to evaluate the benefit of consolidation CT compared to no additional treatment in patients treated with RTCT. Methods. iTh s is a retrospective study including 186 patients with FIGO stage IB2, IIA2, or IIB to IVB (paraaortic lymph nodes only) uterine cervical cancer who were treated with standard RTCT alone or RTCT followed by consolidation CT. Overall survival (OS), progression free survival (PFS), and the risk of distant and local relapses were compared between the two treatment groups. Results. At3 yearsOSwas 91%versus 82.3%(p=0.027), PFS84.3%versus 54.4% (p=0.047), and distant metastasis free survival (DMFS) 80.4% versus 62.5% (p=0.027) in favor of the consolidation CT group. Multivariate analysis confirmed the benefit of consolidation CT. er Th e was no dier ff ence in locoregional free survival (LRFS). Positive lymph node was related to a higher risk of distant relapse. In the lymph node positive subgroup consolidation CT resulted in longer OS (p=0.050), PFS (p=0.014), and DMFS (p=0.022); in the lymph node negative subgroup there was no benefit from consolidation CT. Conclusions. Use of consolidation CT resulted in longer OS and PFS, mostly due to control of distant relapses. Patients at higher risk of distant relapse showed the greatest benefit. This data generates a hypothesis that could help to better select patients to consolidation CT. 1. Introduction the rfi st most frequent among women and in the Northeast and Middle-West it is the second most frequent among Uterine cervical cancer is one of the most prevalent neo- women [2]. plasms among women in the developing word. There were Locally advanced disease (FIGO stages IIB to IVA) and 569,847 new cases and 311,365 deaths due to uterine cervical bulky disease (FIGO stages IB2 and IIA2) are treated with cancer worldwide in2018[1]. InBrazilthere are16,360 new definitive radiotherapy (RT) with concomitant chemotherapy cases expected in 2018, making it the third most frequent (CT). Several trials proved the benefit of the addition of neoplasm among women. In the North Region of Brazil it is concomitant CT to RT [3–10], but the survival rates are still 2 Journal of Oncology unsatisfactory especially for more advanced disease as shown The endpoints analyzed were overall survival (OS) and by the latest of these trials that found an OS at 5 years of 54% progression free survival (PFS). Distant metastasis (DMFS) for patients with FIGO stage IIIB [10]. and locoregional recurrence free survival (LRFS) were also In the last 7 years the use of systemic CT beyond the evaluated. Locoregional relapse was defined as recurrence concomitant phase of CT and RT (RTCT) has been studied as or progression within the pelvis as reported by computer a treatment intensification strategy. Initial studies with induc- tomography or magnetic resonance image reports. Distant tion CT prior to RTCT have not shown promising results relapse was defined as recurrence outside pelvis as reported leading to questions about the novel drug combinations and by computer tomography, magnetic resonance image or timing of therapy [11, 12]. Two phase III trials have shown bone scans reports. OS was calculated from diagnosis until an OS benefit with the addition of consolidation CT after death by any cause. PFS was calculated from diagnosis until concomitant RTCT [13,14].Duena ˜ -Gonzalez at al. evaluated progression or death by any cause. DMFS and LRFS were calculated from diagnosis until the identification of distant the addition of two cycles with gemcitabine and cisplatin aer ft a concomitant phase with gemcitabine and cisplatin while metastasis and locoregional relapse, respectively. Tang et al. evaluated the addition of one cycle with cisplatin and paclitaxel prior to RTCT and two cycles after RTCT [14]. 2.3. Treatment. At A.C.Camargo CancerCenterthe standard The benefit was mostly due to distant relapse control. Despite treatment for patients with locally advanced disease is with the OS benefit showed in the two trials, consolidation CT external pelvic RT given as a 1.8 Gy fraction daily, vfi e days is not considered a standard of care[15, 16], mostly due to per week up to the total dose of 50.4Gy. After external RT, statistical afl ws and the excessive toxicity of the experimental patients received high dose rate brachytherapy in 4 fractions treatment used in the first study [13] and the inclusion of of 7.0 Gy to a total dose of 80Gy to the point A. Patients only patients diagnosed with adenocarcinoma histology in with positive lymph nodes on imaging (or biopsy proven) the second study [14]. receive additional local irradiation (“boost”) up to 54 Gy. For In this retrospective study we aimed to evaluate the paraaortic sites, locorregional drainage is treated up to 45 Gy, benefit of consolidation CT compared to no additional concomitantly to pelvic irradiation and positive nodes receive systemic treatment in uterine cervical cancer patients treated additional boost up to 50-54 Gy, at physician discretion. with RTCT. 2 Cisplatin at a dose of 40mg/m is infused weekly during RT for a minimum of 5 cycles. Consolidation CT with two cycles 2 2 of cisplatin 50mg/m D1 and gemcitabine 1000mg/m D1 and 2. Material and Methods 8 every 21 days for 2 cycles is an option according to the 2.1. Patients. From 2005 to 2017, 227 patients with FIGO stage treating physician discretion. IB2, IIA2, or IIB to IVA and IVB paraaortic lymph nodes only) uterine cervical cancer were treated with definitive RT 2.4. Statistical Analysis. Statistical analyzes were performed at A.C.Camargo Cancer Center, Sao Paulo, Brazil. Twenty- using the SPSS (v. 23.0; SPSS, Chicago, IL, USA) software, eight patients did not receive concomitant CT and 13 patients adopting a two-tailed P< 0.05 value as signica fi nt. Chi- had no data regarding the use of consolidation CT aeft r square or Fisher’s Exact test were used for comparison of RTCT and were excluded, leading to 186 patients included categorical data. Survival curves for OS, PFS, LRFS, and in the present study. Patients with rare histological types DMFS were constructed using the Kaplan–Meier method (neuroendocrine tumors and sarcomas) were not included. A and compared using the Log-Rank Test. A Cox proportional retrospective review of the medical records was performed. hazards regression model was used for multivariate analysis; The Ethics Committee of the A.C.Camargo Cancer Center all variables with p< 0.05 in the univariate analyses were approved this study (CEP# 2219/16). included in the multivariate analyses. After identification of risk factors for shorter DMFS we evaluated the impact of consolidation CT in subgroups according to the category 2.2. Clinical Data and Endpoints. Clinical findings were of the variables associated with DMFS. A propensity score retrieved from the medical records including age, ECOG analysis was done. We calculated the propensity score using a performance status at the beginning of treatment, histology, logistic regression model including characteristics that were histological grade, tumor size, lymph node status, dose of unbalanced between the two treatment groups. A multivari- radiotherapy planned, method of RT used (3D versus 2D), able model for OS and PFS was done including the propensity type of CT used in association with RT in the concomitant, score and the treatment group. Moreover, we did a sensitive number of cycles