- Email: [email protected]
Impact of CT-based brachytherapy in elderly patients with cervical cancer
Brachytherapy
-
(2019)
-
Impact of CT-based brachytherapy in elderly patients with cervical cancer Daijiro Kobayashi1,2, Noriyuki Okonogi1,*, Masaru Wakatsuki3, Yuhei Miyasaka1,2, Hiroki Kiyohara4, Tatsuya Ohno2, Shingo Kato5, Takashi Nakano2, Tadashi Kamada1 1 QST Hospital, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan 3 Department of Radiology, Jichi Medical University, Simotsuke-city, Tochigi, Japan 4 Department of Radiation Oncology, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan 5 Department of Radiation Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan 2
ABSTRACT
PURPOSE: Three-dimensional image-guided brachytherapy (3D-IGBT) has become the standard therapy for patients with cervical cancer. However, in this population, the impact of 3D-IGBT in elderly individuals remains unknown. This study assessed the efficacy of 3D-IGBT for elderly patients with cervical cancer. METHODS AND MATERIALS: We performed a retrospective chart review of 105 consecutive patients with cervical squamous cell carcinoma aged $70 years who received radiotherapy alone between January 2001 and September 2014. All patients were treated with external beam radiotherapy and high-dose-rate intracavitary brachytherapy. We assessed the treatment outcomes in all patients. We then compared outcomes between two groups: patients treated by changing the Point A dose at brachytherapy (Group A, n 5 71) and those treated with 3D-IGBT at least twice (Group B, n 5 34). RESULTS: The median followup period was 59 (range, 6e203) months; the median age was 77 years. The 5-year local control and cause-specific survival rates were 89% and 78%, respectively. The 5-year cumulative rates of late toxicities of the rectum and bladder of Grade $3 were 2.0% and 4.2%, respectively. No statistically significant differences were observed in the local control and cause-specific survival rates, or in the incidence of rectal toxicities between groups. The 3year cumulative rates of urinary toxicity of Grade $1 were 20.4% and 6.9% in Group A and Group B, respectively ( p 5 0.035). CONCLUSION: In elderly patients with cervical cancer, 3D-IGBT could be performed safely and effectively and contributed to decreasing urinary toxicity incidence rates. Ó 2019 The Authors. Published by Elsevier Inc. on behalf of American Brachytherapy Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Radiotherapy; Cervical cancer; Squamous cell carcinoma; Brachytherapy; Elderly
Introduction
Received 28 January 2019; received in revised form 2 August 2019; accepted 7 August 2019. Financial disclosure: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. * Corresponding author. QST Hospital, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inageku, Chiba-city, Chiba 263-8555, Japan. Tel: þ81-43-206-3306; fax: þ81-43-256-6506. E-mail address: [email protected] (N. Okonogi).
Cervical cancer is the fourth most commonly occurring cancer in women, and the seventh overall, with an estimated 528,000 new cases reported in 2012 (1). Radiotherapy (RT) is the definitive therapy for patients with Stage IBeIVA cervical cancer. Concurrent chemoradiotherapy (CCRT) improves overall survival (OS) and progression-free survival and reduces the rates of local and distant recurrence (2e4). The National Cancer Institute strongly recommends the performance of CCRT rather than RT alone for advanced cervical cancer (5). However, acute hematological and gastrointestinal toxicities are significantly more frequently observed in patients who are treated
1538-4721/Ó 2019 The Authors. Published by Elsevier Inc. on behalf of American Brachytherapy Society. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.brachy.2019.08.002
2
D. Kobayashi et al. / Brachytherapy
with CCRT (2e4). An increasing number of elderly patients are being diagnosed with cervical cancer in Europe, and older women account for more than 40% of deaths from cervical cancer annually (6). Comorbidities, such as weak kidney function and cardiovascular complications, are more prevalent in elderly people, making the application of concurrent chemotherapy difficult in such populations. Mitsuhashi et al. (7) reported that 52% of the elderly patients with cervical cancer in their cohort had chronic disease. Thus, elderly patients with cervical cancer are sometimes treated with RT alone, leading to poor treatment results. In addition, the coexistence of chronic diseases is considered an important risk factor for adverse events after radiation (8e10). Indeed, radiation-induced proctitis is twice as likely to occur in elderly patients than in their younger counterparts (11). Brachytherapy is a critical treatment component for all patients with cervical cancer who are receiving RT (12e 15). In cases without concurrent chemotherapy, brachytherapy may have a more crucial role for patients with cervical cancer. The technique behind brachytherapy has evolved over the past few decades, moving from two-dimensional image-based (2D) dosimetry to three-dimensional imageguided brachytherapy (3D-IGBT) (13,14,16e18). The transition from 2D to 3D-IGBT has led to local control (LC) rate improvements and late adverse event rate reductions (15, 17). Previous studies of elderly patients with cervical cancer showed values of 60e70% for the 5-year cause-specific survival (CSS), 46e60% for the 5-year OS, and 0e15% for the occurrence of severe late toxicities (19e23). Patients in these studies were treated using 2D brachytherapy, not 3D-IGBT. Thus, the impact of 3D-IGBT in elderly patients with cervical cancer has not yet been fully examined. As mentioned previously, elderly patients with cervical cancer are often treated with RT alone. In other words, elderly patients are likely to be an ideal cohort for the validation of the influence of 3D-IGBT for cervical cancer without the effect of chemotherapy. In the present study, we retrospectively assessed the efficacy of 3D-IGBT for elderly patients with cervical cancer.
Methods and materials Patient eligibility A retrospective chart review was performed in consecutive patients with cervical cancer, aged 70 years or older, who were treated with RT alone between January 2001 and September 2014. The study concept was approved by the Ethical Review Board committee of our institution (NIRS 16-010). The inclusion criteria for the analysis were as follows: (1) presence of histologically proven, untreated cervical squamous cell carcinoma, (2) International Federation of
-
(2019)
-
Gynecology and Obstetrics (FIGO) Stage IB1eIVA disease using the 2009 FIGO staging system, and (3) treated with curative intent. Patients with para-aortic lymph node metastases at the start of treatment were included in this study.
External beam radiotherapy External beam radiotherapy (EBRT) at a dose of up to approximately 50 Gy was delivered to the whole pelvis, with a daily fraction dose of 1.8 or 2.0 Gy using 10 MV X-rays. Patients were treated with a combination of whole pelvic irradiation and central shielding (24). In principle, patients with early-stage disease (Stage IeII and tumor size #4 cm in maximum diameter) received whole pelvic irradiation at a dose of 19.8 Gy in 11 fractions, followed by central shielding irradiation at a dose of 30.0 Gy in 15 fractions. Patients with disease of Stage IIIeIVA or tumor with a maximum diameter O4 cm received whole pelvic irradiation at a dose of 30.6 Gy in 17 fractions, followed by central shielding irradiation at a dose of 20.0 Gy in 10 fractions. For patients with lymph node metastases in the pelvic region, an additional boost irradiation of 8e10 Gy in 4e5 fractions was administered to the enlarged lymph node.
