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Distant metastasis in patients with cervical cancer after primary radiotherapy with or without chemotherapy and image guided adaptive brachytherapy
Gynecologic Oncology 133 (2014) 256–262
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Distant metastasis in patients with cervical cancer after primary radiotherapy with or without chemotherapy and image guided adaptive brachytherapy M.P. Schmid a,⁎, M. Franckena a,b, K. Kirchheiner a,c, A. Sturdza a, P. Georg a, W. Dörr a,c, R. Pötter a,c a b c
Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, Netherlands Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria
H I G H L I G H T S • FIGO stage and lymph node status are significant predictors for distant metastasis in cervical cancer patients. • 5 year distant metastasis free survival of 91% and 60% in low and high risk patients • Significant impact of number of chemotherapy cycles on the occurrence of distant metastasis in high risk patients
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Article history: Received 8 October 2013 Accepted 4 February 2014 Available online 8 February 2014 Keywords: Cervical cancer Radiotherapy Chemotherapy Cisplatin Distant metastasis Prognostic factors
a b s t r a c t Objective. The aim of this study is to investigate patterns of distant relapse after primary radiochemotherapy in cervical cancer patients. Methods. All patients with cervical cancer treated in curative intent with external beam radiotherapy +/− chemotherapy and image-guided adaptive brachytherapy between January 1998 and June 2009 at the Medical University of Vienna were included in this retrospective analysis. Patients with locoregional recurrences were excluded from this study. Presence, site of and time to distant metastases were recorded. For identifying prognostic factors, uni- and multivariate analyses using Cox regression analysis were performed. Based on the result from the multivariate analysis, patients were stratified into a high and a low risk group. The Kaplan–Meier method was used to estimate distant-metastasis-free-survival in the overall cohort, in the risk groups and for analysing the impact of chemotherapy within the risk groups. Results. A total number of 189 patients were included in this study. After a median follow-up of 54 months, 49 patients developed distant metastases. Overall, distant-metastasis-free-survival 5 years after treatment was 73%. FIGO stage, lymph node status and the extent of tumour regression during treatment were significant predictors for distant metastasis. Distant-metastasis-free-survival 5 years after treatment was 91% and 60% in the low and high risk groups, respectively. The number of the cycles of chemotherapy had a significant impact on the occurrence of distant metastasis in high risk patients, but not in low risk patients. Conclusion. Patients with high risk factors have a 40% probability of developing distant metastasis within 5 years. In these patients, decreasing the number of cycles of cisplatin may increase their probability of developing distant metastasis. © 2014 Elsevier Inc. All rights reserved.
Introduction Cervix cancer is one of the most common malignancies in women worldwide and still remains a prominent cause of female cancer death
⁎ Corresponding author at: Department of Radiotherapy, Comprehensive Cancer Center, Medical University of Vienna, General Hospital of Vienna, Währinger Gürtel 1820, A-1090 Vienna, Austria. Fax: +43 1404002693. E-mail address: [email protected] (M.P. Schmid).
http://dx.doi.org/10.1016/j.ygyno.2014.02.004 0090-8258/© 2014 Elsevier Inc. All rights reserved.
[1,2]. Radiotherapy has been the mainstay of treatment for locally advanced cervix cancer for decades. Since the late nineties chemotherapy is added to standard radiotherapy as this addition improves overall and disease free survival by about 6% at 10 years [3]. Besides improving the effectiveness of radiotherapy in terms of improvement of local tumour control, the addition of chemotherapy also decreases the rate of distant metastases, but to a lesser extent [3,4]. In spite of the clear benefits of adding chemotherapy to radiotherapy for cervix cancer patients, many questions still remain regarding the optimal agent and timing, as well as the added benefit for the higher stages [3,4].
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More recently, technological advances in radiotherapy have led to significant improvements in local tumour control. With image guided adaptive brachytherapy (IGABT) a local control rate of N90–95% appears to be achievable for all tumour stages. These promising findings in several single institution series are currently the subject of a multicenter verification in the EMBRACE study (European study on MRI guided BRAchytherapy in locally advanced CErvix cancer) [5–11]. However, it still needs to be clarified to which extent this improvement in local control translates into an improvement in overall or distant metastasesfree survival [3,5,12,13]. Hence, in the setting of an excellent local control resulting from IGABT for locally advanced cervical cancer, distant failure emerges as the predominant type of failure for these patients. We performed a retrospective analysis of patients with locally advanced cervix cancer treated with definitive radiotherapy including IGABT to (1) investigate time to occurrence of distant metastases and patterns of spread, (2) determine the impact of prognostic factors on the occurrence of distant metastases, (3) analyse the impact of chemotherapy on the occurrence of distant metastases. Methods and materials Patients All patients with cervix cancer FIGO Ib to IVa treated with definitive radiotherapy between January 1998 and June 2009 at the Department of Radiation Oncology of the Medical University of Vienna were included in this retrospective analysis. Patients were excluded from this analysis in case of local/regional recurrence, delivery of neoadjuvant chemotherapy or a contraindication for chemotherapy due to patient age. Pre-treatment evaluation included patient history, complete physical and gynaecological exam, routine laboratory studies, abdomino/ pelvic CT or whole body (FDG-) PET-CT and MRI-scan of the pelvis. Follow up investigations were performed every 3 months in the first two years after treatment, every 6 months in the next two years and then yearly thereafter. These included gynaecological examination and regular MRI-scans of the pelvis and thoraco/abdominal CT scans. Radiotherapy Detailed treatment characteristics are described in previous publications [14–20]. In brief, treatment consisted of whole pelvis EBRT with or without concomitant chemotherapy and IGABT. Before initiation of radiochemotherapy, laparoscopic lymph node staging and debulking of suspicious lymph nodes were performed in the majority of cases. If not, lymph node involvement was assessed by CT or PET-CT. EBRT was performed using a four-field box technique, with the gradual implementation of intensity modulated radiotherapy (IMRT) towards the end of the study period, after individual CT-based treatment planning with 1.8 Gy per fraction up to a total dose of 45 Gy. In case of suspicious lymph nodes (loss of oval shape, size N 1 cm, significant FDG uptake), an additional boost up to ~ 15 Gy was considered. Concomitantly, 5– 6 cycles of cisplatin-based chemotherapy (40 mg/m2 body surface) were administered. If chemotherapy was not delivered, then the total EBRT dose was increased to 50.4 Gy. Additionally three to six (mainly four) fractions of MRI based high dose rate IGABT were performed in the end or after EBRT with the aim of delivering in total (EBRT + IGABT) N85 Gy EQD2 (biologically equieffective dose; reference dose per fraction = 2 Gy, linear quadratic model, α/β = 10 Gy) to the D90 of the high risk clinical target volume (HRCTV). The performance of brachytherapy (including the number of brachytherapy fractions) varied during the learning period of IGABT. Since 2001, a systematic approach was used. Details on the concept of IGABT, the learning period and the systematic period are given in previous publications [5,14,15].
