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Adjuvant concurrent chemoradiation followed by chemotherapy for high-risk endometrial cancer
Gynecologic Oncology 140 (2016) 58–63
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Adjuvant concurrent chemoradiation followed by chemotherapy for high-risk endometrial cancer Yulan Ren a,b, Xiaowei Huang a,b, Boer Shan a,b, Xiaohua Wu a,b, Xiao Huang a,b, Daren Shi b,c, Huaying Wang a,b,⁎ a b c
Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
H I G H L I G H T • Concurrent chemoradiotherapy followed by chemotherapy was safe for HREC. • Majority of patients (85.7%) completed the planned treatment. • Adverse effects were less common in patients who received PC than those with CEP.
a r t i c l e
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Article history: Received 21 August 2015 Received in revised form 10 November 2015 Accepted 18 November 2015 Available online 24 November 2015 Keywords: High-risk endometrial cancer Adjuvant therapy Progression-free survival Overall survival Toxicity
a b s t r a c t Objective. The adjuvant treatment of high-risk endometrial cancer (HREC) remains controversial. This prospective phase-II clinical trial was conducted to evaluate the adjuvant concurrent chemoradiotherapy followed by chemotherapy in patients with HREC. Methods. Altogether 122 patients were enrolled between January 2007 and January 2013, in which 112 were analyzable. The inclusion criteria included endometrioid endometrial cancer of histological grade 3 and with greater than 50% myometrial invasion, cervical stromal invasion, pelvic and/or para-aortic lymph node metastases; non-endometrioid endometrial cancer; no residual disease and distant metastases. Pelvic radiation was administered with cisplatin on days 1 and 28. Para-aortic radiation was administered with confirmed para-aortic lymph node metastases, and vaginal afterloading brachytherapy with cervical stromal invasion after total hysterectomy. Four courses of paclitaxel and carboplatin (PC) or cisplatin, cyclophosphamide and epirubicin (CEP) were administered at three-week interval after radiation. Results. Ninety-six patients (85.7%) completed the planned treatment. Treatment discontinuation was the result of toxicity (5/112, 4.5%), disease progression (8/112, 7.1%), and patients refusal (3/112, 2.7%). There was no life-threatening toxicity. Twenty-five (22.3%) patients recurred, in which 4 cases recurred in the field of radiation, and 13 (11.6%) patients died of endometrial cancer during follow-up. The estimated five-year progression-free survival and overall survival were 73% and 84%, respectively. Adverse effects were less common in patients who received PC than CEP (p = 0.001). Conclusions. This regimen demonstrated acceptable toxicity and good survival outcomes despite a preponderance (62.5%) of late stage disease. PC showed less adverse effects than CEP. A well designed randomized trial is under development. Clinical trial ID. https://clinicaltrials.gov/: 070148-7. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Endometrial cancer is the most common gynecologic malignancy in the western countries, with 287 new cases and 74 deaths per 100,000 worldwide [1], and the same trend was also observed in China [2]. ⁎ Corresponding author at: Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. E-mail address: [email protected] (H. Wang).
http://dx.doi.org/10.1016/j.ygyno.2015.11.021 0090-8258/© 2015 Elsevier Inc. All rights reserved.
There have been an increasing number of deaths due to endometrial cancer in the last two decades, which may be related to an increased rate of high-risk histologies and advanced stage disease [3]. While the optimal management for high risk endometrial cancer (HREC) still remains controversial. Radiotherapy was a traditional postoperative treatment which could significantly reduce the locoregional recurrences but fail to improve the overall survival [4–7]. Chemotherapy could improve survival outcomes of advanced stage disease compared to whole abdominal irradiation
Y. Ren et al. / Gynecologic Oncology 140 (2016) 58–63
(WAR) according to the results of GOG 122 [8]. However, a higher pelvic recurrence rate was observed in the chemotherapy arm compared with WAR (18% vs. 13%). Therefore, chemotherapy alone may not be adequate for achieving local control. In recent years, the attention of gynecologists has been shifted to multimodality treatments [9–11]. There are different ways for combining chemotherapy and radiotherapy, including concurrent chemoradiation, chemoradiation followed by chemotherapy, chemotherapy followed by radiotherapy, and “sandwich”. Several studies have revealed that combined therapy yielded good survival outcomes with acceptable toxicities [12–15]. But more data are needed to a draw a confirmative conclusion. Given the uncertainty of optimal adjuvant therapy for patients with HREC, we conducted this single-institute phase-II study to determine the toxicity, tolerability, and survival outcome of concomitant chemoradiation followed by chemotherapy in patients with HREC in China. 2. Materials and methods 2.1. Study design This study was a prospective, single-institutional, non-randomized phase-II clinical trial approved by the ethics committee of Fudan University Shanghai Cancer Center (clinical trial ID: 070148-7). This study was performed in accordance with the principles of good clinical practice (GCP) and the Declaration of Helsinki. All of the patients provided informed written consent before they were enrolled into this study. 2.2. Patient eligibility Patients were screened for eligibility after surgery consisting of hysterectomy (total or modified radical or radical), bilateral salpingooophorectomy, pelvic lymphadenectomy and/or para-aortic lymphadenectomy, and adequate surgical staging no more than eight weeks prior to the start of radiation therapy. Women ≥18 and ≤75 years of age with high-risk endometrial cancer with one of the following inclusion criteria were eligible for this study: endometrioid endometrial cancer with histological grade 3 and greater than 50% myometrial invasion, stromal invasion of the cervix, pelvic lymph node metastases, para-aortic lymph node metastases, or extrauterine disease confined to the pelvis; nonendometrioid endometrial cancer (including serous/clear cell carcinoma, and carcinosarcoma); no residual disease; and no distant metastases. The patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 to 2, normal hematological, liver and renal function with laboratory parameters within the normal range (including a creatinine clearance ≥ 40 ml/min, leucocytes ≥4.0 × 109/l, platelets ≥100 × 109/l and hemoglobin ≥10 g/ dl). Patients suffering from a secondary malignancy, serious concomitant systemic disorders or psychiatric disease were excluded from the study. No prior radiation therapy or chemotherapy was allowed before enrollment. 2.3. Treatment Treatment was started 14 days at the earliest and eight weeks at the latest after surgery. The patients were treated with external pelvic radiation (PRT) (1.8 Gy/d, d 1–5) at a total dose of 45 Gy. The pelvic radiotherapy fields were a standard four-field with an upper border of L5– S1. Vaginal vault afterloading brachytherapy (VAB) (5 Gy/d, six fractions) was administered to the patients with stromal invasion of the cervix after total hysterectomy following pelvic radiation. External para-aortic intensity-modulated radiation (45 Gy, 1.8 Gy/d) was administered to patients with pathologically confirmed para-aortic lymph nodes metastases. During radiotherapy, two cycles of cisplatin (50 mg/m2) were administered on days 1 and 28.