Brachytherapy High-dose-rate brachytherapy was performed weekly using 192Ir remote afterloading system (microSelectron, Nucletron, Veenendaal, the Netherlands). Four fractions of brachytherapy were administered, at a fraction dose of 6 Gy to Point A, using the Manchester method. When the tumor response was poor, a fifth fraction of brachytherapy was considered. A set of Fletcher-Suit Asian Pacific applicators (tandem and half-size ovoid) was inserted in most of the patients. A tandem-vaginal cylinder applicator was used for some patients with narrow vagina or those with tumor infiltration to the lower vagina. The bladder was filled with 100 mL of normal saline to avoid high-dose irradiation to the whole volume of the bladder. The technique behind brachytherapy has changed in a phased manner. An in-room CT on-rail brachytherapy system was installed in 2001 in our institution. From 2001 to 2006, CT was performed with applicator insertion at only the first brachytherapy session. From 2007 to 2010, CTbased 3D-IGBT was performed at the first and third sessions in each patient. Brachytherapy performance at the second or fourth sessions was decided based on the treatment data from the first or third sessions. From 2011, CTbased 3D-IGBT has been performed in all brachytherapy sessions. From 2011, Trocar Point needles (Nucletron; Elekta, Stockholm, Sweden) were additionally inserted in combination with the applicator for patients with bulky and
D. Kobayashi et al. / Brachytherapy
asymmetric residual tumors, at the discretion of the attending physician (25). Dose prescription and optimization of brachytherapy Before 2007, dose adaptation was performed by changing the dose at Point A so that a dose O6 Gy was delivered to the whole tumor. In case the organs at risk (OARs) were close to the high-dose region (O9 Gy), the dwell time was changed manually using the PLATO treatment-planning system version 13.7 (Nucletron, Veenendaal, the Netherlands). When CT images were not taken, the same Point A dose and dwell time allocation were applied at the last brachytherapy session. If tumor shrinking was found on gynecological examination, the dose at Point A was reduced by 0.5 Gy. From 2007, CT-based 3D-IGBT has been performed according to the recommendations of the Groupe Europeen de Curietherapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) (14, 15) using the Oncentra Treatment Planning System (Nucletron, Veenendaal, the Netherlands). For high-risk clinical target volume (HRCTV) identification on CT images, the findings of gynecological examinations performed at diagnosis and brachytherapy, and MRI examinations performed at diagnosis and within 1 week before the first brachytherapy session, were used as references. The initial plan was generated based on the Point A prescription; thereafter, the dose distribution was modified to allow for the delivery of O6 Gy of HR-CTVD90 at each session. Dose-volume histogram parameters In the present study, we estimated the composited dose to tumor and OARs in patients treated with 3D-IGBT at least twice. The cumulative EBRT and brachytherapy doses were summarized and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2) using a linear-quadratic model with an alpha/beta of 3 Gy for the OARs and 10 Gy for the tumors. In both this study and previous studies, the doses of pelvic irradiation with central shielding were not added to the EQD2 (26, 27). Dose-volume histogram (DVH) parameters were collected with respect to the HR-CTVD90 and D2cc (the minimum dose delivered to the highest irradiated 2-cm3 area) of the OARs. In patients who received 3D-IGBT at the first and third sessions, the DVH parameters of the first and third IGBT sessions were substituted for those of the second and fourth IGBT sessions. Followup and evaluation Patients were followed up every 1e3 months for the first 2 years and every 3e6 months thereafter. Patients’ disease status and the extent of late complications were assessed at each followup through history-taking, and the performance of physical examinations, and/or appropriate laboratory and
-
(2019)
-
3
radiological tests. Suspected recurrent cervical tumors were confirmed using biopsy. Late complications were defined as any complications occurring 6 months after radiotherapy initiation. Late complications were graded using the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer system. Statistical analysis The LC, CSS, OS, and cumulative occurrence rates of late toxicity were estimated using the KaplaneMeier method. The LC and survival durations were calculated from the start of treatment. Comparisons of the clinical factors between the two groups were assessed using the ManneWhitney U test. Significant differences were assessed using two-sided tests with p ! 0.05. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software, version 24.0 (SPSS, Chicago, IL).
Results Patient characteristics and details of radiotherapy A total of 105 patients met the eligibility criteria. The median followup period was 59 (range, 6e203) months and the participants’ median age was 77 (range, 70e89) years. All patients were treated with EBRT and brachytherapy. The number of patients treated by changing the dose at Point A at the first brachytherapy session, treated by 3DIGBT at first and third sessions, and treated by 3D-IGBT every session was 71, 19, and 15, respectively. Only two patients were treated with interstitial brachytherapy. For the assessment of 3D-IGBT influence, the cohort was divided into two groups according to the year of the treatment and strategy: patients treated before 2007 by changing the dose at Point A at the first brachytherapy session (Group A, n 5 71), and patients treated after 2007 by using 3D-IGBT at least twice (Group B, n 5 34). A summary of the patients’ characteristics and details of radiotherapy is listed in Table 1. Clinical outcomes The 5-year LC, CSS, and OS rates for all 105 patients were 89% [95% confidence interval (CI) 79.4e93.8], 78% (95% CI 68.1e85.3), and 62% (95% CI 51.2e70.4), respectively (Fig. 1). Of the 105 patients analyzed, 59 patients were still alive (55%) and 46 patients had died (45%) at the last followup. Of the 46 patients who died, 24 died from primary cancer, 5 from second malignancies which were found after the treatment for uterine cervical cancer (gastric cancer, pancreas cancer, hepatocellular carcinoma, colon cancer, and ovarian cancer), and 17 patients from nonmalignant disease. Of the 59 patients who were
4
D. Kobayashi et al. / Brachytherapy
-
(2019)
-
Table 1 Comparison of patient characteristics between Group A and Group B Total (n 5 105) Data characteristics Followup period (months) Age FIGO stage IB II III IVA Tumor size (cm) #4 cm O4 cm Not applicable Pelvic LN positive Pelvic LN negative PAN positive PAN negative Total dose of WP (Gy) Fractions of WP Total dose of CS (Gy) Fractions of CS Point A dose (Gy) of BT Fractions of BT Total Point A dose (GyEQD2), averagea Total dose of HR-CTVD90 (GyEQD2), averagea
Median or no.
Range
59 77 23 42 27 13 4.1 51 52 2 24 81 3 102 30.6 17 20 10 24 4 56.7 NA
6e203 70e89
1.0e9.0
0e55 0e26 0e45 0e25 10e31 2e5 31.3e89.3
Group A (n 5 71)
Group B (n 5 34)
Median
Median
63 77 11 33 17 10 4.1 36 33 2 17 54 1 70 30.6 17 20 10 24 4 56.2 NA
Range 6e203 70e89
1.0e9.0
0e55 0e26 10e45 5e25 10e31 2e5 31.3e89.3
31 75 12 9 10 3 4.2 15 19 0 7 27 2 32 30.6 17 20 10 24 4 57.8 70.3
Range
p value
6e114 70e89
0.001 0.460 0.210
1.4e8.2
0.878
0.705 0.202 20e40 10e22 0e30 0e15 11e28 3e4 44.5e74.7 42.0e103.6
0.281 0.205 0.071 0.077 0.742 0.221 0.391
No. 5 number; LN 5 lymph node; PAN 5 para-aortic lymph node; WP 5 whole pelvis irradiation; CS 5 pelvis irradiation with central shielding technique; EBRT 5 external beam radiotherapy; BT 5 brachytherapy; EQD2 5 a biological equivalent dose of 2 Gy per fraction; HR-CTV 5 high-risk clinical target volume; NA 5 not applicable. a The doses of pelvic irradiation with central shielding were not added to the EQD2.
alive, 51 were disease-free and 8 were alive with disease. Cancer recurrence was observed in 32 of all 105 patients by the last followup. With regards to the pattern of recurrence, local recurrences occurred in 8 patients, distant metastases in 21, and both local recurrence and distant metastases in 3. We then compared the clinical results of Group A and Group B. The 3-year cumulative LC, CSS, and OS rates in Group A were 91% (95% CI 80.2e95.7), 85% (95% CI 73.7e91.6), and 73% (95% CI 61.3e82.0), respectively, whereas those in Group B were 90% (95% CI 71.3e96.5), 79% (95% CI 58.7e90.0), and 66% (95% CI 46.0e80.3), respectively. There were no statistical differences in the disease control rates between the two groups (Fig. 2). No statistically significant differences were observed in LC classified by tumor size and stage in all cases (Supplementary Fig. 1), Group A (Supplementary Fig. 2), and Group B (Supplementary Fig. 3).
Late toxicity Data on the maximal late toxicity grades during the followup are presented in Table 2. In the 105 cases, the 5-year cumulative rates of toxicities of the rectum and bladder of Grade $3 were 2.0% (95% CI 0.0e37.8) and 4.2% (95% CI 0.0e30.5), respectively.