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Chemotherapy Concomitant weekly cisplatin-based chemotherapy (5–6 × 40 mg/m2) was administered to patients who had a Karnofsky performance score of at least 60, age b80 years, neutrophil count N 3.0 × 109 per litre, platelet count N100 × 10 9 per litre and creatinine clearance N70 ml/min. Chemotherapy was withheld if patients had a neutrophil count b2.0 × 109 per litre or a platelet count b100 × 109 per litre and if creatinine clearance was b50 ml/min. Patients with creatinine clearance in the range 50–70 ml/min received a reduced chemotherapy dose. Methodology and statistics Time to occurrence of distant metastases and patterns of spread/location The probability of distant metastasis free survival (DMFS) at three and five years was estimated with the Kaplan–Meier method, with the date of initial biopsy as a starting point. Distant metastasis was defined as any first site of distant recurrence in the absence of loco-regional failure. Results are given with 95% confidence intervals (CI). The median time to occurrence of distant metastases and the median time from occurrence of distant metastases to death were calculated. Location of distant metastases is described. Impact of prognostic factors on the occurrence of distant metastases Exploratory univariate analyses were performed to assess the impact of known prognostic factors on the development of distant metastasis: FIGO stage, tumour size (grouped as b5 cm and ≥ 5 cm), lymph node status (positive or negative), histology, grade, patient age, overall treatment time, HRCTV size at the time of first brachytherapy, tumour regression during EBRT, D90 (EBRT + IGABT) of HRCTV and the number of cycles of cisplatin received by the patient. The extent of tumour regression was calculated from the gross tumour volume (GTV) on the T2-weighted pelvic MRI-scan at diagnosis and the residual GTV on the T2-weighted pelvic MRI-scan at the time of first brachytherapy, excluding the greyzones. Details on the methodology of the tumour regression analysis are described elsewhere [21]. Two-sided p-values below 0.05 were considered significant. Univariate significant factors were included in a multivariate Cox regression model on DMFS. Based on the hazard ratios of multivariate significant prognostic factors and the sub-analysis within these significant prognostic factors (Figs. 1 and 2), high and low risk groups of patients were defined and compared with a log rank test regarding DMFS. Impact of chemotherapy on the occurrence of distant metastases The dose of concomitant chemotherapy applied was defined as no chemotherapy (0 cycles), reduced number of cycles (1–4 cycles) and full number of cycles (5–6 cycles). The impact of chemotherapy on the occurrence of distant metastases was analysed with log rank tests in both the high risk and the low risk groups. For all calculations, the IBM Statistical Package for Social Sciences (SPSS), version 17.0 was used (IBM Corp., Chicago, Illinois). Results Patient and treatment characteristics A total number of 253 patients with primary locally advanced cervix cancer were treated with definitive radiotherapy with or without chemotherapy between January 1998 and June 2009. Of these 253, 189 met the inclusion criteria for this analysis. The reasons for excluding the 64 patients were loco-regional failure (n = 30) or failure to achieve a complete response (n = 8), no chemotherapy administered due to age (n = 23) or neoadjuvant chemotherapy administered (n = 3). Patient- and tumour characteristics of these 189 patients are summarised in Table 1. Treatment characteristics are
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Fig. 1. Distant metastasis free survival for the various FIGO stages.
summarised in Table 2. Median duration of follow-up for this patient group was 54 months (range: 2–146).
12). The third most common site of metastasis was the abdominal cavity (n = 8). Further locations included the supraclavicular space (n = 4), bones (n = 3), brain (n = 1), skin/soft tissue (n = 3) and liver (n = 1).
Distant metastasis free survival and patterns of distant failure During follow-up, 49 patients developed distant metastases. The probability for DMFS at 3 and 5 years after treatment was 78% (95% CI 72–84%) and 73% (67–80%), respectively. The median time from end of treatment to first occurrence of distant metastasis was 7 months (range: 1–122) and the median time from diagnosis of distant metastasis to death was 6 months (range: 0–42). The main locations of distant failure were the lungs (n = 17) and the para-aortic lymph nodes (n =
Analyses of prognostic factors and influence of tumour regression In exploratory, univariate analyses, FIGO stage, lymph node stage, overall treatment time, size of HRCTV at time of first brachytherapy, D90 of HRCTV and the extent of tumour regression from diagnosis to time of first brachytherapy emerged as significant factors for DMFS for the whole study group (S1: Table 3).
Fig. 2. Distant metastasis free survival for patients with positive (N+) or negative (N0) lymph nodes.
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Table 1 Patient- and tumour characteristics.
FIGO stage
Tumour size Lymph node statusa Histology
Grade
Age OTT a b
Ib IIa IIb IIIa IIIb IVa b5 cm ≥5 cm Negative Positive SCC AC Other 1 2 3 Unknown Mean (range) Mean (range)
All patients n = 189
Low risk group n = 84
High risk group n = 105
25 (13%) 8 (4%) 109 (58%) 4 (2%) 35 (18%) 8 (4%) 74 (39%) 115 (61%) 102 (54%) 87 (46%) 165 (87%) 13 (7%) 11 (6%) 10 (5%) 91 (48%) 56 (30%) 32 (17%) 57 (26–80) 53 (31–115)
11 (13%) 4 (5%) 68 (81%) 1 (1%) – – 48 (57%) 36 (43%) 84 (100%) – 72 (86%) 5 (6%) 7 (8%) 1 (1%) 48 (57%) 21 (25%) 14 (17%) 59 (32–80) 47 (31–71)
14 (13%) 4 (4%) 41 (39%) 3 (3%) 35 (33%) 8 (8%) 26 (25%) 79 (75%) 18 (17%) 87 (83%) 93 (88%) 8 (8%) 4 (4%) 9 (9%) 43 (41%) 35 (33%) 18 (17%) 55 (28–78) 58 (32–115)b
Assessment of lymph node status in 38% by imaging only and in 62% by laparoscopy and imaging. Including lymph node boost and paraaortic irradiation.
