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Small bowel dose in subserosal tandem insertion during cervical cancer brachytherapy
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Small bowel dose in subserosal tandem insertion during cervical cancer brachytherapy ✩ Yu-Lun Tsai, M.D. ∗, Pei-Chieh Yu, Ph.D. ∗,†, Louis Tak Lui, M.D. ∗, Suzun Shaw, M.D. ∗,‡, Ching-Jung Wu, M.D. ∗,§,║,∗∗ ∗
Department of Radiation Oncology, Cathay General Hospital, Taipei, Taiwan School of Medicine, China Medical University, Taichung, Taiwan ‡ Oncology Treatment Center, Sijhih Cathay General Hospital, New Taipei, Taiwan § Department of Radiation Oncology, National Defense Medical Center, Taipei, Taiwan ║ Department of Biomedical Engineering, I-Shou University, Kaohsiung, Taiwan †
a r t i c l e
i n f o
Article history: Received 5 June 2019 Revised 21 November 2019 Accepted 21 November 2019 Available online xxx Keywords: Small bowel Subserosal insertion Brachytherapy Cervical cancer
a b s t r a c t Cervical cancer patients may sometimes experience subserosal tandem insertions during brachytherapy, which can lead to increased but unnoticed irradiations to the small bowel (SB). In this study, we aimed to quantify and further predict individual SB dose increase and to increase focus on the SB in subserosal tandem insertions. Images and dosimetry data of cervical cancer brachytherapy with subserosal insertion (SI) were reviewed. The percentage increases in the SB dose compared with intracavitary insertion (II) at 8 points of D(x)cc with 10 cc intervals were assessed. SI was classified into anterior and posterior SI according to the insertion site. The differences in minimum distance from the tandem tip to the SB on the axial view between these 2 insertions were tested using the Mann-Whitney test. The distance and D(x)cc were involved in the individual dose increase model by linear regression as prediction factors. A total of 27 insertions were evaluated, including 8 insertions with SI and 19 insertions with II. The median percentage increases in the normalized SB dose for all SI showed a logarithmic trend with a 55.4% increase at the hotspot. In contrast to posterior SI, anterior SI demonstrated a more significantly logarithmic trend, which featured highly increased doses at the hotspot (79.1% for the absolute SB dose and 137.8% for the normalized SB dose). The prediction models can predict the percentage dose increases in SI: Increased D(x)cc [%] = 31.370 – 7.865 ln(distance) – 3.949 ln(x) (absolute SB dose), and Increased D(x)cc [%] = 55.618 – 18.591 ln(distance) – 7.232 ln(x) (normalized SB dose). We developed prediction models for individual SB dose increase in SI in our study. SB hotspots in anterior SI require greater attention during cervical cancer brachytherapy. The models are new ones and are given for the first time. © 2019 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.
Introduction Intracavitary brachytherapy is an essential component of cervical cancer treatment. The International Commission on Radiation Units and Measurements (ICRU), the gynecological (GYN) GECESTRO working group, and the American Brachytherapy Society (ABS) have addressed the treatment guidelines for cervical cancer brachytherapy.1–4 Both the GYN GEC-ESTRO working group and the ABS have proposed recommendations for recording and reporting
✩ The research was conducted in the Department of Radiation Oncology, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei, Taiwan. ∗∗ Reprint requests to Ching-Jung Wu, M.D., Department of Radiation Oncology, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei, Taiwan. E-mail address: [email protected] (C.-J. Wu).
3-dimensional brachytherapy.5-7 The specifications include radiation doses that the bladder, rectum, and sigmoid colon receive. Nevertheless, the small bowel (SB) is not in a routine reporting list for organs at risk. During brachytherapy, suboptimal tandem insertion may occur in applications. The incidences of suboptimal insertions are 4.6% to 14.6% of patients and 3.0% to 13.7% of applications.8-11 Among suboptimal insertions, uterine perforation means the tandem truly penetrating through the uterine wall with the tip in the pelvic cavity. Physicians may stop the application and then arrange another insertion a few days later.9 , 10 However, a prolonged treatment duration has an adverse effect on local control and cause-specific survival.12-16 Therefore, some insertions with the tandem tip just extending into the myometrium or minimally through the serosa,
https://doi.org/10.1016/j.meddos.2019.11.002 0958-3947/© 2019 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.
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Fig. 1. An example of anterior and posterior subserosal insertion in contrast to intracavitary insertion with relative positions of the uterine tandem (white arrow), small bowel (black line), and cervical tumor (white line).
so called subserosal insertion (SI), are often left in place and are commonly seen in applications.8 , 11 In cases of SI, the uterine wall near the tandem tip is thin, and the tip may be close to the SB. The detrimental effects on SB dosimetry can therefore increase and thus cause late SB toxicities.17 Despite the importance of this issue, publications focusing on this from a dosimetry aspect are scarce, and the increased SB dose may be underestimated or unnoticed in clinical practice. In addition, cervical cancer patients may experience different types of SI at different insertion sites with different distances from the tandem tip to the SB. The SB dosimetry with respect to the tandem insertion of the anterior vs posterior uterine wall might be distinct, which requires different levels of concern and management strategies. The aim of this study is to quantify and further predict the individual percentage increases in the SB dose, compare the trends of increased SB doses regarding anterior vs posterior SI, and increase focus on the SB in SI during cervical cancer brachytherapy. Methods and Materials Patients Forty-four cervical cancer patients who were treated with computed tomography (CT)-based intracavitary brachytherapy using GammaMedplus iX (Varian Medical Systems, Palo Alto, CA, USA), a high-dose-rate remote afterloading system with an iridium-192 radioactive source, in a single institution were reviewed for potential SI. Patients with both the CT simulation images of the subserosal uterine tandem insertion of a 3-channel Henschke applicator (Mick Radio-Nuclear Instruments Inc., Mount Vernon, NY, USA) and intracavitary insertion (II) were identified for the study (Fig. 1). SI is defined as the tandem tip just extending into the myometrium or minimally through the serosa within 5 mm. Patients were selected via an experienced radiation oncologist slice by slice via CT simulation images. Finally, a total of 6 patients were eligible for the study, with images of 27 applications being analyzed. Treatment planning The studied plans were previously designed plans for brachytherapy treatment using Eclipse version 11.5 (Varian Medical Systems, Palo Alto, CA, USA). The main scheme involved delivering the prescribed dose to the high-risk clinical target volume (HR-CTV) of the cervical tumor while avoiding excessive doses to the bladder, rectum, and sigmoid colon as much as possible. The target delineation and treatment planning principles coincided with the recommendations of the GYN GECESTRO working group, as well as the consensus guidelines from the ABS.4-7 An experienced medical physicist made all plans individually with small individual adjustments for different applications. The final approval of each plan depended on the discretion of the attending physician in charge. Studied dosimetry For this study, the SB at risk adjacent to the cervical tumor was additionally contoured on all of the CT simulation images of SI and II, to assess how much the radiation doses increased in cases of SI during brachytherapy. The assessed doses were basically at 8 points of D(x)cc including D0.1cc , D10cc , D20cc , D30cc , D40cc , D50cc ,
