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Hypofractionated radiation leads to more rapid bleeding cessation in women with vaginal bleeding secondary to gynecologic malignancy

Hypofractionated radiation leads to more rapid bleeding cessation in women with vaginal bleeding... Background: Vaginal bleeding ( VB) is common in women with gynecologic (GYN) malignancies. Radiation therapy (RT ) is used for the definitive treatment of GYN cancers and palliation of bleeding. The historical dogma is that high dose-per-fraction radiation leads to more rapid bleeding cessation, yet there is scant data supporting this claim. We sought to examine the effect of RT fraction size on VB via retrospective analysis of patients receiving hypofractionated radiation (HFRT ) compared to conventionally fractionated radiation (CFRT ) for control of bleeding secondary to GYN malignancies. Methods: We identified patients receiving external beam RT for continuous VB from GYN malignancy treated in our department from 2012 to 2020. RT was classified as HFRT (> 2.0 Gy/fx) or CFRT (1.8–2.0 Gy/fx). Demographic informa- tion, disease characteristics, and treatment details were collected. The primary endpoint was days from RT initiation until bleeding resolution. Characteristics between groups were compared via Fisher’s exact test. Time to bleeding ces- sation was assessed via Kaplan–Meier and log-rank test. Univariable and multivariable Cox-proportional hazards were used to identify factors associated with bleeding cessation. Results: We identified 43 patients meeting inclusion criteria with 26 and 17 patients receiving CFRT and HFRT, respectively. Comparison of baseline characteristics revealed patients receiving HFRT were older (p = 0.001), more likely to be post-menopausal (p = 0.002), and less likely to receive concurrent chemotherapy (p = 0.004). Time to bleeding cessation was significantly shorter for patients receiving HFRT (log-rank p < 0.001) with median time to bleeding cessation of 5 days (HFRT ) versus 16 days (CFRT ). Stratification by dose-per-fraction revealed a dose– response effect with more rapid bleeding cessation with increased dose-per-fraction. While HFRT, age, recurrent disease, prior pelvic RT, and prior systemic therapy were associated with time to bleeding cessation on univariable analysis, HFRT was the only factor significantly associated with time to bleeding cessation in the final multivariable model (HR 3.26, p = 0.008). Conclusions: Patients with continuous VB from GYN tumors receiving HFRT experienced more rapid bleeding cessa- tion than those receiving CFRT. For patients with severe VB, initiation of HFRT to control malignancy related bleeding quickly may be warranted. *Correspondence: smarcrom@uabmc.edu Luke A. Moradi and Craig S. Schneider have contributed equally to this work Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Moradi et al. Radiation Oncology (2022) 17:34 Page 2 of 9 Keywords: Gynecologic cancer, Vaginal bleeding, Radiation, Cervical cancer Background 1.8–2.0  Gy/fx) for bleeding cessation in women with Bleeding is a common sequela of gynecologic (GYN) bleeding secondary to GYN malignancies with inclusion malignancies such as cervical cancer and endometrial of both palliative and curative intent patients. The goal of cancer and in severe cases can lead to life-threatening this study is to provide a better understanding of the rela- anemia requiring transfusions. The pathophysiology tionship between RT dose and time to bleeding cessation, behind tumor associated bleeding is initially believed which may help physicians balance the acute need for to be secondary to tumor friability, which leads to light bleeding cessation with the need to deliver more curative bleeding. Later, as the tumor erodes into larger blood intent cumulative RT doses. vessels, heavier bleeding can develop [1]. Vaginal bleeding (VB) is a common presenting symp- Methods tom for women with newly diagnosed GYN malig- A retrospective analysis was performed on women nancies, especially endometrial and cervical cancer. receiving external beam radiation therapy (EBRT) for Tumor-directed radiotherapy has been shown to be effec - continuous VB related to an underlying GYN malignancy tive in achieving hemostasis in these individuals. There at the University of Alabama at Birmingham (UAB) have been multiple studies demonstrating the effec - from 2012 to 2020. GYN malignancies included in the tiveness of radiation to induce hemostasis with various study were cervical, endometrial, vaginal, or vulvar. All fractionation and dosing schemes [2–7], however, there recorded variables were gathered from UAB electronic remains no consensus on the optimal radiation sched- medical records (EMR) and the study was approved by ule for rapid and durable cessation of bleeding. A large UAB’s Institutional Review Board (UAB IRB 120703005). proportion of these patients present with curable dis- Basic demographic information such as age, race, ease and therefore palliative, hypofractionated RT alone menopausal status was collected. Cancer information is not appropriate and a more protracted, conventionally including primary tumor site (vulvar, vaginal, cervical, or fractionated RT course with curative intent is warranted. uterine), tumor histology, prior systemic therapy, prior While there is a prevailing opinion in the radiation oncol- in-field radiation, and prior pelvic surgery was also col - ogy community that higher dose-per-fraction RT more lected. RT dates, total dose (Gy), total number of frac- rapidly resolves tumor-related bleeding, there is minimal tions delivered, dose-per-fraction, biologically effective objective data to support this. Further, most published dose (α/β = 10 and α/β = 2 or BED and BED , respec- 10 2 literature has focused on patients undergoing palliative, tively), subsequent pelvic boost, subsequent brachy- hypofractionated radiation. While data exists on the therapy, and treatment intent (definitive vs. palliative) effectiveness of conventional fractionation for bleed - were also collected. Patient details during treatment