In Group A, 1 patient developed Grade 4 toxicity of the rectum, including the rectovaginal fistula, which required surgery. This patient was 81 years old with no comorbidities and had a 7.0 cm tumor with bladder invasion at diagnosis. She received EBRT and four sessions for brachytherapy with 6.25 Gy at Point A per fraction. Five months after the treatment, she developed rectovaginal fistula. Regarding urinary toxicity, 3 patients developed Grade 3 hematuria that required blood transfusions, and 1 patient developed Grade 4 vaginal fistula. The patient with urinary toxicity Grade 4 was 81 years old with no comorbidities and had a 7.0 cm tumor with bladder invasion at diagnosis, evaluated as FIGO IVA; she received EBRT and three sessions of brachytherapy. Doses at Point A were 7 Gy, 7 Gy, and 6 Gy, in that order. Thirteen months after the treatment, the patient developed vaginal fistula. However, in Group B, no toxicity of Grade $3 was observed in the rectum, but two patients developed Grade 4 urinary toxicity. One patient with Grade 4 toxicity was 76 years old and had an 8.2 cm tumor with bladder invasion at diagnosis; she received EBRT and three sessions of brachytherapy. D2cc of the bladder was 5.6 Gy, 5.9 Gy, and 6.1 Gy, in that order. The cumulative D2cc of the bladder was 69 GyEQD2. Nine months after the treatment, the patient developed vaginal fistula. The other patient was 79 years old and had a 6.8 cm tumor with bladder invasion at diagnosis; she received EBRT and four sessions of brachytherapy. D2cc
D. Kobayashi et al. / Brachytherapy
-
(2019)
-
5
Fig. 1. Survival curves for all patients.
of the bladder was 7.0 Gy, 8.5 Gy, 6.6 Gy, and 7.1 Gy, in that order. The cumulative D2cc of the bladder was 90 GyEQD2. Six months after the treatment, the patient developed vaginal fistula. The 3-year cumulative rates of toxicity of the rectum of Grade $1 in Group A and Group B were 27% (95% CI 12.5e44.4) and 12% (95% CI 0.1e50.8), respectively ( p 5 0.192). The 3-year cumulative rates of toxicity of the bladder of Grade $1 in Group A and Group B were 20% (95% CI 6.7e39.2) and 6.9% (95% CI 0.0e 51.5), respectively ( p 5 0.035) (Fig. 3).
Dose-volume histogram parameters The average SD value of the Point A dose in Group A was 56.2 9.7 GyEQD2. Owing to the absence of DVH parameters, we were unable to assess the relationship between clinical outcomes and DVH parameters in Group A. The composited doses to tumor and OARs in patients treated after 2007 with 3D-IGBT at least twice (Group B) were as follows. The average SD values of the HR-CTVD90 and Point A dose were 70.3 13.2 GyEQD2 and
Fig. 2. Survival curves for all patients according to the two groups: Group A (n 5 74) and Group B (n 5 31).
6
D. Kobayashi et al. / Brachytherapy
Table 2 The maximal late toxicity grading during the followup RTOG/EORTC grade Subgroups Bladder Group A (n 5 71) Group B (n 5 34) Rectum Group A (n 5 71) Group B (n 5 34)
0
1
2
3
4
49 32
11 0
7 0
3 0
1 2
52 29
9 1
8 4
1 0
1 0
RTOG/EORTC 5 Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer.
57.8 7.2 GyEQD2, respectively. The average SD values of the HR-CTVD90 in patients without and with local recurrence were 68.8 3.8 GyEQD2 and 53.6 11.6 GyEQD2, respectively. Although no statistically significant difference was observed in the HR-CTVD90 value between patients without and with local recurrence ( p 5 0.284), all cases with local recurrence showed lower HR-CTVD90 due to bulky or asymmetric tumors. The images of recurrent cases are shown in Supplementary Fig. 4. Two patients developed toxicity of Grade $1 in the bladder in Group B. The D2cc values for the bladder were 70.4 12.5 GyEQD2 and 79.7 10.4 GyEQD2 in those without and with urinary toxicity, respectively. No statistical significance was observed ( p 5 0.336). Five patients in Group B developed toxicities in the rectum. The D2cc values for the rectum were 57.3 3.2 GyEQD2 and 63.1 11.9 GyEQD2 in those without and with rectal toxicity, respectively. The D2cc value for the rectum in patients with any rectal toxicity was higher than that in those without toxicity, although no statistical significance was observed ( p 5 0.558).
Discussion Since 2005, when the gynecological GEC-ESTRO reports were published, the usefulness of and methodology
-
(2019)
-
behind 3D-IGBT have spread to clinical practice in a phased manner (14e18). To the best of our knowledge, the present study is the first to analyze the effectiveness of CT-based 3D-IGBT for cervical cancer with a focus on elderly patients. Previous studies that concentrated on conventional brachytherapy showed that the 5-year CSS rate was 60e70% in elderly patients with cervical cancer (19e22) (Table 3). In the present study, the 5-year CSS rate was 78% in the total cohort. The overall 5-year LC rate was 89%. Owing to the absence of LC rate descriptions in previous studies (19e22), we were unable to assess the superiority of 3D-IGBT in elderly patients compared to these 2D-brachytherapy studies. However, the LC rate in the present study was comparable to those in recent studies using 3D-IGBT (28). Thus, IGBT may contribute to excellent LC rates, even in elderly patients with cervical cancer. Nakano et al. (29) reported that 2D brachytherapy was associated with insufficient LC rates, especially in advanced cervical cancer cases. In the present study, favorable LC rates were found in both groups; the 3-year LC rates in Group A and Group B were 91% and 90%, respectively. There were no statistical differences in the LC rates between the two groups. A possible explanation for this is the modification of the Point A dose while the dose distribution on the CT images with applicator insertion was checked. There was no consensus guideline for IGBT before 2005 (14, 15). However, even before the consensus guideline, it was recognized that an insufficient radiation dose to the tumor led to poor LC in patients with a large tumor volume (30). Thus, the treatment plans in Group A were adjusted to allow for the delivery of O6 Gy to the whole tumor by changing the Point A dose. Even such modification of the Point A dose according to the tumor size only in the first fraction of brachytherapy may have contributed to the favorable LC rates. Considering the favorable LC in Group A, the improvement in CSS and OS might be attributable to higher doses. However, in terms of late toxicity, 3D-IGBT implementation is desired in every session. In the present study, the incidence of rectal toxicities of all grades showed a
Fig. 3. Cumulative incidence rates for any complications of the rectum and bladder.
D. Kobayashi et al. / Brachytherapy
-
(2019)
-
7
Table 3 Comparison of previous studies and the present study for uterine cervical cancer which focuses on elderly patients
Authors
No. of patients (age)
FIGO Stage III or IV
Mitchell (19) Sakurai (20)
60 ($70) 129 (70e79)
23% 61%
Chen (21) Ikushima (22) Present study (n 5 105)
79 ($70) 132 ($75) 71 ($70)
20% 50% 39%
34 ($70)
35%
Source/treatment method Cs137/non-IGBT Ra226, Cs137/nonIGBT Ir192/non-IGBT Cs137/non-IGBT Ir192/non-IGBT (Group A) Ir192/IGBT (Group B)
Late toxicity Grade $3
Median followup period (months)
Efficacy 5-year LC
5-year CSS
5-year OS
Bladder
Rectum
81 NR
NR NR
60% 70%
46% 50%
0% 11.3%
8.1% 11.3%
56 68 63
NR NR 89%
63% 66% 82%
60% 49% 65%
2.5% 0% 3.1%
15% 0% 2.8%
31
90% (3-year)
79% (3-year)
66% (3-year)
6.9%a (3-year)
0% (3-year)
y.o. 5 years old, Cs 5 cesium; Ra 5 radium; IGBT 5 image-guided brachytherapy; LC 5 local control; CSS 5 cause-specific survival; OS 5 overall survival; NR 5 not reported. a All patients had tumor with bladder invasion at diagnosis.