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After completion of concurrent chemoradiation, the patients were administered four additional courses of chemotherapy every 21 days. Two regimens were allowed: paclitaxel [135 mg/m2] (i.v. over 3 h) and carboplatin [AUC = 5] (i.v. over 30 min) or cisplatin [50 mg/m2], cyclophosphamide [600 mg/m2] and epirubicin [60 mg/m2], and the latter regimen was allowed because of the insurance policy and the costefficiency consideration in China. If the pathological type was carcinosarcoma, ifosfamide [1.5 g/m2] was added in combination with paclitaxel and carboplatin (according to the revised version of the protocol). A 5-HT3-antagonist, a H1-/H2-receptor antagonist and dexamethasone were administered intravenously 30 min prior to each cycle of chemotherapy. The patients received oral dexamethasone tablets 12 and 6 h prior to paclitaxel infusion. The treatment was continued during the four cycles of chemotherapy if the hematological count recovered (leucocytes N3.0 × 109/l, platelets ≥ 100 × 109/l and hemoglobin N 10 g/dl). The treatment could be postponed up to two weeks in cases of hematological and nonhematological toxicities (except NCI-CTC grade 3 nausea/emesis). The primary prophylactic use of granulocyte colony-stimulating factor (GCSF) was not allowed. 2.4. Baseline evaluation At baseline assessment, all patients had complete history, normal blood count, biochemistry, liver and renal function tests, a chest X-ray, ECG, liver and renal ultrasound and physical examination. Blood counts and biochemistry were repeated every week and prior to each cycle of chemotherapy and radiotherapy. Cut-off values for eligibility included leucocytes ≥4000, granulocytes ≥1500, platelets ≥ 100,000, creatinine ≤ 1.4, and bilirubin and ALT (serum glutamic pyruvic transaminase) ≤ two times normal. Pathology was all reviewed in Fudan University Shanghai Cancer Center. 2.5. Follow-up of patients During treatment, the patients were followed weekly through physical examination, ECOG, complete blood count (CBC) with platelets, and documentation of major symptoms or adverse effects. Toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria (NCI-CTC) for Adverse Events (AE) (v. 3.0) prior to each cycle of chemotherapy and weekly during radiotherapy. After treatment, the patients were followed-up clinically every three months for two years, then every six months for one year and then yearly. The last follow-up was in September 2015. 2.6. Study endpoints The primary endpoint of the protocol was disease-free survival (DFS). DFS was defined as the time from the date of enrollment to the date of disease progression or death from any cause. The secondary endpoints included local-regional failure, distant failure, and overall survival (OS). Local-regional failure was defined as recurrence in the pelvis, abdomen, and/or paraaortic area encompassed by the radiation field. Treatment completion per protocol and acute and late toxicity were also recorded and reported. 2.7. Statistical analysis Safety analyses were conducted, and the results are presented as raw numbers, rates, and ranges according to the underlying distribution. The local-regional failure and distant metastases failure rates were estimated using the cumulative incidence method [16]. The disease-free survival and overall survival rates were estimated using the Kaplan–Meier method [17]. The SPSS software package for Windows (SPSS Inc., version 16.0) was employed for all of the analyses. A p-value less than 0.05 was set as significant.
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3. Results 3.1. Patient characteristics One hundred and twenty-two patients were entered between January 2007 and January 2013. Ten patients were considered ineligible (six with distant metastasis, one with early stage IA, one with incomplete pelvic lymphadenectomy, one with prior chemo-radiation, and one with prior malignancy). Altogether, 112 patients were analyzable. The characteristics of 112 patients are displayed in Table 1. The median age was 54 years (range 33–75 years). The pathological type consisted primarily of endometrioid carcinoma (75.9%). Seventy patients (62.5%) were in an advanced stage (stage IIIA–IIIC2). 3.2. Treatment and modifications Altogether, ninety-six patients (85.7%) completed the planned treatment. Fifteen patients discontinued therapy early as a result of toxicity (5/112, 3.6%), patient refusal (3/112, 2.7%), and disease progression (8/112, 7.1%), in which four patients died before completing the therapy because of disease progression. 3.2.1. Concurrent chemoradiation After surgery, 90 (80.4%) patients received only pelvic radiation (PRT), 14 (12.5%) patients received additional para-aortic radiation
Table 1 Patient's characteristics (n = 112). Characteristic
Number of patients (%)
Median age, years (range) ECOG performance score 0 1 2 FIGO stage (2009) IA IB II IIIA IIIC1 IIIC2 Pathological subtype Endometrioid carcinoma UPSC Clear cell carcinoma Carcinosarcoma Neuroendocrine carcinoma Rhabdomyosarcoma Histological grade I II III Pelvic lymph node Positive Negative Para-aortic lymph node Positive Negative Not done Both pelvic and para-aortic lymph node Positive LVSI Positive Negative Not known Myometrial invasion b1/2 ≥1/2 Serosa Median follow-up, months (range)
54 (33–75) 69 (61.6) 36 (32.1) 7 (6.2) 11 (9.8) 10 (8.9) 21 (18.8) 23 (20.5) 33 (29.5) 14 (12.5) 85 (75.9) 6 (5.4) 7 (6.2) 9 (8.0) 3 (2.7) 1 (0.9) 9 (8.0) 52 (46.4) 51 (45.5)
(PAR), 6 (5.4%) patients received additional vaginal vault afterloading brachytherapy (VAB), and 2 patients received both additional PAR and VAB. The median radiation dose of pelvic radiation and para-aortic radiation was 45 Gy (range 36-47Gy), and the median number of fractions was 25 (range 20–25 fractions). The total dose of afterloading brachytherapy was 30 Gy with six fractions. Two cycles of cisplatin at a dose of 50 mg/m2 were administered at a four-week interval. During radiation, one patient discontinued the radiation after 20 fractions because of bowel obstruction, one patient had a one-week delay, two patients had a two-week delay because of diarrhea, and an additional patient had a two-week delay because of bowel obstruction (Table 2). The median duration of concurrent chemoradiation was 35 days (range 31–51 days). 3.2.2. Chemotherapy After concurrent chemoradiation, 85 patients (75.9%) received paclitaxel and carboplatin (PC), 20 patients (17.9%) received cisplatin, cyclophosphamide, and epirubicin (CEP), and five patients (4.5%) received paclitaxel, carboplatin, and ifosfamide (PCI). Two patients switched from PC to CEP because of allergy to paclitaxel, and 1 patient switched from CEP to PC because of the patient's request after one cycle. Ninety-seven patients (86.6%) completed the four cycles of chemotherapy, four patients received three cycles, two patients received two cycles, seven patients received one cycle, and two patients did not receive any chemotherapy. Some of the patients received less cycles of chemotherapy as a result of toxicity (n = 4), patient refusal (n = 3), disease progression and death (n = 8). A total of 20 cycles of chemotherapy were delayed for one week, and 10 cycles were delayed for two weeks. The treatment delays were related to toxicity (18 grade 3–4 neutropenia, eight grade 3–4 thrombocytopenia, one grade 4 anemia, one grade 3 diarrhea, two grade 3 bowel obstruction, two grade 3 vomiting, two grade 2 ALT disorder, and one deep vein thrombosis). Chemotherapy dose reductions were performed for 24 patients (21.4%) according to the protocol: the doses for 22 patients were reduced once, and the doses for two patients were reduced twice (Table 2). 3.3. Toxicity There was no life-threatening toxicity or treatment-related deaths. The acute toxicity during radiotherapy and chemotherapy included hematological and non-hematological toxicity. Hematological toxicity was the most leading adverse event. During concurrent chemo-radiotherapy, no acute radiation-related grade 4 hematological toxicity occurred. Altogether, the following toxicity grades were observed: grade 1 in 25 cases (22.3%), grade 2 in 18 cases (16.1%), and grade 3 in 5 cases (4.5%) (Supplement Table 1).
Table 2 Treatment modification.
39 (34.8) 73 (65.2) 14 (12.5) 67 (59.8) 31 (27.7) 6 (5.36) 42 (37.5) 45 (40.2) 25 (22.3) 39 (34.8) 61 (54.5) 12 (10.7) 41 (3–101)
Note. ECOG, the Eastern Cooperative Oncology Group; FIGO, the International Federation of Gynecology and Obstetrics; LVSI, Lymph-vascular space invasion.
Number of patient Chemoradiation PRT PRT + PAR PRT + VAB PRT + PAR + VAB Chemotherapy PC CEP PCI
1-week delay
2-week delay
Dose reduction
90 14 6 2
1 0 0 0
1 1 0 0
0 1a 0 0
85 20 5
17 2 1
6 3 1
13b 9 2
Note. PRT, pelvic radiation; PAR, para-aortic radiation; VAB, vaginal vault afterloading brachytherapy; PC, paclitaxel and carboplatin; CEP, cisplatin, cyclophosphamide, and epirubicin; PCI, paclitaxel, carboplatin, and ifosfamide. a Radiotherapy was canceled because of bowel obstruction. b 2 patients reduced for twice.
Y. Ren et al. / Gynecologic Oncology 140 (2016) 58–63 Table 3 Toxicity during chemotherapy (n = 110a). PC (n = 90b)
CEP(n = 20)
Grade
Hematological toxicity Leukopenia Neutropenia Anemia Thrombocytopenia Non-hematological toxicity Fatigue Diarrhea Vomiting ALT AST Creatinine Sensory Venous thrombosis Maximal toxicity per patient (%) P value
Grade
1
2
3
4
1
2
3
4
5 13 24 21
34 22 15 19
32 22 6 9
15 22 1 0
1 1 7 0
2 0 2 4
6 5 1 3
11 13 0 2
0 0 0 1 0 0 0 0 24 (26.7)
0 0 0 0 0 0 0 0 21 (23.3)
11 1 9 5 0 1 1 0 0 (0)
2 0 0 0 0 0 0 1 2 (10)
0 0 2 0 0 0 0 0 5 (25)
0 0 0 0 0 0 0 0 13 (65)
20 1 3 0 16 1 17 3 2 2 0 0 3 1 0 0 3 26 (3.3) (28.9) p = 0.001
Note. ALT, serum glutamic pyruvic transaminase; AST, serum glutamic oxaloacetic transaminase. a Two cases didn't receive chemotherapy because of disease progression. b Including 5 cases who received PCI.