of concomitant CT, use of consolidation analysis in a propensity score matched cohort for OS and PFS. CT, type of CT used as consolidation CT, number of cycles of consolidation CT, date of disease progression, sites of disease recurrence, treatments after progression, and date 3. Results of death or last follow-up. We adopted the FIGO stage as identified at gynecological examination. All patients had One hundred and eighty-six patients were included. Median data on abdomen and pelvic computer tomography or mag- age was 48.0 years-old (IQR 37.6-58.7), ECOG performance netic resonance image to evaluate lymph node status. No status was zero in 63.9% of patients, only two patients patient received surgical staging of the paraaortic lymph presented ECOG performance status of 2, tumor histology nodes. was squamous cell carcinoma in 76.4%, tumor histological Journal of Oncology 3 Table 1: Clinical characteristics of the patients. Characteristic Freq. (%) Consolidation CT No Consolidation CT p∗ Number of patients 58 (31.2) 128 (68.8) Age (median/IQR) 41.5 (34.5 – 54.5) 51.3 (41.7 – 63.0) < 0.0001 ECOG performance status 0 36 (62.1) 81 (64.8) 0.720 ≥ 1 22 (37.9) 44 (35.2) Histology Squamous cell carcinoma 41 (70.7) 98 (79.0) 0.217 Adenocarcinoma 17 (29.3) 26 (21.0) Grade 1 and 2 34 (77.3) 59 (60.8) 0.056 3 10 (22.7) 38 (39.2) FIGO stage 0.637 IB2 3 (5.2) 7 (5.5) IIA2 2 (3.4) 5 (3.9) IIB 26 (44.8) 62 (48.8) IIIA 2 (3.4) 4 (3.1) IIIB 15 (25.9) 36 (28.3) IVA 9 (15.5) 7 (5.5) IVB 1(1.7) 5(3.9) Tumor size < 6cm 28 (75.7) 56 (76.7) 0.904 ≥ 6cm 9 (24.3) 17 (23.3) Lymph node Negative 25 (43.1) 55 (46.2) 0.732 Pelvic 32 (55.2) 60 (50.4) Paraaortic 1 (1.7) 4 (3.4) Concurrent CT< 6cycles No 46 (79.3) 75 (64.7) 0.048 Yes 12 (20.7) 41 (35.3) Radiotherapy technique 3D 53 (91.4) 88 (71.0) 0.002 2D 5 (8.6) 36 (29.0) Brachytherapy No 3 (5.2) 15 (12.0) 0.149 Yes 55 (94.8) 110 (88.0) ∗All p values calculated using Chi square test or Fisher’s exact test. CT = chemotherapy. IQR = Interquartile Range. Paraaortic lymph nodes only. grade was 2 in 58.2% and 3 in 34.0% of patients, FIGO cohort, at 3 and 5 years, OS was 74.3% and 69.5%, PFS was stage IB2-IIA2 in 9.3%, IIB in 48.1%, and III-IV in 42.6% 60.9% and 56.6%, DMFS was 68.2% and 62.1%, and LRFS of patients, median tumor size was 5.0cm (IQR 41.0-60.0), was 83.6% and 83.6%, respectively (Supplementary Figure and positive lymph nodes were present in 54.8% of patients. S1). Clinical and pathological characteristics are summarized in Table 1. 3.1. Consolidation Chemotherapy versus Observation aer ft Median follow-up time was 37.7 months. Forty-five deaths RTCT. Fifty-eight patients were treated with consolidation have occurred, 63 patients are experiencing disease progres- CT. Only vfi e patients (8.6%) could not receive the two cycles sion, 52 have presented distant recurrences, and 23 have due to toxicity, while 53 (91.4%) received the 2 planned cycles. presented locorregional recurrences. Six of the 45 deaths Median follow-up times were 30.9 months for patients in were not caused directly by the cancer: 2 patients with FIGO stage IIB, 3 patients with FIGO stage IIIB, and 1 the consolidation CT group and 45.5 months in the RTCT patient with positive paraaortic lymph node. For the whole alone group (p<0.001). 4 Journal of Oncology 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.016 p = 0.005 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (a) (b) 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.010 p = 0.041 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (c) (d) Figure 1: Survival outcomes according to groups by treatment with consolidation CT and without consolidation CT. (a) Overall survival; (b) progression free survival; (c) distant metastasis free survival; (d) locorregional free survival. CT = chemotherapy. All p values calculated by Log-Rank Test. OS at 3 years was 91% versus 82.3% and at 5 years with consolidation CT. Median DMFS was not reached it was 82.3% versus 64.3% in favor of patients who were in both groups (p=0.027) (Figure 1). In the multivariate treated with consolidation CT. Median OS was not reached analysis the use of consolidation CT remained independently associated with a higher DMFS (HR 0.43; 0.21-0.91, 95% CI, in both groups (p=0.016) (Figure 1). In the multivariate analysis the use of consolidation CT remained indepen- p = 0.028) (Table 3). dently associated with a higher OS, with a decrease in the LRFS at 3 years was 92.7% versus 79.5% and at 5 years it risk of death of 59% (HR 0.41; 0.16-0.99, 95%CI; p=0.047) was 92.7% versus 79.5% in favor of patients who were treated (Table 2). with consolidation CT. Median LRFS was not reached in both PFS at 3 years was 84.3% versus 54.4% and at 5 years it groups (p=0.027) (Figure 1). In the multivariate analysis the was 84.3% versus 49.1% in favor of patients who were treated use of consolidation CT decreased the risk of progression by with consolidation CT. Median PFS was not reached in the 41% but it was not statistically signicfi ant (HR 0.59; 0.26-1.32, consolidation CT group and 54.8 months for patients who 95%CI; p=0.199) (Table 3). did not receive consolidation CT (p=0.027) (Figure 1). In the We did a sensitivity analysis excluding the 18 patients who multivariate analysis the use of consolidation CT decreased did not receive brachytherapy. After excluding these patients, in the multivariate models, consolidation CT remained asso- the risk of progression by 61% (HR 0.39; 0.19-0.82, 95%CI; p=0.012) (Table 2). ciated with OS (HR 0.41; 0.17-0.99, 95%CI; p = 0.047), PFS DMFS at 3 years was 80.4% versus 62.5% and at 5 years it (HR 0.39; 0.19-0.82, 95%CI; p = 0.012), and DMFS (HR 0.40; was80.4% versus54.8% in favor of patients who were treated 0.20-0.83, 95%CI; p = 0.0413). Distant Metastasis Free Survival Overall Survival Local Recurrence Free Survival Progression Free Survival Journal of Oncology 5 Table 2: Multivariate analysis for overall survival and progression free survival. OS PFS Characteristic HR (95% CI) p value HR (95% CI) p value Consolidation CT No 1 0.047 1 0.012 Yes 0.41 (0.16-0.99) 0.39 (0.18-0.81) FIGO Stage < IIB 1 0.049 - - > IIIA 1.97 (1.00-3.85) - Grade 1 and 2 1 0.090 1 0.077 3 1.78 (0.91-3.47) 1.71 (0.94-3.10) Lymph node Negative - - 1 0.006 Positive - 2.48 (1.29-4.75) Concurrent CT< 6cycles No - - 1 0.071 Yes - 1.78 (0.95-3.33) 136 patients with complete data included in the multivariate analysis, 35 events. 135 patients with complete data included in the multivariate analysis, 46 events. DMFS = distant metastasis free survival; LRFS = locorregional free survival; CT = chemotherapy. Table 3: Multivariate analysis for distant metastasis free survival and locorregional free survival. 1 2 DMFS LRFS Characteristic HR (95% CI) p value HR (95% CI) p value Consolidation CT No 1 0.028 - - Yes 0.43 (0.21-0.91) - FIGO Stage < IIB - - 1 0.009 > IIIA - 3.62 (1.37-9.49) Grade 1 and 2 - - 1 0.009 3- 3.36(1.35-8.32) Lymph node Negative 1 0.001 - - Positive 2.99 (1.54-5.81) - Concurrent CT< 6cycles No - - 1 0.022 Yes - 2.82 (1.16-6.81) Radiotherapy technique 3D 1 0.196 2D 1.51 (0.81-2.80) 174 patients with complete data included in the multivariate analysis, 46 events. 133 patients with complete data included in the multivariate analysis, 20 events. DMFS = distant metastasis free survival; LRFS = locorregional free survival; CT = chemotherapy. 