ing cessation as a component of definitive treatment of such as concurrent systemic therapy, anticoagulation or GYN malignancies, there is a paucity of data evaluating antiplatelet use, pre-treatment hemoglobin and platelet the rate of bleeding cessation with conventional frac- count (on first day or within 15  days of treatment start), tionation as compared to hypofractionation. In particu- lowest intra-treatment hemoglobin, post-treatment lar, for curative intent patients (e.g., patients with newly hemoglobin and platelet count (on final day or within diagnosed locally advanced cervical cancer) with severe 15  days of final treatment), and whether blood transfu - bleeding (e.g., requiring frequent transfusions), the opti- sion was needed (during or since cancer diagnosis) were mal radiation regimen for both prompt bleeding ces- also collected. Patients with intermittent bleeding or sation and long-term tumor control is not well defined. spotting were excluded, as well as patients with docu- For example, the merits of starting with a hypofraction- mented bleeding cessation prior to RT initiation, leav- ated RT course to more rapidly halt bleeding followed ing only patients with continuous bleeding from GYN later by more protracted, conventional fractionation to a malignancy. Patients with inadequate documentation of curative intent RT dose (e.g., based on total biologically bleeding were excluded, as were patients who received effective dose, BED) compared to delivering the entirety interventional radiology (IR) or surgical intervention to of the RT course with conventional fractionation is not correct VB. well understood. The primary endpoint was days from RT initiation until The purpose of this study was to retrospectively com - complete bleeding resolution. Complete bleeding resolu- pare the efficacy of hypofractionated RT (HFRT, > 2.0 Gy/ tion was defined by the first documentation of “no bleed - fraction) to conventionally fractionated RT (CFRT, ing/bleeding resolved” in the EMR. Documentation of M oradi et al. Radiation Oncology (2022) 17:34 Page 3 of 9 rebleeding, date of rebleeding, and acute toxicities (grade Linear regression with Pearson’s correlation was per- II+) were collected. Acute toxicities (during or within formed to assess the relationship between dose-per-frac- one month following treatment) were graded using Com- tion and time to bleeding cessation. The mean BED and mon Terminology Criteria for Adverse Events (CTCAE) BED dose delivered (in Gy) at the time of bleeding cessa- v5.0. tion for HFRT and CFRT was compared with the Mann– Radiation was classified as HFRT (> 2.0  Gy/fx) or Whitney test. CFRT (1.8–2.0  Gy/fx) based on the overall dose-per- fraction from their treatment course. The hypofractiona - tion group was subsequently further sub-stratified into Results 2.0–2.5  Gy/fraction and > 2.5  Gy/fraction for further We identified 43 patients meeting the pre-determined investigation of the effect of increasing dose-per-fraction inclusion/exclusion criteria (Fig.  1). Of those patients, on bleeding cessation. Baseline characteristics between 26 patients received CFRT (1.8–2 Gy/fx) and 17 patients groups were compared via Fisher’s exact test and Mann– received HFRT (> 2.0  Gy/fx). Comparison of patient Whitney test for categorical and continuous variables, characteristics between the groups are shown in Table 1. respectively. Time to bleeding cessation was assessed Patients in the HFRT group were more like to be older, via Kaplan–Meier and log-rank test. Univariable Cox- post-menopausal, and have metastatic disease, while proportional hazard models was used to identify factors patients in the CFRT group were more likely to receive associated with bleeding cessation. Factors with p < 0.2 concurrent chemotherapy. Otherwise, there were no sta- on univariable analysis were subsequently included in tistically significant differences in patient characteristics a final multivariable Cox-proportional hazards model. between the groups. Fig. 1 Flow diagram detailing patient inclusion and exclusion criteria for study cohort Moradi et al. Radiation Oncology (2022) 17:34 Page 4 of 9 Table 1 Baseline patient characteristics and demographics Variable CFRT (N = 26) HFRT (N = 17) P value Age (years) P = 0.001 Less than 50 21 (80.7%) 5 (29.4%) 50 or older 5 (19.3%) 12 (70.6%) Race P = 1.000 White 15 (57.7%) 9 (52.9%) Non-White 11 (42.3%) 8 (47.1%) Primary cancer P = 0.310 Cervical 20 (76.9%) 10 (58.8%) Non-Cervical 6 (23.1%) 7 (41.2%) Anticoagulation or antiplatelet use P = 1.000 Yes 3 (11.5%) 1 (5.9%) No 23 (88.5%) 16 (94.4%) Menopausal status P = 0.002 Post-menopausal 7 (26.9%) 13 (76.5%) Pre-menopausal 19 (73.1%) 4 (23.5%) Transfusion received P = 1.000 Yes 18 (69.2%) 11 (64.7%) No 8 (30.8%) 6 (35.3%) Concurrent chemotherapy P = 0.004 Yes 21 (80.7%) 6 (35.3%) No 5 (19.3%) 11 (64.7%) Metastatic disease Yes 4 (15.4%) 7 (41.2%) P = 0.007 No 22 (84.6%) 10 (58.8%) Recurrent disease Yes 2 (7.7%) 4 (23.5%) P = 0.193 No 24 (92.3%) 13 (76.5%) Prior pelvic RT Yes 0 (0%) 1 (5.9%) P = 0.395 No 26 (100%) 16 (94.1%) Prior pelvic surgery Yes 5 (19.2%) 6 (35.3%) P = 0.295 No 21 (80.8%) 11 (64.7%) Prior systemic therapy Yes 0 (0%) 6 (35.3%) P = 0.001 No 26 (100%) 11 (54.7%) Pre-treatment hemoglobin 10.00 8.57 P = 0.084 The numbers in the parentheses represent the percent of patients within each group. Values reported for continuous variables are the arithmetic mean. P values listed were calculated via Fisher’s exact test for categorical variables and Mann–Whitney test for continuous variables For the CFRT group, all 26 patients received a dosing BED of 53.1 Gy versus 46.9 Gy for CFRT versus HFRT, scheme of 45 Gy in 25 fractions. In the HFRT group, the respectively (p = 0.002). A total of 25 patients went on dosing schemes were varied with regards to total dose to receive brachytherapy (24 patients in the CFRT and received and dose-per-fraction (Table  2). For the CFRT 1 patient in the HFRT group). However, bleeding cessa- group, the median number of fractions received was 25, tion was achieved in all patients prior to first