In the multivariate model (S2: Table 4) FIGO stage, lymph node status and the extent of tumour regression remained of significant influence on DMFS. Risk stratification and the influence of concomitant chemotherapy The results of uni- and multivariate analyses show clearly that FIGO stage and lymph node status are the most important predictors of DMFS, which can be assessed already at the time of diagnosis. Based on these two parameters, a high and a low risk group were defined. From the Kaplan–Meier curve, there is a decrease in DMFS with increasing FIGO stage (Fig. 1). For lymph node stage, as expected, patients with negative lymph nodes are significantly less likely to develop distant metastasis than patients with positive lymph nodes (Fig. 2, p = 0.003). For patients with negative lymph nodes DMFS was 85% (CI: 77–92%) and 83% (CI: 76–91%) at 3 and 5 years, respectively, while for patients with positive lymph nodes 70% (CI: 61–80%) was free of distant metastasis at 3 years and 62% (CI: 51–73%) at 5 years (p = 0.003). We defined a low risk group of patients staged Ib to IIIa and negative lymph nodes and a high risk group of patients with FIGO stage IIIb to IVa or any stage and positive lymph nodes. Patient, tumour and treatment characteristics for these subgroups are summarised in the Tables 1 and 2. Forty-four percent of patients (n = 84) contributed to the low risk group. Of them, only 9 (11%) developed distant metastasis. DMFS in the low risk group was 91% at 3 years (CI: 85–97%) and 90% at 5 years (CI: 82–96%). The high risk group encompassed 105 patients and of them, 40 (38%) developed distant metastasis during follow-up. DMFS in the high risk group was 67% at 3 years (CI: 58–76%) and 60% at 5 years after treatment (CI: 50–70%). The probability to develop distant metastases was significantly higher in the high risk group (p = 0.000). As stated in Table 2, 45 of all 189 patients did not receive any chemotherapy. Of these 45, 22 patients did not receive chemotherapy because they had a co-existent disease prohibiting the administration of cisplatin (mainly poor renal function). A further 20 did not receive chemotherapy because they were treated before May of 1999 when chemoradiation became standard clinical practice at the Medical University of Vienna. The remaining three patients received radiation alone because they refused the simultaneous administration of chemotherapy. The complete chemotherapy schedule (5–6 cycles with 40 mg/m2) was delivered in 26.2% of the low risk patients and in 37.1% of the high risk patients. In consequence, dose modifications (reduction of dose, reduction of cycles,
reduction of dose and cycles due to, e.g. hematologic or renal toxicity) occurred in 73.8% of the low risk patients and 62.9% of the high risk patients. The number of chemotherapy cycles showed no significant impact on DMFS in the low risk group (p = 0.782), but in the high risk group (p = 0.022). Figs. 3 and 4 illustrate that for patients in the high risk group the risk for the development of distant metastases increases with decreasing number of chemotherapy cycles.
Table 2 Treatment characteristics. a For all 189 patients EBRT
Brachytherapy
Chemotherapy
Pelvic field Paraaortic field Lymph node boost HRCTV size HRCTVD90a Tumour regressionb 0 cycles 1–4 cycles 5–6 cycles
n = 189 (100%) n = 41 (22%) n = 20 (11%) 39.7 cm2 91.9 Gy 72.1% 45 (25%) 64 (34%) 80 (42%)
dose 45.6 Gy (36.0–56.8) dose 42.9 Gy (36.8–49.6) dose 9.3 Gy (4.0–14.4) (7.6–167.3) (55.1–136.3) (3–98%)
b For the patients in the low risk group (n = 84) EBRT
Brachytherapy
Chemotherapy
Pelvic field Paraaortic field Lymph node boost HRCTV size HRCTVD90a Tumour regressionb 0 cycles 1–4 cycles 5–6 cycles
n = 84 (100%) n.a. n.a. 33.6 cm2 94.9 Gy 71.0% 30 (36%) 24 (28%) 30 (36%)
dose 45.3 Gy (37.8–53.0)
(7.6–155.7) (61.9–136.3) (3–98%)
c For the patients in the high risk group (n = 105) EBRT
Brachytherapy
Chemotherapy
a b
Pelvic field Paraaortic field Lymph node boost HRCTV size HRCTVD90a Tumour regressionb 0 cycles 1–4 cycles 5–6 cycles
n = 105 (100%) n = 40 (38%) n = 21 (20%) 44.5 cm2 89.4 Gy 73.2% 15 (14%) 40 (38%) 50 (48%)
Total dose (EBRT + brachytherapy) in EQD2α/β 10 Gy. Greyzones not included.
dose 45.9 Gy (36–56.8) dose 42.8 (36.8–49.6) dose 9.3 Gy (4.0–14.4) (12.8–167.3) (55.1–117) (4–98%)
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Fig. 3. Distant metastasis free survival for patients in the low risk group depending on the number of cycles of concomitant chemotherapy.
Discussion Chemoradiation as a standard treatment approach for patients with locally advanced cervix cancer gained widespread acceptance since several large randomised trials showed improved local control and overall survival with the addition of chemotherapy to radiotherapy [22–27]. However, the optimal timing, dose and sequence of chemotherapy are still not fully elucidated. Concomitant chemotherapy, though administered at low dose, may also decrease the incidence of distant metastases. The present results confirm previous suggestions on the decreased
probability of distant metastasis due to concomitant chemotherapy as well as the inverse relationship between the administered cycles of cisplatin and the occurrence of distant metastasis. Association between completion of the schedule and prognosis has also not been the subject of large-scale investigation yet. However, the relationship between the dose of cisplatin and the incidence of distant metastasis has also been previously recognised in a smaller patient cohort with less follow-up and in patients treated before the era of IGABT [28]. The results from this study are in accordance with ours in that the administration of 5–6 full dose cycles of cisplatin can reduce a patient's risk of developing
Fig. 4. Distant metastasis free survival for patients in the high risk group depending on the number of cycles of concomitant chemotherapy.