3.2. Propensity Score Analysis. Age, number of concomitant consolidation CT for OS and confirmed a significant benefit cisplatin to RT cycles, and type of RT were unbalanced for PFS. For OS HR was 0.49 (0.20-1.21, 95% CI; p=0.124) and between the two treatment groups and were included in for PFS HR was 0.50 (0.25-0.98, 95% CI; p=0.043). the propensity score. A multivariable model including the We then evaluated a selected sample of patients matching propensity score and the use of consolidation CT for OS 58 patients treated with consolidation CT and 58 patients and PFS showed a nonstatistically significant benefit of treated with RTCT alone one-to-one according to propensity 6 Journal of Oncology score. Clinical characteristics were balanced between the two relapse. Lymph node status was associated with DMFS. When treatment groups (Supplementary Table S1). In the matched analyzing the impact of consolidation CT according to lymph cohort OS at 3 years was 85.8% and PFS at 3 years was 69.3%. node status the OS, PFS, and DMFS benefit of consolidation At 3 years OS was 91.0% versus 80.8% (p=0.364) and PFS CT was seen only in the lymph node positive subgroup. was 75.3% versus 63.6% (p=0.113) in favor of consolidation At least 3 other comparative studies support the benefit of CT group; however itwas notstatistically signicfi ant (Sup- consolidation CT. The Mexican phase III trial [13] evaluated plementary Figure S2). the impact of two cycles of gemcitabine plus cisplatin as consolidation CT and found a 9% absolute improvement in the primary outcome of PFS at 3 years, from 65% to 74%. 3.3. Risk Factors for Death, Recurrence, Distant Recurrence, The experimental arm differed from the standard treatment and Locorregional Recurrence. Histological grade 3 and also by the addition of gemcitabine to cisplatin in the FIGO stage≥ IIIA were related to a shorter OS in univariate concomitant phase hampering the conclusion of which of cox regression analysis (Supplementary Table S2 and Supple- the two treatment intensification strategies were responsible mentary Figure S3). In the multivariate analysis FIGO stage for the survival improvement. The second study is a Chinese ≥ IIIA remained independently associated with a shorter OS trial [14] that differed from ours by its prospective design, (HR 1.97; 1.00-3.85, 95% CI, p = 0.049) (Table 2). including only adenocarcinoma and using cisplatin plus Histological grade 3, positive lymph node, and concur- paclitaxel as systemic chemotherapy, with one cycle prior rent CT< 6 cycles were related to shorter PFS in univariate to RT and two cycles aer ft RT. PFS at 5 years was 71.4% analysis (Supplementary Table S3 and Supplementary Fig- versus 60.4% in favor of the systemic CT arm. The third study ure S3). In the multivariate analysis positive lymph nodes [17] is a Korean retrospective study including 80 patients remained independently associated with a lower PFS (HR treated with cisplatin plus 5FU concomitantly to RT and half 2.48; 1.30-4.78, 95% CI, p = 0.006) (Table 2). of the patients treated with additional 3 cycle of cisplatin Positive lymph nodes and 2D conformal radiation ther- plus 5FU, PFS at 3 years of 74.4% versus 59.0% in favor of apy (RT2D) were related to shorter DMFS (Supplementary consolidation CT. Our study is the only study that included Table S4 and Supplementary Figure S4). In the multivariate both squamous cell carcinoma and adenocarcinoma patients analysis positive lymph node remained independently asso- and treated patients with the standard concomitant treatment ciated with a shorter DMFS (HR 2.99; 1.54-5.81, 95% CI, p = with weekly cisplatin and RT in both groups. 0.001) (Table 3). We found a benefit in DMFS in favor of consolidation Histological grade 3, concurrent CT< 6cycles, and FIGO CT and did not find a benefit of consolidation CT in LRFS. stage≥ IIIA were related to shorter LRFS (Supplementary This is in accordance with the Mexican trial and the Korean Table S5 and Supplementary Figure S4). In the multivariate study [13, 17], while the Chinese trial showed a benefit both analysis these 3 variables remained independently associated in reduction of distant and local relapses[14]. with a shorter LRFS (Table 3). In our study LRFS at 3 years was 92.7% versus 79.5% but the difference was not statistically significant in multivariate 3.4. Benefit of Consolidation Chemotherapy by Subgroups analysis. In the Mexican study local recurrences occurred according to Risk of Distant Relapse. Positive lymph node in 16.4% of patients in the consolidation CT arm versus was the risk factor with a stronger association with distant 11.2% in the RTCT alone arm and in the Korean study relapse. Once the benefit of consolidation CT was mostly 10.3% versus 5.1%. In both studies these differences were not due to control of distant relapse we tested if the benefit statistically significant. The lack of statistical significance may of consolidation CT was different in patients with negative be due to the smaller frequency of local relapses compared lymph nodes and in patients with positive lymph nodes. In to distant relapses in locally advanced cervical cancer treated thenodenegative subgroupat vfi e years, OSwas77.8% versus with concomitant RTCT and to a weaker association of 78.2% (p=0.259), PFS was 80.0% versus 68.1% (p=0.176), and consolidation CT with reduction of local relapse making a DMFS was 86.7% versus 78.2% (p=0.285), for consolidation large number of patients to prove a statistically significant CT and no consolidation CT, respectively. In the node difference necessary. Indeed, the Chinese study included 880 positive subgroup, at vfi e years, OS was 84.6% versus 58.4% patients while the Mexican study included 515 patients. u Th s (p=0.050), PFS was 73.2% versus 37.9% (p=0.014), and DMFS the benefit of consolidation CT seems to be driven mostly by was 76.6% versus 40.7% (p=0.022), for consolidation CT and the control of distant recurrences but a benefit in local control no consolidation CT, respectively (Figure 2). The interaction can not be excluded. test between consolidation CT and lymph node status showed Positive lymph nodes have been shown to be the most a p value of 0.227 for OS, 0.266 for PFS, and 0.419 for DMFS. important prognostic factor for distant relapses in locally advanced cervical cancer [18–20]. We found a three times higher risk of distant relapse for patients with positive lymph 4. Discussion nodes. Considering the hypothesis that the befit of consolida- tion CT is mostly driven by improvement of distant control Inthepresentstudyweevaluated therole of consolidationCT in the treatment of 186 patients with uterine cervical cancer we performed a subgroup analysis according to lymph node treated with definitive concomitant RTCT plus consolidation status. We found a benetfi for consolidation CT regarding OS, PFS, and DMFS only in the subgroup of patients with positive CT or RTCT alone. We found OS and PFS benefit for patients treated with consolidation CT mostly due to control of distant lymph nodes. Journal of Oncology 7 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.259 p = 0.176 0.2 0.2 0.0 0.0 0 10 20 30 40 50 60 05 10 20 30 400 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (a) (b) 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.285 p = 0.050 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (c) (d) 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.022 