fraction of while the median number of fractions received in the brachytherapy. HFRT group was 15. Biologically effective doses (BED To examine differences in time to bleeding cessation with α/β = 10 or BED ) were calculated based on the between the groups, Kaplan–Meier analysis and log-rank different dosing schemes within the cohort with median testing were performed (Fig. 2). Median time to bleeding M oradi et al. Radiation Oncology (2022) 17:34 Page 5 of 9 Table 2 External beam radiation regimens utilized in patient cohort. BED10 represents the overall BED calculated with α/β = 10 RT regimen BED (Gy) # (%) MTTBC (days) CFRT (N = 26) 1.8 Gy × 25 fx = 45 Gy 53.1 26 (100%) 16 [6–41] HFRT (N = 17) 2.5 Gy × 16 fx = 40 Gy 50.0 4 (24%) 15.5 [5–28] 2.5 Gy × 15 fx = 37.5 Gy 46.9 4 (24%) 11 [5–17] 2.5 Gy × 10 fx = 25 Gy 31.3 1 (6%) 13 1.8 Gy × 1 fx − > 3 Gy × 3 fx − > 1.8 Gy × 20 fx = 46.8 Gy total 56.3 1 (6%) 1 2.2 Gy × 20 = 44 Gy 53.7 1 (6%) 6 4 Gy × 2 − > 3 Gy × 10 fx = 38 Gy total 50.2 1 (6%) 4 4 Gy × 3 fx − > 3 Gy × 4 fx = 24 Gy total 32.4 1 (6%) 1 4Gy × 5 = 20 Gy 28.0 1 (6%) 1 3.7Gy × 4 = 14.8 Gy delivered BID 20.3 1 (6%) 1 3.7 Gy × 4 = 14.8 Gy 20.3 1 (6%) 1 2.5 Gy × 3 = 7.5 Gy 9.4 1 (6%) 2 Initially planned for 1.8 Gy × 25 = 45 Gy but had worsening bleeding so switched to 3 Gy × 3 fx = 9 Gy, later followed by completion of definitive RT 36 Gy in 20 fx Patient planned for 2.5 Gy × 16 fx = 40 Gy but decided to go on hospice and stopped RT Patients with multiple fractionation schemes delivered sequentially are denoted with forward arrow sign (− >). Median time to bleeding cessation (MTTBC) is reported in days with number in brackets representing the range for fractionation schemes with multiple patients RT type (HFRT vs. CFRT, HR = 3.23, p < 0.001) age (< 50  years old vs. 50+ years old, HR = 2.17, p = 0.022), recurrent disease (recurrent disease vs. newly diag- nosed, HR 3.53, p = 0.007), prior pelvic RT (yes vs. no, HR = 10.50, p = 0.035), and prior systemic therapy (yes vs. no, HR 6.12, p < 0.001) were significantly associated with time to bleeding cessation. However, in the final multivariable cox proportional hazards model, only RT type (HFRT vs. CFRT) was significantly associated with time to bleeding cessation (HR 3.26, p = 0.008). To further investigate the effect of more hypofraction - Fig. 2 The effect of radiation type on time to bleeding cessation. ated RT courses (with increasing dose-per-fraction) on Time to bleeding cessation from initiation of first fraction of time to bleeding cessation, we performed a subset analy- radiation is presented via Kaplan–Meier analysis for patients receiving conventionally fractionated radiation therapy (CFRT ) and sis of time to bleeding cessation where the HFRT group hypofractionated radiation therapy (HFRT ). Log-rank p value was was further divided based on dose-per-fraction (2.0– used to compare time-to-bleeding cessation between the groups 2.5  Gy/fraction vs. > 2.5  Gy/fraction). The Kaplan–Meier (p < 0.001). Median time to bleeding cessation was 16 days and 5 days results of this analysis are shown in Fig.  3 and shows an for CFRT and HFRT, respectively apparent dose response effect with rapid bleeding ces - sation for the highest dose cohort (> 2.5  Gy/fraction). In fact, all patients receiving more than 2.5  Gy/fraction cessation was 5 days for those receiving HFRT compared had bleeding cessation within 4  days of initiation of RT to 16  days for those receiving CFRT. Log-rank testing and median time to bleeding cessation of 1  day. Over- confirmed more rapid time to bleeding cessation for the all, median time to bleeding cessation decreased with patients receiving HFRT compared to those receiving increasing dose-per-fraction with median values of CFRT (log rank p < 0.001). 16  days, 6  days, and 1  day for dose-per-fraction values To identify other factors that might contribute to dif- of ≤ 2.0  Gy, 2.1–2.5  Gy, and > 2.5  Gy, respectively. Lin- ferences in time to bleeding cessation, cox univariable ear regression analysis of time to bleeding cessation ver- regression was performed (Table  3) with a pre-deter- sus dose-per-fraction demonstrated a significant inverse mined p-value cut point of p < 0.2 set for inclusion in correlation (Additional file  1: Figure S1, r = − 0.4684, a final multivariable model. On univariable analysis, p = 0.0015). Moradi et al. Radiation Oncology (2022) 17:34 Page 6 of 9 Table 3 Univariable and multivariable cox proportional hazards analysis of the association of listed dichotomized variables with time to bleeding cessation Variable Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value CFRT 3.23 1.65–6.32 0.001 3.26 1.37–7.80 0.008 Age 50+ 2.17 1.11–4.22 0.022 0.74 0.28–1.96 0.543 Concurrent chemo 0.54 0.29–1.02 0.057 0.76 0.31–1.88 0.550 Non-White 0.97 0.53–1.80 0.941 AC or AP use 0.62 0.22–1.77 0.373 Non-cervical primary 1.20 0.62–2.33 0.581 Pre-menopausal 0.70 0.38–1.29 0.259 Transfusion required 1.14 0.60–2.21 0.680 Metastatic 1.15 0.60–2.20 0.669 Recurrence 3.53 1.42–8.82 0.007 1.96 0.51–7.54 0.326 Prior pelvic RT 10.50 1.17–93.9 0.035 2.06 0.16–27.00 0.582 Prior pelvic surgery 1.87 0.93–3.77 0.080 1.76 0.68–4.57 0.243 Prior systemic therapy 6.12 2.30–16.33 < 0.001 2.17 0.64–7.28 0.211 Pretreatment Hgb (continuous) 0.96 0.82–1.12 0.597 Pre-specified criteria for inclusion in a final multivariable model was p < 0.2 on univariable analysis compared to 25.5  Gy for CFRT (p = 0.041). We also cal- culated BED (biologically effective dose at α/β = 2) dose delivered at the time of bleeding cessation to estimate the biologically effective dose to tumor-associated endothe - lial cells (assuming normal endothelial tissue α/β = 2). For the entire cohort, the median BED dose at time of bleeding cessation was 37.6  Gy. While the median BED dose at time of bleeding cessation was lower for HFRT compared to CFRT (28.1 Gy vs. 41.0 Gy), this difference was not statistically significant (p = 0.269). We additionally looked at overall bleeding control and Fig. 3 The effect of radiation dose per fraction on time to bleeding rates of rebleeding