decreasing trend, although there was no statistically significant difference between Group A and B. In addition, the incidence of bladder toxicities was significantly decreased in Group B. As shown in Table 3, previous studies involving conventional brachytherapy showed a higher incidence of severe late toxicities. Furthermore, a few patients in Group B developed severe late toxicity. In addition, the 2 patients with Grade 4 urinary toxicity had bladder invasion at diagnosis and the high risk of vaginal fistula was evaluated. Taken together, these findings suggest that IGBT use may reduce the incidence of toxicity, even in elderly patients with cervical cancer. If serious adverse events occur in elderly patients, their quality of life may be severely impaired. Reducing the rate of adverse events through IGBT performance may benefit the maintenance of post-treatment quality of life, particularly for elderly patients. With regards to DVH parameters, the average SD values of the HR-CTVD90 in patients without and with local recurrence were 68.8 3.8 GyEQD2 and 53.6 11.6 GyEQD2, respectively ( p 5 0.284). Murakami et al. reported that both LC and progression-free survival were significantly better in patients with an HR-CTVD90 $60 Gy (31). Thus, the present study findings seem to be consistent with those observed in the aforementioned studies. Indeed, only three patients developed local recurrence in Group B in the present study. Therefore, further analysis to validate the correlation between the HRCTVD90 value and LC in a larger number of elderly patients is needed. Regarding the dose constraint for the OARs, Kato et al. reported that the probability of occurrence of late rectal complications in the group with a D2cc value for the rectum !60 Gy was significantly lower than that in the group with a D2cc value for the rectum $60 Gy (32). In our analysis, the D2cc value for the rectum in Group B was 57.9 15.4 GyEQD2, which may have contributed to the low probability of late rectal complication occurrence. With regard to urinary toxicity, the average SD
values of the D2cc for the bladder in patients without and with urinary toxicity were 70.4 12.5 GyEQD2 and 79.7 10.4 GyEQD2, respectively ( p 5 0.336). We could not define the dose constraint for the bladder because only two cases with late toxicity of the bladder were observed in Group B. Thus, there is a need for further analyses to validate the correlation between the D2cc value of the OARs and complications in a larger number of elderly patients. Our study has some limitations, such as the retrospective study design and the short followup period due to the none cancer-related deaths of the elderly patients. In addition, the number of implementations of 3D-IGBT differed depending on the era. The large difference in median followup between the two groups may affect the disease outcome and toxicity rates. The two cohorts were not contemporaneous (all patients in Group A were treated before patients in Group B) and there could be other time-based biases in other aspects of the patients’ care. The EMBRACE II study of intensity-modulated RT (IMRT) and brachytherapy (MRI-based IGBT or interstitial brachytherapy) is currently ongoing (33). Interstitial brachytherapy may become a treatment solution for bulky cervical cancer. As shown in Supplementary Fig. 4, locally recurrent cases originally had bulky/asymmetrical cervical cancer, so the curative dose did not cover the tumor sufficiently. Importantly, previous studies indicated that patients with higher HR-CTVD90 dose showed not only better LC but also better survival rates (28, 31). Although clinicians must consider the feasibility of interstitial brachytherapy, interstitial brachytherapy may be considered even for elderly patients with cervical cancer. IMRT can reduce the risk of late bowel toxicities (34), which may bring important benefits for elderly patients, considering their high rates of comorbidities and overall vulnerability to various toxicities. The present study applied 3D-IGBT with WP and CS techniques and did not apply IMRT technique. Improved techniques for administering RT may also affect the results. To determine the best methods of applying RT
8
D. Kobayashi et al. / Brachytherapy
and to overcome the limitations described previously, a prospective clinical trial including 3D-IGBT for elderly patients with cervical cancer is warranted. In conclusion, our study showed that 3D-IGBT use for cervical cancer was safe and effective in elderly patients. Further study is needed to validate the doseeresponse relationship between DVH parameters and LC and to determine the dose constraints for the OARs in elderly patients with cervical cancer.
Supplementary data
[15]
[16]
[17]
Supplementary data related to this article can be found at https://doi.org/10.1016/j.brachy.2019.08.002. [18]
References [1] Cervical cancer: Estimated incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer and World Health Organization; 2012. Available at: http://gco.iarc. fr/today/data/pdf/fact-sheets/cancers/cancer-fact-sheets-16.pdf. Accessed August 31, 2019. [2] Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 2001;358:781e786. [3] Green JA, Kirwan JM, Tierney JF, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;20:CD002225. [4] Chemoradiotherapy for Cervical cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: A systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008;26: 5802e5812. [5] Thomas GM. Improved treatment for cervical cancer–concurrent chemotherapy and radiotherapy. N Engl J Med 1999;340:1198e1200. [6] Fox KV, Shah CA, Swisher EM, et al. An evaluation of cervical cancer in women age sixty and over. Gynecol Oncol 2008;109:53e58. [7] Mitsuhashi N, Takahashi M, Nozaki M, et al. Squamous cell carcinoma of the uterine cervix: Radiation therapy for patients aged 70 years and older. Radiology 1995;194:141e145. [8] Herold DM, Hanlon AL, Hanks GE. Diabetes mellitus: A predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys 1999;43: 475e479. [9] Shadad AK, Sullivan FJ, Martin JD, et al. Gastrointestinal radiation injury: Symptoms, risk factors and mechanisms. World J Gastroenterol 2013;19:185e198. [10] Chon BH, Loeffler JS. The effect of nonmalignant systemic disease on tolerance to radiation therapy. Oncologist 2002;7:136e143. [11] Wang YM, Wang CJ, Fang FM, et al. Differences in the outcomes and complications between elderly and younger uterine cervical cancer patients treated by definitive radiotherapy d a propensity score-matched study. Gynecol Oncol 2017;145:277e283. [12] Logsdon MD, Eifel PJ. Figo IIIB squamous cell carcinoma of the cervix: An analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys 1999;43:763e775. [13] Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Biol Phys 2000;48: 201e211. [14] Haie-Meder C, P€ otter R, Van Limbergen E, et al., Gynaecological (GYN) GEC-ESTRO Working Group. Recommendations from
[19]
[20]
[21]
[22] [23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
-
(2019)
-
Gynaecological (GYN) GEC-ESTRO working group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235e245. P€otter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67e77. Charra-Brunaud C, Harter V, Delannes M, et al. Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study. Radiother Oncol 2012;103:305e313. P€otter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol 2007;83:148e155. P€otter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116e123. Mitchell PA, Waggoner S, Rotmensch J, et al. Cervical cancer in the elderly treated with radiation therapy. Gynecol Oncol 1998;71:291e 298. Sakurai H, Mitsuhashi N, Takahashi M, et al. Radiation therapy for elderly patient with squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2000;77:116e120. Chen SW, Liang JA, Yang SN, et al. High Dose-rate brachytherapy for elderly patients with uterine cervical cancer. Jpn J Clin Oncol 2003;33:221e228. Ikushima H, Takegawa Y, Osaki K, et al. Radiation therapy for cervical cancer in the elderly. Gynecol Oncol 2007;107:339e343. Elliott SP, Fan Y, Jarosek S, et al. Propensity-weighted comparison of long-term risk of urinary adverse events in elderly women treated for cervical cancer. Int J Radiat Oncol Biol Phys 2015; 92:586e593. Japan Society of Obstetrics and GynecologyThe Japanese Pathological societyJapan radiological society. The general rules for clinical and pathological management of uterine cervical cancer. Tokyo: Kanehara Shuppan; 1987. Wakatsuki M, Ohno T, Yoshida D, et al. Intracavitary combined with CT-guided interstitial brachytherapy for locally advanced uterine cervical cancer: Introduction of the technique and a case presentation. J Radiat Res 2011;52:54e58. Ohno T, Noda SE, Okonogi N, et al. In-room computed tomographybased brachytherapy for uterine cervical cancer: Results of a 5-year retrospective study. J Radiat Res 2017;58:543e551. Toita T, Kitagawa R, Hamano T, et al., Cervical cancer (Vulva Cancer) Committee of Japanese Gynecologic Oncology Group (JGOG). Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: Efficacy and toxicity of a low cumulative radiation dose schedule. Gynecol Oncol 2012;126: 211e216. Sturdza A, P€otter R, Fokdal LU, et al. Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol 2016;120:428e443. Nakano T, Kato S, Ohno T, et al. Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix. Cancer 2005;103:92e101. Terahara A, Nakano T, Ishikawa A, et al. Dose-volume histogram analysis of high dose rate intracavitary brachytherapy for uterine cervix cancer. Int J Radiat Oncol Biol Phys 1996;35: 549e554.
D. Kobayashi et al. / Brachytherapy [31] Murakami N, Kasamatsu T, Wakita A, et al. CT based three dimensional dose-volume evaluations for high-dose rate intracavitary brachytherapy for cervical cancer. BMC Cancer 2014;14: 447. [32] Kato S, Tran DN, Ohno T, et al. CT-based 3D dose-volume parameter of the rectum and late rectal complication in patients with cervical cancer treated with high-dose-rate intracavitary brachytherapy. J Radiat Res 2010;51:215e221.
-
(2019)
-
9
[33] P€otter R, Tanderup K, Kirisits C, et al. The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol 2018;9:48e60. [34] Mundt AJ, Mell LK, Roeske JC, et al. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56:1354e1360.