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distant metastasis. Future studies will have to provide clinical evidence to what extent the improvement of local control through IGABT will decrease distant failure. The occurrence of distant metastases is linked to some degree to local and regional failures and IGABT can reduce the incidence of local failure by maximising the radiation dose to the tumour area [29–32]. In this study, the D90 of HRCTV was a significant factor for the occurrence of distant metastasis in the univariate analysis for high risk patients. The present investigation provides the distant failure pattern following chemoradiation including IGABT. Our analysis included prognostic factors well known to influence local control and survival in cervix cancer patients [33–35]. Based on the results of the multivariate analysis, we stratified our patient group in 2 risk groups based on FIGO stage and lymph node status. There is a clear and distinct effect of the number of cycles of concomitant chemotherapy on the development of distant metastases in the high risk group. This shows that the addition of concomitant chemotherapy indeed decreases a patient's chances of developing distant metastasis for those at high risk. Therefore, the results of the study may suggest that completion of all chemotherapy cycles should be intensively sought in high risk patients, whereas in low risk patients a reduced number of cycles may be arguable in certain clinical situations—such as impairment of blood count and/or kidney function during chemoradiation close to chemotherapy preconditioning cut-off values. To identify patients at high risk for developing distant metastasis, patients with loco-regional recurrences were excluded from analysis. Local recurrences are in the majority of cases the result of inadequate local treatment and may induce distant metastasis itself. Patients not receiving chemotherapy due to age were also excluded, because of limited life expectancy, which could prohibit the occurrence of distant metastasis. A surprising correlation found in this study is the significant relationship between the occurrence of distant metastasis and the extent of tumour regression between diagnosis and the time of first brachytherapy application. Therefore, the extent of tumour regression could be potentially used as an early response indicator, not only for local tumour control (as shown by others) but also as a risk factor for the development of distant metastasis. Subsequently, it may be used to identify patients in need of intensified systemic treatment. The impact of tumour regression was most pronounced in high risk patients suggesting a more aggressive tumour biology with a higher tendency towards distant metastasis in less responding tumours in comparison to fast responding tumours. In previous MRI studies, tumour regression was shown to be significantly influenced by different patterns of tumour spread and differences in dynamic contrast enhancement, indicating possible differences in tumour biology such as hypoxia [36,37]. Further research will be necessary to clarify the correlation of tumour regression and the occurrence of distant metastasis. Patients in our high risk group seem to benefit from a higher number of chemotherapy cycles but still 23% of them develop distant metastasis despite receiving an adequate dose of cisplatin. Therefore, further research should be aimed at systemic treatment intensification to reduce distant spread. As concurrent chemotherapy already adds to early treatment-related toxicity compared to radiotherapy alone and its effects on long term morbidity remain unclear, further intensification of the concomitant scheme seems rather unattractive [38,39]. Adjuvant chemotherapy may be a more effective approach. For example, Duneas Gonzales showed an increase in progression free and overall survival by adjuvant chemotherapy after randomizing 515 patients with locally advanced cervix cancer to receive either cisplatin-based chemoradiation with concurrent gemcitabine or cisplatin-based chemoradiation with concurrent gemcitabine and adjuvant gemcitabine and cisplatin [40,41]. Currently, there are 2 large-scale international randomised studies investigating the role of additional chemotherapy in locally advanced cervix cancer with different approaches. The OUTBACK trial is investigating the benefit of 4 cycles of adjuvant carboplatin paclitaxel after
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standard chemoradiation for locally advanced cervix cancer [42]. The second study is the CRUK INTERLACE study investigating the role of weekly induction carboplatin paclitaxel before standard chemoradiation in patients with locally advanced cervix cancer [43]. Unfortunately both studies do not systematically include modern radiotherapy techniques like IGABT +/− interstitial applications or IMRT. To assess the value of adjuvant chemotherapy for patients at high or intermediate risk of distant metastases treated with chemoradiation and IGABT, an appropriate international trial is mandatory. Such a trial must be designed to assess if adjuvant chemotherapy (e.g. carboplatin/paclitaxel) will increase overall survival for patients with locally advanced cervix cancer at high or intermediate risk of developing distant metastases as defined by FIGO stage and lymph node status and receiving simultaneous radiochemotherapy and IGABT. In conclusion, from our retrospective analysis of 189 patients with locally advanced cervix cancer treated with chemoradiation and IGABT, it becomes clear that patients with a higher tumour stage at diagnosis and those with positive lymph nodes are at high risk of developing distant metastasis and for these high risk patients, decreasing the number of cycles of cisplatin may increase their probability of developing distant metastasis. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2014.02.004. Conflict of interest statement The Department of Radiotherapy at the Medical University of Vienna receives/received financial and/or equipment support for research and educational purposes from Nucletron an Elekta company and Varian Medical Systems, Inc. The financial support by the Austrian Federal Ministry of Economy, Family, and Youth and the Austrian Foundation for Research, Technology, and Development is gratefully acknowledged.