D60cc , and D70cc . In the comparison of anterior vs posterior SI, the doses at D1cc , D2cc , and D5cc were additionally assessed to obtain more precise regression models for a better comparison. The D90 of the HR-CTV of the cervical tumor was also evaluated to derive a normalized SB dose for analysis. Data analysis Our first goal is to illustrate a general trend of percentage increases in the SB dose in SI. Specifically, the percentage increases were the percentage differences of the SB dose in SI compared with II. For each observed percentage difference, the denominator was the baseline containing the average dose of all applications with II for a patient, and the numerator was the single dose of an application with SI for the same patient minus her average dose of II. The percentage increase in the SB dose was defined according to the following formula: Increased dose [%] =
Dose(SI,
single )
− Dose(II,average)
Dose(II,average)
× 100%
where Increased dose [%] is the percentage increase in the SB dose in SI, Dose(SI,single) is the single dose of an application with SI, and Dose(II,average) is the average dose of all applications with II for the same patient. Both the absolute SB dose and the normalized SB dose, which was normalized to 90% of the D90 of HR-CTV in II in the study to evaluate all the SB doses with SI at the level in case the tumor dose coverage was 90% of that of II, were involved in the analysis. The normalized SB dose with SI regarding absolute SB dose was defined according to the following formula: Normalized SB dose(SI) =
Absolute SB dose(SI) D90(SI)
(D90(II) × 90% )
where Normalized SB dose(SI) is the normalized SB dose with SI, Absolute SB dose(SI) is the absolute SB dose with SI, D90(SI) is the D90 of HR-CTV in SI, and D90(II) is the D90 of HR-CTV in II. A box plot was used to demonstrate the median percentage increase at each assessed D(x)cc as well as the trend of the medians. Our second goal is to compare the percentage increases in anterior vs posterior SI. The percentage increases at each assessed D(x)cc were separately averaged for these 2 groups. A line graph of the average percentage increase was used to illustrate the differences in the SB doses in these 2 types of SI. Both the absolute SB dose and the normalized SB dose were analyzed. Our third goal is to develop an individual dose increase model to predict the SB dose increases with respect to any individual patient in the case of SI. To choose the prediction factors in the model, the minimum distance in centimeters (cm) from the tandem tip to the SB on the axial view of anterior SI was statistically compared with the distance of posterior SI. Figure 2 demonstrates how to measure the minimum distance from the tandem tip to the SB on the axial view. The distance and D(x)cc were further involved in the regression model as independent prediction factors, and their significance was tested for the model. The significant factors, along with their coefficients, constituted the final model.
Statistics The differences in minimum distance from the tandem tip to the SB on the axial view between anterior and posterior SI were tested using the Mann-Whitney test. The individual dose increase model was used to analyze the correlation between the percentage increase in the SB dose in SI and the distance and D(x)cc , which was
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Fig. 2. An example of the measurement of minimum distance from the tandem tip to the SB on the axial view (red marks). Anterior subserosal insertion has a shorter distance than posterior subserosal insertion. (Color version of figure is available online.).
Table 1 Patient and application characteristics
Dosimetry
Characteristics
Patients n (%)
Age Tumor size (diagnosis) Retroverted uterus Yes No Pathology SCC ADC
Median 69 years (range 48-74 years) Median 5.75 cm (range 1-7.5 cm)
Characteristics Insertion type Intracavitary Anterior SI Posterior SI Treated application Yes No
1 (17%) 5 (83%) 5 (83%) 1 (17%) Applications n (%) 19 (70%) 4 (15%) 4 (15%) 25 (93%) 2 (7%)
Abbreviations: ADC, adenocarcinoma; SCC, squamous cell carcinoma; SI, subserosal insertion.
regressed using linear regression with a logarithmic model. The model involved the natural logarithm of the distance ( ln(distance)) and the natural logarithm of the D(x)cc ( ln(x)) as independent prediction factors. The final model was established based on the significant factors and their coefficients. A p value less than 0.05 was considered significant. All of the statistical calculations and figure illustrations were applied in the R version 3.5.2., which is a programming language and free software environment for statistical computing and graphics supported by the R Foundation for Statistical Computing. Results Patients and applications Six patients who experienced both the SI and II in their applications during brachytherapy were identified. Their ages ranged from 48 to 74 years old, with a median age of 69. The tumor sizes at diagnosis ranged from 1 to 7.5 cm, with a median size of 5.75 cm. One patient had a retroverted uterus, and the rest had anteverted uteruses. Squamous cell carcinoma accounted for 83% of pathology reports. The patient characteristics are listed in Table 1. A total of 27 applications for the 6 patients were studied, including 4 applications with anterior SI, 4 with posterior SI, and 19 with II. Twenty-five applications (93%) were truly implemented according to the planning. The application characteristics are also listed in Table 1.
Figure 3 illustrates the box plot of the percentage increase in the absolute SB dose of all SI. The medians of the increase were consistent at 8 points of assessed D(x)cc, which ranged from 20.8% at D30cc to 29.4% at D0.1cc . The increases were more centralized at D20cc, D30cc , and D40cc , with smaller interquartile ranges. However, when the SB doses were normalized to 90% of the D90 of HR-CTV in II, the percentage increases demonstrated a logarithmic trend with a 55.4% increase at the hotspot, and centralization at D20cc, D30cc , and D40cc was no longer found. Figure 4 illustrates the box plot of the percentage increase in the normalized SB dose of all SI. Regarding the comparison of percentage increases in anterior vs posterior SI, the results revealed large differences between these 2 types of insertion. Figure 5 illustrates the line graph of the average percentage increase in the absolute SB dose, and Figure 6 illustrates the increase in the normalized SB dose. Both showed highly increased percentages in anterior SI at small SB volumes irradiated to high doses and significantly logarithmic trends for the curves of the lines, which were not seen in posterior SI. The average percentage increases at D0.1cc in anterior SI were 79.1% for the absolute dose and 137.8% for the normalized dose. Figure 7 and Figure 8 shows the representative isodose curves in anterior and posterior SI, respectively. The Mann-Whitney test demonstrated that the minimum distance from the tandem tip to the SB on the axial view in anterior SI was statistically shorter than the distance in posterior SI (p = 0.029). Figure 9 and Figure 10 illustrate the relationships between the distance and individual dose increase. The distance and D(x)cc , which showed significantly logarithmic trends in dose increase, could therefore be the prediction factors. In further linear regression, both the ln(distance) and ln(x) displayed statistical significance with the SB dose increase regarding the absolute dose (p < 0.001 and 0.011, respectively) and the normalized dose (p < 0.001 and 0.046, respectively). The final individual dose increase models, which can be used to predict the individual percentage increases in the SB dose in SI, are as follows: Increased D(x)cc [%] = 31.370 – 7.865 ln(distance) – 3.949 ln(x) (absolute SB dose), and Increased D(x)cc [%] = 55.618 – 18.591 ln(distance) – 7.232 ln(x) (normalized SB dose).