-
(2019)
-
Impact of CT-based brachytherapy in elderly patients with cervical cancer Daijiro Kobayashi1,2, Noriyuki Okonogi1,*, Masaru Wakatsuki3, Yuhei Miyasaka1,2, Hiroki Kiyohara4, Tatsuya Ohno2, Shingo Kato5, Takashi Nakano2, Tadashi Kamada1 1 QST Hospital, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan 3 Department of Radiology, Jichi Medical University, Simotsuke-city, Tochigi, Japan 4 Department of Radiation Oncology, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan 5 Department of Radiation Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan 2
ABSTRACT
PURPOSE: Three-dimensional image-guided brachytherapy (3D-IGBT) has become the standard therapy for patients with cervical cancer. However, in this population, the impact of 3D-IGBT in elderly individuals remains unknown. This study assessed the efficacy of 3D-IGBT for elderly patients with cervical cancer. METHODS AND MATERIALS: We performed a retrospective chart review of 105 consecutive patients with cervical squamous cell carcinoma aged $70 years who received radiotherapy alone between January 2001 and September 2014. All patients were treated with external beam radiotherapy and high-dose-rate intracavitary brachytherapy. We assessed the treatment outcomes in all patients. We then compared outcomes between two groups: patients treated by changing the Point A dose at brachytherapy (Group A, n 5 71) and those treated with 3D-IGBT at least twice (Group B, n 5 34). RESULTS: The median followup period was 59 (range, 6e203) months; the median age was 77 years. The 5-year local control and cause-specific survival rates were 89% and 78%, respectively. The 5-year cumulative rates of late toxicities of the rectum and bladder of Grade $3 were 2.0% and 4.2%, respectively. No statistically significant differences were observed in the local control and cause-specific survival rates, or in the incidence of rectal toxicities between groups. The 3year cumulative rates of urinary toxicity of Grade $1 were 20.4% and 6.9% in Group A and Group B, respectively ( p 5 0.035). CONCLUSION: In elderly patients with cervical cancer, 3D-IGBT could be performed safely and effectively and contributed to decreasing urinary toxicity incidence rates. Ó 2019 The Authors. Published by Elsevier Inc. on behalf of American Brachytherapy Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Radiotherapy; Cervical cancer; Squamous cell carcinoma; Brachytherapy; Elderly
Introduction
Received 28 January 2019; received in revised form 2 August 2019; accepted 7 August 2019. Financial disclosure: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. * Corresponding author. QST Hospital, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inageku, Chiba-city, Chiba 263-8555, Japan. Tel: þ81-43-206-3306; fax: þ81-43-256-6506. E-mail address: [email protected] (N. Okonogi).
Cervical cancer is the fourth most commonly occurring cancer in women, and the seventh overall, with an estimated 528,000 new cases reported in 2012 (1). Radiotherapy (RT) is the definitive therapy for patients with Stage IBeIVA cervical cancer. Concurrent chemoradiotherapy (CCRT) improves overall survival (OS) and progression-free survival and reduces the rates of local and distant recurrence (2e4). The National Cancer Institute strongly recommends the performance of CCRT rather than RT alone for advanced cervical cancer (5). However, acute hematological and gastrointestinal toxicities are significantly more frequently observed in patients who are treated
1538-4721/Ó 2019 The Authors. Published by Elsevier Inc. on behalf of American Brachytherapy Society. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.brachy.2019.08.002
2
D. Kobayashi et al. / Brachytherapy
with CCRT (2e4). An increasing number of elderly patients are being diagnosed with cervical cancer in Europe, and older women account for more than 40% of deaths from cervical cancer annually (6). Comorbidities, such as weak kidney function and cardiovascular complications, are more prevalent in elderly people, making the application of concurrent chemotherapy difficult in such populations. Mitsuhashi et al. (7) reported that 52% of the elderly patients with cervical cancer in their cohort had chronic disease. Thus, elderly patients with cervical cancer are sometimes treated with RT alone, leading to poor treatment results. In addition, the coexistence of chronic diseases is considered an important risk factor for adverse events after radiation (8e10). Indeed, radiation-induced proctitis is twice as likely to occur in elderly patients than in their younger counterparts (11). Brachytherapy is a critical treatment component for all patients with cervical cancer who are receiving RT (12e 15). In cases without concurrent chemotherapy, brachytherapy may have a more crucial role for patients with cervical cancer. The technique behind brachytherapy has evolved over the past few decades, moving from two-dimensional image-based (2D) dosimetry to three-dimensional imageguided brachytherapy (3D-IGBT) (13,14,16e18). The transition from 2D to 3D-IGBT has led to local control (LC) rate improvements and late adverse event rate reductions (15, 17). Previous studies of elderly patients with cervical cancer showed values of 60e70% for the 5-year cause-specific survival (CSS), 46e60% for the 5-year OS, and 0e15% for the occurrence of severe late toxicities (19e23). Patients in these studies were treated using 2D brachytherapy, not 3D-IGBT. Thus, the impact of 3D-IGBT in elderly patients with cervical cancer has not yet been fully examined. As mentioned previously, elderly patients with cervical cancer are often treated with RT alone. In other words, elderly patients are likely to be an ideal cohort for the validation of the influence of 3D-IGBT for cervical cancer without the effect of chemotherapy. In the present study, we retrospectively assessed the efficacy of 3D-IGBT for elderly patients with cervical cancer.
Methods and materials Patient eligibility A retrospective chart review was performed in consecutive patients with cervical cancer, aged 70 years or older, who were treated with RT alone between January 2001 and September 2014. The study concept was approved by the Ethical Review Board committee of our institution (NIRS 16-010). The inclusion criteria for the analysis were as follows: (1) presence of histologically proven, untreated cervical squamous cell carcinoma, (2) International Federation of
-
(2019)
-
Gynecology and Obstetrics (FIGO) Stage IB1eIVA disease using the 2009 FIGO staging system, and (3) treated with curative intent. Patients with para-aortic lymph node metastases at the start of treatment were included in this study.
External beam radiotherapy External beam radiotherapy (EBRT) at a dose of up to approximately 50 Gy was delivered to the whole pelvis, with a daily fraction dose of 1.8 or 2.0 Gy using 10 MV X-rays. Patients were treated with a combination of whole pelvic irradiation and central shielding (24). In principle, patients with early-stage disease (Stage IeII and tumor size #4 cm in maximum diameter) received whole pelvic irradiation at a dose of 19.8 Gy in 11 fractions, followed by central shielding irradiation at a dose of 30.0 Gy in 15 fractions. Patients with disease of Stage IIIeIVA or tumor with a maximum diameter O4 cm received whole pelvic irradiation at a dose of 30.6 Gy in 17 fractions, followed by central shielding irradiation at a dose of 20.0 Gy in 10 fractions. For patients with lymph node metastases in the pelvic region, an additional boost irradiation of 8e10 Gy in 4e5 fractions was administered to the enlarged lymph node.