in our patient population. All patients cessation. Time to bleeding cessation is presented for patients in the study had cessation of bleeding with bleeding receiving less than 2.0 Gy per fraction (≤ 2.0 Gy/fx), 2.1–2.5 Gy per control rates of 100%, irrespective of RT type (CFRT vs. fraction (2.1–2.5 Gy/fx) and more than 2.5 Gy per fraction (> 2.5 Gy/ fx). Log-rank p value was calculated at p < 0.001. Log-rank p testing HFRT). In all cases, bleeding cessation was achieved with between each individual group pairing was tested and yielded external beam RT and prior to initiation of any brachy- p = 0.2457 for the low dose compared to intermediate dose per therapy. A total of 4 patients (9.3%) within the cohort fraction (≤ 2.0 Gy/fx vs. 2.1–2.5 Gy/fx) but comparison of high dose experienced rebleeding after initial bleeding resolution per fraction (> 2.5 Gy/fx) with the other two groups yielded p < 0.001 with a median time to rebleeding of 128  days (range on log-rank p-testing 48–216 days). Of those four patients, two received HFRT and 2 received CFRT, resulting in rebleeding rates of 7.7% and 11.4%, respectively (χ p = 0.653). The rate of acute To investigate the relationship between BED dose 10 grade 2+ toxicity was higher in patients receiving CFRT delivered to the tumor and bleeding cessation, we plotted compared to HFRT (61.5% vs. 23.5%, p = 0.027) with histograms of the cumulative BED dose delivered at the 10 upper GI (nausea), lower GI (diarrhea), and GU (dysuria) time of bleeding cessation for individual patients in each the most common toxicities observed (Additional file  2: group (Fig.  4). For the whole cohort, the median BED 10 Table  S2). Grade 3+ toxicity was rare with two patients delivered at the time of bleeding cessation was 21.9  Gy. experiencing Grade 3 upper GI toxicity in the CFRT Patients receiving HFRT had bleeding cessation at lower group and one patient experiencing Grade 3 bladder total delivered BE D doses compared to those in the 10 outlet obstruction (secondary to blood clot from tumor CFRT group with median values of 15.2  Gy for HFRT invasion of the bladder) in the HFRT group. Pre- and M oradi et al. Radiation Oncology (2022) 17:34 Page 7 of 9 Fig. 4 Histogram showing the cumulative dose in A BED10 or B BED2 delivered at the time bleeding cessation was documented for patients receiving CFRT (white bars) and HFRT (black bars). Median BED10 at time of bleeding cessation was 25.5 Gy and 15.2 Gy for CFRT and HFRT, respectively (p = 0.041 by Mann–Whitney test). Median BED2 at time of bleeding cessation was 41.0 Gy and 28.1 Gy for CFRT and HFRT, respectively (p = 0.269 by Mann–Whitney test) post-RT hemoglobin and platelet counts for patients on incurable, palliative intent patients and in many cases, with available data, as well as the lowest hemoglobin level very hypofractionated RT regimens (e.g., 10 Gy in a sin- recorded during RT treatment are shown in Additional gle fraction) [2, 3, 5, 6]. Further, most of these studies file  1: Figure S1. There was a trend towards a lower pre- reported only overall response rates but no information RT hemoglobin for patients receiving HFRT compared to regarding how quickly bleeding cessation was achieved. CFRT (10.00 vs. 8.57, p = 0.084), but, otherwise, no dif- Other studies lumped patients with bleeding GYN malig- ference in any of the other parameters. nancies together with other bleeding tumor sites (e.g., bladder/hematuria, lung/hematemesis, etc.), making Discussion interpretation of the combined results challenging [4]. Despite being a common issue encountered in radiation One of the few contemporary studies that focused spe- oncology, the optimal RT regimen for palliation of VB cifically on patients with bleeding GYN malignancies fol - and implications of RT fractionation scheme on time to lowing palliative RT reported similar overall findings to bleeding cessation are not well defined. We found that those reported here [8]. While they did not find a statisti - women receiving HFRT had significantly decreased time cally significant difference in the time to bleeding cessa - to bleeding cessation compared to CFRT with median tion in their small cohort of incurable patients receiving time to bleeding cessation of 5  days versus 16  days, palliative RT, time to bleeding cessation was numerically respectively. When HFRT was further subdivided by the less with more hypofractionated RT and with similar amount of dose delivered per fraction, the data contin- times to bleeding cessation compared to those reported ued to demonstrate that increasing dose-per-fraction here. decreased time to bleeding cessation with an apparent Our study is somewhat unique in that we have included dose–response effect. On multivariable analysis, receipt both patients treated with curative and palliative intent of HFRT (as opposed to CFRT) was the only variable radiation. The data presented here provides information with a statistically significant association with time to on bleeding cessation with more protracted RT regimens bleeding cessation. Altogether, these data suggest that and gives useful insight into the relative effectiveness and in our cohort of patients, more hypofractionated radia- kinetics of bleeding cessation for more curative-intent tion regimens leads to more rapid bleeding cessation in RT compared to shorter-course hypofractionated RT. For patients with tumor-associated VB. example, this data may be helpful in the management of While the main result of this study, that higher dose- patients with newly diagnosed, curable cervical cancer per-fraction RT leads to more rapid tumor-related with severe bleeding at presentation. If a patient presents bleeding cessation, seems somewhat intuitive and is a with severe bleeding at presentation (e.g., requiring fre- commonly held belief by radiation oncologists, there is a quent transfusions), initiation of RT with a few fractions paucity of modern data supporting this point. The limited of HFRT may be warranted before switching to a more studies that have investigated the relationship between conventionally fractionated