Discussion The individual dose increase models from our work highlight the SB dose increase in SI. The results disclose the importance of the issue of SB hotspots in anterior SI with a short distance from the tandem tip to the SB. The increased dose percentages can be far beyond our imagination and now can be predicted using our models. To our knowledge, few publications have focused on the topic of SI, and none of them addressed anterior SI with SB hotspots.11 Earlier researchers studied the SB dose-volume effects during whole pelvic radiotherapy.18-22 However, the dosimetry of brachytherapy is quite different from whole pelvic radiotherapy, which usually generates a large irradiated field with homogeneity, as brachytherapy generally creates a local irradiated area with a high-dose gradient containing focal hotspots. The ICRU Report 89 addressed the SB as a serial organ consisting of a chain of
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Fig. 3. Box plot of percentage increase in absolute SB dose of all subserosal insertions. The medians are all within 20% to 30% (horizontal dark bars). (The percentage increase is a fraction. The denominator is the average dose of all applications with intracavitary insertion for a patient, and the numerator is the single dose of an application with subserosal insertion for the same patient minus her average dose of intracavitary insertion.).
Fig. 4. Box plot of percentage increase in normalized SB dose of all subserosal insertions. The medians have a logarithmic trend with a 55.4% increase at hotspot (horizontal dark bars).
functional units that all need to be preserved to guarantee tissue functionality.2 As shown in our results, the SB hotspots in anterior SI may damage a small part of the SB and lead to greater functional impairments. To correctly interpret the SB dosimetry in SI in the study, the percentage increases were intensively analyzed with only 10cc intervals for D(x)cc, and the doses at D1cc , D2cc , and D5cc in anterior SI were additionally assessed to clearly demonstrate the increased trend. Due to the fact that the studied plans were individually designed plans with different cervical tumor doses, normalized SB
doses under the same benchmark were also evaluated. The extents of the increase in normalized SB doses were more significant than those of the absolute doses were. This phenomenon probably means that when one is trying to decrease the doses to the bladder, rectum, and sigmoid colon in SI, the tumor coverage may be compromised, and the SB dose may be partially lowered synchronously. Nevertheless, the approximately 80% increase in doses at hotspots in anterior SI emphasizes the seriousness of this issue. To understand more about the hotspots and SB complications, Kim et al. conducted a study to analyze the hotspots in cervi-
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Fig. 5. Differences of anterior (red solid line) vs posterior subserosal insertion (blue dash line) in the average percentage increase in absolute SB dose. (Color version of figure is available online.)
Fig. 6. Differences of anterior (red solid line) vs posterior subserosal insertion (blue dash line) in the average percentage increase in normalized SB dose. (Color version of figure is available online.)
cal cancer brachytherapy. They stated that the sizes and shapes of hotspots varied substantially with an average thickness of 0.4 cm. The SB was the dose-limiting organ in 39% of patients. The SB D2cc was usually multiple fragments that were often clustered together at the anterior or posterior surface around the superior endocervix, which is the narrowest portion of the uterus. Additionally, almost all D0.1cc hotspots were located within the largest fragment of the D2cc hotspot.23
The complication rate of the SB is high in cervical cancer brachytherapy. SB obstruction is the most frequent complication among all types of high-grade toxicity. The actuarial risks of SB obstruction with grade 3 or more are 3.9% at 5 years, 4.3% at 10 years, and 5.3% at 20 years.24 Regarding all grades of toxicity, the late complication rates are 4% at 2 years and 14% at 5 years for the SB, which are less than that of the rectum and more than that of the bladder.25 , 26 Malabsorption is another SB complication among
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Fig. 7. Representative isodose curves in anterior subserosal insertion. SB is indicated by the black line.
Fig. 8. Representative isodose curves in posterior subserosal insertion. SB is indicated by the black line.
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Fig. 9. Dot plot to show the relationship between minimum distance from the tandem tip to the SB on the axial view and individual dose increase in absolute SB dose. The dose increase can be predicted using the individual dose increase model: Increased D(x)cc [%] = 31.370-7.865 ln(distance)-3.949 ln(x).
Fig. 10. Dot plot to show the relationship between minimum distance from the tandem tip to the SB on the axial view and individual dose increase in normalized SB dose. The dose increase can be predicted using the individual dose increase model: Increased D(x)cc [%] = 55.618-18.591 ln(distance) – 7.232 ln(x).
long-term survivors of cervical cancer treated with radiotherapy. Significant cobalamin deficiency and low calcium levels occur in 15 to 20% of patients within 6 to 12 years after radiotherapy.27 The amount of the radiation dose delivered to the SB is correlated with SB complications. In treating cervical cancer, the incidences of grade 3 SB sequelae are 1% with doses of 50 Gy, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall.28 Regarding the dose that the SB receives directly, both the D0.1cc and D2cc have an increased trend in patients with grade zero to grade 3 SB morbidities, which are, respectively, 79.5 Gy and 66.5 Gy for grade zero morbidities but up to 100.4 Gy and 78.1 Gy for grade 3 morbidities.29
Although SI is commonly seen in applications and is acceptable for some cases, it is still a kind of suboptimal insertion, and preventions for it might be helpful. To prevent suboptimal insertions, ultrasound-guided tandem insertion is the most often used strategy, which reduces the incidence to as low as 1.4%.30-35 Preoperative magnetic resonance imaging (MRI) is another practical strategy, while ultrasound guidance is not performed. It yields a decreased incidence from 11% to 4%.10 Other strategies mentioned in the literature include laparoscopy-assisted placement for difficult cases or direct endoscopic evaluation during tandem insertion.36 , 37 All of the strategies try to avoid suboptimal insertions in advance.