Brachytherapy High-dose-rate brachytherapy was performed weekly using 192Ir remote afterloading system (microSelectron, Nucletron, Veenendaal, the Netherlands). Four fractions of brachytherapy were administered, at a fraction dose of 6 Gy to Point A, using the Manchester method. When the tumor response was poor, a fifth fraction of brachytherapy was considered. A set of Fletcher-Suit Asian Pacific applicators (tandem and half-size ovoid) was inserted in most of the patients. A tandem-vaginal cylinder applicator was used for some patients with narrow vagina or those with tumor infiltration to the lower vagina. The bladder was filled with 100 mL of normal saline to avoid high-dose irradiation to the whole volume of the bladder. The technique behind brachytherapy has changed in a phased manner. An in-room CT on-rail brachytherapy system was installed in 2001 in our institution. From 2001 to 2006, CT was performed with applicator insertion at only the first brachytherapy session. From 2007 to 2010, CTbased 3D-IGBT was performed at the first and third sessions in each patient. Brachytherapy performance at the second or fourth sessions was decided based on the treatment data from the first or third sessions. From 2011, CTbased 3D-IGBT has been performed in all brachytherapy sessions. From 2011, Trocar Point needles (Nucletron; Elekta, Stockholm, Sweden) were additionally inserted in combination with the applicator for patients with bulky and
D. Kobayashi et al. / Brachytherapy
asymmetric residual tumors, at the discretion of the attending physician (25). Dose prescription and optimization of brachytherapy Before 2007, dose adaptation was performed by changing the dose at Point A so that a dose O6 Gy was delivered to the whole tumor. In case the organs at risk (OARs) were close to the high-dose region (O9 Gy), the dwell time was changed manually using the PLATO treatment-planning system version 13.7 (Nucletron, Veenendaal, the Netherlands). When CT images were not taken, the same Point A dose and dwell time allocation were applied at the last brachytherapy session. If tumor shrinking was found on gynecological examination, the dose at Point A was reduced by 0.5 Gy. From 2007, CT-based 3D-IGBT has been performed according to the recommendations of the Groupe Europeen de Curietherapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) (14, 15) using the Oncentra Treatment Planning System (Nucletron, Veenendaal, the Netherlands). For high-risk clinical target volume (HRCTV) identification on CT images, the findings of gynecological examinations performed at diagnosis and brachytherapy, and MRI examinations performed at diagnosis and within 1 week before the first brachytherapy session, were used as references. The initial plan was generated based on the Point A prescription; thereafter, the dose distribution was modified to allow for the delivery of O6 Gy of HR-CTVD90 at each session. Dose-volume histogram parameters In the present study, we estimated the composited dose to tumor and OARs in patients treated with 3D-IGBT at least twice. The cumulative EBRT and brachytherapy doses were summarized and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2) using a linear-quadratic model with an alpha/beta of 3 Gy for the OARs and 10 Gy for the tumors. In both this study and previous studies, the doses of pelvic irradiation with central shielding were not added to the EQD2 (26, 27). Dose-volume histogram (DVH) parameters were collected with respect to the HR-CTVD90 and D2cc (the minimum dose delivered to the highest irradiated 2-cm3 area) of the OARs. In patients who received 3D-IGBT at the first and third sessions, the DVH parameters of the first and third IGBT sessions were substituted for those of the second and fourth IGBT sessions. Followup and evaluation Patients were followed up every 1e3 months for the first 2 years and every 3e6 months thereafter. Patients’ disease status and the extent of late complications were assessed at each followup through history-taking, and the performance of physical examinations, and/or appropriate laboratory and
-
(2019)
-
3
radiological tests. Suspected recurrent cervical tumors were confirmed using biopsy. Late complications were defined as any complications occurring 6 months after radiotherapy initiation. Late complications were graded using the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer system. Statistical analysis The LC, CSS, OS, and cumulative occurrence rates of late toxicity were estimated using the KaplaneMeier method. The LC and survival durations were calculated from the start of treatment. Comparisons of the clinical factors between the two groups were assessed using the ManneWhitney U test. Significant differences were assessed using two-sided tests with p ! 0.05. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software, version 24.0 (SPSS, Chicago, IL).
Results Patient characteristics and details of radiotherapy A total of 105 patients met the eligibility criteria. The median followup period was 59 (range, 6e203) months and the participants’ median age was 77 (range, 70e89) years. All patients were treated with EBRT and brachytherapy. The number of patients treated by changing the dose at Point A at the first brachytherapy session, treated by 3DIGBT at first and third sessions, and treated by 3D-IGBT every session was 71, 19, and 15, respectively. Only two patients were treated with interstitial brachytherapy. For the assessment of 3D-IGBT influence, the cohort was divided into two groups according to the year of the treatment and strategy: patients treated before 2007 by changing the dose at Point A at the first brachytherapy session (Group A, n 5 71), and patients treated after 2007 by using 3D-IGBT at least twice (Group B, n 5 34). A summary of the patients’ characteristics and details of radiotherapy is listed in Table 1. Clinical outcomes The 5-year LC, CSS, and OS rates for all 105 patients were 89% [95% confidence interval (CI) 79.4e93.8], 78% (95% CI 68.1e85.3), and 62% (95% CI 51.2e70.4), respectively (Fig. 1). Of the 105 patients analyzed, 59 patients were still alive (55%) and 46 patients had died (45%) at the last followup. Of the 46 patients who died, 24 died from primary cancer, 5 from second malignancies which were found after the treatment for uterine cervical cancer (gastric cancer, pancreas cancer, hepatocellular carcinoma, colon cancer, and ovarian cancer), and 17 patients from nonmalignant disease. Of the 59 patients who were
4
D. Kobayashi et al. / Brachytherapy
-
(2019)
-
Table 1 Comparison of patient characteristics between Group A and Group B Total (n 5 105) Data characteristics Followup period (months) Age FIGO stage IB II III IVA Tumor size (cm) #4 cm O4 cm Not applicable Pelvic LN positive Pelvic LN negative PAN positive PAN negative Total dose of WP (Gy) Fractions of WP Total dose of CS (Gy) Fractions of CS Point A dose (Gy) of BT Fractions of BT Total Point A dose (GyEQD2), averagea Total dose of HR-CTVD90 (GyEQD2), averagea
Median or no.
Range
59 77 23 42 27 13 4.1 51 52 2 24 81 3 102 30.6 17 20 10 24 4 56.7 NA
6e203 70e89
1.0e9.0
0e55 0e26 0e45 0e25 10e31 2e5 31.3e89.3
Group A (n 5 71)
Group B (n 5 34)
Median
Median
63 77 11 33 17 10 4.1 36 33 2 17 54 1 70 30.6 17 20 10 24 4 56.2 NA
Range 6e203 70e89
1.0e9.0
0e55 0e26 10e45 5e25 10e31 2e5 31.3e89.3
31 75 12 9 10 3 4.2 15 19 0 7 27 2 32 30.6 17 20 10 24 4 57.8 70.3
Range
p value
6e114 70e89
0.001 0.460 0.210
1.4e8.2
0.878
0.705 0.202 20e40 10e22 0e30 0e15 11e28 3e4 44.5e74.7 42.0e103.6
0.281 0.205 0.071 0.077 0.742 0.221 0.391
No. 5 number; LN 5 lymph node; PAN 5 para-aortic lymph node; WP 5 whole pelvis irradiation; CS 5 pelvis irradiation with central shielding technique; EBRT 5 external beam radiotherapy; BT 5 brachytherapy; EQD2 5 a biological equivalent dose of 2 Gy per fraction; HR-CTV 5 high-risk clinical target volume; NA 5 not applicable. a The doses of pelvic irradiation with central shielding were not added to the EQD2.
alive, 51 were disease-free and 8 were alive with disease. Cancer recurrence was observed in 32 of all 105 patients by the last followup. With regards to the pattern of recurrence, local recurrences occurred in 8 patients, distant metastases in 21, and both local recurrence and distant metastases in 3. We then compared the clinical results of Group A and Group B. The 3-year cumulative LC, CSS, and OS rates in Group A were 91% (95% CI 80.2e95.7), 85% (95% CI 73.7e91.6), and 73% (95% CI 61.3e82.0), respectively, whereas those in Group B were 90% (95% CI 71.3e96.5), 79% (95% CI 58.7e90.0), and 66% (95% CI 46.0e80.3), respectively. There were no statistical differences in the disease control rates between the two groups (Fig. 2). No statistically significant differences were observed in LC classified by tumor size and stage in all cases (Supplementary Fig. 1), Group A (Supplementary Fig. 2), and Group B (Supplementary Fig. 3).
Late toxicity Data on the maximal late toxicity grades during the followup are presented in Table 2. In the 105 cases, the 5-year cumulative rates of toxicities of the rectum and bladder of Grade $3 were 2.0% (95% CI 0.0e37.8) and 4.2% (95% CI 0.0e30.5), respectively.