Three patients exhibited grade 3 toxicity because of diarrhea, and two patients because of bowel obstruction. During adjuvant chemotherapy, all grade 4 toxicity was hematological toxicity. Of the patients who received the PC or PCI regimen, 24 cases (26.7%) exhibited grade 3 toxicity, and 21 cases (23.3%) exhibited grade 4 toxicity. Of the patients who received the CEP regimen, five cases (25.0%) exhibited grade 3 toxicity, and 13 cases (65.0%) had grade 4 toxicity (Table 3). Adverse effects were less common in the patients who received PC compared with those who received CEP (p = 0.001). To manage the grade 3/4 hematological side effects, 16 patients were hospitalized and received G-CSF, prophylactic antibiotics and other supportive care during hospitalization. Chronic toxicity (toxicity observed N90 days after completion of all therapies) occurred in 24 patients, including grade 1 in five cases (4.5%), grade 2 in thirteen cases (11.6%), grade 3 in four cases (3.6%), and grade 4 in two cases (1.8%) (Supplement Table 2). All grade 3/4 toxicity was because of bowel obstruction. Of the six patients who had grade 3/4 bowel obstruction, two patients received small intestine resection and enterodialysis, one received enterodialysis, and three received hospitalized supportive treatment. 3.4. Outcomes The median follow-up was 41 months (range 3–101 months). During follow-up, 25 (22.3%) patients recurred, of which four recurred in the field of radiation, and all the sites of recurrence were documented (Table 4). One patient had recurrence simultaneously in the lung and retroperitoneal lymph nodes, and another patient recurred simultaneously in the lung and the peritoneal cavity. The other sites of recurrence included the following: pelvic (n = 1), retroperitoneal lymph
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nodes (n = 2), supraclavicular lymph node (n = 2), lung (n = 6), liver (n = 3), brain (n = 2), bone (n = 2), and peritoneal cavity (n = 5). During follow-up, 13 (11.6%) patients died of endometrial cancer. The estimated five-year PFS and OS were 73% and 84%, respectively (Table 4) (Fig. 1). The estimated five-year OS for early and late stages were 94% and 77%, respectively (HR = 3.710; 95%CI, 1.819–16.820; p = 0.048). Although 5-year PFS and OS appears better for chemotherapy with PC, there was no significant difference between PC and CEP (77% vs. 66%, 85% vs, 84%, p = 0.28 and 0.59, respectively). 4. Discussion For high-risk endometrial cancer, multimodality treatments have been explored by several retrospective and prospective studies and showed superiority than single modality therapy [12,18]. Our study also revealed that concurrent chemoradiation followed by chemotherapy had an excellent treatment completion rate (85.7%) and good disease control with a five-year PFS of 73% and an OS of 84%, considering that more patients (62.5%) enrolled in our study were in an advanced stage (stage IIIA-C2) comparing to the previous studies [11,13]. Hogberg et al. reported the results of two randomized phase-III studies evaluating combination radiation and chemotherapy for early stage high-risk endometrial cancer, which were conducted by the Nordic Society of Gynecological Oncology/European Organization for the Research and Treatment of Cancer (NSGO/EORTC) and Mario Negri Institute (MaNGO) [19]. Altogether 540 patients (383 in the NSGO/ EORTC study and 157 in the MaNGO study) were enrolled in the studies in which pelvic radiotherapy (PRT) was compared with sequential radiotherapy and chemotherapy (RT-CT). With PRT alone, 26.2% of the patients recurred compared to 16% in the RT-CT group. The adjusted hazard ratio for recurrence was 0.65 (95% CI 0.43–0.99) in favor of the RT-CT group. Therefore, the addition of adjuvant CT to RT improves PFS in HREC. Although there was no significant difference in OS in either trial, there was a significant improvement in cancer-specific survival in the pooled analysis with a 45% reduction in death for those treated with combination therapy. A multi-center phase-II study conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) evaluated the adjuvant CT with sequential RT in patients with highrisk endometrial cancer, which showed that CT with sequential RT was tolerated and is feasible with a two-year PFS and OS of 75.8% [20]. “Sandwich” therapy was also reported by several studies [18,21–22]. Secord et al. reported a multicenter retrospective analysis of postoperative chemotherapy and radiation for surgical stages III and IV endometrial cancer, and found that sequential CRC was associated with improved survival compared to other sequencing modalities, with those receiving CRC having superior 3-year OS (88%) and PFS (69%) compared to RC (54% and 47%) or CR (57% and 52%) [18]. Despite of so many results of different studies, more convincing results were needed to determine which combination is the most favorable therapy for HREC. At the time of our study design, the data of RTOG-9708 in adjuvant treatment for high-risk endometrial cancer were just released [13]. We designed our study with several different points. Firstly, all of the patients were required to receive a pelvic lymphadenectomy before enrollment. Although para-aortic lymphadenectomy was an optional
Table 4 End points.
Recurrence in the field of radiation Local-regional failure Distant metastases failure Progression-free survival Overall survival a
Number of events
Estimated 2-year rate (%)
Estimated 3-year rate (%)
Estimated 5-year ratea (%)
4 9 18 25 13
3 7 16 80 91
4 9 17 77 89
4 11 20 73 84
The 5-year rate was estimated with median follow-up of 41 months.
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Fig. 1. Progression-free survival (A) and overall survival (B) of patients in the study.
eligibility criteria, 70% of the patients in our study received para-aortic lymphadenectomy, which makes the surgical stage more accurate than the previous study. Secondly, patients with papillary serous, clear cell, and carcinosarcoma were included in our study because these patients are more likely to gain benefits from multi-modality adjuvant treatment. As RTOG-9708, our study also showed acceptable toxicity and good locoregional control for HREC. Two regimens (PC and CEP) were allowed in our study. Both of them were validated and widely used in the treatment of advanced and recurrent endometrial cancer. An increasing number of phase-II studies have demonstrated excellent response rates and low toxicity with paclitaxel and carboplatin [23–27]. According to the results of a phase-III GOG trial which compared paclitaxel-carboplatin and paclitaxel-doxorubicincisplatin, paclitaxel and carboplatin was not inferior in terms of PFS and OS and was associated with reduced toxicity [28]. In our study, 75.9% of the patients received paclitaxel and carboplatin (PC). Although there was no significant difference of 5-year PFS and OS between PC and CEP (77% vs. 66%, 85% vs, 84%, p = 0.28 and 0.59, respectively), adverse effects were less common in patients with PC compared with patients with CEP (p = 0.001), which is in accordance with the results of the GOG study. The toxicity should be highly concerned in the combination of radiotherapy and chemotherapy. Soper et al. [29] reported high hematologic toxicity profiles in a GOG trial with concurrent weekly cisplatin and whole abdominal radiation followed by doxorubicin and cisplatin, and grade 4 neutropenia occurred in 100% of all patients. Another GOG phase-I trial [30] evaluating the feasibility of sequential chemotherapy and irradiation in advanced-stage endometrial cancer with doxorubicin–cisplatin followed by whole-abdomen irradiation included 31 patients. Twenty-nine patients were used for the evaluation of the feasibility of the regimen, and 22 patients had chronic radiation toxicity after a median follow-up time of 21 months. Three patients (14%) experienced severe chronic toxicity, including one treatment-related death. In our study, almost all of grade 3–4 toxicity was hematological toxicity during treatment, with only 3.6% grade 3 and 1.8% grade 4 bowel obstructions during follow-up. Therefore, this treatment is feasible and tolerable for most patients. Although the combination of radiotherapy and chemotherapy did not induce the high rate of bowel complication observed in the previous study [13], it should still be concerned during the multi-modality treatment. There are several limitations of our study. Firstly, this study is a onearm phase-II clinical trial with no control arm. Therefore, a randomized phase-III clinical trial is in preparation according to the results of our
study. Secondly, different chemotherapy regimens were allowed in our study. However, both regimens were validated and are widely used in the treatment of endometrial cancer, and it gave us a chance to observe the efficacy and toxicity of two different regimens based on our data. Thirdly, data of quality of life were only registered for some of the patients and have not been analyzed. Several randomized phase III clinical trials focused on the adjuvant treatment of high-risk endometrial cancer are still ongoing, which include GOG 258, a randomized phase III trial comparing cisplatin and radiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked and advanced endometrial carcinoma, and PORTEC-3, which compares concurrent pelvic RT/chemotherapy with pelvic RT alone. All of these results are expected to optimize the treatment for HREC. 5. Conclusion Our study found that concurrent cisplatin with radiation followed by paclitaxel and carboplatin showed less toxicity and achieved both good local and distant control. A phase III randomized clinical trial which compares adjuvant chemotherapy with concurrent chemoradiation is under development for high-risk endometrial cancer. Role of funding source The study was funded by the Ministry of Education of China (No. 20110071120099) which provided the fund to data collection and analysis. Conflict of interest The authors have declared no conflicts of interest.