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[28] Nugent EK, Case AS, Hoff JT, Zighelboim I, DeWitt LL, Trinkhaus K, et al. Chemoradiation in locally advanced cervical carcinoma: an analysis of cisplatin dosing and other clinical prognostic factors. Gynecol Oncol 2010;116:438–41. [29] Fagundes H, Perez CA, Grigsby PW, Lockett MA. Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1992;24:197–204. [30] Sakurai H, Mitsuhashi N, Takahashi M, Akimoto T, Muramatsu H, Ishikawa H, et al. Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone: patterns of recurrence, latent periods, and prognosis. Int J Radiat Oncol Biol Phys 2001;50:1136–44. [31] Park TK, Kwon JY, Kim SW, Kim SH, Kim SN, Kim GE. Patterns of treatment failure following radiotherapy with combination chemotherapy for patients with highrisk stage IIB cervical carcinoma. Int J Clin Oncol 2004;9:120–4. [32] Schmid MP, Kirisits C, Nesvacil N, Dimopoulos JC, Berger D, Potter R. Local recurrences in cervical cancer patients in the setting of image-guided brachytherapy: a comparison of spatial dose distribution within a matched-pair analysis. Radiother Oncol 2011;100:468–72. [33] Polterauer S, Grimm C, Hofstetter G, Concin N, Natter C, Sturdza A, et al. Nomogram prediction for overall survival of patients diagnosed with cervical cancer. Br J Cancer 2012;107:918–24. [34] Polterauer S, Zhou Q, Grimm C, Seebacher V, Reinthaller A, Hofstetter G, et al. External validation of a nomogram predicting overall survival of patients diagnosed with endometrial cancer. Gynecol Oncol 2012;125:526–30. [35] Shim SH, Lee SW, Park JY, Kim YS, Kim DY, Kim JH, et al. Risk assessment model for overall survival in patients with locally advanced cervical cancer treated with definitive concurrent chemoradiotherapy. Gynecol Oncol 2013;128. [36] Schmid MP, Fidarova E, Potter R, Petric P, Bauer V, Woehs V, et al. Magnetic resonance imaging for assessment of parametrial tumour spread and regression patterns in adaptive cervix cancer radiotherapy. Acta Oncol 2013;52:1384–90. [37] Mayr NA, Yuh WT, Jajoura D, Wang JZ, Lo SS, Montebello JF, et al. Ultra-early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer. Cancer 2010;116:903–12. [38] Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217–26. [39] Eifel PJ. Chemoradiotherapy in the treatment of cervical cancer. Semin Radiat Oncol 2006;16:177–85. [40] Duenas-Gonzalez A, Zarba JJ, Patel F, Alcedo JC, Beslija S, Casanova L, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 2011;29:1678–85. [41] Duenas-Gonzalez A, Orlando M, Zhou Y, Quinlivan M, Barraclough H. Efficacy in high burden locally advanced cervical cancer with concurrent gemcitabine and cisplatin chemoradiotherapy plus adjuvant gemcitabine and cisplatin: prognostic and predictive factors and the impact of disease stage on outcomes from a prospective randomized phase III trial. Gynecol Oncol 2012;126:334–40. [42] Group ANZGO. www.anzgog.org.au/clinicaltrials/ [43] UK CR. www.cancerresearchuk.org/cancer-help/trials/a-trial-of-chemotherapybefore-chemoradiation-for-cervical-cancer-interlace
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Distant metastasis in patients with cervical cancer after primary radiotherapy with or without chemotherapy and image guided adaptive brachytherapy M.P. Schmid a,⁎, M. Franckena a,b, K. Kirchheiner a,c, A. Sturdza a, P. Georg a, W. Dörr a,c, R. Pötter a,c a b c
Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, Netherlands Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria
H I G H L I G H T S • FIGO stage and lymph node status are significant predictors for distant metastasis in cervical cancer patients. • 5 year distant metastasis free survival of 91% and 60% in low and high risk patients • Significant impact of number of chemotherapy cycles on the occurrence of distant metastasis in high risk patients
a r t i c l e
i n f o
Article history: Received 8 October 2013 Accepted 4 February 2014 Available online 8 February 2014 Keywords: Cervical cancer Radiotherapy Chemotherapy Cisplatin Distant metastasis Prognostic factors
a b s t r a c t Objective. The aim of this study is to investigate patterns of distant relapse after primary radiochemotherapy in cervical cancer patients. Methods. All patients with cervical cancer treated in curative intent with external beam radiotherapy +/− chemotherapy and image-guided adaptive brachytherapy between January 1998 and June 2009 at the Medical University of Vienna were included in this retrospective analysis. Patients with locoregional recurrences were excluded from this study. Presence, site of and time to distant metastases were recorded. For identifying prognostic factors, uni- and multivariate analyses using Cox regression analysis were performed. Based on the result from the multivariate analysis, patients were stratified into a high and a low risk group. The Kaplan–Meier method was used to estimate distant-metastasis-free-survival in the overall cohort, in the risk groups and for analysing the impact of chemotherapy within the risk groups. Results. A total number of 189 patients were included in this study. After a median follow-up of 54 months, 49 patients developed distant metastases. Overall, distant-metastasis-free-survival 5 years after treatment was 73%. FIGO stage, lymph node status and the extent of tumour regression during treatment were significant predictors for distant metastasis. Distant-metastasis-free-survival 5 years after treatment was 91% and 60% in the low and high risk groups, respectively. The number of the cycles of chemotherapy had a significant impact on the occurrence of distant metastasis in high risk patients, but not in low risk patients. Conclusion. Patients with high risk factors have a 40% probability of developing distant metastasis within 5 years. In these patients, decreasing the number of cycles of cisplatin may increase their probability of developing distant metastasis. © 2014 Elsevier Inc. All rights reserved.
Introduction Cervix cancer is one of the most common malignancies in women worldwide and still remains a prominent cause of female cancer death
⁎ Corresponding author at: Department of Radiotherapy, Comprehensive Cancer Center, Medical University of Vienna, General Hospital of Vienna, Währinger Gürtel 1820, A-1090 Vienna, Austria. Fax: +43 1404002693. E-mail address: [email protected] (M.P. Schmid).
http://dx.doi.org/10.1016/j.ygyno.2014.02.004 0090-8258/© 2014 Elsevier Inc. All rights reserved.
[1,2]. Radiotherapy has been the mainstay of treatment for locally advanced cervix cancer for decades. Since the late nineties chemotherapy is added to standard radiotherapy as this addition improves overall and disease free survival by about 6% at 10 years [3]. Besides improving the effectiveness of radiotherapy in terms of improvement of local tumour control, the addition of chemotherapy also decreases the rate of distant metastases, but to a lesser extent [3,4]. In spite of the clear benefits of adding chemotherapy to radiotherapy for cervix cancer patients, many questions still remain regarding the optimal agent and timing, as well as the added benefit for the higher stages [3,4].
