International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Gynecologic Tumor
Manifestation Pattern of Early-Late Vaginal Morbidity After Definitive Radiation (Chemo)Therapy and Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: An Analysis From the EMBRACE Study Kathrin Kirchheiner, MSc,*,y Remi A. Nout, MD, PhD,z Kari Tanderup, PhD,x Jacob C. Lindegaard, MD, DMSc,x Henrike Westerveld, MD, PhD,k Christine Haie-Meder, MD,{ Primoz Petric, MD, PhD,#,** Umesh Mahantshetty, DMRT, MD, DNB,yy Wolfgang Do¨rr, DVM, PhD,*,y and Richard Po¨tter, MD, PhD*,y *Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria; yChristian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria; zDepartment of Clinical Oncology, Leiden University Medical Center, The Netherlands; xDepartment of Oncology, Aarhus University Hospital, Denmark; kDepartment of Radiotherapy, Academic Medical Centre, University of Amsterdam, The Netherlands; {Department of Radiotherapy, Gustave-Roussy, Villejuif, France; #Department of Radiotherapy, Institute of Oncology Ljubljana, Slovenia; **Department of Radiotherapy, National Center for Cancer Care and Research, Doha, Qatar; and yyDepartment of Radiation Oncology, Tata Memorial Hospital, Mumbai, India Received Dec 10, 2013, and in revised form Jan 14, 2014. Accepted for publication Jan 21, 2014.
Summary Severe vaginal morbidity within the first 2 years after definitive radiation (chemo) therapy including imageguided adaptive brachytherapy with intracavitary/interstitial techniques for locally advanced cervical cancer, is limited (grade 3, 3.6%) and is significantly less than
Background and Purpose: Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on imageguided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up. Methods and Materials: In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every
Reprint requests to: Kathrin Kirchheiner, MSc, Department of Radiation Oncology, Comprehensive Cancer Center, Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel: þ(43) 1 40400 2639; E-mail: [email protected] Supported by the Austrian Federal Ministry of Economy, Family, and Youth and the Austrian Foundation for Research, Technology, and Int J Radiation Oncol Biol Phys, Vol. 89, No. 1, pp. 88e95, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.01.032
Development and CIRROdthe Lundbeck Foundation Center for Investigational Research in Radiation Oncology. Sponsored by the Medical University of Vienna. Research funds have been provided by Nucletron, an Elekta company, and Varian Medical Systems. Conflict of interest: none. Supplementary material for this article can be found at www.redjournal.org.
Volume 89 Number 1 2014
reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild and moderate vaginal morbidity is still pronounced (grade 1, 89%; grade 2, 29%) with currently applied imageguided adaptive brachytherapy, and it needs further attention.
Vaginal morbidity after IGABT for cervical cancer
89
6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed. Results: At 2 years, the actuarial probability of severe vaginal morbidity (grade 3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade 1, 89%; grade 2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported. Conclusion: Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention. Ó 2014 Elsevier Inc.