Acknowledgments We would like to thank the patients and the nurses who participated in this trial, and associated professor Ji Zhu, data manager Huixun Jia and Li Xie for the data collection and their thoughtful advice and discussions. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.11.021.
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References [1] J. Ferlay, H.R. Shin, F. Bray, D. Forman, C. Mathers, D.M. Parkin, Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008, Int. J. Cancer 127 (2010) 2893–2917. [2] K.R. Wei, W.Q. Chen, S.W. Zhang, R.S. Zheng, Y.N. Wang, Z.H. Liang, Epidemiology of uterine corpus cancer in some cancer registering areas of China from 2003–2007, Chinese Journal of Obstetrics and Gynecology 47 (2012) 445–451. [3] S.M. Ueda, D.S. Kapp, M.K. Cheung, J.Y. Shin, K. Osann, A. Husain, et al., Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths, Am. J. Obstet. Gynecol. 198 (2) (2008) 218 e1-6. [4] H.M. Keys, J.A. Roberts, V.L. Brunetto, R.J. Zaino, N.M. Spirtos, J.D. Bloss, et al., A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study, Gynecol. Oncol. 92 (2004) 744–751. [5] C.L. Creutzberg, W.L. van Putten, P.C. Koper, M.L. Lybeert, J.J. Jobsen, C.C. WárlámRodenhuis, et al., Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Postoperative radiation therapy in endometrial carcinoma, Lancet 355 (2000) 1404–1411. [6] C.L. Creutzberg, R.A. Nout, M.L. Lybeert, C.C. Wárlám-Rodenhuis, J.J. Jobsen, J.W. Mens, et al., Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma, Int. J. Radiat. Oncol. Biol. Phys. 81 (2011) 631–638. [7] ASTEC/EN.5 Study Group, P. Blake, A.M. Swart, J. Orton, H. Kichener, T. Whelan, et al., Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis, Lancet 373 (2009) 137–146. [8] M.E. Randall, V.L. Filiaci, H. Muss, N.M. Spirtos, R.S. Mannel, L. Fowler, et al., Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study, J. Clin. Oncol. 24 (2006) 36–44. [9] M. Bruzzone, L. Miglietta, P. Franzone, A. Gadducci, F. Boccardo, Combined treatment with chemotherapy and radiotherapy in high-risk FIGO stage III–IV endometrial cancer patients, Gynecol. Oncol. 93 (2004) 345–352. [10] P.J. Hoskins, K.D. Swenerton, J.A. Pike, F. Wong, P. Lim, C. Acquino-Parsons, et al., Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study, J. Clin. Oncol. 19 (2001) 4048–4053. [11] P. De Marzi, L. Frigerio, S. Cipriani, F. Parazzini, L. Busci, L. Carlini, et al., Adjuvant treatment with concomitant radiotherapy and chemotherapy in high-risk endometrial cancer: a clinical experience, Gynecol. Oncol. 116 (2010) 408–412. [12] A.A. Secord, L.J. Havrilesky, V. Bae-Jump, J. Chin, B. Calingaert, A. Bland, et al., The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer, Gynecol. Oncol. 107 (2) (2007) 285–291. [13] K. Greven, K. Winter, K. Underhill, J. Fontenesci, J. Cooper, T. Burke, Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer, Gynecol. Oncol. 103 (2006) 155–159. [14] K.M. Alektiar, V. Makker, N.R. Abu-Rustum, R.A. Soslow, D.S. Chi, R.R. Barakat, et al., Concurrent carboplatin/paclitaxel and intravaginal radiation in surgical stage I–II serous endometrial cancer, Gynecol. Oncol. 112 (2009) 142–145. [15] H.J. Park, E.J. Nam, S. Kim, Y.B. Kim, Y.T. Kim, The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis, Eur. J. Obstet. Gynecol. Reprod. Biol. 170 (2013) 39–44.
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[16] R.J. Gray, A class of K-sample tests for comparing the cumulative incidence of a competing risk, Ann. Stat. 16 (1988) 1141–1154. [17] E.L. Kaplan, P. Meier, Nonparameteric estimation from incomplete observations, J. Am. Stat. Assoc. 53 (1958) 457–481. [18] A.A. Secord, L.J. Havrilesky, D.M. O'Malley, V. Bae-Jump, N.D. Fleming, G. Broadwater, et al., A multicenter evaluation of sequential multimodality therapy and clinical outcome for the treatment of advanced endometrial cancer, Gynecol. Oncol. 114 (3) (2009) 442–447. [19] T. Hogberg, M. Signorelli, C.F. de Oliveira, R. Fossati, A.A. Lissoni, B. Sorbe, et al., Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer–results from two randomised studies, Eur. J. Cancer 46 (2010) 2422–2431. [20] A. Mustea, D. Koensgen, A. Belau, J. Sehouli, W. Lichtenegger, L. Schneidewind, et al., Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology), Cancer Chemother. Pharmacol. 72 (2013) 975–983. [21] K. Lupe, D.P. D'Souza, J.S. Kwon, J.S. Radwan, I.A. Harle, J.A. Hammond, et al., Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer, Gynecol. Oncol. 114 (2009) 94–98. [22] M.A. Geller, J.J. Ivy, R. Ghebre, L.S. Downs Jr., P.L. Judson, L.F. Carson, et al., A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a “sandwich” method for stage III, IV, and recurrent endometrial cancer, Gynecol. Oncol. 121 (2011) 112–117. [23] T. Hidaka, T. Nakamura, T. Shima, H. Yuki, S. Saito, Paclitaxel/carboplatin versus cyclophosphamide/adriamycin/cisplatin as postoperative adjuvant chemotherapy for advanced endometrial adenocarcinoma, J. Obstet. Gynaecol. Res. 32 (2006) 330–337. [24] M. Sovak, M. Hensley, J. Dupont, N. Ishill, K.M. Alektiar, N. Abu-Rustum, et al., Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study, Gynecol. Oncol. 03 (2006) 451–457. [25] T. Akram, P. Maseelall, J. Fanning, Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer, Am. J. Obstet. Gynecol. 92 (2005) 1365–1367. [26] D. Pectasides, N. Xiros, G. Papaxoinis, E. Pectasides, C. Sykiotis, A. Koumarianou, et al., Carboplatin and paclitaxel in advanced or metastatic endometrial cancer, Gynecol. Oncol. 109 (2008) 250–254. [27] B. Sorbe, H. Andersson, K. Boman, P. Rosenberg, M. Kalling, Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up, Int. J. Gynecol. Cancer 18 (2008) 803–808. [28] D. Miller, V. Filiaci, G. Fleming, R. Mannel, D. Cohn, T. Matsumoto, et al., Latebreaking Abstract 1: Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study, Gynecol. Oncol. 125 (2012) 771. [29] J. Soper, S. Reisinger, R. Ashbury, E. Jones, D.L. Clarke-Pearson, Feasibility study of concurrent weekly cisplatin and whole abdominopelvic irradiation followed by doxorubicin/cisplatin chemotherapy for advanced stage endometrial cancer: a Gynecologic Oncology Group trial, Gynecol. Oncol. 95 (2004) 95–100. [30] J.M. Fowler, W.E. Brady, P.W. Grigsby, D.E. Cohn, R.S. Mannel, J.S. Rader, Sequential chemotherapy and irradiation in advanced stage endometrial cancer: a Gynecologic Oncology Group phase I trial of doxorubicin-cisplatin followed by whole abdomen irradiation, Gynecol. Oncol. 112 (2009) 553–557.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Adjuvant concurrent chemoradiation followed by chemotherapy for high-risk endometrial cancer Yulan Ren a,b, Xiaowei Huang a,b, Boer Shan a,b, Xiaohua Wu a,b, Xiao Huang a,b, Daren Shi b,c, Huaying Wang a,b,⁎ a b c
Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
H I G H L I G H T • Concurrent chemoradiotherapy followed by chemotherapy was safe for HREC. • Majority of patients (85.7%) completed the planned treatment. • Adverse effects were less common in patients who received PC than those with CEP.