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More recently, technological advances in radiotherapy have led to significant improvements in local tumour control. With image guided adaptive brachytherapy (IGABT) a local control rate of N90–95% appears to be achievable for all tumour stages. These promising findings in several single institution series are currently the subject of a multicenter verification in the EMBRACE study (European study on MRI guided BRAchytherapy in locally advanced CErvix cancer) [5–11]. However, it still needs to be clarified to which extent this improvement in local control translates into an improvement in overall or distant metastasesfree survival [3,5,12,13]. Hence, in the setting of an excellent local control resulting from IGABT for locally advanced cervical cancer, distant failure emerges as the predominant type of failure for these patients. We performed a retrospective analysis of patients with locally advanced cervix cancer treated with definitive radiotherapy including IGABT to (1) investigate time to occurrence of distant metastases and patterns of spread, (2) determine the impact of prognostic factors on the occurrence of distant metastases, (3) analyse the impact of chemotherapy on the occurrence of distant metastases. Methods and materials Patients All patients with cervix cancer FIGO Ib to IVa treated with definitive radiotherapy between January 1998 and June 2009 at the Department of Radiation Oncology of the Medical University of Vienna were included in this retrospective analysis. Patients were excluded from this analysis in case of local/regional recurrence, delivery of neoadjuvant chemotherapy or a contraindication for chemotherapy due to patient age. Pre-treatment evaluation included patient history, complete physical and gynaecological exam, routine laboratory studies, abdomino/ pelvic CT or whole body (FDG-) PET-CT and MRI-scan of the pelvis. Follow up investigations were performed every 3 months in the first two years after treatment, every 6 months in the next two years and then yearly thereafter. These included gynaecological examination and regular MRI-scans of the pelvis and thoraco/abdominal CT scans. Radiotherapy Detailed treatment characteristics are described in previous publications [14–20]. In brief, treatment consisted of whole pelvis EBRT with or without concomitant chemotherapy and IGABT. Before initiation of radiochemotherapy, laparoscopic lymph node staging and debulking of suspicious lymph nodes were performed in the majority of cases. If not, lymph node involvement was assessed by CT or PET-CT. EBRT was performed using a four-field box technique, with the gradual implementation of intensity modulated radiotherapy (IMRT) towards the end of the study period, after individual CT-based treatment planning with 1.8 Gy per fraction up to a total dose of 45 Gy. In case of suspicious lymph nodes (loss of oval shape, size N 1 cm, significant FDG uptake), an additional boost up to ~ 15 Gy was considered. Concomitantly, 5– 6 cycles of cisplatin-based chemotherapy (40 mg/m2 body surface) were administered. If chemotherapy was not delivered, then the total EBRT dose was increased to 50.4 Gy. Additionally three to six (mainly four) fractions of MRI based high dose rate IGABT were performed in the end or after EBRT with the aim of delivering in total (EBRT + IGABT) N85 Gy EQD2 (biologically equieffective dose; reference dose per fraction = 2 Gy, linear quadratic model, α/β = 10 Gy) to the D90 of the high risk clinical target volume (HRCTV). The performance of brachytherapy (including the number of brachytherapy fractions) varied during the learning period of IGABT. Since 2001, a systematic approach was used. Details on the concept of IGABT, the learning period and the systematic period are given in previous publications [5,14,15].
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Chemotherapy Concomitant weekly cisplatin-based chemotherapy (5–6 × 40 mg/m2) was administered to patients who had a Karnofsky performance score of at least 60, age b80 years, neutrophil count N 3.0 × 109 per litre, platelet count N100 × 10 9 per litre and creatinine clearance N70 ml/min. Chemotherapy was withheld if patients had a neutrophil count b2.0 × 109 per litre or a platelet count b100 × 109 per litre and if creatinine clearance was b50 ml/min. Patients with creatinine clearance in the range 50–70 ml/min received a reduced chemotherapy dose. Methodology and statistics Time to occurrence of distant metastases and patterns of spread/location The probability of distant metastasis free survival (DMFS) at three and five years was estimated with the Kaplan–Meier method, with the date of initial biopsy as a starting point. Distant metastasis was defined as any first site of distant recurrence in the absence of loco-regional failure. Results are given with 95% confidence intervals (CI). The median time to occurrence of distant metastases and the median time from occurrence of distant metastases to death were calculated. Location of distant metastases is described. Impact of prognostic factors on the occurrence of distant metastases Exploratory univariate analyses were performed to assess the impact of known prognostic factors on the development of distant metastasis: FIGO stage, tumour size (grouped as b5 cm and ≥ 5 cm), lymph node status (positive or negative), histology, grade, patient age, overall treatment time, HRCTV size at the time of first brachytherapy, tumour regression during EBRT, D90 (EBRT + IGABT) of HRCTV and the number of cycles of cisplatin received by the patient. The extent of tumour regression was calculated from the gross tumour volume (GTV) on the T2-weighted pelvic MRI-scan at diagnosis and the residual GTV on the T2-weighted pelvic MRI-scan at the time of first brachytherapy, excluding the greyzones. Details on the methodology of the tumour regression analysis are described elsewhere [21]. Two-sided p-values below 0.05 were considered significant. Univariate significant factors were included in a multivariate Cox regression model on DMFS. Based on the hazard ratios of multivariate significant prognostic factors and the sub-analysis within these significant prognostic factors (Figs. 1 and 2), high and low risk groups of patients were defined and compared with a log rank test regarding DMFS. Impact of chemotherapy on the occurrence of distant metastases The dose of concomitant chemotherapy applied was defined as no chemotherapy (0 cycles), reduced number of cycles (1–4 cycles) and full number of cycles (5–6 cycles). The impact of chemotherapy on the occurrence of distant metastases was analysed with log rank tests in both the high risk and the low risk groups. For all calculations, the IBM Statistical Package for Social Sciences (SPSS), version 17.0 was used (IBM Corp., Chicago, Illinois). Results Patient and treatment characteristics A total number of 253 patients with primary locally advanced cervix cancer were treated with definitive radiotherapy with or without chemotherapy between January 1998 and June 2009. Of these 253, 189 met the inclusion criteria for this analysis. The reasons for excluding the 64 patients were loco-regional failure (n = 30) or failure to achieve a complete response (n = 8), no chemotherapy administered due to age (n = 23) or neoadjuvant chemotherapy administered (n = 3). Patient- and tumour characteristics of these 189 patients are summarised in Table 1. Treatment characteristics are
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Fig. 1. Distant metastasis free survival for the various FIGO stages.
summarised in Table 2. Median duration of follow-up for this patient group was 54 months (range: 2–146).
12). The third most common site of metastasis was the abdominal cavity (n = 8). Further locations included the supraclavicular space (n = 4), bones (n = 3), brain (n = 1), skin/soft tissue (n = 3) and liver (n = 1).
Distant metastasis free survival and patterns of distant failure During follow-up, 49 patients developed distant metastases. The probability for DMFS at 3 and 5 years after treatment was 78% (95% CI 72–84%) and 73% (67–80%), respectively. The median time from end of treatment to first occurrence of distant metastasis was 7 months (range: 1–122) and the median time from diagnosis of distant metastasis to death was 6 months (range: 0–42). The main locations of distant failure were the lungs (n = 17) and the para-aortic lymph nodes (n =
Analyses of prognostic factors and influence of tumour regression In exploratory, univariate analyses, FIGO stage, lymph node stage, overall treatment time, size of HRCTV at time of first brachytherapy, D90 of HRCTV and the extent of tumour regression from diagnosis to time of first brachytherapy emerged as significant factors for DMFS for the whole study group (S1: Table 3).