Introduction The state-of-the-art treatment for patients with locally advanced cervical cancer is definitive radiation (chemo) therapy, with brachytherapy being an essential component (1). In the past 2 decades, with the introduction of imageguided adaptive brachytherapy (IGABT) based on repeated volumetric imaging (computed tomography [CT], magnetic resonance imaging [MRI]), local control has substantially improved. This implies the detailed delineation of target volumes and organs at risk (OAR) and dose adaptation according to pre-established dose aims and constraints, without prescribing the dose to the traditional point A but rather to a precisely specified target volume (2, 3). The overall incidence of (late) side effects shows also a decreasing trend in comparison with the 2-dimensional (2D) era (4-8). This new target concept, however, also has a significant impact on the dose to some OAR (9), including the vagina, where the dose can vary substantially, with some patients receiving much less dose to the vagina and some receiving considerably more (10). Large doses are most notably present in patients with large tumors treated with combined intracavitary/transvaginal interstitial brachytherapy. However, information about the clinical consequences of these doses in the vagina as OAR and their impact on the patient’s quality of life is very limited (11). Owing to the improvements in treatment outcome, a progressively increasing number of long-term survivors of cervical cancer is expected in the future. Severe treatmentrelated side effects are rare, but mild to moderate morbidity can have a significant impact on the patients’ well-being and health-related quality of life (12). With regard to vaginal morbidity, changes related to feminine self-perception and sexual functioning are a particularly important source of symptom-related distress in the years after treatment (13). To characterize vaginal morbidity associated with current treatment strategies for locally advanced cervical cancer, the
present analysis of the prospective multi-institutional EMBRACE study (www.embracestudy.dk) was initiated. The primary objective of this report is to evaluate early to late vaginal morbidity during the first 2 years of follow-up. This is the first prospective study in the frame of IGABT focusing on detailed evaluation of individual vaginal symptoms with regard to their contribution to overall vaginal morbidity and to the manifestation pattern of symptoms over time in a large, multi-institutional patient cohort.
Methods and Materials The EMBRACE study is a prospective observational study with 24 participating centers worldwide. It was approved in all participating centers by the respective National Ethics Committees. Since July 2008, the study has included more than 1000 patients and is about to finish accrual. For this report, patients with data from at least 1 completed follow-up visit regarding morbidity and tumor control were included in the analysis.
Patients The inclusion criteria were a primary biopsy-proven squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, International Federation of Gynecology and Obstetrics stage IB-IVA (and stage IVB with para-aortic metastatic nodes below L1-L2 only), treated with curative intent with definitive radiation (chemo)therapy. The minimum staging requirements were gynecologic examination, MRI of the pelvis, abdominal CT or MRI, and chest radiography.
Treatment All patients were treated by a combination of external beam radiation therapy (EBRT) with or without chemotherapy and IGABT, within a maximal overall treatment time of 50 days.
90
Kirchheiner et al.
EBRT was delivered either by 3-D conformal radiation therapy or by intensity modulated radiation therapy. The clinical target volume (CTV) of the elective EBRT consisted of the gross tumor volume (GTV), uterus, parametria, the proximal vagina at least 2 cm below the GTV, and at least all pelvic lymph node regions. The elective CTV received 45 to 50 Gy in 1.8- to 2.0-Gy fractions, and the pathologic lymph nodes received a boost to 60 to 65 Gy in 2.0- to 2.4-Gy fractions. IGABT was delivered either by pulsed dose rate or high-dose-rate brachytherapy. MRI was required for the first brachytherapy applicator implant; 3-dimensional (3D) imaging (MRI or CT) was required for each subsequent applicator implant, although more than 1 fraction could be delivered by the use of the same implant. In over 90% of EMBRACE patients, MRI was used for each application. The target concept and dose prescription to the high-risk CTV (HR-CTV), intermediate-risk CTV (IR-CTV), and OAR (bladder, rectum, sigmoid, and bowel) could be chosen according to the institutional practice of the individual participating center but were reported in a uniform way according to the Gynaecological Groupe Europe´en de Curiethe´rapie - European Society for Therapeutic Radiology and Oncology (2, 3).
Assessment of vaginal morbidity In the EMBRACE study, morbidity is assessed at baseline and after the end of treatment every 3 months during the first year, every 6 months during the second and third years, and yearly thereafter up to 5 years. The Common Terminology Criteria for Adverse Events, version 3 (CTCAE v3.0) (14), were used to grade vaginal morbidity and included the following individual vaginal symptoms: dryness, stenosis, mucositis, bleeding, fistula, and other (free text entry) (15). An overview about the CTCAE v3.0 scoring is given in the supplementary material (table E1, available online at www.redjournal.org). Each individual vaginal endpoint was scored prospectively at baseline and each follow-up visit by the treating physician.