a r t i c l e
i n f o
Article history: Received 21 August 2015 Received in revised form 10 November 2015 Accepted 18 November 2015 Available online 24 November 2015 Keywords: High-risk endometrial cancer Adjuvant therapy Progression-free survival Overall survival Toxicity
a b s t r a c t Objective. The adjuvant treatment of high-risk endometrial cancer (HREC) remains controversial. This prospective phase-II clinical trial was conducted to evaluate the adjuvant concurrent chemoradiotherapy followed by chemotherapy in patients with HREC. Methods. Altogether 122 patients were enrolled between January 2007 and January 2013, in which 112 were analyzable. The inclusion criteria included endometrioid endometrial cancer of histological grade 3 and with greater than 50% myometrial invasion, cervical stromal invasion, pelvic and/or para-aortic lymph node metastases; non-endometrioid endometrial cancer; no residual disease and distant metastases. Pelvic radiation was administered with cisplatin on days 1 and 28. Para-aortic radiation was administered with confirmed para-aortic lymph node metastases, and vaginal afterloading brachytherapy with cervical stromal invasion after total hysterectomy. Four courses of paclitaxel and carboplatin (PC) or cisplatin, cyclophosphamide and epirubicin (CEP) were administered at three-week interval after radiation. Results. Ninety-six patients (85.7%) completed the planned treatment. Treatment discontinuation was the result of toxicity (5/112, 4.5%), disease progression (8/112, 7.1%), and patients refusal (3/112, 2.7%). There was no life-threatening toxicity. Twenty-five (22.3%) patients recurred, in which 4 cases recurred in the field of radiation, and 13 (11.6%) patients died of endometrial cancer during follow-up. The estimated five-year progression-free survival and overall survival were 73% and 84%, respectively. Adverse effects were less common in patients who received PC than CEP (p = 0.001). Conclusions. This regimen demonstrated acceptable toxicity and good survival outcomes despite a preponderance (62.5%) of late stage disease. PC showed less adverse effects than CEP. A well designed randomized trial is under development. Clinical trial ID. https://clinicaltrials.gov/: 070148-7. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Endometrial cancer is the most common gynecologic malignancy in the western countries, with 287 new cases and 74 deaths per 100,000 worldwide [1], and the same trend was also observed in China [2]. ⁎ Corresponding author at: Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. E-mail address: [email protected] (H. Wang).
http://dx.doi.org/10.1016/j.ygyno.2015.11.021 0090-8258/© 2015 Elsevier Inc. All rights reserved.
There have been an increasing number of deaths due to endometrial cancer in the last two decades, which may be related to an increased rate of high-risk histologies and advanced stage disease [3]. While the optimal management for high risk endometrial cancer (HREC) still remains controversial. Radiotherapy was a traditional postoperative treatment which could significantly reduce the locoregional recurrences but fail to improve the overall survival [4–7]. Chemotherapy could improve survival outcomes of advanced stage disease compared to whole abdominal irradiation
Y. Ren et al. / Gynecologic Oncology 140 (2016) 58–63
(WAR) according to the results of GOG 122 [8]. However, a higher pelvic recurrence rate was observed in the chemotherapy arm compared with WAR (18% vs. 13%). Therefore, chemotherapy alone may not be adequate for achieving local control. In recent years, the attention of gynecologists has been shifted to multimodality treatments [9–11]. There are different ways for combining chemotherapy and radiotherapy, including concurrent chemoradiation, chemoradiation followed by chemotherapy, chemotherapy followed by radiotherapy, and “sandwich”. Several studies have revealed that combined therapy yielded good survival outcomes with acceptable toxicities [12–15]. But more data are needed to a draw a confirmative conclusion. Given the uncertainty of optimal adjuvant therapy for patients with HREC, we conducted this single-institute phase-II study to determine the toxicity, tolerability, and survival outcome of concomitant chemoradiation followed by chemotherapy in patients with HREC in China. 2. Materials and methods 2.1. Study design This study was a prospective, single-institutional, non-randomized phase-II clinical trial approved by the ethics committee of Fudan University Shanghai Cancer Center (clinical trial ID: 070148-7). This study was performed in accordance with the principles of good clinical practice (GCP) and the Declaration of Helsinki. All of the patients provided informed written consent before they were enrolled into this study. 2.2. Patient eligibility Patients were screened for eligibility after surgery consisting of hysterectomy (total or modified radical or radical), bilateral salpingooophorectomy, pelvic lymphadenectomy and/or para-aortic lymphadenectomy, and adequate surgical staging no more than eight weeks prior to the start of radiation therapy. Women ≥18 and ≤75 years of age with high-risk endometrial cancer with one of the following inclusion criteria were eligible for this study: endometrioid endometrial cancer with histological grade 3 and greater than 50% myometrial invasion, stromal invasion of the cervix, pelvic lymph node metastases, para-aortic lymph node metastases, or extrauterine disease confined to the pelvis; nonendometrioid endometrial cancer (including serous/clear cell carcinoma, and carcinosarcoma); no residual disease; and no distant metastases. The patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 to 2, normal hematological, liver and renal function with laboratory parameters within the normal range (including a creatinine clearance ≥ 40 ml/min, leucocytes ≥4.0 × 109/l, platelets ≥100 × 109/l and hemoglobin ≥10 g/ dl). Patients suffering from a secondary malignancy, serious concomitant systemic disorders or psychiatric disease were excluded from the study. No prior radiation therapy or chemotherapy was allowed before enrollment. 2.3. Treatment Treatment was started 14 days at the earliest and eight weeks at the latest after surgery. The patients were treated with external pelvic radiation (PRT) (1.8 Gy/d, d 1–5) at a total dose of 45 Gy. The pelvic radiotherapy fields were a standard four-field with an upper border of L5– S1. Vaginal vault afterloading brachytherapy (VAB) (5 Gy/d, six fractions) was administered to the patients with stromal invasion of the cervix after total hysterectomy following pelvic radiation. External para-aortic intensity-modulated radiation (45 Gy, 1.8 Gy/d) was administered to patients with pathologically confirmed para-aortic lymph nodes metastases. During radiotherapy, two cycles of cisplatin (50 mg/m2) were administered on days 1 and 28.
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After completion of concurrent chemoradiation, the patients were administered four additional courses of chemotherapy every 21 days. Two regimens were allowed: paclitaxel [135 mg/m2] (i.v. over 3 h) and carboplatin [AUC = 5] (i.v. over 30 min) or cisplatin [50 mg/m2], cyclophosphamide [600 mg/m2] and epirubicin [60 mg/m2], and the latter regimen was allowed because of the insurance policy and the costefficiency consideration in China. If the pathological type was carcinosarcoma, ifosfamide [1.5 g/m2] was added in combination with paclitaxel and carboplatin (according to the revised version of the protocol). A 5-HT3-antagonist, a H1-/H2-receptor antagonist and dexamethasone were administered intravenously 30 min prior to each cycle of chemotherapy. The patients received oral dexamethasone tablets 12 and 6 h prior to paclitaxel infusion. The treatment was continued during the four cycles of chemotherapy if the hematological count recovered (leucocytes N3.0 × 109/l, platelets ≥ 100 × 109/l and hemoglobin N 10 g/dl). The treatment could be postponed up to two weeks in cases of hematological and nonhematological toxicities (except NCI-CTC grade 3 nausea/emesis). The primary prophylactic use of granulocyte colony-stimulating factor (GCSF) was not allowed. 2.4. Baseline evaluation At baseline assessment, all patients had complete history, normal blood count, biochemistry, liver and renal function tests, a chest X-ray, ECG, liver and renal ultrasound and physical examination. Blood counts and biochemistry were repeated every week and prior to each cycle of chemotherapy and radiotherapy. Cut-off values for eligibility included leucocytes ≥4000, granulocytes ≥1500, platelets ≥ 100,000, creatinine ≤ 1.4, and bilirubin and ALT (serum glutamic pyruvic transaminase) ≤ two times normal. Pathology was all reviewed in Fudan University Shanghai Cancer Center. 2.5. Follow-up of patients During treatment, the patients were followed weekly through physical examination, ECOG, complete blood count (CBC) with platelets, and documentation of major symptoms or adverse effects. Toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria (NCI-CTC) for Adverse Events (AE) (v. 3.0) prior to each cycle of chemotherapy and weekly during radiotherapy. After treatment, the patients were followed-up clinically every three months for two years, then every six months for one year and then yearly. The last follow-up was in September 2015. 2.6. Study endpoints The primary endpoint of the protocol was disease-free survival (DFS). DFS was defined as the time from the date of enrollment to the date of disease progression or death from any cause. The secondary endpoints included local-regional failure, distant failure, and overall survival (OS). Local-regional failure was defined as recurrence in the pelvis, abdomen, and/or paraaortic area encompassed by the radiation field. Treatment completion per protocol and acute and late toxicity were also recorded and reported. 2.7. Statistical analysis Safety analyses were conducted, and the results are presented as raw numbers, rates, and ranges according to the underlying distribution. The local-regional failure and distant metastases failure rates were estimated using the cumulative incidence method [16]. The disease-free survival and overall survival rates were estimated using the Kaplan–Meier method [17]. The SPSS software package for Windows (SPSS Inc., version 16.0) was employed for all of the analyses. A p-value less than 0.05 was set as significant.