Fig. 2. Distant metastasis free survival for patients with positive (N+) or negative (N0) lymph nodes.
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Table 1 Patient- and tumour characteristics.
FIGO stage
Tumour size Lymph node statusa Histology
Grade
Age OTT a b
Ib IIa IIb IIIa IIIb IVa b5 cm ≥5 cm Negative Positive SCC AC Other 1 2 3 Unknown Mean (range) Mean (range)
All patients n = 189
Low risk group n = 84
High risk group n = 105
25 (13%) 8 (4%) 109 (58%) 4 (2%) 35 (18%) 8 (4%) 74 (39%) 115 (61%) 102 (54%) 87 (46%) 165 (87%) 13 (7%) 11 (6%) 10 (5%) 91 (48%) 56 (30%) 32 (17%) 57 (26–80) 53 (31–115)
11 (13%) 4 (5%) 68 (81%) 1 (1%) – – 48 (57%) 36 (43%) 84 (100%) – 72 (86%) 5 (6%) 7 (8%) 1 (1%) 48 (57%) 21 (25%) 14 (17%) 59 (32–80) 47 (31–71)
14 (13%) 4 (4%) 41 (39%) 3 (3%) 35 (33%) 8 (8%) 26 (25%) 79 (75%) 18 (17%) 87 (83%) 93 (88%) 8 (8%) 4 (4%) 9 (9%) 43 (41%) 35 (33%) 18 (17%) 55 (28–78) 58 (32–115)b
Assessment of lymph node status in 38% by imaging only and in 62% by laparoscopy and imaging. Including lymph node boost and paraaortic irradiation.
In the multivariate model (S2: Table 4) FIGO stage, lymph node status and the extent of tumour regression remained of significant influence on DMFS. Risk stratification and the influence of concomitant chemotherapy The results of uni- and multivariate analyses show clearly that FIGO stage and lymph node status are the most important predictors of DMFS, which can be assessed already at the time of diagnosis. Based on these two parameters, a high and a low risk group were defined. From the Kaplan–Meier curve, there is a decrease in DMFS with increasing FIGO stage (Fig. 1). For lymph node stage, as expected, patients with negative lymph nodes are significantly less likely to develop distant metastasis than patients with positive lymph nodes (Fig. 2, p = 0.003). For patients with negative lymph nodes DMFS was 85% (CI: 77–92%) and 83% (CI: 76–91%) at 3 and 5 years, respectively, while for patients with positive lymph nodes 70% (CI: 61–80%) was free of distant metastasis at 3 years and 62% (CI: 51–73%) at 5 years (p = 0.003). We defined a low risk group of patients staged Ib to IIIa and negative lymph nodes and a high risk group of patients with FIGO stage IIIb to IVa or any stage and positive lymph nodes. Patient, tumour and treatment characteristics for these subgroups are summarised in the Tables 1 and 2. Forty-four percent of patients (n = 84) contributed to the low risk group. Of them, only 9 (11%) developed distant metastasis. DMFS in the low risk group was 91% at 3 years (CI: 85–97%) and 90% at 5 years (CI: 82–96%). The high risk group encompassed 105 patients and of them, 40 (38%) developed distant metastasis during follow-up. DMFS in the high risk group was 67% at 3 years (CI: 58–76%) and 60% at 5 years after treatment (CI: 50–70%). The probability to develop distant metastases was significantly higher in the high risk group (p = 0.000). As stated in Table 2, 45 of all 189 patients did not receive any chemotherapy. Of these 45, 22 patients did not receive chemotherapy because they had a co-existent disease prohibiting the administration of cisplatin (mainly poor renal function). A further 20 did not receive chemotherapy because they were treated before May of 1999 when chemoradiation became standard clinical practice at the Medical University of Vienna. The remaining three patients received radiation alone because they refused the simultaneous administration of chemotherapy. The complete chemotherapy schedule (5–6 cycles with 40 mg/m2) was delivered in 26.2% of the low risk patients and in 37.1% of the high risk patients. In consequence, dose modifications (reduction of dose, reduction of cycles,
reduction of dose and cycles due to, e.g. hematologic or renal toxicity) occurred in 73.8% of the low risk patients and 62.9% of the high risk patients. The number of chemotherapy cycles showed no significant impact on DMFS in the low risk group (p = 0.782), but in the high risk group (p = 0.022). Figs. 3 and 4 illustrate that for patients in the high risk group the risk for the development of distant metastases increases with decreasing number of chemotherapy cycles.
Table 2 Treatment characteristics. a For all 189 patients EBRT
Brachytherapy
Chemotherapy
Pelvic field Paraaortic field Lymph node boost HRCTV size HRCTVD90a Tumour regressionb 0 cycles 1–4 cycles 5–6 cycles
n = 189 (100%) n = 41 (22%) n = 20 (11%) 39.7 cm2 91.9 Gy 72.1% 45 (25%) 64 (34%) 80 (42%)
dose 45.6 Gy (36.0–56.8) dose 42.9 Gy (36.8–49.6) dose 9.3 Gy (4.0–14.4) (7.6–167.3) (55.1–136.3) (3–98%)
b For the patients in the low risk group (n = 84) EBRT
Brachytherapy
Chemotherapy
Pelvic field Paraaortic field Lymph node boost HRCTV size HRCTVD90a Tumour regressionb 0 cycles 1–4 cycles 5–6 cycles
n = 84 (100%) n.a. n.a. 33.6 cm2 94.9 Gy 71.0% 30 (36%) 24 (28%) 30 (36%)
dose 45.3 Gy (37.8–53.0)
(7.6–155.7) (61.9–136.3) (3–98%)
c For the patients in the high risk group (n = 105) EBRT
Brachytherapy
Chemotherapy
a b
Pelvic field Paraaortic field Lymph node boost HRCTV size HRCTVD90a Tumour regressionb 0 cycles 1–4 cycles 5–6 cycles
n = 105 (100%) n = 40 (38%) n = 21 (20%) 44.5 cm2 89.4 Gy 73.2% 15 (14%) 40 (38%) 50 (48%)
Total dose (EBRT + brachytherapy) in EQD2α/β 10 Gy. Greyzones not included.
dose 45.9 Gy (36–56.8) dose 42.8 (36.8–49.6) dose 9.3 Gy (4.0–14.4) (12.8–167.3) (55.1–117) (4–98%)
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Fig. 3. Distant metastasis free survival for patients in the low risk group depending on the number of cycles of concomitant chemotherapy.