In Group A, 1 patient developed Grade 4 toxicity of the rectum, including the rectovaginal fistula, which required surgery. This patient was 81 years old with no comorbidities and had a 7.0 cm tumor with bladder invasion at diagnosis. She received EBRT and four sessions for brachytherapy with 6.25 Gy at Point A per fraction. Five months after the treatment, she developed rectovaginal fistula. Regarding urinary toxicity, 3 patients developed Grade 3 hematuria that required blood transfusions, and 1 patient developed Grade 4 vaginal fistula. The patient with urinary toxicity Grade 4 was 81 years old with no comorbidities and had a 7.0 cm tumor with bladder invasion at diagnosis, evaluated as FIGO IVA; she received EBRT and three sessions of brachytherapy. Doses at Point A were 7 Gy, 7 Gy, and 6 Gy, in that order. Thirteen months after the treatment, the patient developed vaginal fistula. However, in Group B, no toxicity of Grade $3 was observed in the rectum, but two patients developed Grade 4 urinary toxicity. One patient with Grade 4 toxicity was 76 years old and had an 8.2 cm tumor with bladder invasion at diagnosis; she received EBRT and three sessions of brachytherapy. D2cc of the bladder was 5.6 Gy, 5.9 Gy, and 6.1 Gy, in that order. The cumulative D2cc of the bladder was 69 GyEQD2. Nine months after the treatment, the patient developed vaginal fistula. The other patient was 79 years old and had a 6.8 cm tumor with bladder invasion at diagnosis; she received EBRT and four sessions of brachytherapy. D2cc
D. Kobayashi et al. / Brachytherapy
-
(2019)
-
5
Fig. 1. Survival curves for all patients.
of the bladder was 7.0 Gy, 8.5 Gy, 6.6 Gy, and 7.1 Gy, in that order. The cumulative D2cc of the bladder was 90 GyEQD2. Six months after the treatment, the patient developed vaginal fistula. The 3-year cumulative rates of toxicity of the rectum of Grade $1 in Group A and Group B were 27% (95% CI 12.5e44.4) and 12% (95% CI 0.1e50.8), respectively ( p 5 0.192). The 3-year cumulative rates of toxicity of the bladder of Grade $1 in Group A and Group B were 20% (95% CI 6.7e39.2) and 6.9% (95% CI 0.0e 51.5), respectively ( p 5 0.035) (Fig. 3).
Dose-volume histogram parameters The average SD value of the Point A dose in Group A was 56.2 9.7 GyEQD2. Owing to the absence of DVH parameters, we were unable to assess the relationship between clinical outcomes and DVH parameters in Group A. The composited doses to tumor and OARs in patients treated after 2007 with 3D-IGBT at least twice (Group B) were as follows. The average SD values of the HR-CTVD90 and Point A dose were 70.3 13.2 GyEQD2 and
Fig. 2. Survival curves for all patients according to the two groups: Group A (n 5 74) and Group B (n 5 31).
6
D. Kobayashi et al. / Brachytherapy
Table 2 The maximal late toxicity grading during the followup RTOG/EORTC grade Subgroups Bladder Group A (n 5 71) Group B (n 5 34) Rectum Group A (n 5 71) Group B (n 5 34)
0
1
2
3
4
49 32
11 0
7 0
3 0
1 2
52 29
9 1
8 4
1 0
1 0
RTOG/EORTC 5 Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer.
57.8 7.2 GyEQD2, respectively. The average SD values of the HR-CTVD90 in patients without and with local recurrence were 68.8 3.8 GyEQD2 and 53.6 11.6 GyEQD2, respectively. Although no statistically significant difference was observed in the HR-CTVD90 value between patients without and with local recurrence ( p 5 0.284), all cases with local recurrence showed lower HR-CTVD90 due to bulky or asymmetric tumors. The images of recurrent cases are shown in Supplementary Fig. 4. Two patients developed toxicity of Grade $1 in the bladder in Group B. The D2cc values for the bladder were 70.4 12.5 GyEQD2 and 79.7 10.4 GyEQD2 in those without and with urinary toxicity, respectively. No statistical significance was observed ( p 5 0.336). Five patients in Group B developed toxicities in the rectum. The D2cc values for the rectum were 57.3 3.2 GyEQD2 and 63.1 11.9 GyEQD2 in those without and with rectal toxicity, respectively. The D2cc value for the rectum in patients with any rectal toxicity was higher than that in those without toxicity, although no statistical significance was observed ( p 5 0.558).
Discussion Since 2005, when the gynecological GEC-ESTRO reports were published, the usefulness of and methodology
-
(2019)
-
behind 3D-IGBT have spread to clinical practice in a phased manner (14e18). To the best of our knowledge, the present study is the first to analyze the effectiveness of CT-based 3D-IGBT for cervical cancer with a focus on elderly patients. Previous studies that concentrated on conventional brachytherapy showed that the 5-year CSS rate was 60e70% in elderly patients with cervical cancer (19e22) (Table 3). In the present study, the 5-year CSS rate was 78% in the total cohort. The overall 5-year LC rate was 89%. Owing to the absence of LC rate descriptions in previous studies (19e22), we were unable to assess the superiority of 3D-IGBT in elderly patients compared to these 2D-brachytherapy studies. However, the LC rate in the present study was comparable to those in recent studies using 3D-IGBT (28). Thus, IGBT may contribute to excellent LC rates, even in elderly patients with cervical cancer. Nakano et al. (29) reported that 2D brachytherapy was associated with insufficient LC rates, especially in advanced cervical cancer cases. In the present study, favorable LC rates were found in both groups; the 3-year LC rates in Group A and Group B were 91% and 90%, respectively. There were no statistical differences in the LC rates between the two groups. A possible explanation for this is the modification of the Point A dose while the dose distribution on the CT images with applicator insertion was checked. There was no consensus guideline for IGBT before 2005 (14, 15). However, even before the consensus guideline, it was recognized that an insufficient radiation dose to the tumor led to poor LC in patients with a large tumor volume (30). Thus, the treatment plans in Group A were adjusted to allow for the delivery of O6 Gy to the whole tumor by changing the Point A dose. Even such modification of the Point A dose according to the tumor size only in the first fraction of brachytherapy may have contributed to the favorable LC rates. Considering the favorable LC in Group A, the improvement in CSS and OS might be attributable to higher doses. However, in terms of late toxicity, 3D-IGBT implementation is desired in every session. In the present study, the incidence of rectal toxicities of all grades showed a
Fig. 3. Cumulative incidence rates for any complications of the rectum and bladder.
D. Kobayashi et al. / Brachytherapy
-
(2019)
-
7
Table 3 Comparison of previous studies and the present study for uterine cervical cancer which focuses on elderly patients
Authors
No. of patients (age)
FIGO Stage III or IV
Mitchell (19) Sakurai (20)
60 ($70) 129 (70e79)
23% 61%
Chen (21) Ikushima (22) Present study (n 5 105)
79 ($70) 132 ($75) 71 ($70)
20% 50% 39%
34 ($70)
35%
Source/treatment method Cs137/non-IGBT Ra226, Cs137/nonIGBT Ir192/non-IGBT Cs137/non-IGBT Ir192/non-IGBT (Group A) Ir192/IGBT (Group B)
Late toxicity Grade $3
Median followup period (months)
Efficacy 5-year LC
5-year CSS
5-year OS
Bladder
Rectum
81 NR
NR NR
60% 70%
46% 50%
0% 11.3%
8.1% 11.3%
56 68 63
NR NR 89%
63% 66% 82%
60% 49% 65%
2.5% 0% 3.1%
15% 0% 2.8%
31
90% (3-year)
79% (3-year)
66% (3-year)
6.9%a (3-year)
0% (3-year)
y.o. 5 years old, Cs 5 cesium; Ra 5 radium; IGBT 5 image-guided brachytherapy; LC 5 local control; CSS 5 cause-specific survival; OS 5 overall survival; NR 5 not reported. a All patients had tumor with bladder invasion at diagnosis.