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In case SI still appears in spite of the preventions, the SB dose can be reduced if increased SB dosimetry is evaluated. Bladder distension was the most commonly used method for reducing the SB dose during cervical cancer brachytherapy despite the expense of more bladder doses mentioned in some references.38-42 Earlier researchers applied internal pelvic displacement prosthesis or external SB displacement systems in sparing the SB during whole pelvic radiotherapy.43 , 44 The feasibility and efficacy of using a similar device in brachytherapy has potential. The SB can also be spared more in the treatment planning. Liao et al. revised the plans with SB D2cc of more than 5 Gy and achieved an average reduction of 19% in D2cc .45 This study has some limitations. First, the sample size was relatively small, with a total of only 27 brachytherapy applications assessed. However, this was sufficient for demonstrating the significant and meaningful result that anterior SI led to much higher SB hotspots, and we successfully developed prediction models for the dose increase in our study. The dose increase was due to the location of the SB in the anatomy and the fact that the uterine tandem was close to the SB in anterior SI, resulting in a higher radiation dose delivered to the adjacent SB. Second, the prediction models provide general estimations of the dose increase by using the distance from the tandem tip to the SB and D(x)cc as prediction factors. Other anatomical differences which were not involved in the regression cannot be accounted for by the models. In clinical practice, if pelvic difference seems to have large influence on the dose, it is crucial to evaluate the dose for the application individually. Third, the dosimetry data in the study were derived from the real treated plans. The advantages of this include the authenticity of the assessed doses, which cervical cancer patients truly received, and the reliability of the presented SB dose, as the SB was additionally contoured after the plans were designed and delivered. However, because the plans were individually designed, the cervical tumor dose amounts in different applications were not exactly the same. For the purpose of producing a better comparison under the same benchmark, 90% of the D90 of HR-CTV in II was used to obtain a normalized SB result. Fourth, the SB doses were assessed at 10 cc intervals for D(x)cc so that the increased trend could be analyzed. Larger intervals lead to less accurate results, and smaller intervals are difficult to implement. The limitation of 10 cc intervals was that we did not know whether the doses within these intervals still fit to the regression line. Nevertheless, due to the continuity of the dosimetry, the limitation is unlikely to affect the results.
Conclusions Subserosal tandem insertion is a clinical scenario commonly seen in cervical cancer brachytherapy. Anterior SI is the type that may cause greatly increased yet unnoticed SB doses. The increased doses demonstrate a logarithmic trend with highly increased percentages at hotspots. In our study, we developed prediction models for individual SB dose increase in SI and provided them for the first time to help medical professionals having more understanding of this issue.
Declaration of Competing Interest All authors have no conflicts of interest to disclose.
Acknowledgments Not applicable.
Ethics Approval and Consent to Participate The present study is ethically approved by institutional review board of the Cathay General Hospital. The reference number is CGH-P106080. Authors’ Contributions YLT participated in the design of the study, data collection, and paper writing. PCY designed the treatment plans. LTL involved in the acquisition of data and patient care. SS involved in the acquisition of data and patient care. CJW participated in the revising of the manuscript critically for important intellectual content. All authors read and approved the final manuscript. References 1. Potter, R.; Van Limbergen, E.; Gerstner, N.; et al. Survey of the use of the ICRU 38 in recording and reporting cervical cancer brachytherapy. Radiother Oncol 58:11–18; 2001. 2. Report 89. J ICRU 2013;13:Np. 3. Nag, S.; Erickson, B.; Thomadsen, B.; et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. 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and without abdominal surgery: A prospective study with computed tomography-based dosimetry. Int J Radiat Oncol Biol Phys 69:732–9; 2007. Robertson, J.M.; Lockman, D.; Yan, D.; et al. The dose-volume relationship of small bowel irradiation and acute grade 3 diarrhea during chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 70:413–18; 2008. Kim, R.Y.; Dragovic, A.F.; Whitley, A.C.; et al. Image-guided brachytherapy for cervical cancer: Analysis of D2 cc hot spot in three-dimensional and anatomic factors affecting D2 cc hot spot in organs at risk. Brachytherapy 13:203–9; 2014. Eifel, P.J.; Levenback, C.; Wharton, J.T.; et al. Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 32:1289–300; 1995. Toita, T.; Kato, S.; Niibe, Y.; et al. Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage I and II uterine cervical cancer (JAROG0401/JROSG04-2). Int J Radiat Oncol Biol Phys 82:e49–56; 2012. Ferrigno, R.; dos Santos Novaes, P.E.; Pellizzon, A.C.; et al. High-dose-rate brachytherapy in the treatment of uterine cervix cancer. Analysis of dose effectiveness and late complications. Int J Radiat Oncol Biol Phys 50:1123–35; 2001. Vistad, I.; Kristensen, G.B.; Fossa, S.D.; et al. Intestinal malabsorption in long-term survivors of cervical cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 73:1141–7; 2009. Perez, C.A.; Grigsby, P.W.; Lockett, M.A.; Chao, K.S.; Williamson, J. Radiation therapy morbidity in carcinoma of the uterine cervix: Dosimetric and clinical correlation. Int J Radiat Oncol Biol Phys 44:855–66; 1999. Petit, C.; Dumas, I.; Chargari, C.; et al. MRI-guided brachytherapy in locally advanced cervical cancer: Small bowel D0.1cm³ and D2cm³ are not predictive of late morbidity. Brachytherapy 15:463–70; 2016. Mayr, N.A.; Montebello, J.F.; Sorosky, J.I.; et al. Brachytherapy management of the retroverted uterus using ultrasound-guided implant applicator placement. Brachytherapy 4:24–9; 2005. Davidson, M.T.; Yuen, J.; D’Souza, D.P.; et al. Optimization of high-dose-rate cervix brachytherapy applicator placement: The benefits of intraoperative ultrasound guidance. Brachytherapy 7:248–53; 2008. Small Jr., W.; Strauss, J.B.; Hwang, C.S.; et al. Should uterine tandem applicators ever be placed without ultrasound guidance? No: A brief report and review of the literature. Int J Gynecol Cancer 21:941–4; 2011. Rao, P.B.; Ghosh, S. Routine use of ultrasound guided tandem placement in intracavitary brachytherapy for the treatment of cervical cancer - a South Indian institutional experience. J Contemp Brachytherapy 7:352–6; 2015.