Discussion Chemoradiation as a standard treatment approach for patients with locally advanced cervix cancer gained widespread acceptance since several large randomised trials showed improved local control and overall survival with the addition of chemotherapy to radiotherapy [22–27]. However, the optimal timing, dose and sequence of chemotherapy are still not fully elucidated. Concomitant chemotherapy, though administered at low dose, may also decrease the incidence of distant metastases. The present results confirm previous suggestions on the decreased
probability of distant metastasis due to concomitant chemotherapy as well as the inverse relationship between the administered cycles of cisplatin and the occurrence of distant metastasis. Association between completion of the schedule and prognosis has also not been the subject of large-scale investigation yet. However, the relationship between the dose of cisplatin and the incidence of distant metastasis has also been previously recognised in a smaller patient cohort with less follow-up and in patients treated before the era of IGABT [28]. The results from this study are in accordance with ours in that the administration of 5–6 full dose cycles of cisplatin can reduce a patient's risk of developing
Fig. 4. Distant metastasis free survival for patients in the high risk group depending on the number of cycles of concomitant chemotherapy.
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distant metastasis. Future studies will have to provide clinical evidence to what extent the improvement of local control through IGABT will decrease distant failure. The occurrence of distant metastases is linked to some degree to local and regional failures and IGABT can reduce the incidence of local failure by maximising the radiation dose to the tumour area [29–32]. In this study, the D90 of HRCTV was a significant factor for the occurrence of distant metastasis in the univariate analysis for high risk patients. The present investigation provides the distant failure pattern following chemoradiation including IGABT. Our analysis included prognostic factors well known to influence local control and survival in cervix cancer patients [33–35]. Based on the results of the multivariate analysis, we stratified our patient group in 2 risk groups based on FIGO stage and lymph node status. There is a clear and distinct effect of the number of cycles of concomitant chemotherapy on the development of distant metastases in the high risk group. This shows that the addition of concomitant chemotherapy indeed decreases a patient's chances of developing distant metastasis for those at high risk. Therefore, the results of the study may suggest that completion of all chemotherapy cycles should be intensively sought in high risk patients, whereas in low risk patients a reduced number of cycles may be arguable in certain clinical situations—such as impairment of blood count and/or kidney function during chemoradiation close to chemotherapy preconditioning cut-off values. To identify patients at high risk for developing distant metastasis, patients with loco-regional recurrences were excluded from analysis. Local recurrences are in the majority of cases the result of inadequate local treatment and may induce distant metastasis itself. Patients not receiving chemotherapy due to age were also excluded, because of limited life expectancy, which could prohibit the occurrence of distant metastasis. A surprising correlation found in this study is the significant relationship between the occurrence of distant metastasis and the extent of tumour regression between diagnosis and the time of first brachytherapy application. Therefore, the extent of tumour regression could be potentially used as an early response indicator, not only for local tumour control (as shown by others) but also as a risk factor for the development of distant metastasis. Subsequently, it may be used to identify patients in need of intensified systemic treatment. The impact of tumour regression was most pronounced in high risk patients suggesting a more aggressive tumour biology with a higher tendency towards distant metastasis in less responding tumours in comparison to fast responding tumours. In previous MRI studies, tumour regression was shown to be significantly influenced by different patterns of tumour spread and differences in dynamic contrast enhancement, indicating possible differences in tumour biology such as hypoxia [36,37]. Further research will be necessary to clarify the correlation of tumour regression and the occurrence of distant metastasis. Patients in our high risk group seem to benefit from a higher number of chemotherapy cycles but still 23% of them develop distant metastasis despite receiving an adequate dose of cisplatin. Therefore, further research should be aimed at systemic treatment intensification to reduce distant spread. As concurrent chemotherapy already adds to early treatment-related toxicity compared to radiotherapy alone and its effects on long term morbidity remain unclear, further intensification of the concomitant scheme seems rather unattractive [38,39]. Adjuvant chemotherapy may be a more effective approach. For example, Duneas Gonzales showed an increase in progression free and overall survival by adjuvant chemotherapy after randomizing 515 patients with locally advanced cervix cancer to receive either cisplatin-based chemoradiation with concurrent gemcitabine or cisplatin-based chemoradiation with concurrent gemcitabine and adjuvant gemcitabine and cisplatin [40,41]. Currently, there are 2 large-scale international randomised studies investigating the role of additional chemotherapy in locally advanced cervix cancer with different approaches. The OUTBACK trial is investigating the benefit of 4 cycles of adjuvant carboplatin paclitaxel after
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standard chemoradiation for locally advanced cervix cancer [42]. The second study is the CRUK INTERLACE study investigating the role of weekly induction carboplatin paclitaxel before standard chemoradiation in patients with locally advanced cervix cancer [43]. Unfortunately both studies do not systematically include modern radiotherapy techniques like IGABT +/− interstitial applications or IMRT. To assess the value of adjuvant chemotherapy for patients at high or intermediate risk of distant metastases treated with chemoradiation and IGABT, an appropriate international trial is mandatory. Such a trial must be designed to assess if adjuvant chemotherapy (e.g. carboplatin/paclitaxel) will increase overall survival for patients with locally advanced cervix cancer at high or intermediate risk of developing distant metastases as defined by FIGO stage and lymph node status and receiving simultaneous radiochemotherapy and IGABT. In conclusion, from our retrospective analysis of 189 patients with locally advanced cervix cancer treated with chemoradiation and IGABT, it becomes clear that patients with a higher tumour stage at diagnosis and those with positive lymph nodes are at high risk of developing distant metastasis and for these high risk patients, decreasing the number of cycles of cisplatin may increase their probability of developing distant metastasis. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2014.02.004. Conflict of interest statement The Department of Radiotherapy at the Medical University of Vienna receives/received financial and/or equipment support for research and educational purposes from Nucletron an Elekta company and Varian Medical Systems, Inc. The financial support by the Austrian Federal Ministry of Economy, Family, and Youth and the Austrian Foundation for Research, Technology, and Development is gratefully acknowledged.
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