p = 0.014 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (e) (f) Figure 2: (a) Overall survival in node negative subgroup according to treatment; (b) progression free survival in node negative subgroup according to treatment; (c) distant metastasis free survival in node negative subgroup according to treatment; (d) overall survival in node positive subgroup according to treatment; (e) progression free survival in node positive subgroup according to treatment; (f) distant metastasis free survival in node positive subgroup according to treatment. CT = chemotherapy. All p values calculated by Log-Rank Test. Progression Free Survival Overall Survival Distant Metastasis Free Survival Progression Free Survival Distant Metastasis Free Survival Overall Survival 8 Journal of Oncology The Mexican trial was the only other study that did a alone in uterine cervical cancer patients with bulky or locally subgroup analysis [21]. They found a greater benefit of consol- advanced disease. Patients with higher risk of distant relapse idation CT in patients with FIGO stage III and IV compared such as those who present positive lymph node are those who to stage IIB, adenocarcinoma compared to squamous cell mostly benefit from this treatment intensification strategy. carcinoma, in tumors larger than 5cm and in patients with We eagerly await the results from the phase III OUTBACK positive paraaortic lymph nodes. There was no subgroup trial comparing 4 cycles of carboplatin plus paclitaxel aer ft analysis according to pelvic lymph node status. RTCT in patients with stage IB to IVA uterine cervical cancer. Our study confirmed the higher rate of distant relapse in lymphnodepositivepatientsand corroboratesthehypothesis Data Availability of greater benefit from consolidation CT in patients with higher risk of distant relapse. This finding could help to The data used to support the findings of this study are better identify patients for whom it is worthy to pursue with available from the corresponding author upon request. consolidation CT. Our study has limitations intrinsic to its retrospective Conflicts of Interest nature. Selection bias is an issue as we can see by the imbalance in baseline characteristics between the two groups. The authors declare that there are no conflicts of interest Patients in the consolidation CT were younger and completed regarding the publication of this paper. 6 cycles of concomitant weekly cisplatin more often than the RTCT alone group. To address the selection bias we Supplementary Materials performed a Cox regression multivariable analysis including all variables related to each endpoint in the univariate Supplementary Figure S1: overall survival (A), progression analysis. The benetfi of consolidation CT was conrfi med in free survival (B), distant metastasis free survival (C), and multivariate analysis for OS, PFS, and DMFS. Moreover, locorregional free survival (D) in the 186 patients treated we performed a propensity score analysis doing a covariate with concomitant chemotherapy and radiotherapy. Supple- adjustment using the propensity score and a sensitive survival mentary Figure S2: survival outcomes according to groups by analysis in a selected sample matched by the propensity score. treatment with consolidation CT and without consolidation In these two analyses the benefit of consolidation CT was CT in the matched sample of 116 patients: (A) overall survival; not statistically significant anymore. This could be to a loss (B) progression free survival. All p values calculated by Log- of statistical power in the propensity score analysis or due Rank Test. Supplementary Figure S3: (A) overall survival to a real confounding effect of the imbalance between the according to histological grade; (B) overall survival according two treatment groups regarding age, number of concomitant to FIGO stage; (C) progression free survival according to cisplatin cycles, and use of 2D RT. Notably, age and 2D histological grade; (D) progression free survival according RT compared to 3D RT were not independently associated to lymph node status; (E) progression free survival accord- with any of the outcomes, and use of less than 6 cycles of ing to number of chemotherapy cycles concomitantly to concomitant CT was associated only with higher risk of local radiotherapy. CT = chemotherapy. All p values calculated relapse. The lack of association of these variables with the by Log-Rank Test. Supplementary Figure S4: (A) distant outcomes points against their role as confounding factors metastasis free survival according to lymph node status; (B) even if it cannot be excluded. Moreover, there were less death distant metastasis free survival according to radiotherapy events than progression events as expected, and consolidation technique; (C) locorregional free survival according to his- CT remained associated with PFS but not with OS with tological grade; (D) locorregional free survival according p value less than 0.05. These n fi dings put together suggest to number of chemotherapy cycles concomitantly to radio- the higher p values in the propensity score analysis may be therapy; (E) locorregional free survival according to FIGO due more to lack of statistical power than to confounding stage. CT = chemotherapy. All p values calculated by Log- effects. Median follow-up time is significantly shorter in the Rank Test. Supplementary Table S1: clinical characteristics consolidation CT group, this implies more immature data on of the one-to-one matched sample according to propen- outcomes in this group, and longer follow-up is needed to sity. Supplementary Table S2: univariate analysis for overall confirm our initial results. survival. Supplementary Table S3: univariate analysis for One strength of our study is that the two treatment groups progression free survival. Supplementary Table S4: univariate differed in their treatment only in the use of consolidation analysis for distance metastasis free survival. Supplementary CT, since all patients were treated with weekly cisplatin Table S5: univariate analysis for locorregional free survival. concomitantly to RT. Moreover, we have detailed data on sites (Supplementary Materials) of recurrences allowing the discrimination of factors related to distant and local relapses. References 5. Conclusion [1] F. Bray, J. Ferlay, I. 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The Impact of Addition of Consolidation Chemotherapy to Standard Cisplatin-Based Chemoradiotherapy in Uterine Cervical Cancer: Matter of Distant Relapse