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34. Watkins, J.M.; Kearney, P.L.; Opfermann, K.J.; et al. Ultrasound-guided tandem placement for low-dose-rate brachytherapy in advanced cervical cancer minimizes risk of intraoperative uterine perforation. Ultrasound Obstet Gynecol 37:241–4; 2011. 35. Schaner, P.E.; Caudell, J.J.; De Los Santos, J.F.; et al. Intraoperative ultrasound guidance during intracavitary brachytherapy applicator placement in cervical cancer: The University of Alabama at Birmingham experience. Int J Gynecol Cancer 23:559–66; 2013. 36. Lim, M.C.; Jung, D.C.; Kim, J.Y.; et al. Laparoscopy-assisted intracavitary radiotherapy tandem placement for patients with cervical cancer. Int J Gynecol Cancer 19:1125–30; 2009. 37. Irvin, W.; Rice, L.; Taylor, P.; et al. Uterine perforation at the time of brachytherapy for carcinoma of the cervix. Gynecol Oncol 90:113–22; 2003. 38. Cengiz, M.; Gurdalli, S.; Selek, U.; et al. Effect of bladder distension on dose distribution of intracavitary brachytherapy for cervical cancer: Three-dimensional computed tomography plan evaluation. Int J Radiat Oncol Biol Phys 70:464–8; 2008. 39. Kim, R.Y.; Shen, S.; Lin, H.Y.; et al. Effects of bladder distension on organs at risk in 3D image-based planning of intracavitary brachytherapy for cervical cancer. Int J Radiat Oncol Biol Phys 76:485–9; 2010. 40. Yamashita, H.; Nakagawa, K.; Okuma, K.; et al. Correlation between bladder volume and irradiated dose of small bowel in CT-based planning of intracavitary brachytherapy for cervical cancer. Jpn J Clin Oncol 42:302–8; 2012. 41. Patra, N.B.; Manir, K.S.; Basu, S.; et al. Effect of bladder distension on dosimetry of organs at risk in computer tomography based planning of high-dose-rate intracavitary brachytherapy for cervical cancer. J Contemp Brachytherapy 5:3–9; 2013. 42. Harmon, G.; Chinsky, B.; Surucu, M.; et al. Bladder distension improves the dosimetry of organs at risk during intracavitary cervical high-dose-rate brachytherapy. Brachytherapy 15:30–4; 2016. 43. Burnett, A.F.; Coe, F.L.; Klement, V.; et al. The use of a pelvic displacement prosthesis to exclude the small intestine from the radiation field following radical hysterectomy. Gynecol Oncol 79:438–43; 20 0 0. 44. Huh, S.J.; Kang, M.K.; Han, Y. Small bowel displacement system-assisted intensity-modulated radiotherapy for cervical cancer. Gynecol Oncol 93:40 0–6; 20 04. 45. Liao, Y.; Dandekar, V.; Chu, J.C.; et al. Reporting small bowel dose in cervix cancer high-dose-rate brachytherapy. Med Dosim 41:28–33; 2016.
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Small bowel dose in subserosal tandem insertion during cervical cancer brachytherapy ✩ Yu-Lun Tsai, M.D. ∗, Pei-Chieh Yu, Ph.D. ∗,†, Louis Tak Lui, M.D. ∗, Suzun Shaw, M.D. ∗,‡, Ching-Jung Wu, M.D. ∗,§,║,∗∗ ∗
Department of Radiation Oncology, Cathay General Hospital, Taipei, Taiwan School of Medicine, China Medical University, Taichung, Taiwan ‡ Oncology Treatment Center, Sijhih Cathay General Hospital, New Taipei, Taiwan § Department of Radiation Oncology, National Defense Medical Center, Taipei, Taiwan ║ Department of Biomedical Engineering, I-Shou University, Kaohsiung, Taiwan †
a r t i c l e
i n f o
Article history: Received 5 June 2019 Revised 21 November 2019 Accepted 21 November 2019 Available online xxx Keywords: Small bowel Subserosal insertion Brachytherapy Cervical cancer
a b s t r a c t Cervical cancer patients may sometimes experience subserosal tandem insertions during brachytherapy, which can lead to increased but unnoticed irradiations to the small bowel (SB). In this study, we aimed to quantify and further predict individual SB dose increase and to increase focus on the SB in subserosal tandem insertions. Images and dosimetry data of cervical cancer brachytherapy with subserosal insertion (SI) were reviewed. The percentage increases in the SB dose compared with intracavitary insertion (II) at 8 points of D(x)cc with 10 cc intervals were assessed. SI was classified into anterior and posterior SI according to the insertion site. The differences in minimum distance from the tandem tip to the SB on the axial view between these 2 insertions were tested using the Mann-Whitney test. The distance and D(x)cc were involved in the individual dose increase model by linear regression as prediction factors. A total of 27 insertions were evaluated, including 8 insertions with SI and 19 insertions with II. The median percentage increases in the normalized SB dose for all SI showed a logarithmic trend with a 55.4% increase at the hotspot. In contrast to posterior SI, anterior SI demonstrated a more significantly logarithmic trend, which featured highly increased doses at the hotspot (79.1% for the absolute SB dose and 137.8% for the normalized SB dose). The prediction models can predict the percentage dose increases in SI: Increased D(x)cc [%] = 31.370 – 7.865 ln(distance) – 3.949 ln(x) (absolute SB dose), and Increased D(x)cc [%] = 55.618 – 18.591 ln(distance) – 7.232 ln(x) (normalized SB dose). We developed prediction models for individual SB dose increase in SI in our study. SB hotspots in anterior SI require greater attention during cervical cancer brachytherapy. The models are new ones and are given for the first time. © 2019 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.
Introduction Intracavitary brachytherapy is an essential component of cervical cancer treatment. The International Commission on Radiation Units and Measurements (ICRU), the gynecological (GYN) GECESTRO working group, and the American Brachytherapy Society (ABS) have addressed the treatment guidelines for cervical cancer brachytherapy.1–4 Both the GYN GEC-ESTRO working group and the ABS have proposed recommendations for recording and reporting
✩ The research was conducted in the Department of Radiation Oncology, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei, Taiwan. ∗∗ Reprint requests to Ching-Jung Wu, M.D., Department of Radiation Oncology, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei, Taiwan. E-mail address: [email protected] (C.-J. Wu).