definitive RT course, as our radiation dose and GYN bleeding cessation have focused data suggests a significant reduction in median time to Moradi et al. Radiation Oncology (2022) 17:34 Page 8 of 9 bleeding cessation (5 days vs. 16 days) with HFRT. Alter- regarding the granularity of bleeding cessation data that natively, patients with less severe bleeding may be man- was obtained. Despite this, we still saw a statistically sig- aged appropriately with CFRT with expected bleeding nificant difference in time to bleeding cessation for CFRT cessation most likely within approximately 2  weeks of versus HFRT, and our median time to bleeding cessation RT initiation. Several studies have found an association and bleeding control rates were similar to those reported between anemia and worse oncologic outcomes in cervi- in contemporary studies as discussed above. Addition- cal cancer patients receiving radiation, possibly related ally, assessment of bleeding cessation was reliant on the to tumor hypoxia leading to increased radioresistance somewhat subjective measure of physician documen- [9–12]. While the exact mechanism for this association tation of bleeding cessation. While we did collect more is not well understood, these data suggest that more rapid objective data related to bleeding, such as hemoglobin cessation of bleeding may limit or prevent anemia and in levels and need for blood transfusion, being a retrospec- turn improve oncologic outcomes, which may also be a tive study, not all patients had this data available and it consideration when choosing RT dose and strategy. was also confounded by other factors, such as chemo- As we did include both curative and palliative intent therapy induced anemia. Given these limitations, it was patients with bleeding GYN malignancy, we must not feasible to use these data as a more objective end- acknowledge that patients receiving CFRT and HFRT point for bleeding cessation/control. While our cohort were inherently different. Patients being treated with size of 43 patients is quite sizeable compared to similar curative intent CFRT were more likely to be younger, analyses in the literature, from a statistical standpoint treatment naïve patients with cervical cancer and were this is a relatively small sample size with limited power more likely to receive concurrent chemotherapy, whereas and risk of type 2 error. Despite this, we did still see sig- patients receiving HFRT were more likely to be older nificant differences in time to bleeding cessation with RT patients with non-cervical malignancy with recurrent regimen choice. However, other variables that one might disease. Further, physicians likely elected to use HFRT expect to influence bleeding cessation, such as receipt of for patients with more severe bleeding. This is consist - anticoagulant or antiplatelet medications, were not sig- ent with the lower pre-RT hemoglobin levels seen in the nificantly associated with time to bleeding cessation, pos - HFRT group compared to CFRT (10.00  g/dL vs. 8.57  g/ sibly due to the limited sample size and power. dL, p = 0.084). Taking all these facts together, patients in the HFRT group likely had more severe bleeding and more recalcitrant tumors, making the significant reduc - Conclusion tion in time to bleeding cessation between HFRT and Women with continuous VB from GYN malignancies CFRT even more meaningful. receiving HFRT experienced more rapid bleeding cessa- Another unique aspect of our study is that we calcu- tion than those receiving CFRT with an apparent dose lated the individual BED and BED doses that were response effect with increasing dose-per-fraction. For 10 2 delivered for individual patients at the time of physician- patients with severe GYN bleeding, initiation of high documented bleeding cessation. The goal of this analy - dose-per-fraction radiation to rapidly halt malignancy sis was to provide physicians a tool to estimate time to related bleeding may be warranted. bleeding cessation for various RT fractionation schemes (via calculation of BED and BED ) when considering 2 10 Abbreviations various regimens for patients with active bleeding. We VB: Vaginal bleeding; GYN: Gynecologic; RT: Radiation therapy; HFRT: Hypofrac- found that the BE D dose delivered at time of bleeding tionated radiation; CFRT: Conventionally fractionated radiation; EBRT: External beam radiation therapy; EMR: Electronic medical record; BED: Biologically cessation was statistically significantly greater for CFRT effective dose; CTCAE: Common Terminology Criteria for Adverse Events; HR: compared to HFRT. However, the BE D dose delivered Hazard ratio; IR: Interventional radiology. at time of bleeding cessation was not statistically differ - ent. This suggests that time to initial bleeding cessation Supplementary Information may be more driven by the effect of RT on tumor asso - The online version contains supplementary material available at https:// doi. ciated endothelium (with lower associated α/β) rather org/ 10. 1186/ s13014- 022- 01995-7. than on tumor cells. Indeed, there is some data to suggest that more hypofractionated RT doses may more greatly Additional file 1. Supplemental Figures: Supplemental Figure 1. Relationship between dose per day delivered and time to bleeding ces- impact/damage tumor-associated endothelium, which sation. Line shown is simple linear regression demonstrating an inverse may have led to earlier bleeding cessation for patients correlation (Pearson’s correlation r = -0.4684, p = 0.0015) receiving HFRT in this study [13–15]. Additional file 2. Supplemental Tables: Supplemental Table 1. There are several limitations to the present study. Hemoglobin and platelet levels before and after completion of radiation. Values reported are the arithmetic mean. P-values were calculated by Given the retrospective nature, there are limitations M oradi et al. Radiation Oncology (2022) 17:34 Page 9 of 9 palliative radiation therapy: less is more. J Pain Symptom Manage. Mann-Whitney test. Supplemental Table 2 Acute toxicities reported 2021;61(2):377-383.e372. by RT type received. Grade 2+ toxicities per CTCAE criteria are reported. 