Endpoints and statistical evaluation The crude incidences of the individual vaginal symptoms were calculated with the maximum symptom grading per patient over all follow-up visits. The crude incidence for the overall vaginal morbidity was calculated by use of the maximum symptom grading observed for any of the vaginal endpoints per patient over all follow-up visits. The prevalence rates show the proportion of patients with individual vaginal symptoms in relation to all patients at a certain follow-up time point. The prevalence rate for overall vaginal morbidity was calculated by use of the maximum grading observed in any of the vaginal morbidity endpoints. The fixed time points for prevalence rates reflect the scheduled follow-up of the EMBRACE web database and include certain variations.
International Journal of Radiation Oncology Biology Physics
Actuarial incidences were calculated by Kaplan-Meier method, with end of treatment as the starting point. Events were defined in patients with any vaginal morbidity (grade 1), in patients with vaginal morbidity grade2 and higher (grade 2), and in those with grade3 and higher (grade 3). Ninety-five percent confidence intervals (CI) are given. In patients with local and/or regional and/or systemic recurrence of disease, the vaginal morbidity was censored at the time of recurrence. Patients who were not in complete remission directly after treatment but who had 3 consecutive follow-up investigations showing tumor control were kept in the analysis; patients with persistent disease were excluded from analysis. In 162 patients, follow-up data of at least 24 months were present for the analysis of manifestation pattern over time. Individual symptoms were defined as persistent if they were present with any grade 1 in at least 3 consecutive follow-up visits, or as fluctuating if they were present with any grade 1 but resolved to grade0 in a shorter time (single and multiple occurrences possible). Patients were not evaluated in the analysis of manifestation pattern over time if any grade 1 occurred in their last follow-up visit or their last 2 follow-up visits. The SPSS statistical software system , version 17 (SPSS Inc., Chicago, IL), was used for calculations.
Results At the date of closure of the database for this analysis in January 2013, 767 patients from 19 centers were included in the EMBRACE study. Follow-up data regarding morbidity and tumor control were available in 588 patients, who were thus included in this analysis. The median follow-up time was 15 months (range, 1-49 months), with 162 patients (28%) having at least 24 months of follow-up. The patient, disease, and treatment characteristics are reported in Table 1.
Tumor-related individual vaginal symptoms before treatment The crude incidences of individual vaginal symptoms before treatment are reported in Table 2. In summary, vaginal dryness, stenosis, and mucositis played a minor role before treatment (grade0 incidence >90%). By contrast, tumor-related vaginal bleeding occurred in the majority of patients with 49% mild grade1, 15% moderate grade2, and 3% severe grade3. In 2 patients, grade4 vaginal bleeding with life-threatening consequences was reported before treatment.
Overall vaginal morbidity (any individual vaginal symptom) Crude incidence rates of the overall vaginal morbidity (any individual vaginal symptom) showed that mild (grade1, 53%) to moderate (grade2, 19%) vaginal morbidity was frequently observed, the rate of any severe vaginal morbidity was low (grade3, 2%), and life-threatening
Volume 89 Number 1 2014 Table 1
Vaginal morbidity after IGABT for cervical cancer
Patient, disease and treatment characteristics