3-dimensional brachytherapy.5-7 The specifications include radiation doses that the bladder, rectum, and sigmoid colon receive. Nevertheless, the small bowel (SB) is not in a routine reporting list for organs at risk. During brachytherapy, suboptimal tandem insertion may occur in applications. The incidences of suboptimal insertions are 4.6% to 14.6% of patients and 3.0% to 13.7% of applications.8-11 Among suboptimal insertions, uterine perforation means the tandem truly penetrating through the uterine wall with the tip in the pelvic cavity. Physicians may stop the application and then arrange another insertion a few days later.9 , 10 However, a prolonged treatment duration has an adverse effect on local control and cause-specific survival.12-16 Therefore, some insertions with the tandem tip just extending into the myometrium or minimally through the serosa,
https://doi.org/10.1016/j.meddos.2019.11.002 0958-3947/© 2019 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.
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Fig. 1. An example of anterior and posterior subserosal insertion in contrast to intracavitary insertion with relative positions of the uterine tandem (white arrow), small bowel (black line), and cervical tumor (white line).
so called subserosal insertion (SI), are often left in place and are commonly seen in applications.8 , 11 In cases of SI, the uterine wall near the tandem tip is thin, and the tip may be close to the SB. The detrimental effects on SB dosimetry can therefore increase and thus cause late SB toxicities.17 Despite the importance of this issue, publications focusing on this from a dosimetry aspect are scarce, and the increased SB dose may be underestimated or unnoticed in clinical practice. In addition, cervical cancer patients may experience different types of SI at different insertion sites with different distances from the tandem tip to the SB. The SB dosimetry with respect to the tandem insertion of the anterior vs posterior uterine wall might be distinct, which requires different levels of concern and management strategies. The aim of this study is to quantify and further predict the individual percentage increases in the SB dose, compare the trends of increased SB doses regarding anterior vs posterior SI, and increase focus on the SB in SI during cervical cancer brachytherapy. Methods and Materials Patients Forty-four cervical cancer patients who were treated with computed tomography (CT)-based intracavitary brachytherapy using GammaMedplus iX (Varian Medical Systems, Palo Alto, CA, USA), a high-dose-rate remote afterloading system with an iridium-192 radioactive source, in a single institution were reviewed for potential SI. Patients with both the CT simulation images of the subserosal uterine tandem insertion of a 3-channel Henschke applicator (Mick Radio-Nuclear Instruments Inc., Mount Vernon, NY, USA) and intracavitary insertion (II) were identified for the study (Fig. 1). SI is defined as the tandem tip just extending into the myometrium or minimally through the serosa within 5 mm. Patients were selected via an experienced radiation oncologist slice by slice via CT simulation images. Finally, a total of 6 patients were eligible for the study, with images of 27 applications being analyzed. Treatment planning The studied plans were previously designed plans for brachytherapy treatment using Eclipse version 11.5 (Varian Medical Systems, Palo Alto, CA, USA). The main scheme involved delivering the prescribed dose to the high-risk clinical target volume (HR-CTV) of the cervical tumor while avoiding excessive doses to the bladder, rectum, and sigmoid colon as much as possible. The target delineation and treatment planning principles coincided with the recommendations of the GYN GECESTRO working group, as well as the consensus guidelines from the ABS.4-7 An experienced medical physicist made all plans individually with small individual adjustments for different applications. The final approval of each plan depended on the discretion of the attending physician in charge. Studied dosimetry For this study, the SB at risk adjacent to the cervical tumor was additionally contoured on all of the CT simulation images of SI and II, to assess how much the radiation doses increased in cases of SI during brachytherapy. The assessed doses were basically at 8 points of D(x)cc including D0.1cc , D10cc , D20cc , D30cc , D40cc , D50cc ,
D60cc , and D70cc . In the comparison of anterior vs posterior SI, the doses at D1cc , D2cc , and D5cc were additionally assessed to obtain more precise regression models for a better comparison. The D90 of the HR-CTV of the cervical tumor was also evaluated to derive a normalized SB dose for analysis. Data analysis Our first goal is to illustrate a general trend of percentage increases in the SB dose in SI. Specifically, the percentage increases were the percentage differences of the SB dose in SI compared with II. For each observed percentage difference, the denominator was the baseline containing the average dose of all applications with II for a patient, and the numerator was the single dose of an application with SI for the same patient minus her average dose of II. The percentage increase in the SB dose was defined according to the following formula: Increased dose [%] =
Dose(SI,
single )
− Dose(II,average)
Dose(II,average)
× 100%
where Increased dose [%] is the percentage increase in the SB dose in SI, Dose(SI,single) is the single dose of an application with SI, and Dose(II,average) is the average dose of all applications with II for the same patient. Both the absolute SB dose and the normalized SB dose, which was normalized to 90% of the D90 of HR-CTV in II in the study to evaluate all the SB doses with SI at the level in case the tumor dose coverage was 90% of that of II, were involved in the analysis. The normalized SB dose with SI regarding absolute SB dose was defined according to the following formula: Normalized SB dose(SI) =
Absolute SB dose(SI) D90(SI)
(D90(II) × 90% )
where Normalized SB dose(SI) is the normalized SB dose with SI, Absolute SB dose(SI) is the absolute SB dose with SI, D90(SI) is the D90 of HR-CTV in SI, and D90(II) is the D90 of HR-CTV in II. A box plot was used to demonstrate the median percentage increase at each assessed D(x)cc as well as the trend of the medians. Our second goal is to compare the percentage increases in anterior vs posterior SI. The percentage increases at each assessed D(x)cc were separately averaged for these 2 groups. A line graph of the average percentage increase was used to illustrate the differences in the SB doses in these 2 types of SI. Both the absolute SB dose and the normalized SB dose were analyzed. Our third goal is to develop an individual dose increase model to predict the SB dose increases with respect to any individual patient in the case of SI. To choose the prediction factors in the model, the minimum distance in centimeters (cm) from the tandem tip to the SB on the axial view of anterior SI was statistically compared with the distance of posterior SI. Figure 2 demonstrates how to measure the minimum distance from the tandem tip to the SB on the axial view. The distance and D(x)cc were further involved in the regression model as independent prediction factors, and their significance was tested for the model. The significant factors, along with their coefficients, constituted the final model.
Statistics The differences in minimum distance from the tandem tip to the SB on the axial view between anterior and posterior SI were tested using the Mann-Whitney test. The individual dose increase model was used to analyze the correlation between the percentage increase in the SB dose in SI and the distance and D(x)cc , which was
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Fig. 2. An example of the measurement of minimum distance from the tandem tip to the SB on the axial view (red marks). Anterior subserosal insertion has a shorter distance than posterior subserosal insertion. (Color version of figure is available online.).