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Copyright © 2019 Vanessa A. Fabri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Oncology Volume 2019, Article ID 1217838, 9 pages https://doi.org/10.1155/2019/1217838 Research Article The Impact of Addition of Consolidation Chemotherapy to Standard Cisplatin-Based Chemoradiotherapy in Uterine Cervical Cancer: Matter of Distant Relapse 1 1 2 1 Vanessa A. Fabri, Ana C.M.Queiroz , Henrique Mantoan, Solange M. Sanches, 1 1 1 1 Andrea P. G. Guimarães, AdrianaR.G.Ribeiro, Ronaldo P. Souza, Joyce M. L. Maya, 1 1 1 3 Elizabeth S. Santos , Fabr-cio S. Castro, João P. N. S. Lima, Michael J. Chen , 2 1 Glauco Baiocchi, and Alexandre A. B. A. da Costa Medical Oncology Department, A.C.Camargo Cancer Center, Sao Paulo, 211 Professor Antonio Prudente Street, 01509-900 Liberdade, Brazil Gynecology Oncology Department, A.C.Camargo Cancer Center, Sao Paulo, 211 Professor Antonio Prudente Street, 01509-900 Liberdade, Brazil Radiotherapy Department, A.C.Camargo Cancer Center, Sao Paulo, 211 Professor Antonio Prudente Street, 01509-900 Liberdade, Brazil Correspondence should be addressed to Alexandre A. B. A. da Costa; alexandreandredacosta@gmail.com Received 5 December 2018; Accepted 17 February 2019; Published 11 March 2019 Academic Editor: Ozkan Kanat Copyright © 2019 Vanessa A. Fabri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Treatment of advanced uterine cervical cancer has advanced little in the last 15 years. Although two phase III trials showed survival benefit with the addition of consolidation chemotherapy (CT) aeft r cisplatin-based chemoradiotherapy (RTCT), it is not considered standard of care. We aimed to evaluate the benefit of consolidation CT compared to no additional treatment in patients treated with RTCT. Methods. iTh s is a retrospective study including 186 patients with FIGO stage IB2, IIA2, or IIB to IVB (paraaortic lymph nodes only) uterine cervical cancer who were treated with standard RTCT alone or RTCT followed by consolidation CT. Overall survival (OS), progression free survival (PFS), and the risk of distant and local relapses were compared between the two treatment groups. Results. At3 yearsOSwas 91%versus 82.3%(p=0.027), PFS84.3%versus 54.4% (p=0.047), and distant metastasis free survival (DMFS) 80.4% versus 62.5% (p=0.027) in favor of the consolidation CT group. Multivariate analysis confirmed the benefit of consolidation CT. er Th e was no dier ff ence in locoregional free survival (LRFS). Positive lymph node was related to a higher risk of distant relapse. In the lymph node positive subgroup consolidation CT resulted in longer OS (p=0.050), PFS (p=0.014), and DMFS (p=0.022); in the lymph node negative subgroup there was no benefit from consolidation CT. Conclusions. Use of consolidation CT resulted in longer OS and PFS, mostly due to control of distant relapses. Patients at higher risk of distant relapse showed the greatest benefit. This data generates a hypothesis that could help to better select patients to consolidation CT. 1. Introduction the rfi st most frequent among women and in the Northeast and Middle-West it is the second most frequent among Uterine cervical cancer is one of the most prevalent neo- women [2]. plasms among women in the developing word. There were Locally advanced disease (FIGO stages IIB to IVA) and 569,847 new cases and 311,365 deaths due to uterine cervical bulky disease (FIGO stages IB2 and IIA2) are treated with cancer worldwide in2018[1]. InBrazilthere are16,360 new definitive radiotherapy (RT) with concomitant chemotherapy cases expected in 2018, making it the third most frequent (CT). Several trials proved the benefit of the addition of neoplasm among women. In the North Region of Brazil it is concomitant CT to RT [3–10], but the survival rates are still 2 Journal of Oncology unsatisfactory especially for more advanced disease as shown The endpoints analyzed were overall survival (OS) and by the latest of these trials that found an OS at 5 years of 54% progression free survival (PFS). Distant metastasis (DMFS) for patients with FIGO stage IIIB [10]. and locoregional recurrence free survival (LRFS) were also In the last 7 years the use of systemic CT beyond the evaluated. Locoregional relapse was defined as recurrence concomitant phase of CT and RT (RTCT) has been studied as or progression within the pelvis as reported by computer a treatment intensification strategy. Initial studies with induc- tomography or magnetic resonance image reports. Distant tion CT prior to RTCT have not shown promising results relapse was defined as recurrence outside pelvis as reported leading to questions about the novel drug combinations and by computer tomography, magnetic resonance image or timing of therapy [11, 12]. Two phase III trials have shown bone scans reports. OS was calculated from diagnosis until an OS benefit with the addition of consolidation CT after death by any cause. PFS was calculated from diagnosis until concomitant RTCT [13,14].Duena ˜ -Gonzalez at al. evaluated progression or death by any cause. DMFS and LRFS were calculated from diagnosis until the identification of distant the addition of two cycles with gemcitabine and cisplatin aer ft a concomitant phase with gemcitabine and cisplatin while metastasis and locoregional relapse, respectively. Tang et al. evaluated the addition of one cycle with cisplatin and paclitaxel prior to RTCT and two cycles after RTCT [14]. 2.3. Treatment. At A.C.Camargo CancerCenterthe standard The benefit was mostly due to distant relapse control. Despite treatment for patients with locally advanced disease is with the OS benefit showed in the two trials, consolidation CT external pelvic RT given as a 1.8 Gy fraction daily, vfi e days is not considered a standard of care[15, 16], mostly due to per week up to the total dose of 50.4Gy. After external RT, statistical afl ws and the excessive toxicity of the experimental patients received high dose rate brachytherapy in 4 fractions treatment used in the first study [13] and the inclusion of of 7.0 Gy to a total dose of 80Gy to the point A. Patients only patients diagnosed with adenocarcinoma histology in with positive lymph nodes on imaging (or biopsy proven) the second study [14]. receive additional local irradiation (“boost”) up to 54 Gy. For In this retrospective study we aimed to evaluate the paraaortic sites, locorregional drainage is treated up to 45 Gy, benefit of consolidation CT compared to no additional concomitantly to pelvic irradiation and positive nodes receive systemic treatment in uterine cervical cancer patients treated additional boost up to 50-54 Gy, at physician discretion. with RTCT. 2 Cisplatin at a dose of 40mg/m is infused weekly during RT for a minimum of 5 cycles. Consolidation CT with two cycles 2 2 of cisplatin 50mg/m D1 and gemcitabine 1000mg/m D1 and 2. Material and Methods 8 every 21 days for 2 cycles is an option according to the 2.1. Patients. From 2005 to 2017, 227 patients with FIGO stage treating physician discretion. IB2, IIA2, or IIB to IVA and IVB paraaortic lymph nodes only) uterine cervical cancer were treated with definitive RT 2.4. Statistical Analysis. Statistical analyzes were performed at A.C.Camargo Cancer Center, Sao Paulo, Brazil. Twenty- using the SPSS (v. 23.0; SPSS, Chicago, IL, USA) software, eight patients did not receive concomitant CT and 13 patients adopting a two-tailed P< 0.05 value as signica fi nt. Chi- had no data regarding the use of consolidation CT aeft r square or Fisher’s Exact test were used for comparison of RTCT and were excluded, leading to 186 patients included categorical data. Survival curves for OS, PFS, LRFS, and in the present study. Patients with rare histological types DMFS were constructed using the Kaplan–Meier method (neuroendocrine tumors and sarcomas) were not included. A and compared using the Log-Rank Test. A Cox proportional retrospective review of the medical records was performed. hazards regression model was used for multivariate analysis; The Ethics Committee of the A.C.Camargo Cancer Center all variables with p< 0.05 in the univariate analyses were approved this study (CEP# 2219/16). included in the multivariate