Patient and disease characteristics (NZ588) Age, y, median (range) Missing, n (%) FIGO tumor stage IB IIA IIB IIIA IIIB IVA IVB Tumor dimensions at MRI, mm Mean width (SD) Mean height (SD) Mean thickness (SD) Missing, n (%) Histology SQ AC AdSQ Vaginal involvement (MRI) Not involved Upper third Middle third Lower third Treatment characteristics EBRT PTV-E total dose D95 in EQD2 Median dose, Gy (IQR) Missing, n (%) EBRT technique 3D conformal IMRT Concomitant chemotherapy No Yes BT HR-CTV D90 in EQD2 Median dose, Gy (IQR) Missing, N (%) Dose rate HDR PDR Applicator Ring Ovoids Molds Other Application Intracavitary Intracavitary/interstitial
49 (22-91) 23 (4%) 105 41 291 2 111 15 8
(18%) (7%) (50%) (
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Gynecologic Tumor
Manifestation Pattern of Early-Late Vaginal Morbidity After Definitive Radiation (Chemo)Therapy and Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: An Analysis From the EMBRACE Study Kathrin Kirchheiner, MSc,*,y Remi A. Nout, MD, PhD,z Kari Tanderup, PhD,x Jacob C. Lindegaard, MD, DMSc,x Henrike Westerveld, MD, PhD,k Christine Haie-Meder, MD,{ Primoz Petric, MD, PhD,#,** Umesh Mahantshetty, DMRT, MD, DNB,yy Wolfgang Do¨rr, DVM, PhD,*,y and Richard Po¨tter, MD, PhD*,y *Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria; yChristian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria; zDepartment of Clinical Oncology, Leiden University Medical Center, The Netherlands; xDepartment of Oncology, Aarhus University Hospital, Denmark; kDepartment of Radiotherapy, Academic Medical Centre, University of Amsterdam, The Netherlands; {Department of Radiotherapy, Gustave-Roussy, Villejuif, France; #Department of Radiotherapy, Institute of Oncology Ljubljana, Slovenia; **Department of Radiotherapy, National Center for Cancer Care and Research, Doha, Qatar; and yyDepartment of Radiation Oncology, Tata Memorial Hospital, Mumbai, India Received Dec 10, 2013, and in revised form Jan 14, 2014. Accepted for publication Jan 21, 2014.
Summary Severe vaginal morbidity within the first 2 years after definitive radiation (chemo) therapy including imageguided adaptive brachytherapy with intracavitary/interstitial techniques for locally advanced cervical cancer, is limited (grade 3, 3.6%) and is significantly less than
Background and Purpose: Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on imageguided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up. Methods and Materials: In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every
Reprint requests to: Kathrin Kirchheiner, MSc, Department of Radiation Oncology, Comprehensive Cancer Center, Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel: þ(43) 1 40400 2639; E-mail: [email protected] Supported by the Austrian Federal Ministry of Economy, Family, and Youth and the Austrian Foundation for Research, Technology, and Int J Radiation Oncol Biol Phys, Vol. 89, No. 1, pp. 88e95, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.01.032
Development and CIRROdthe Lundbeck Foundation Center for Investigational Research in Radiation Oncology. Sponsored by the Medical University of Vienna. Research funds have been provided by Nucletron, an Elekta company, and Varian Medical Systems. Conflict of interest: none. Supplementary material for this article can be found at www.redjournal.org.
Volume 89 Number 1 2014
reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild and moderate vaginal morbidity is still pronounced (grade 1, 89%; grade 2, 29%) with currently applied imageguided adaptive brachytherapy, and it needs further attention.
Vaginal morbidity after IGABT for cervical cancer
89
6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed. Results: At 2 years, the actuarial probability of severe vaginal morbidity (grade 3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade 1, 89%; grade 2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported. Conclusion: Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention. Ó 2014 Elsevier Inc.