Table 1 Patient and application characteristics
Dosimetry
Characteristics
Patients n (%)
Age Tumor size (diagnosis) Retroverted uterus Yes No Pathology SCC ADC
Median 69 years (range 48-74 years) Median 5.75 cm (range 1-7.5 cm)
Characteristics Insertion type Intracavitary Anterior SI Posterior SI Treated application Yes No
1 (17%) 5 (83%) 5 (83%) 1 (17%) Applications n (%) 19 (70%) 4 (15%) 4 (15%) 25 (93%) 2 (7%)
Abbreviations: ADC, adenocarcinoma; SCC, squamous cell carcinoma; SI, subserosal insertion.
regressed using linear regression with a logarithmic model. The model involved the natural logarithm of the distance ( ln(distance)) and the natural logarithm of the D(x)cc ( ln(x)) as independent prediction factors. The final model was established based on the significant factors and their coefficients. A p value less than 0.05 was considered significant. All of the statistical calculations and figure illustrations were applied in the R version 3.5.2., which is a programming language and free software environment for statistical computing and graphics supported by the R Foundation for Statistical Computing. Results Patients and applications Six patients who experienced both the SI and II in their applications during brachytherapy were identified. Their ages ranged from 48 to 74 years old, with a median age of 69. The tumor sizes at diagnosis ranged from 1 to 7.5 cm, with a median size of 5.75 cm. One patient had a retroverted uterus, and the rest had anteverted uteruses. Squamous cell carcinoma accounted for 83% of pathology reports. The patient characteristics are listed in Table 1. A total of 27 applications for the 6 patients were studied, including 4 applications with anterior SI, 4 with posterior SI, and 19 with II. Twenty-five applications (93%) were truly implemented according to the planning. The application characteristics are also listed in Table 1.
Figure 3 illustrates the box plot of the percentage increase in the absolute SB dose of all SI. The medians of the increase were consistent at 8 points of assessed D(x)cc, which ranged from 20.8% at D30cc to 29.4% at D0.1cc . The increases were more centralized at D20cc, D30cc , and D40cc , with smaller interquartile ranges. However, when the SB doses were normalized to 90% of the D90 of HR-CTV in II, the percentage increases demonstrated a logarithmic trend with a 55.4% increase at the hotspot, and centralization at D20cc, D30cc , and D40cc was no longer found. Figure 4 illustrates the box plot of the percentage increase in the normalized SB dose of all SI. Regarding the comparison of percentage increases in anterior vs posterior SI, the results revealed large differences between these 2 types of insertion. Figure 5 illustrates the line graph of the average percentage increase in the absolute SB dose, and Figure 6 illustrates the increase in the normalized SB dose. Both showed highly increased percentages in anterior SI at small SB volumes irradiated to high doses and significantly logarithmic trends for the curves of the lines, which were not seen in posterior SI. The average percentage increases at D0.1cc in anterior SI were 79.1% for the absolute dose and 137.8% for the normalized dose. Figure 7 and Figure 8 shows the representative isodose curves in anterior and posterior SI, respectively. The Mann-Whitney test demonstrated that the minimum distance from the tandem tip to the SB on the axial view in anterior SI was statistically shorter than the distance in posterior SI (p = 0.029). Figure 9 and Figure 10 illustrate the relationships between the distance and individual dose increase. The distance and D(x)cc , which showed significantly logarithmic trends in dose increase, could therefore be the prediction factors. In further linear regression, both the ln(distance) and ln(x) displayed statistical significance with the SB dose increase regarding the absolute dose (p < 0.001 and 0.011, respectively) and the normalized dose (p < 0.001 and 0.046, respectively). The final individual dose increase models, which can be used to predict the individual percentage increases in the SB dose in SI, are as follows: Increased D(x)cc [%] = 31.370 – 7.865 ln(distance) – 3.949 ln(x) (absolute SB dose), and Increased D(x)cc [%] = 55.618 – 18.591 ln(distance) – 7.232 ln(x) (normalized SB dose).
Discussion The individual dose increase models from our work highlight the SB dose increase in SI. The results disclose the importance of the issue of SB hotspots in anterior SI with a short distance from the tandem tip to the SB. The increased dose percentages can be far beyond our imagination and now can be predicted using our models. To our knowledge, few publications have focused on the topic of SI, and none of them addressed anterior SI with SB hotspots.11 Earlier researchers studied the SB dose-volume effects during whole pelvic radiotherapy.18-22 However, the dosimetry of brachytherapy is quite different from whole pelvic radiotherapy, which usually generates a large irradiated field with homogeneity, as brachytherapy generally creates a local irradiated area with a high-dose gradient containing focal hotspots. The ICRU Report 89 addressed the SB as a serial organ consisting of a chain of
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Fig. 3. Box plot of percentage increase in absolute SB dose of all subserosal insertions. The medians are all within 20% to 30% (horizontal dark bars). (The percentage increase is a fraction. The denominator is the average dose of all applications with intracavitary insertion for a patient, and the numerator is the single dose of an application with subserosal insertion for the same patient minus her average dose of intracavitary insertion.).
Fig. 4. Box plot of percentage increase in normalized SB dose of all subserosal insertions. The medians have a logarithmic trend with a 55.4% increase at hotspot (horizontal dark bars).
functional units that all need to be preserved to guarantee tissue functionality.2 As shown in our results, the SB hotspots in anterior SI may damage a small part of the SB and lead to greater functional impairments. To correctly interpret the SB dosimetry in SI in the study, the percentage increases were intensively analyzed with only 10cc intervals for D(x)cc, and the doses at D1cc , D2cc , and D5cc in anterior SI were additionally assessed to clearly demonstrate the increased trend. Due to the fact that the studied plans were individually designed plans with different cervical tumor doses, normalized SB
doses under the same benchmark were also evaluated. The extents of the increase in normalized SB doses were more significant than those of the absolute doses were. This phenomenon probably means that when one is trying to decrease the doses to the bladder, rectum, and sigmoid colon in SI, the tumor coverage may be compromised, and the SB dose may be partially lowered synchronously. Nevertheless, the approximately 80% increase in doses at hotspots in anterior SI emphasizes the seriousness of this issue. To understand more about the hotspots and SB complications, Kim et al. conducted a study to analyze the hotspots in cervi-
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Fig. 5. Differences of anterior (red solid line) vs posterior subserosal insertion (blue dash line) in the average percentage increase in absolute SB dose. (Color version of figure is available online.)