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3. Results 3.1. Patient characteristics One hundred and twenty-two patients were entered between January 2007 and January 2013. Ten patients were considered ineligible (six with distant metastasis, one with early stage IA, one with incomplete pelvic lymphadenectomy, one with prior chemo-radiation, and one with prior malignancy). Altogether, 112 patients were analyzable. The characteristics of 112 patients are displayed in Table 1. The median age was 54 years (range 33–75 years). The pathological type consisted primarily of endometrioid carcinoma (75.9%). Seventy patients (62.5%) were in an advanced stage (stage IIIA–IIIC2). 3.2. Treatment and modifications Altogether, ninety-six patients (85.7%) completed the planned treatment. Fifteen patients discontinued therapy early as a result of toxicity (5/112, 3.6%), patient refusal (3/112, 2.7%), and disease progression (8/112, 7.1%), in which four patients died before completing the therapy because of disease progression. 3.2.1. Concurrent chemoradiation After surgery, 90 (80.4%) patients received only pelvic radiation (PRT), 14 (12.5%) patients received additional para-aortic radiation
Table 1 Patient's characteristics (n = 112). Characteristic
Number of patients (%)
Median age, years (range) ECOG performance score 0 1 2 FIGO stage (2009) IA IB II IIIA IIIC1 IIIC2 Pathological subtype Endometrioid carcinoma UPSC Clear cell carcinoma Carcinosarcoma Neuroendocrine carcinoma Rhabdomyosarcoma Histological grade I II III Pelvic lymph node Positive Negative Para-aortic lymph node Positive Negative Not done Both pelvic and para-aortic lymph node Positive LVSI Positive Negative Not known Myometrial invasion b1/2 ≥1/2 Serosa Median follow-up, months (range)
54 (33–75) 69 (61.6) 36 (32.1) 7 (6.2) 11 (9.8) 10 (8.9) 21 (18.8) 23 (20.5) 33 (29.5) 14 (12.5) 85 (75.9) 6 (5.4) 7 (6.2) 9 (8.0) 3 (2.7) 1 (0.9) 9 (8.0) 52 (46.4) 51 (45.5)
(PAR), 6 (5.4%) patients received additional vaginal vault afterloading brachytherapy (VAB), and 2 patients received both additional PAR and VAB. The median radiation dose of pelvic radiation and para-aortic radiation was 45 Gy (range 36-47Gy), and the median number of fractions was 25 (range 20–25 fractions). The total dose of afterloading brachytherapy was 30 Gy with six fractions. Two cycles of cisplatin at a dose of 50 mg/m2 were administered at a four-week interval. During radiation, one patient discontinued the radiation after 20 fractions because of bowel obstruction, one patient had a one-week delay, two patients had a two-week delay because of diarrhea, and an additional patient had a two-week delay because of bowel obstruction (Table 2). The median duration of concurrent chemoradiation was 35 days (range 31–51 days). 3.2.2. Chemotherapy After concurrent chemoradiation, 85 patients (75.9%) received paclitaxel and carboplatin (PC), 20 patients (17.9%) received cisplatin, cyclophosphamide, and epirubicin (CEP), and five patients (4.5%) received paclitaxel, carboplatin, and ifosfamide (PCI). Two patients switched from PC to CEP because of allergy to paclitaxel, and 1 patient switched from CEP to PC because of the patient's request after one cycle. Ninety-seven patients (86.6%) completed the four cycles of chemotherapy, four patients received three cycles, two patients received two cycles, seven patients received one cycle, and two patients did not receive any chemotherapy. Some of the patients received less cycles of chemotherapy as a result of toxicity (n = 4), patient refusal (n = 3), disease progression and death (n = 8). A total of 20 cycles of chemotherapy were delayed for one week, and 10 cycles were delayed for two weeks. The treatment delays were related to toxicity (18 grade 3–4 neutropenia, eight grade 3–4 thrombocytopenia, one grade 4 anemia, one grade 3 diarrhea, two grade 3 bowel obstruction, two grade 3 vomiting, two grade 2 ALT disorder, and one deep vein thrombosis). Chemotherapy dose reductions were performed for 24 patients (21.4%) according to the protocol: the doses for 22 patients were reduced once, and the doses for two patients were reduced twice (Table 2). 3.3. Toxicity There was no life-threatening toxicity or treatment-related deaths. The acute toxicity during radiotherapy and chemotherapy included hematological and non-hematological toxicity. Hematological toxicity was the most leading adverse event. During concurrent chemo-radiotherapy, no acute radiation-related grade 4 hematological toxicity occurred. Altogether, the following toxicity grades were observed: grade 1 in 25 cases (22.3%), grade 2 in 18 cases (16.1%), and grade 3 in 5 cases (4.5%) (Supplement Table 1).
Table 2 Treatment modification.
39 (34.8) 73 (65.2) 14 (12.5) 67 (59.8) 31 (27.7) 6 (5.36) 42 (37.5) 45 (40.2) 25 (22.3) 39 (34.8) 61 (54.5) 12 (10.7) 41 (3–101)
Note. ECOG, the Eastern Cooperative Oncology Group; FIGO, the International Federation of Gynecology and Obstetrics; LVSI, Lymph-vascular space invasion.
Number of patient Chemoradiation PRT PRT + PAR PRT + VAB PRT + PAR + VAB Chemotherapy PC CEP PCI
1-week delay
2-week delay
Dose reduction
90 14 6 2
1 0 0 0
1 1 0 0
0 1a 0 0
85 20 5
17 2 1
6 3 1
13b 9 2
Note. PRT, pelvic radiation; PAR, para-aortic radiation; VAB, vaginal vault afterloading brachytherapy; PC, paclitaxel and carboplatin; CEP, cisplatin, cyclophosphamide, and epirubicin; PCI, paclitaxel, carboplatin, and ifosfamide. a Radiotherapy was canceled because of bowel obstruction. b 2 patients reduced for twice.
Y. Ren et al. / Gynecologic Oncology 140 (2016) 58–63 Table 3 Toxicity during chemotherapy (n = 110a). PC (n = 90b)
CEP(n = 20)
Grade
Hematological toxicity Leukopenia Neutropenia Anemia Thrombocytopenia Non-hematological toxicity Fatigue Diarrhea Vomiting ALT AST Creatinine Sensory Venous thrombosis Maximal toxicity per patient (%) P value
Grade
1
2
3
4
1
2
3
4
5 13 24 21
34 22 15 19
32 22 6 9
15 22 1 0
1 1 7 0
2 0 2 4
6 5 1 3
11 13 0 2
0 0 0 1 0 0 0 0 24 (26.7)
0 0 0 0 0 0 0 0 21 (23.3)
11 1 9 5 0 1 1 0 0 (0)
2 0 0 0 0 0 0 1 2 (10)
0 0 2 0 0 0 0 0 5 (25)
0 0 0 0 0 0 0 0 13 (65)
20 1 3 0 16 1 17 3 2 2 0 0 3 1 0 0 3 26 (3.3) (28.9) p = 0.001
Note. ALT, serum glutamic pyruvic transaminase; AST, serum glutamic oxaloacetic transaminase. a Two cases didn't receive chemotherapy because of disease progression. b Including 5 cases who received PCI.