9. Bishop AJ, Allen PK, Klopp AH, Meyer LA, Eifel PJ. Relationship between P-values were determined via Fisher’s exact test. low hemoglobin levels and outcomes after treatment with radiation or chemoradiation in patients with cervical cancer: has the impact of ane- mia been overstated? Int J Radiat Oncol Biol Phys. 2015;91(1):196–205. Acknowledgements 10. Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensi- The authors would like to thank Hollye Kelly for her help in querying depart- tivity to radiation therapy and chemotherapy? Oncologist. 2004;9(Suppl mental databases for patient identification. 5):31–40. 11. Zayed S, Nguyen TK, Lin C, et al. Red blood cell transfusion practices Authors’ contributions for patients with cervical cancer undergoing radiotherapy. JAMA Netw CS, LM and SM devised the study. LM and RP identified eligible patients Open. 2021;4(4):e213531. and collected data. CS and AD analyzed the data. CS, LM, and AD were the 12. Moreno-Acosta P, Vallard A, Carrillo S, et al. Biomarkers of resistance to major contributors to writing of the manuscript. All authors read, edited, and radiation therapy: a prospective study in cervical carcinoma. Radiat approved the final manuscript. Oncol. 2017;12(1):120. 13. Park HJ, Griffin RJ, Hui S, Levitt SH, Song CW. Radiation-induced vascular Funding damage in tumors: implications of vascular damage in ablative hypofrac- No external funding source was utilized for the submitted research. All fund- tionated radiotherapy (SBRT and SRS). Radiat Res. 2012;177(3):311–27. ing support was from the University of Alabama Department of Radiation 14. Song CW, Kim MS, Cho LC, Dusenbery K, Sperduto PW. Radiobiological Oncology. basis of SBRT and SRS. Int J Clin Oncol. 2014;19(4):570–8. 15. Song CW, Glatstein E, Marks LB, et al. Biological principles of stereotactic Availability of data and materials body radiation therapy (SBRT ) and stereotactic radiation surgery (SRS): The datasets used and/or analysed during the current study are available from indirect cell death. Int J Radiat Oncol Biol Phys. 2021;110(1):21–34. the corresponding author on reasonable request. Publisher’s Note Declarations Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Ethics approval and consent to participate This retrospective study was performed per departmental IRB as approved by UAB’s Institutional Review Board (UAB IRB 120703005). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA. Case Western Reserve University School of Medicine, Cleveland, OH, USA. Received: 22 October 2021 Accepted: 19 January 2022 References 1. Smith SC, Koh WJ. Palliative radiation therapy for gynaecological malig- nancies. Best Pract Res Clin Obstet Gynaecol. 2001;15(2):265–78. 2. Hodson DI, Krepart GV. Once-monthly radiotherapy for the palliation of pelvic gynecological malignancy. Gynecol Oncol. 1983;16(1):112–6. 3. Spanos WJ Jr, Wasserman T, Meoz R, Sala J, Kong J, Stetz J. Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: final report of RTOG phase I/II study. Int J Radiat Oncol Biol Phys. 1987;13(10):1479–82. 4. Sapienza LG, Ning MS, Jhingran A, et al. Short-course palliative radiation Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : therapy leads to excellent bleeding control: a single centre retrospective study. Clin Transl Radiat Oncol. 2019;14:40–6. fast, convenient online submission 5. Halle JS, Rosenman JG, Varia MA, Fowler WC, Walton LA, Currie JL. 1000 thorough peer review by experienced researchers in your field cGy single dose palliation for advanced carcinoma of the cervix or endo- rapid publication on acceptance metrium. Int J Radiat Oncol Biol Phys. 1986;12(11):1947–50. 6. Yan J, Milosevic M, Fyles A, Manchul L, Kelly V, Levin W. A hypofraction- support for research data, including large and complex data types ated radiotherapy regimen (0-7-21) for advanced gynaecological cancer • gold Open Access which fosters wider collaboration and increased citations patients. Clin Oncol (R Coll Radiol). 2011;23(7):476–81. maximum visibility for your research: over 100M website views per year 7. Pereira J, Phan T. Management of bleeding in patients with advanced cancer. Oncologist. 2004;9(5):561–70. At BMC, research is always in progress. 8. Butala AA, Lee DY, Patel RR, et al. A retrospective study of rapid symptom response in bleeding gynecologic malignancies with short course Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Hypofractionated radiation leads to more rapid bleeding cessation in women with vaginal bleeding secondary to gynecologic malignancy

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Abstract

Background: Vaginal bleeding ( VB) is common in women with gynecologic (GYN) malignancies. Radiation therapy (RT ) is used for the definitive treatment of GYN cancers and palliation of bleeding. The historical dogma is that high dose-per-fraction radiation leads to more rapid bleeding cessation, yet there is scant data supporting this claim. We sought to examine the effect of RT fraction size on VB via retrospective analysis of patients receiving hypofractionated radiation (HFRT ) compared to conventionally fractionated radiation (CFRT ) for control of bleeding secondary to GYN malignancies. Methods: We identified patients receiving external beam RT for continuous VB from GYN malignancy treated in our department from 2012 to 2020. RT was classified as HFRT (> 2.0 Gy/fx) or CFRT (1.8–2.0 Gy/fx). Demographic informa- tion, disease characteristics, and treatment details were collected. The primary endpoint was days from RT initiation until bleeding resolution. Characteristics between groups were compared via Fisher’s exact test. Time to bleeding ces- sation was assessed via Kaplan–Meier and log-rank test. Univariable and multivariable Cox-proportional hazards were used to identify factors associated with bleeding cessation. Results: We identified 43 patients meeting inclusion criteria with 26 and 17 patients receiving CFRT and HFRT, respectively. Comparison of baseline characteristics revealed patients receiving HFRT were older (p = 0.001), more