Introduction The state-of-the-art treatment for patients with locally advanced cervical cancer is definitive radiation (chemo) therapy, with brachytherapy being an essential component (1). In the past 2 decades, with the introduction of imageguided adaptive brachytherapy (IGABT) based on repeated volumetric imaging (computed tomography [CT], magnetic resonance imaging [MRI]), local control has substantially improved. This implies the detailed delineation of target volumes and organs at risk (OAR) and dose adaptation according to pre-established dose aims and constraints, without prescribing the dose to the traditional point A but rather to a precisely specified target volume (2, 3). The overall incidence of (late) side effects shows also a decreasing trend in comparison with the 2-dimensional (2D) era (4-8). This new target concept, however, also has a significant impact on the dose to some OAR (9), including the vagina, where the dose can vary substantially, with some patients receiving much less dose to the vagina and some receiving considerably more (10). Large doses are most notably present in patients with large tumors treated with combined intracavitary/transvaginal interstitial brachytherapy. However, information about the clinical consequences of these doses in the vagina as OAR and their impact on the patient’s quality of life is very limited (11). Owing to the improvements in treatment outcome, a progressively increasing number of long-term survivors of cervical cancer is expected in the future. Severe treatmentrelated side effects are rare, but mild to moderate morbidity can have a significant impact on the patients’ well-being and health-related quality of life (12). With regard to vaginal morbidity, changes related to feminine self-perception and sexual functioning are a particularly important source of symptom-related distress in the years after treatment (13). To characterize vaginal morbidity associated with current treatment strategies for locally advanced cervical cancer, the
present analysis of the prospective multi-institutional EMBRACE study (www.embracestudy.dk) was initiated. The primary objective of this report is to evaluate early to late vaginal morbidity during the first 2 years of follow-up. This is the first prospective study in the frame of IGABT focusing on detailed evaluation of individual vaginal symptoms with regard to their contribution to overall vaginal morbidity and to the manifestation pattern of symptoms over time in a large, multi-institutional patient cohort.
Methods and Materials The EMBRACE study is a prospective observational study with 24 participating centers worldwide. It was approved in all participating centers by the respective National Ethics Committees. Since July 2008, the study has included more than 1000 patients and is about to finish accrual. For this report, patients with data from at least 1 completed follow-up visit regarding morbidity and tumor control were included in the analysis.
Patients The inclusion criteria were a primary biopsy-proven squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, International Federation of Gynecology and Obstetrics stage IB-IVA (and stage IVB with para-aortic metastatic nodes below L1-L2 only), treated with curative intent with definitive radiation (chemo)therapy. The minimum staging requirements were gynecologic examination, MRI of the pelvis, abdominal CT or MRI, and chest radiography.
Treatment All patients were treated by a combination of external beam radiation therapy (EBRT) with or without chemotherapy and IGABT, within a maximal overall treatment time of 50 days.
90
Kirchheiner et al.
EBRT was delivered either by 3-D conformal radiation therapy or by intensity modulated radiation therapy. The clinical target volume (CTV) of the elective EBRT consisted of the gross tumor volume (GTV), uterus, parametria, the proximal vagina at least 2 cm below the GTV, and at least all pelvic lymph node regions. The elective CTV received 45 to 50 Gy in 1.8- to 2.0-Gy fractions, and the pathologic lymph nodes received a boost to 60 to 65 Gy in 2.0- to 2.4-Gy fractions. IGABT was delivered either by pulsed dose rate or high-dose-rate brachytherapy. MRI was required for the first brachytherapy applicator implant; 3-dimensional (3D) imaging (MRI or CT) was required for each subsequent applicator implant, although more than 1 fraction could be delivered by the use of the same implant. In over 90% of EMBRACE patients, MRI was used for each application. The target concept and dose prescription to the high-risk CTV (HR-CTV), intermediate-risk CTV (IR-CTV), and OAR (bladder, rectum, sigmoid, and bowel) could be chosen according to the institutional practice of the individual participating center but were reported in a uniform way according to the Gynaecological Groupe Europe´en de Curiethe´rapie - European Society for Therapeutic Radiology and Oncology (2, 3).
Assessment of vaginal morbidity In the EMBRACE study, morbidity is assessed at baseline and after the end of treatment every 3 months during the first year, every 6 months during the second and third years, and yearly thereafter up to 5 years. The Common Terminology Criteria for Adverse Events, version 3 (CTCAE v3.0) (14), were used to grade vaginal morbidity and included the following individual vaginal symptoms: dryness, stenosis, mucositis, bleeding, fistula, and other (free text entry) (15). An overview about the CTCAE v3.0 scoring is given in the supplementary material (table E1, available online at www.redjournal.org). Each individual vaginal endpoint was scored prospectively at baseline and each follow-up visit by the treating physician.