analyses. After identification of risk factors for shorter DMFS we evaluated the impact of consolidation CT in subgroups according to the category 2.2. Clinical Data and Endpoints. Clinical findings were of the variables associated with DMFS. A propensity score retrieved from the medical records including age, ECOG analysis was done. We calculated the propensity score using a performance status at the beginning of treatment, histology, logistic regression model including characteristics that were histological grade, tumor size, lymph node status, dose of unbalanced between the two treatment groups. A multivari- radiotherapy planned, method of RT used (3D versus 2D), able model for OS and PFS was done including the propensity type of CT used in association with RT in the concomitant, score and the treatment group. Moreover, we did a sensitive number of cycles of concomitant CT, use of consolidation analysis in a propensity score matched cohort for OS and PFS. CT, type of CT used as consolidation CT, number of cycles of consolidation CT, date of disease progression, sites of disease recurrence, treatments after progression, and date 3. Results of death or last follow-up. We adopted the FIGO stage as identified at gynecological examination. All patients had One hundred and eighty-six patients were included. Median data on abdomen and pelvic computer tomography or mag- age was 48.0 years-old (IQR 37.6-58.7), ECOG performance netic resonance image to evaluate lymph node status. No status was zero in 63.9% of patients, only two patients patient received surgical staging of the paraaortic lymph presented ECOG performance status of 2, tumor histology nodes. was squamous cell carcinoma in 76.4%, tumor histological Journal of Oncology 3 Table 1: Clinical characteristics of the patients. Characteristic Freq. (%) Consolidation CT No Consolidation CT p∗ Number of patients 58 (31.2) 128 (68.8) Age (median/IQR) 41.5 (34.5 – 54.5) 51.3 (41.7 – 63.0) < 0.0001 ECOG performance status 0 36 (62.1) 81 (64.8) 0.720 ≥ 1 22 (37.9) 44 (35.2) Histology Squamous cell carcinoma 41 (70.7) 98 (79.0) 0.217 Adenocarcinoma 17 (29.3) 26 (21.0) Grade 1 and 2 34 (77.3) 59 (60.8) 0.056 3 10 (22.7) 38 (39.2) FIGO stage 0.637 IB2 3 (5.2) 7 (5.5) IIA2 2 (3.4) 5 (3.9) IIB 26 (44.8) 62 (48.8) IIIA 2 (3.4) 4 (3.1) IIIB 15 (25.9) 36 (28.3) IVA 9 (15.5) 7 (5.5) IVB 1(1.7) 5(3.9) Tumor size < 6cm 28 (75.7) 56 (76.7) 0.904 ≥ 6cm 9 (24.3) 17 (23.3) Lymph node Negative 25 (43.1) 55 (46.2) 0.732 Pelvic 32 (55.2) 60 (50.4) Paraaortic 1 (1.7) 4 (3.4) Concurrent CT< 6cycles No 46 (79.3) 75 (64.7) 0.048 Yes 12 (20.7) 41 (35.3) Radiotherapy technique 3D 53 (91.4) 88 (71.0) 0.002 2D 5 (8.6) 36 (29.0) Brachytherapy No 3 (5.2) 15 (12.0) 0.149 Yes 55 (94.8) 110 (88.0) ∗All p values calculated using Chi square test or Fisher’s exact test. CT = chemotherapy. IQR = Interquartile Range. Paraaortic lymph nodes only. grade was 2 in 58.2% and 3 in 34.0% of patients, FIGO cohort, at 3 and 5 years, OS was 74.3% and 69.5%, PFS was stage IB2-IIA2 in 9.3%, IIB in 48.1%, and III-IV in 42.6% 60.9% and 56.6%, DMFS was 68.2% and 62.1%, and LRFS of patients, median tumor size was 5.0cm (IQR 41.0-60.0), was 83.6% and 83.6%, respectively (Supplementary Figure and positive lymph nodes were present in 54.8% of patients. S1). Clinical and pathological characteristics are summarized in Table 1. 3.1. Consolidation Chemotherapy versus Observation aer ft Median follow-up time was 37.7 months. Forty-five deaths RTCT. Fifty-eight patients were treated with consolidation have occurred, 63 patients are experiencing disease progres- CT. Only vfi e patients (8.6%) could not receive the two cycles sion, 52 have presented distant recurrences, and 23 have due to toxicity, while 53 (91.4%) received the 2 planned cycles. presented locorregional recurrences. Six of the 45 deaths Median follow-up times were 30.9 months for patients in were not caused directly by the cancer: 2 patients with FIGO stage IIB, 3 patients with FIGO stage IIIB, and 1 the consolidation CT group and 45.5 months in the RTCT patient with positive paraaortic lymph node. For the whole alone group (p<0.001). 4 Journal of Oncology 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.016 p = 0.005 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (a) (b) 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.010 p = 0.041 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (c) (d) Figure 1: Survival outcomes according to groups by treatment with consolidation CT and without consolidation CT. (a) Overall survival; (b) progression free survival; (c) distant metastasis free survival; (d) locorregional free survival. CT = chemotherapy. All p values calculated by Log-Rank Test. OS at 3 years was 91% versus 82.3% and at 5 years with consolidation CT. Median DMFS was not reached it was 82.3% versus 64.3% in favor of patients who were in both groups (p=0.027) (Figure 1). In the multivariate treated with consolidation CT. Median OS was not reached analysis the use of consolidation CT remained independently associated with a higher DMFS (HR 0.43; 0.21-0.91, 95% CI, in both groups (p=0.016) (Figure 1). In the multivariate analysis the use of consolidation CT remained indepen- p = 0.028) (Table 3). dently associated with a higher OS, with a decrease in the LRFS at 3 years was 92.7% versus 79.5% and at 5 years it risk of death of 59% (HR 0.41; 0.16-0.99, 95%CI; p=0.047) was 92.7% versus 79.5% in favor of patients who were treated (Table 2). with consolidation CT. Median LRFS was not reached in both PFS at 3 years was 84.3% versus 54.4% and at 5 years it groups (p=0.027) (Figure 1). In the multivariate analysis the was 84.3% versus 49.1% in favor of patients who were treated use of consolidation CT decreased the risk of progression by with consolidation CT. Median PFS was not reached in the 41% but it was not statistically signicfi ant (HR 0.59; 0.26-1.32, consolidation CT group and 54.8 months for patients who 95%CI; p=0.199) (Table 3). did not receive consolidation CT (p=0.027) (Figure 1). In the We did a sensitivity analysis excluding the 18 patients who multivariate analysis the use of consolidation CT decreased did not receive brachytherapy. After excluding these patients, in the multivariate models, consolidation CT remained asso- the risk of progression by 61% (HR 0.39; 0.19-0.82, 95%CI; p=0.012) (Table 2). ciated with OS (HR 0.41; 0.17-0.99, 95%CI; p = 0.047), PFS DMFS at 3 years was 80.4% versus 62.5% and at 5 years it (HR 0.39; 0.19-0.82, 95%CI; p = 0.012), and DMFS (HR 0.40; was80.4% versus54.8% in favor of patients who were treated 0.20-0.83, 95%CI; p = 0.0413). Distant Metastasis Free Survival Overall Survival Local Recurrence Free Survival Progression Free Survival Journal of Oncology 5 Table 2: Multivariate analysis for overall survival and progression free survival. OS PFS Characteristic HR (95% CI) p value HR (95% CI) p value Consolidation CT No 1 0.047 1 0.012 Yes 0.41 (0.16-0.99) 0.39 (0.18-0.81) FIGO Stage < IIB 1 0.049 - - > IIIA 1.97 (1.00-3.85) - Grade 1 and 2 1 0.090 1 0.077 3 1.78 (0.91-3.47) 1.71 (0.94-3.10) Lymph node Negative - - 1 0.006 Positive - 2.48 (1.29-4.75) Concurrent CT< 6cycles No - - 1 0.071 Yes - 1.78 (0.95-3.33) 136 patients with complete data included in the multivariate analysis, 35 events. 