likely to be post-menopausal (p = 0.002), and less likely to receive concurrent chemotherapy (p = 0.004). Time to bleeding cessation was significantly shorter for patients receiving HFRT (log-rank p < 0.001) with median time to bleeding cessation of 5 days (HFRT ) versus 16 days (CFRT ). Stratification by dose-per-fraction revealed a dose– response effect with more rapid bleeding cessation with increased dose-per-fraction. While HFRT, age, recurrent disease, prior pelvic RT, and prior systemic therapy were associated with time to bleeding cessation on univariable analysis, HFRT was the only factor significantly associated with time to bleeding cessation in the final multivariable model (HR 3.26, p = 0.008). Conclusions: Patients with continuous VB from GYN tumors receiving HFRT experienced more rapid bleeding cessa- tion than those receiving CFRT. For patients with severe VB, initiation of HFRT to control malignancy related bleeding quickly may be warranted. *Correspondence: smarcrom@uabmc.edu Luke A. Moradi and Craig S. Schneider have contributed equally to this work Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Moradi et al. Radiation Oncology (2022) 17:34 Page 2 of 9 Keywords: Gynecologic cancer, Vaginal bleeding, Radiation, Cervical cancer Background 1.8–2.0  Gy/fx) for bleeding cessation in women with Bleeding is a common sequela of gynecologic (GYN) bleeding secondary to GYN malignancies with inclusion malignancies such as cervical cancer and endometrial of both palliative and curative intent patients. The goal of cancer and in severe cases can lead to life-threatening this study is to provide a better understanding of the rela- anemia requiring transfusions. The pathophysiology tionship between RT dose and time to bleeding cessation, behind tumor associated bleeding is initially believed which may help physicians balance the acute need for to be secondary to tumor friability, which leads to light bleeding cessation with the need to deliver more curative bleeding. Later, as the tumor erodes into larger blood intent cumulative RT doses. vessels, heavier bleeding can develop [1]. Vaginal bleeding (VB) is a common presenting symp- Methods tom for women with newly diagnosed GYN malig- A retrospective analysis was performed on women nancies, especially endometrial and cervical cancer. receiving external beam radiation therapy (EBRT) for Tumor-directed radiotherapy has been shown to be effec - continuous VB related to an underlying GYN malignancy tive in achieving hemostasis in these individuals. There at the University of Alabama at Birmingham (UAB) have been multiple studies demonstrating the effec - from 2012 to 2020. GYN malignancies included in the tiveness of radiation to induce hemostasis with various study were cervical, endometrial, vaginal, or vulvar. All fractionation and dosing schemes [2–7], however, there recorded variables were gathered from UAB electronic remains no consensus on the optimal radiation sched- medical records (EMR) and the study was approved by ule for rapid and durable cessation of bleeding. A large UAB’s Institutional Review Board (UAB IRB 120703005). proportion of these patients present with curable dis- Basic demographic information such as age, race, ease and therefore palliative, hypofractionated RT alone menopausal status was collected. Cancer information is not appropriate and a more protracted, conventionally including primary tumor site (vulvar, vaginal, cervical, or fractionated RT course with curative intent is warranted. uterine), tumor histology, prior systemic therapy, prior While there is a prevailing opinion in the radiation oncol- in-field radiation, and prior pelvic surgery was also col - ogy community that higher dose-per-fraction RT more lected. RT dates, total dose (Gy), total number of frac- rapidly resolves tumor-related bleeding, there is minimal tions delivered, dose-per-fraction, biologically effective objective data to support this. Further, most published dose (α/β = 10 and α/β = 2 or BED and BED , respec- 10 2 literature has focused on patients undergoing palliative, tively), subsequent pelvic boost, subsequent brachy- hypofractionated radiation. While data exists on the therapy, and treatment intent (definitive vs. palliative) effectiveness of conventional fractionation for bleed - were also collected. Patient details during treatment ing cessation as a component of definitive treatment of such as concurrent systemic therapy, anticoagulation or GYN malignancies, there is a paucity of data evaluating antiplatelet use, pre-treatment hemoglobin and platelet the rate of bleeding cessation with conventional frac- count (on first day or within 15  days of treatment start), tionation as compared to hypofractionation. In particu- lowest intra-treatment hemoglobin, post-treatment lar, for curative intent patients (e.g., patients with newly hemoglobin and platelet count (on final day or within diagnosed locally advanced cervical cancer) with severe 15  days of final treatment), and whether blood transfu - bleeding (e.g., requiring frequent transfusions), the opti- sion was needed (during or since cancer diagnosis) were mal radiation regimen for both prompt bleeding ces- also collected. Patients with intermittent bleeding or sation and long-term tumor control is not well defined. spotting were excluded, as well as patients with docu- For example, the merits of starting with a hypofraction- mented bleeding cessation prior to RT initiation, leav- ated RT course to more rapidly halt bleeding followed ing only patients with continuous bleeding from GYN later by more protracted, conventional fractionation to a malignancy. Patients with inadequate documentation of curative intent RT dose (e.g., based on total biologically bleeding were excluded, as were patients who received effective dose, BED) compared to delivering the entirety interventional radiology (IR) or surgical intervention to of the RT course with conventional fractionation is not correct VB. well understood. The primary endpoint was days from RT initiation until The purpose of this study was to retrospectively