Three patients exhibited grade 3 toxicity because of diarrhea, and two patients because of bowel obstruction. During adjuvant chemotherapy, all grade 4 toxicity was hematological toxicity. Of the patients who received the PC or PCI regimen, 24 cases (26.7%) exhibited grade 3 toxicity, and 21 cases (23.3%) exhibited grade 4 toxicity. Of the patients who received the CEP regimen, five cases (25.0%) exhibited grade 3 toxicity, and 13 cases (65.0%) had grade 4 toxicity (Table 3). Adverse effects were less common in the patients who received PC compared with those who received CEP (p = 0.001). To manage the grade 3/4 hematological side effects, 16 patients were hospitalized and received G-CSF, prophylactic antibiotics and other supportive care during hospitalization. Chronic toxicity (toxicity observed N90 days after completion of all therapies) occurred in 24 patients, including grade 1 in five cases (4.5%), grade 2 in thirteen cases (11.6%), grade 3 in four cases (3.6%), and grade 4 in two cases (1.8%) (Supplement Table 2). All grade 3/4 toxicity was because of bowel obstruction. Of the six patients who had grade 3/4 bowel obstruction, two patients received small intestine resection and enterodialysis, one received enterodialysis, and three received hospitalized supportive treatment. 3.4. Outcomes The median follow-up was 41 months (range 3–101 months). During follow-up, 25 (22.3%) patients recurred, of which four recurred in the field of radiation, and all the sites of recurrence were documented (Table 4). One patient had recurrence simultaneously in the lung and retroperitoneal lymph nodes, and another patient recurred simultaneously in the lung and the peritoneal cavity. The other sites of recurrence included the following: pelvic (n = 1), retroperitoneal lymph
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nodes (n = 2), supraclavicular lymph node (n = 2), lung (n = 6), liver (n = 3), brain (n = 2), bone (n = 2), and peritoneal cavity (n = 5). During follow-up, 13 (11.6%) patients died of endometrial cancer. The estimated five-year PFS and OS were 73% and 84%, respectively (Table 4) (Fig. 1). The estimated five-year OS for early and late stages were 94% and 77%, respectively (HR = 3.710; 95%CI, 1.819–16.820; p = 0.048). Although 5-year PFS and OS appears better for chemotherapy with PC, there was no significant difference between PC and CEP (77% vs. 66%, 85% vs, 84%, p = 0.28 and 0.59, respectively). 4. Discussion For high-risk endometrial cancer, multimodality treatments have been explored by several retrospective and prospective studies and showed superiority than single modality therapy [12,18]. Our study also revealed that concurrent chemoradiation followed by chemotherapy had an excellent treatment completion rate (85.7%) and good disease control with a five-year PFS of 73% and an OS of 84%, considering that more patients (62.5%) enrolled in our study were in an advanced stage (stage IIIA-C2) comparing to the previous studies [11,13]. Hogberg et al. reported the results of two randomized phase-III studies evaluating combination radiation and chemotherapy for early stage high-risk endometrial cancer, which were conducted by the Nordic Society of Gynecological Oncology/European Organization for the Research and Treatment of Cancer (NSGO/EORTC) and Mario Negri Institute (MaNGO) [19]. Altogether 540 patients (383 in the NSGO/ EORTC study and 157 in the MaNGO study) were enrolled in the studies in which pelvic radiotherapy (PRT) was compared with sequential radiotherapy and chemotherapy (RT-CT). With PRT alone, 26.2% of the patients recurred compared to 16% in the RT-CT group. The adjusted hazard ratio for recurrence was 0.65 (95% CI 0.43–0.99) in favor of the RT-CT group. Therefore, the addition of adjuvant CT to RT improves PFS in HREC. Although there was no significant difference in OS in either trial, there was a significant improvement in cancer-specific survival in the pooled analysis with a 45% reduction in death for those treated with combination therapy. A multi-center phase-II study conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) evaluated the adjuvant CT with sequential RT in patients with highrisk endometrial cancer, which showed that CT with sequential RT was tolerated and is feasible with a two-year PFS and OS of 75.8% [20]. “Sandwich” therapy was also reported by several studies [18,21–22]. Secord et al. reported a multicenter retrospective analysis of postoperative chemotherapy and radiation for surgical stages III and IV endometrial cancer, and found that sequential CRC was associated with improved survival compared to other sequencing modalities, with those receiving CRC having superior 3-year OS (88%) and PFS (69%) compared to RC (54% and 47%) or CR (57% and 52%) [18]. Despite of so many results of different studies, more convincing results were needed to determine which combination is the most favorable therapy for HREC. At the time of our study design, the data of RTOG-9708 in adjuvant treatment for high-risk endometrial cancer were just released [13]. We designed our study with several different points. Firstly, all of the patients were required to receive a pelvic lymphadenectomy before enrollment. Although para-aortic lymphadenectomy was an optional
Table 4 End points.
Recurrence in the field of radiation Local-regional failure Distant metastases failure Progression-free survival Overall survival a
Number of events
Estimated 2-year rate (%)
Estimated 3-year rate (%)
Estimated 5-year ratea (%)
4 9 18 25 13
3 7 16 80 91
4 9 17 77 89
4 11 20 73 84
The 5-year rate was estimated with median follow-up of 41 months.
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Fig. 1. Progression-free survival (A) and overall survival (B) of patients in the study.
eligibility criteria, 70% of the patients in our study received para-aortic lymphadenectomy, which makes the surgical stage more accurate than the previous study. Secondly, patients with papillary serous, clear cell, and carcinosarcoma were included in our study because these patients are more likely to gain benefits from multi-modality adjuvant treatment. As RTOG-9708, our study also showed acceptable toxicity and good locoregional control for HREC. Two regimens (PC and CEP) were allowed in our study. Both of them were validated and widely used in the treatment of advanced and recurrent endometrial cancer. An increasing number of phase-II studies have demonstrated excellent response rates and low toxicity with paclitaxel and carboplatin [23–27]. According to the results of a phase-III GOG trial which compared paclitaxel-carboplatin and paclitaxel-doxorubicincisplatin, paclitaxel and carboplatin was not inferior in terms of PFS and OS and was associated with reduced toxicity [28]. In our study, 75.9% of the patients received paclitaxel and carboplatin (PC). Although there was no significant difference of 5-year PFS and OS between PC and CEP (77% vs. 66%, 85% vs, 84%, p = 0.28 and 0.59, respectively), adverse effects were less common in patients with PC compared with patients with CEP (p = 0.001), which is in accordance with the results of the GOG study. The toxicity should be highly concerned in the combination of radiotherapy and chemotherapy. Soper et al. [29] reported high hematologic toxicity profiles in a GOG trial with concurrent weekly cisplatin and whole abdominal radiation followed by doxorubicin and cisplatin, and grade 4 neutropenia occurred in 100% of all patients. Another GOG phase-I trial [30] evaluating the feasibility of sequential chemotherapy and irradiation in advanced-stage endometrial cancer with doxorubicin–cisplatin followed by whole-abdomen irradiation included 31 patients. Twenty-nine patients were used for the evaluation of the feasibility of the regimen, and 22 patients had chronic radiation toxicity after a median follow-up time of 21 months. Three patients (14%) experienced severe chronic toxicity, including one treatment-related death. In our study, almost all of grade 3–4 toxicity was hematological toxicity during treatment, with only 3.6% grade 3 and 1.8% grade 4 bowel obstructions during follow-up. Therefore, this treatment is feasible and tolerable for most patients. Although the combination of radiotherapy and chemotherapy did not induce the high rate of bowel complication observed in the previous study [13], it should still be concerned during the multi-modality treatment. There are several limitations of our study. Firstly, this study is a onearm phase-II clinical trial with no control arm. Therefore, a randomized phase-III clinical trial is in preparation according to the results of our
study. Secondly, different chemotherapy regimens were allowed in our study. However, both regimens were validated and are widely used in the treatment of endometrial cancer, and it gave us a chance to observe the efficacy and toxicity of two different regimens based on our data. Thirdly, data of quality of life were only registered for some of the patients and have not been analyzed. Several randomized phase III clinical trials focused on the adjuvant treatment of high-risk endometrial cancer are still ongoing, which include GOG 258, a randomized phase III trial comparing cisplatin and radiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked and advanced endometrial carcinoma, and PORTEC-3, which compares concurrent pelvic RT/chemotherapy with pelvic RT alone. All of these results are expected to optimize the treatment for HREC. 5. Conclusion Our study found that concurrent cisplatin with radiation followed by paclitaxel and carboplatin showed less toxicity and achieved both good local and distant control. A phase III randomized clinical trial which compares adjuvant chemotherapy with concurrent chemoradiation is under development for high-risk endometrial cancer. Role of funding source The study was funded by the Ministry of Education of China (No. 20110071120099) which provided the fund to data collection and analysis. Conflict of interest The authors have declared no conflicts of interest.