135 patients with complete data included in the multivariate analysis, 46 events. DMFS = distant metastasis free survival; LRFS = locorregional free survival; CT = chemotherapy. Table 3: Multivariate analysis for distant metastasis free survival and locorregional free survival. 1 2 DMFS LRFS Characteristic HR (95% CI) p value HR (95% CI) p value Consolidation CT No 1 0.028 - - Yes 0.43 (0.21-0.91) - FIGO Stage < IIB - - 1 0.009 > IIIA - 3.62 (1.37-9.49) Grade 1 and 2 - - 1 0.009 3- 3.36(1.35-8.32) Lymph node Negative 1 0.001 - - Positive 2.99 (1.54-5.81) - Concurrent CT< 6cycles No - - 1 0.022 Yes - 2.82 (1.16-6.81) Radiotherapy technique 3D 1 0.196 2D 1.51 (0.81-2.80) 174 patients with complete data included in the multivariate analysis, 46 events. 133 patients with complete data included in the multivariate analysis, 20 events. DMFS = distant metastasis free survival; LRFS = locorregional free survival; CT = chemotherapy. 3.2. Propensity Score Analysis. Age, number of concomitant consolidation CT for OS and confirmed a significant benefit cisplatin to RT cycles, and type of RT were unbalanced for PFS. For OS HR was 0.49 (0.20-1.21, 95% CI; p=0.124) and between the two treatment groups and were included in for PFS HR was 0.50 (0.25-0.98, 95% CI; p=0.043). the propensity score. A multivariable model including the We then evaluated a selected sample of patients matching propensity score and the use of consolidation CT for OS 58 patients treated with consolidation CT and 58 patients and PFS showed a nonstatistically significant benefit of treated with RTCT alone one-to-one according to propensity 6 Journal of Oncology score. Clinical characteristics were balanced between the two relapse. Lymph node status was associated with DMFS. When treatment groups (Supplementary Table S1). In the matched analyzing the impact of consolidation CT according to lymph cohort OS at 3 years was 85.8% and PFS at 3 years was 69.3%. node status the OS, PFS, and DMFS benefit of consolidation At 3 years OS was 91.0% versus 80.8% (p=0.364) and PFS CT was seen only in the lymph node positive subgroup. was 75.3% versus 63.6% (p=0.113) in favor of consolidation At least 3 other comparative studies support the benefit of CT group; however itwas notstatistically signicfi ant (Sup- consolidation CT. The Mexican phase III trial [13] evaluated plementary Figure S2). the impact of two cycles of gemcitabine plus cisplatin as consolidation CT and found a 9% absolute improvement in the primary outcome of PFS at 3 years, from 65% to 74%. 3.3. Risk Factors for Death, Recurrence, Distant Recurrence, The experimental arm differed from the standard treatment and Locorregional Recurrence. Histological grade 3 and also by the addition of gemcitabine to cisplatin in the FIGO stage≥ IIIA were related to a shorter OS in univariate concomitant phase hampering the conclusion of which of cox regression analysis (Supplementary Table S2 and Supple- the two treatment intensification strategies were responsible mentary Figure S3). In the multivariate analysis FIGO stage for the survival improvement. The second study is a Chinese ≥ IIIA remained independently associated with a shorter OS trial [14] that differed from ours by its prospective design, (HR 1.97; 1.00-3.85, 95% CI, p = 0.049) (Table 2). including only adenocarcinoma and using cisplatin plus Histological grade 3, positive lymph node, and concur- paclitaxel as systemic chemotherapy, with one cycle prior rent CT< 6 cycles were related to shorter PFS in univariate to RT and two cycles aer ft RT. PFS at 5 years was 71.4% analysis (Supplementary Table S3 and Supplementary Fig- versus 60.4% in favor of the systemic CT arm. The third study ure S3). In the multivariate analysis positive lymph nodes [17] is a Korean retrospective study including 80 patients remained independently associated with a lower PFS (HR treated with cisplatin plus 5FU concomitantly to RT and half 2.48; 1.30-4.78, 95% CI, p = 0.006) (Table 2). of the patients treated with additional 3 cycle of cisplatin Positive lymph nodes and 2D conformal radiation ther- plus 5FU, PFS at 3 years of 74.4% versus 59.0% in favor of apy (RT2D) were related to shorter DMFS (Supplementary consolidation CT. Our study is the only study that included Table S4 and Supplementary Figure S4). In the multivariate both squamous cell carcinoma and adenocarcinoma patients analysis positive lymph node remained independently asso- and treated patients with the standard concomitant treatment ciated with a shorter DMFS (HR 2.99; 1.54-5.81, 95% CI, p = with weekly cisplatin and RT in both groups. 0.001) (Table 3). We found a benefit in DMFS in favor of consolidation Histological grade 3, concurrent CT< 6cycles, and FIGO CT and did not find a benefit of consolidation CT in LRFS. stage≥ IIIA were related to shorter LRFS (Supplementary This is in accordance with the Mexican trial and the Korean Table S5 and Supplementary Figure S4). In the multivariate study [13, 17], while the Chinese trial showed a benefit both analysis these 3 variables remained independently associated in reduction of distant and local relapses[14]. with a shorter LRFS (Table 3). In our study LRFS at 3 years was 92.7% versus 79.5% but the difference was not statistically significant in multivariate 3.4. Benefit of Consolidation Chemotherapy by Subgroups analysis. In the Mexican study local recurrences occurred according to Risk of Distant Relapse. Positive lymph node in 16.4% of patients in the consolidation CT arm versus was the risk factor with a stronger association with distant 11.2% in the RTCT alone arm and in the Korean study relapse. Once the benefit of consolidation CT was mostly 10.3% versus 5.1%. In both studies these differences were not due to control of distant relapse we tested if the benefit statistically significant. The lack of statistical significance may of consolidation CT was different in patients with negative be due to the smaller frequency of local relapses compared lymph nodes and in patients with positive lymph nodes. In to distant relapses in locally advanced cervical cancer treated thenodenegative subgroupat vfi e years, OSwas77.8% versus with concomitant RTCT and to a weaker association of 78.2% (p=0.259), PFS was 80.0% versus 68.1% (p=0.176), and consolidation CT with reduction of local relapse making a DMFS was 86.7% versus 78.2% (p=0.285), for consolidation large number of patients to prove a statistically significant CT and no consolidation CT, respectively. In the node difference necessary. Indeed, the Chinese study included 880 positive subgroup, at vfi e years, OS was 84.6% versus 58.4% patients while the Mexican study included 515 patients. u Th s (p=0.050), PFS was 73.2% versus 37.9% (p=0.014), and DMFS the benefit of consolidation CT seems to be driven mostly by was 76.6% versus 40.7% (p=0.022), for consolidation CT and the control of distant recurrences but a benefit in local control no consolidation CT, respectively (Figure 2). The interaction can not be excluded. test between consolidation CT and lymph node status showed Positive lymph nodes have been shown to be the most a p value of 0.227 for OS, 0.266 for PFS, and 0.419 for DMFS. important prognostic factor for distant relapses in locally advanced cervical cancer [18–20]. We found a three times higher risk of distant relapse for patients with positive lymph 4. Discussion nodes. Considering the hypothesis that the befit of consolida- tion CT is mostly driven by improvement of distant