decreasing trend, although there was no statistically significant difference between Group A and B. In addition, the incidence of bladder toxicities was significantly decreased in Group B. As shown in Table 3, previous studies involving conventional brachytherapy showed a higher incidence of severe late toxicities. Furthermore, a few patients in Group B developed severe late toxicity. In addition, the 2 patients with Grade 4 urinary toxicity had bladder invasion at diagnosis and the high risk of vaginal fistula was evaluated. Taken together, these findings suggest that IGBT use may reduce the incidence of toxicity, even in elderly patients with cervical cancer. If serious adverse events occur in elderly patients, their quality of life may be severely impaired. Reducing the rate of adverse events through IGBT performance may benefit the maintenance of post-treatment quality of life, particularly for elderly patients. With regards to DVH parameters, the average SD values of the HR-CTVD90 in patients without and with local recurrence were 68.8 3.8 GyEQD2 and 53.6 11.6 GyEQD2, respectively ( p 5 0.284). Murakami et al. reported that both LC and progression-free survival were significantly better in patients with an HR-CTVD90 $60 Gy (31). Thus, the present study findings seem to be consistent with those observed in the aforementioned studies. Indeed, only three patients developed local recurrence in Group B in the present study. Therefore, further analysis to validate the correlation between the HRCTVD90 value and LC in a larger number of elderly patients is needed. Regarding the dose constraint for the OARs, Kato et al. reported that the probability of occurrence of late rectal complications in the group with a D2cc value for the rectum !60 Gy was significantly lower than that in the group with a D2cc value for the rectum $60 Gy (32). In our analysis, the D2cc value for the rectum in Group B was 57.9 15.4 GyEQD2, which may have contributed to the low probability of late rectal complication occurrence. With regard to urinary toxicity, the average SD
values of the D2cc for the bladder in patients without and with urinary toxicity were 70.4 12.5 GyEQD2 and 79.7 10.4 GyEQD2, respectively ( p 5 0.336). We could not define the dose constraint for the bladder because only two cases with late toxicity of the bladder were observed in Group B. Thus, there is a need for further analyses to validate the correlation between the D2cc value of the OARs and complications in a larger number of elderly patients. Our study has some limitations, such as the retrospective study design and the short followup period due to the none cancer-related deaths of the elderly patients. In addition, the number of implementations of 3D-IGBT differed depending on the era. The large difference in median followup between the two groups may affect the disease outcome and toxicity rates. The two cohorts were not contemporaneous (all patients in Group A were treated before patients in Group B) and there could be other time-based biases in other aspects of the patients’ care. The EMBRACE II study of intensity-modulated RT (IMRT) and brachytherapy (MRI-based IGBT or interstitial brachytherapy) is currently ongoing (33). Interstitial brachytherapy may become a treatment solution for bulky cervical cancer. As shown in Supplementary Fig. 4, locally recurrent cases originally had bulky/asymmetrical cervical cancer, so the curative dose did not cover the tumor sufficiently. Importantly, previous studies indicated that patients with higher HR-CTVD90 dose showed not only better LC but also better survival rates (28, 31). Although clinicians must consider the feasibility of interstitial brachytherapy, interstitial brachytherapy may be considered even for elderly patients with cervical cancer. IMRT can reduce the risk of late bowel toxicities (34), which may bring important benefits for elderly patients, considering their high rates of comorbidities and overall vulnerability to various toxicities. The present study applied 3D-IGBT with WP and CS techniques and did not apply IMRT technique. Improved techniques for administering RT may also affect the results. To determine the best methods of applying RT
8
D. Kobayashi et al. / Brachytherapy
and to overcome the limitations described previously, a prospective clinical trial including 3D-IGBT for elderly patients with cervical cancer is warranted. In conclusion, our study showed that 3D-IGBT use for cervical cancer was safe and effective in elderly patients. Further study is needed to validate the doseeresponse relationship between DVH parameters and LC and to determine the dose constraints for the OARs in elderly patients with cervical cancer.
Supplementary data
[15]
[16]
[17]
Supplementary data related to this article can be found at https://doi.org/10.1016/j.brachy.2019.08.002. [18]
References [1] Cervical cancer: Estimated incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer and World Health Organization; 2012. Available at: http://gco.iarc. fr/today/data/pdf/fact-sheets/cancers/cancer-fact-sheets-16.pdf. Accessed August 31, 2019. [2] Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 2001;358:781e786. [3] Green JA, Kirwan JM, Tierney JF, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;20:CD002225. [4] Chemoradiotherapy for Cervical cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: A systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008;26: 5802e5812. [5] Thomas GM. Improved treatment for cervical cancer–concurrent chemotherapy and radiotherapy. N Engl J Med 1999;340:1198e1200. [6] Fox KV, Shah CA, Swisher EM, et al. An evaluation of cervical cancer in women age sixty and over. Gynecol Oncol 2008;109:53e58. [7] Mitsuhashi N, Takahashi M, Nozaki M, et al. Squamous cell carcinoma of the uterine cervix: Radiation therapy for patients aged 70 years and older. Radiology 1995;194:141e145. [8] Herold DM, Hanlon AL, Hanks GE. Diabetes mellitus: A predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys 1999;43: 475e479. [9] Shadad AK, Sullivan FJ, Martin JD, et al. Gastrointestinal radiation injury: Symptoms, risk factors and mechanisms. World J Gastroenterol 2013;19:185e198. [10] Chon BH, Loeffler JS. The effect of nonmalignant systemic disease on tolerance to radiation therapy. Oncologist 2002;7:136e143. [11] Wang YM, Wang CJ, Fang FM, et al. Differences in the outcomes and complications between elderly and younger uterine cervical cancer patients treated by definitive radiotherapy d a propensity score-matched study. Gynecol Oncol 2017;145:277e283. [12] Logsdon MD, Eifel PJ. Figo IIIB squamous cell carcinoma of the cervix: An analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys 1999;43:763e775. [13] Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Biol Phys 2000;48: 201e211. [14] Haie-Meder C, P€ otter R, Van Limbergen E, et al., Gynaecological (GYN) GEC-ESTRO Working Group. Recommendations from
[19]
[20]
[21]
[22] [23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
-
(2019)
-
Gynaecological (GYN) GEC-ESTRO working group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235e245. P€otter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67e77. Charra-Brunaud C, Harter V, Delannes M, et al. Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study. Radiother Oncol 2012;103:305e313. P€otter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol 2007;83:148e155. P€otter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116e123. Mitchell PA, Waggoner S, Rotmensch J, et al. Cervical cancer in the elderly treated with radiation therapy. Gynecol Oncol 1998;71:291e 298. Sakurai H, Mitsuhashi N, Takahashi M, et al. Radiation therapy for elderly patient with squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2000;77:116e120. Chen SW, Liang JA, Yang SN, et al. High Dose-rate brachytherapy for elderly patients with uterine cervical cancer. Jpn J Clin Oncol 2003;33:221e228. Ikushima H, Takegawa Y, Osaki K, et al. Radiation therapy for cervical cancer in the elderly. Gynecol Oncol 2007;107:339e343. Elliott SP, Fan Y, Jarosek S, et al. Propensity-weighted comparison of long-term risk of urinary adverse events in elderly women treated for cervical cancer. Int J Radiat Oncol Biol Phys 2015; 92:586e593. Japan Society of Obstetrics and GynecologyThe Japanese Pathological societyJapan radiological society. The general rules for clinical and pathological management of uterine cervical cancer. Tokyo: Kanehara Shuppan; 1987. Wakatsuki M, Ohno T, Yoshida D, et al. Intracavitary combined with CT-guided interstitial brachytherapy for locally advanced uterine cervical cancer: Introduction of the technique and a case presentation. J Radiat Res 2011;52:54e58. Ohno T, Noda SE, Okonogi N, et al. In-room computed tomographybased brachytherapy for uterine cervical cancer: Results of a 5-year retrospective study. J Radiat Res 2017;58:543e551. Toita T, Kitagawa R, Hamano T, et al., Cervical cancer (Vulva Cancer) Committee of Japanese Gynecologic Oncology Group (JGOG). Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: Efficacy and toxicity of a low cumulative radiation dose schedule. Gynecol Oncol 2012;126: 211e216. Sturdza A, P€otter R, Fokdal LU, et al. Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol 2016;120:428e443. Nakano T, Kato S, Ohno T, et al. Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix. Cancer 2005;103:92e101. Terahara A, Nakano T, Ishikawa A, et al. Dose-volume histogram analysis of high dose rate intracavitary brachytherapy for uterine cervix cancer. Int J Radiat Oncol Biol Phys 1996;35: 549e554.
D. Kobayashi et al. / Brachytherapy [31] Murakami N, Kasamatsu T, Wakita A, et al. CT based three dimensional dose-volume evaluations for high-dose rate intracavitary brachytherapy for cervical cancer. BMC Cancer 2014;14: 447. [32] Kato S, Tran DN, Ohno T, et al. CT-based 3D dose-volume parameter of the rectum and late rectal complication in patients with cervical cancer treated with high-dose-rate intracavitary brachytherapy. J Radiat Res 2010;51:215e221.
-
(2019)
-
9
[33] P€otter R, Tanderup K, Kirisits C, et al. The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol 2018;9:48e60. [34] Mundt AJ, Mell LK, Roeske JC, et al. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56:1354e1360.