Fig. 6. Differences of anterior (red solid line) vs posterior subserosal insertion (blue dash line) in the average percentage increase in normalized SB dose. (Color version of figure is available online.)
cal cancer brachytherapy. They stated that the sizes and shapes of hotspots varied substantially with an average thickness of 0.4 cm. The SB was the dose-limiting organ in 39% of patients. The SB D2cc was usually multiple fragments that were often clustered together at the anterior or posterior surface around the superior endocervix, which is the narrowest portion of the uterus. Additionally, almost all D0.1cc hotspots were located within the largest fragment of the D2cc hotspot.23
The complication rate of the SB is high in cervical cancer brachytherapy. SB obstruction is the most frequent complication among all types of high-grade toxicity. The actuarial risks of SB obstruction with grade 3 or more are 3.9% at 5 years, 4.3% at 10 years, and 5.3% at 20 years.24 Regarding all grades of toxicity, the late complication rates are 4% at 2 years and 14% at 5 years for the SB, which are less than that of the rectum and more than that of the bladder.25 , 26 Malabsorption is another SB complication among
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Fig. 7. Representative isodose curves in anterior subserosal insertion. SB is indicated by the black line.
Fig. 8. Representative isodose curves in posterior subserosal insertion. SB is indicated by the black line.
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Fig. 9. Dot plot to show the relationship between minimum distance from the tandem tip to the SB on the axial view and individual dose increase in absolute SB dose. The dose increase can be predicted using the individual dose increase model: Increased D(x)cc [%] = 31.370-7.865 ln(distance)-3.949 ln(x).
Fig. 10. Dot plot to show the relationship between minimum distance from the tandem tip to the SB on the axial view and individual dose increase in normalized SB dose. The dose increase can be predicted using the individual dose increase model: Increased D(x)cc [%] = 55.618-18.591 ln(distance) – 7.232 ln(x).
long-term survivors of cervical cancer treated with radiotherapy. Significant cobalamin deficiency and low calcium levels occur in 15 to 20% of patients within 6 to 12 years after radiotherapy.27 The amount of the radiation dose delivered to the SB is correlated with SB complications. In treating cervical cancer, the incidences of grade 3 SB sequelae are 1% with doses of 50 Gy, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall.28 Regarding the dose that the SB receives directly, both the D0.1cc and D2cc have an increased trend in patients with grade zero to grade 3 SB morbidities, which are, respectively, 79.5 Gy and 66.5 Gy for grade zero morbidities but up to 100.4 Gy and 78.1 Gy for grade 3 morbidities.29
Although SI is commonly seen in applications and is acceptable for some cases, it is still a kind of suboptimal insertion, and preventions for it might be helpful. To prevent suboptimal insertions, ultrasound-guided tandem insertion is the most often used strategy, which reduces the incidence to as low as 1.4%.30-35 Preoperative magnetic resonance imaging (MRI) is another practical strategy, while ultrasound guidance is not performed. It yields a decreased incidence from 11% to 4%.10 Other strategies mentioned in the literature include laparoscopy-assisted placement for difficult cases or direct endoscopic evaluation during tandem insertion.36 , 37 All of the strategies try to avoid suboptimal insertions in advance.
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In case SI still appears in spite of the preventions, the SB dose can be reduced if increased SB dosimetry is evaluated. Bladder distension was the most commonly used method for reducing the SB dose during cervical cancer brachytherapy despite the expense of more bladder doses mentioned in some references.38-42 Earlier researchers applied internal pelvic displacement prosthesis or external SB displacement systems in sparing the SB during whole pelvic radiotherapy.43 , 44 The feasibility and efficacy of using a similar device in brachytherapy has potential. The SB can also be spared more in the treatment planning. Liao et al. revised the plans with SB D2cc of more than 5 Gy and achieved an average reduction of 19% in D2cc .45 This study has some limitations. First, the sample size was relatively small, with a total of only 27 brachytherapy applications assessed. However, this was sufficient for demonstrating the significant and meaningful result that anterior SI led to much higher SB hotspots, and we successfully developed prediction models for the dose increase in our study. The dose increase was due to the location of the SB in the anatomy and the fact that the uterine tandem was close to the SB in anterior SI, resulting in a higher radiation dose delivered to the adjacent SB. Second, the prediction models provide general estimations of the dose increase by using the distance from the tandem tip to the SB and D(x)cc as prediction factors. Other anatomical differences which were not involved in the regression cannot be accounted for by the models. In clinical practice, if pelvic difference seems to have large influence on the dose, it is crucial to evaluate the dose for the application individually. Third, the dosimetry data in the study were derived from the real treated plans. The advantages of this include the authenticity of the assessed doses, which cervical cancer patients truly received, and the reliability of the presented SB dose, as the SB was additionally contoured after the plans were designed and delivered. However, because the plans were individually designed, the cervical tumor dose amounts in different applications were not exactly the same. For the purpose of producing a better comparison under the same benchmark, 90% of the D90 of HR-CTV in II was used to obtain a normalized SB result. Fourth, the SB doses were assessed at 10 cc intervals for D(x)cc so that the increased trend could be analyzed. Larger intervals lead to less accurate results, and smaller intervals are difficult to implement. The limitation of 10 cc intervals was that we did not know whether the doses within these intervals still fit to the regression line. Nevertheless, due to the continuity of the dosimetry, the limitation is unlikely to affect the results.
Conclusions Subserosal tandem insertion is a clinical scenario commonly seen in cervical cancer brachytherapy. Anterior SI is the type that may cause greatly increased yet unnoticed SB doses. The increased doses demonstrate a logarithmic trend with highly increased percentages at hotspots. In our study, we developed prediction models for individual SB dose increase in SI and provided them for the first time to help medical professionals having more understanding of this issue.
Declaration of Competing Interest All authors have no conflicts of interest to disclose.
Acknowledgments Not applicable.
Ethics Approval and Consent to Participate The present study is ethically approved by institutional review board of the Cathay General Hospital. The reference number is CGH-P106080. Authors’ Contributions YLT participated in the design of the study, data collection, and paper writing. PCY designed the treatment plans. LTL involved in the acquisition of data and patient care. SS involved in the acquisition of data and patient care. CJW participated in the revising of the manuscript critically for important intellectual content. All authors read and approved the final manuscript. References 1. Potter, R.; Van Limbergen, E.; Gerstner, N.; et al. Survey of the use of the ICRU 38 in recording and reporting cervical cancer brachytherapy. Radiother Oncol 58:11–18; 2001. 2. Report 89. J ICRU 2013;13:Np. 3. Nag, S.; Erickson, B.; Thomadsen, B.; et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. 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