control Inthepresentstudyweevaluated therole of consolidationCT in the treatment of 186 patients with uterine cervical cancer we performed a subgroup analysis according to lymph node treated with definitive concomitant RTCT plus consolidation status. We found a benetfi for consolidation CT regarding OS, PFS, and DMFS only in the subgroup of patients with positive CT or RTCT alone. We found OS and PFS benefit for patients treated with consolidation CT mostly due to control of distant lymph nodes. Journal of Oncology 7 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.259 p = 0.176 0.2 0.2 0.0 0.0 0 10 20 30 40 50 60 05 10 20 30 400 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (a) (b) 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.285 p = 0.050 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (c) (d) 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 p = 0.022 p = 0.014 0.2 0.2 0.0 0.0 05 10 20 30 400 60 0 10 20 30 40 50 60 Time (months) Time (months) Consolidation CT Consolidation CT No consolidation CT No consolidation CT (e) (f) Figure 2: (a) Overall survival in node negative subgroup according to treatment; (b) progression free survival in node negative subgroup according to treatment; (c) distant metastasis free survival in node negative subgroup according to treatment; (d) overall survival in node positive subgroup according to treatment; (e) progression free survival in node positive subgroup according to treatment; (f) distant metastasis free survival in node positive subgroup according to treatment. CT = chemotherapy. All p values calculated by Log-Rank Test. Progression Free Survival Overall Survival Distant Metastasis Free Survival Progression Free Survival Distant Metastasis Free Survival Overall Survival 8 Journal of Oncology The Mexican trial was the only other study that did a alone in uterine cervical cancer patients with bulky or locally subgroup analysis [21]. They found a greater benefit of consol- advanced disease. Patients with higher risk of distant relapse idation CT in patients with FIGO stage III and IV compared such as those who present positive lymph node are those who to stage IIB, adenocarcinoma compared to squamous cell mostly benefit from this treatment intensification strategy. carcinoma, in tumors larger than 5cm and in patients with We eagerly await the results from the phase III OUTBACK positive paraaortic lymph nodes. There was no subgroup trial comparing 4 cycles of carboplatin plus paclitaxel aer ft analysis according to pelvic lymph node status. RTCT in patients with stage IB to IVA uterine cervical cancer. Our study confirmed the higher rate of distant relapse in lymphnodepositivepatientsand corroboratesthehypothesis Data Availability of greater benefit from consolidation CT in patients with higher risk of distant relapse. This finding could help to The data used to support the findings of this study are better identify patients for whom it is worthy to pursue with available from the corresponding author upon request. consolidation CT. Our study has limitations intrinsic to its retrospective Conflicts of Interest nature. Selection bias is an issue as we can see by the imbalance in baseline characteristics between the two groups. The authors declare that there are no conflicts of interest Patients in the consolidation CT were younger and completed regarding the publication of this paper. 6 cycles of concomitant weekly cisplatin more often than the RTCT alone group. To address the selection bias we Supplementary Materials performed a Cox regression multivariable analysis including all variables related to each endpoint in the univariate Supplementary Figure S1: overall survival (A), progression analysis. The benetfi of consolidation CT was conrfi med in free survival (B), distant metastasis free survival (C), and multivariate analysis for OS, PFS, and DMFS. Moreover, locorregional free survival (D) in the 186 patients treated we performed a propensity score analysis doing a covariate with concomitant chemotherapy and radiotherapy. Supple- adjustment using the propensity score and a sensitive survival mentary Figure S2: survival outcomes according to groups by analysis in a selected sample matched by the propensity score. treatment with consolidation CT and without consolidation In these two analyses the benefit of consolidation CT was CT in the matched sample of 116 patients: (A) overall survival; not statistically significant anymore. This could be to a loss (B) progression free survival. All p values calculated by Log- of statistical power in the propensity score analysis or due Rank Test. Supplementary Figure S3: (A) overall survival to a real confounding effect of the imbalance between the according to histological grade; (B) overall survival according two treatment groups regarding age, number of concomitant to FIGO stage; (C) progression free survival according to cisplatin cycles, and use of 2D RT. Notably, age and 2D histological grade; (D) progression free survival according RT compared to 3D RT were not independently associated to lymph node status; (E) progression free survival accord- with any of the outcomes, and use of less than 6 cycles of ing to number of chemotherapy cycles concomitantly to concomitant CT was associated only with higher risk of local radiotherapy. CT = chemotherapy. All p values calculated relapse. The lack of association of these variables with the by Log-Rank Test. Supplementary Figure S4: (A) distant outcomes points against their role as confounding factors metastasis free survival according to lymph node status; (B) even if it cannot be excluded. Moreover, there were less death distant metastasis free survival according to radiotherapy events than progression events as expected, and consolidation technique; (C) locorregional free survival according to his- CT remained associated with PFS but not with OS with tological grade; (D) locorregional free survival according p value less than 0.05. These n fi dings put together suggest to number of chemotherapy cycles concomitantly to radio- the higher p values in the propensity score analysis may be therapy; (E) locorregional free survival according to FIGO due more to lack of statistical power than to confounding stage. CT = chemotherapy. All p values calculated by Log- effects. Median follow-up time is significantly shorter in the Rank Test. Supplementary Table S1: clinical characteristics consolidation CT group, this implies more immature data on of the one-to-one matched sample according to propen- outcomes in this group, and longer follow-up is needed to sity. Supplementary Table S2: univariate analysis for overall confirm our initial results. survival. Supplementary Table S3: univariate analysis for One strength of our study is that the two treatment groups progression free survival. Supplementary Table S4: univariate differed in their treatment only in the use of consolidation analysis for distance metastasis free survival. Supplementary CT, since all patients were treated with weekly cisplatin Table S5: univariate analysis for locorregional free survival. concomitantly to RT. Moreover, we have detailed data on sites (Supplementary Materials) of recurrences allowing the discrimination of factors related to distant and local relapses. References 5. Conclusion [1] F. Bray, J. Ferlay, I. 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