Endpoints and statistical evaluation The crude incidences of the individual vaginal symptoms were calculated with the maximum symptom grading per patient over all follow-up visits. The crude incidence for the overall vaginal morbidity was calculated by use of the maximum symptom grading observed for any of the vaginal endpoints per patient over all follow-up visits. The prevalence rates show the proportion of patients with individual vaginal symptoms in relation to all patients at a certain follow-up time point. The prevalence rate for overall vaginal morbidity was calculated by use of the maximum grading observed in any of the vaginal morbidity endpoints. The fixed time points for prevalence rates reflect the scheduled follow-up of the EMBRACE web database and include certain variations.
International Journal of Radiation Oncology Biology Physics
Actuarial incidences were calculated by Kaplan-Meier method, with end of treatment as the starting point. Events were defined in patients with any vaginal morbidity (grade 1), in patients with vaginal morbidity grade2 and higher (grade 2), and in those with grade3 and higher (grade 3). Ninety-five percent confidence intervals (CI) are given. In patients with local and/or regional and/or systemic recurrence of disease, the vaginal morbidity was censored at the time of recurrence. Patients who were not in complete remission directly after treatment but who had 3 consecutive follow-up investigations showing tumor control were kept in the analysis; patients with persistent disease were excluded from analysis. In 162 patients, follow-up data of at least 24 months were present for the analysis of manifestation pattern over time. Individual symptoms were defined as persistent if they were present with any grade 1 in at least 3 consecutive follow-up visits, or as fluctuating if they were present with any grade 1 but resolved to grade0 in a shorter time (single and multiple occurrences possible). Patients were not evaluated in the analysis of manifestation pattern over time if any grade 1 occurred in their last follow-up visit or their last 2 follow-up visits. The SPSS statistical software system , version 17 (SPSS Inc., Chicago, IL), was used for calculations.
Results At the date of closure of the database for this analysis in January 2013, 767 patients from 19 centers were included in the EMBRACE study. Follow-up data regarding morbidity and tumor control were available in 588 patients, who were thus included in this analysis. The median follow-up time was 15 months (range, 1-49 months), with 162 patients (28%) having at least 24 months of follow-up. The patient, disease, and treatment characteristics are reported in Table 1.
Tumor-related individual vaginal symptoms before treatment The crude incidences of individual vaginal symptoms before treatment are reported in Table 2. In summary, vaginal dryness, stenosis, and mucositis played a minor role before treatment (grade0 incidence >90%). By contrast, tumor-related vaginal bleeding occurred in the majority of patients with 49% mild grade1, 15% moderate grade2, and 3% severe grade3. In 2 patients, grade4 vaginal bleeding with life-threatening consequences was reported before treatment.
Overall vaginal morbidity (any individual vaginal symptom) Crude incidence rates of the overall vaginal morbidity (any individual vaginal symptom) showed that mild (grade1, 53%) to moderate (grade2, 19%) vaginal morbidity was frequently observed, the rate of any severe vaginal morbidity was low (grade3, 2%), and life-threatening
Volume 89 Number 1 2014 Table 1
Vaginal morbidity after IGABT for cervical cancer
Patient, disease and treatment characteristics
Patient and disease characteristics (NZ588) Age, y, median (range) Missing, n (%) FIGO tumor stage IB IIA IIB IIIA IIIB IVA IVB Tumor dimensions at MRI, mm Mean width (SD) Mean height (SD) Mean thickness (SD) Missing, n (%) Histology SQ AC AdSQ Vaginal involvement (MRI) Not involved Upper third Middle third Lower third Treatment characteristics EBRT PTV-E total dose D95 in EQD2 Median dose, Gy (IQR) Missing, n (%) EBRT technique 3D conformal IMRT Concomitant chemotherapy No Yes BT HR-CTV D90 in EQD2 Median dose, Gy (IQR) Missing, N (%) Dose rate HDR PDR Applicator Ring Ovoids Molds Other Application Intracavitary Intracavitary/interstitial
49 (22-91) 23 (4%) 105 41 291 2 111 15 8
(18%) (7%) (50%) (