Acknowledgments We would like to thank the patients and the nurses who participated in this trial, and associated professor Ji Zhu, data manager Huixun Jia and Li Xie for the data collection and their thoughtful advice and discussions. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.11.021.
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References [1] J. Ferlay, H.R. Shin, F. Bray, D. Forman, C. Mathers, D.M. Parkin, Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008, Int. J. Cancer 127 (2010) 2893–2917. [2] K.R. Wei, W.Q. Chen, S.W. Zhang, R.S. Zheng, Y.N. Wang, Z.H. Liang, Epidemiology of uterine corpus cancer in some cancer registering areas of China from 2003–2007, Chinese Journal of Obstetrics and Gynecology 47 (2012) 445–451. [3] S.M. Ueda, D.S. Kapp, M.K. Cheung, J.Y. Shin, K. Osann, A. Husain, et al., Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths, Am. J. Obstet. Gynecol. 198 (2) (2008) 218 e1-6. [4] H.M. Keys, J.A. Roberts, V.L. Brunetto, R.J. Zaino, N.M. Spirtos, J.D. Bloss, et al., A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study, Gynecol. Oncol. 92 (2004) 744–751. [5] C.L. Creutzberg, W.L. van Putten, P.C. Koper, M.L. Lybeert, J.J. Jobsen, C.C. WárlámRodenhuis, et al., Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Postoperative radiation therapy in endometrial carcinoma, Lancet 355 (2000) 1404–1411. [6] C.L. Creutzberg, R.A. Nout, M.L. Lybeert, C.C. Wárlám-Rodenhuis, J.J. Jobsen, J.W. Mens, et al., Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma, Int. J. Radiat. Oncol. Biol. Phys. 81 (2011) 631–638. [7] ASTEC/EN.5 Study Group, P. Blake, A.M. Swart, J. Orton, H. Kichener, T. Whelan, et al., Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis, Lancet 373 (2009) 137–146. [8] M.E. Randall, V.L. Filiaci, H. Muss, N.M. Spirtos, R.S. Mannel, L. Fowler, et al., Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study, J. Clin. Oncol. 24 (2006) 36–44. [9] M. Bruzzone, L. Miglietta, P. Franzone, A. Gadducci, F. Boccardo, Combined treatment with chemotherapy and radiotherapy in high-risk FIGO stage III–IV endometrial cancer patients, Gynecol. Oncol. 93 (2004) 345–352. [10] P.J. Hoskins, K.D. Swenerton, J.A. Pike, F. Wong, P. Lim, C. Acquino-Parsons, et al., Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study, J. Clin. Oncol. 19 (2001) 4048–4053. [11] P. De Marzi, L. Frigerio, S. Cipriani, F. Parazzini, L. Busci, L. Carlini, et al., Adjuvant treatment with concomitant radiotherapy and chemotherapy in high-risk endometrial cancer: a clinical experience, Gynecol. Oncol. 116 (2010) 408–412. [12] A.A. Secord, L.J. Havrilesky, V. Bae-Jump, J. Chin, B. Calingaert, A. Bland, et al., The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer, Gynecol. Oncol. 107 (2) (2007) 285–291. [13] K. Greven, K. Winter, K. Underhill, J. Fontenesci, J. Cooper, T. Burke, Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer, Gynecol. Oncol. 103 (2006) 155–159. [14] K.M. Alektiar, V. Makker, N.R. Abu-Rustum, R.A. Soslow, D.S. Chi, R.R. Barakat, et al., Concurrent carboplatin/paclitaxel and intravaginal radiation in surgical stage I–II serous endometrial cancer, Gynecol. Oncol. 112 (2009) 142–145. [15] H.J. Park, E.J. Nam, S. Kim, Y.B. Kim, Y.T. Kim, The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis, Eur. J. Obstet. Gynecol. Reprod. Biol. 170 (2013) 39–44.
63
[16] R.J. Gray, A class of K-sample tests for comparing the cumulative incidence of a competing risk, Ann. Stat. 16 (1988) 1141–1154. [17] E.L. Kaplan, P. Meier, Nonparameteric estimation from incomplete observations, J. Am. Stat. Assoc. 53 (1958) 457–481. [18] A.A. Secord, L.J. Havrilesky, D.M. O'Malley, V. Bae-Jump, N.D. Fleming, G. Broadwater, et al., A multicenter evaluation of sequential multimodality therapy and clinical outcome for the treatment of advanced endometrial cancer, Gynecol. Oncol. 114 (3) (2009) 442–447. [19] T. Hogberg, M. Signorelli, C.F. de Oliveira, R. Fossati, A.A. Lissoni, B. Sorbe, et al., Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer–results from two randomised studies, Eur. J. Cancer 46 (2010) 2422–2431. [20] A. Mustea, D. Koensgen, A. Belau, J. Sehouli, W. Lichtenegger, L. Schneidewind, et al., Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology), Cancer Chemother. Pharmacol. 72 (2013) 975–983. [21] K. Lupe, D.P. D'Souza, J.S. Kwon, J.S. Radwan, I.A. Harle, J.A. Hammond, et al., Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer, Gynecol. Oncol. 114 (2009) 94–98. [22] M.A. Geller, J.J. Ivy, R. Ghebre, L.S. Downs Jr., P.L. Judson, L.F. Carson, et al., A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a “sandwich” method for stage III, IV, and recurrent endometrial cancer, Gynecol. Oncol. 121 (2011) 112–117. [23] T. Hidaka, T. Nakamura, T. Shima, H. Yuki, S. Saito, Paclitaxel/carboplatin versus cyclophosphamide/adriamycin/cisplatin as postoperative adjuvant chemotherapy for advanced endometrial adenocarcinoma, J. Obstet. Gynaecol. Res. 32 (2006) 330–337. [24] M. Sovak, M. Hensley, J. Dupont, N. Ishill, K.M. Alektiar, N. Abu-Rustum, et al., Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study, Gynecol. Oncol. 03 (2006) 451–457. [25] T. Akram, P. Maseelall, J. Fanning, Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer, Am. J. Obstet. Gynecol. 92 (2005) 1365–1367. [26] D. Pectasides, N. Xiros, G. Papaxoinis, E. Pectasides, C. Sykiotis, A. Koumarianou, et al., Carboplatin and paclitaxel in advanced or metastatic endometrial cancer, Gynecol. Oncol. 109 (2008) 250–254. [27] B. Sorbe, H. Andersson, K. Boman, P. Rosenberg, M. Kalling, Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up, Int. J. Gynecol. Cancer 18 (2008) 803–808. [28] D. Miller, V. Filiaci, G. Fleming, R. Mannel, D. Cohn, T. Matsumoto, et al., Latebreaking Abstract 1: Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study, Gynecol. Oncol. 125 (2012) 771. [29] J. Soper, S. Reisinger, R. Ashbury, E. Jones, D.L. Clarke-Pearson, Feasibility study of concurrent weekly cisplatin and whole abdominopelvic irradiation followed by doxorubicin/cisplatin chemotherapy for advanced stage endometrial cancer: a Gynecologic Oncology Group trial, Gynecol. Oncol. 95 (2004) 95–100. [30] J.M. Fowler, W.E. Brady, P.W. Grigsby, D.E. Cohn, R.S. Mannel, J.S. Rader, Sequential chemotherapy and irradiation in advanced stage endometrial cancer: a Gynecologic Oncology Group phase I trial of doxorubicin-cisplatin followed by whole abdomen irradiation, Gynecol. Oncol. 112 (2009) 553–557.