com - complete bleeding resolution. Complete bleeding resolu- pare the efficacy of hypofractionated RT (HFRT, > 2.0 Gy/ tion was defined by the first documentation of “no bleed - fraction) to conventionally fractionated RT (CFRT, ing/bleeding resolved” in the EMR. Documentation of M oradi et al. Radiation Oncology (2022) 17:34 Page 3 of 9 rebleeding, date of rebleeding, and acute toxicities (grade Linear regression with Pearson’s correlation was per- II+) were collected. Acute toxicities (during or within formed to assess the relationship between dose-per-frac- one month following treatment) were graded using Com- tion and time to bleeding cessation. The mean BED and mon Terminology Criteria for Adverse Events (CTCAE) BED dose delivered (in Gy) at the time of bleeding cessa- v5.0. tion for HFRT and CFRT was compared with the Mann– Radiation was classified as HFRT (> 2.0  Gy/fx) or Whitney test. CFRT (1.8–2.0  Gy/fx) based on the overall dose-per- fraction from their treatment course. The hypofractiona - tion group was subsequently further sub-stratified into Results 2.0–2.5  Gy/fraction and > 2.5  Gy/fraction for further We identified 43 patients meeting the pre-determined investigation of the effect of increasing dose-per-fraction inclusion/exclusion criteria (Fig.  1). Of those patients, on bleeding cessation. Baseline characteristics between 26 patients received CFRT (1.8–2 Gy/fx) and 17 patients groups were compared via Fisher’s exact test and Mann– received HFRT (> 2.0  Gy/fx). Comparison of patient Whitney test for categorical and continuous variables, characteristics between the groups are shown in Table 1. respectively. Time to bleeding cessation was assessed Patients in the HFRT group were more like to be older, via Kaplan–Meier and log-rank test. Univariable Cox- post-menopausal, and have metastatic disease, while proportional hazard models was used to identify factors patients in the CFRT group were more likely to receive associated with bleeding cessation. Factors with p < 0.2 concurrent chemotherapy. Otherwise, there were no sta- on univariable analysis were subsequently included in tistically significant differences in patient characteristics a final multivariable Cox-proportional hazards model. between the groups. Fig. 1 Flow diagram detailing patient inclusion and exclusion criteria for study cohort Moradi et al. Radiation Oncology (2022) 17:34 Page 4 of 9 Table 1 Baseline patient characteristics and demographics Variable CFRT (N = 26) HFRT (N = 17) P value Age (years) P = 0.001 Less than 50 21 (80.7%) 5 (29.4%) 50 or older 5 (19.3%) 12 (70.6%) Race P = 1.000 White 15 (57.7%) 9 (52.9%) Non-White 11 (42.3%) 8 (47.1%) Primary cancer P = 0.310 Cervical 20 (76.9%) 10 (58.8%) Non-Cervical 6 (23.1%) 7 (41.2%) Anticoagulation or antiplatelet use P = 1.000 Yes 3 (11.5%) 1 (5.9%) No 23 (88.5%) 16 (94.4%) Menopausal status P = 0.002 Post-menopausal 7 (26.9%) 13 (76.5%) Pre-menopausal 19 (73.1%) 4 (23.5%) Transfusion received P = 1.000 Yes 18 (69.2%) 11 (64.7%) No 8 (30.8%) 6 (35.3%) Concurrent chemotherapy P = 0.004 Yes 21 (80.7%) 6 (35.3%) No 5 (19.3%) 11 (64.7%) Metastatic disease Yes 4 (15.4%) 7 (41.2%) P = 0.007 No 22 (84.6%) 10 (58.8%) Recurrent disease Yes 2 (7.7%) 4 (23.5%) P = 0.193 No 24 (92.3%) 13 (76.5%) Prior pelvic RT Yes 0 (0%) 1 (5.9%) P = 0.395 No 26 (100%) 16 (94.1%) Prior pelvic surgery Yes 5 (19.2%) 6 (35.3%) P = 0.295 No 21 (80.8%) 11 (64.7%) Prior systemic therapy Yes 0 (0%) 6 (35.3%) P = 0.001 No 26 (100%) 11 (54.7%) Pre-treatment hemoglobin 10.00 8.57 P = 0.084 The numbers in the parentheses represent the percent of patients within each group. Values reported for continuous variables are the arithmetic mean. P values listed were calculated via Fisher’s exact test for categorical variables and Mann–Whitney test for continuous variables For the CFRT group, all 26 patients received a dosing BED of 53.1 Gy versus 46.9 Gy for CFRT versus HFRT, scheme of 45 Gy in 25 fractions. In the HFRT group, the respectively (p = 0.002). A total of 25 patients went on dosing schemes were varied with regards to total dose to receive brachytherapy (24 patients in the CFRT and received and dose-per-fraction (Table  2). For the CFRT 1 patient in the HFRT group). However, bleeding cessa- group, the median number of fractions received was 25, tion was achieved in all patients prior to first fraction of while the median number of fractions received in the brachytherapy. HFRT group was 15. Biologically effective doses (BED To examine differences in time to bleeding cessation with α/β = 10 or BED ) were calculated based on the between the groups, Kaplan–Meier analysis and log-rank different dosing schemes within the cohort with median testing were performed (Fig. 2). Median time to bleeding M oradi et al. Radiation Oncology (2022) 17:34 Page 5 of 9 Table 2 External beam radiation regimens utilized in patient cohort. BED10 represents the overall BED calculated with α/β = 10 RT regimen BED (Gy) # (%) MTTBC (days) CFRT (N = 26) 1.8 Gy × 25 fx = 45 Gy 53.1 26 (100%) 16 [6–41] HFRT (N = 17) 2.5 Gy × 16 fx = 40 Gy 50.0 4 (24%) 15.5 [5–28] 2.5 Gy × 15 fx = 37.5 Gy 46.9 4 (24%) 11 [5–17] 2.5 Gy × 10 fx = 25 Gy 31.3 1 (6%) 13 1.8 Gy × 1 fx − > 3 Gy × 3 fx − > 1.8 Gy × 20 fx = 46.8 Gy total 56.3 1 (6%) 1 2.2 Gy × 20 = 44 Gy 53.7 1 (6%) 6 4 Gy × 2 − > 3 Gy × 10 fx = 38 Gy total 50.2 1 (6%) 4 4 Gy × 3 fx − > 3 Gy × 4 fx = 24 Gy total 32.4 1 (6%) 1 4Gy × 5 = 20 Gy 28.0 1 (6%) 1 3.7Gy × 4 = 14.8 Gy delivered BID 20.3 1 (6%) 1 3.7 Gy × 4 = 14.8 Gy 20.3 1 (6%) 1 2.5 Gy × 3 = 7.5 Gy 9.4 1 (6%) 2 Initially planned for 1.8 Gy × 25 = 45 Gy but had worsening bleeding so switched to 3 Gy × 3 fx = 9 Gy, later followed by completion of definitive RT 36 Gy in 20 fx Patient planned for 2.5 Gy × 16 fx = 40 Gy but decided to go on hospice and stopped RT Patients with multiple fractionation schemes delivered sequentially are denoted with forward arrow sign (− >). Median time to bleeding cessation (MTTBC) is reported in days with number in brackets representing the range for fractionation schemes with multiple patients RT type (HFRT vs. CFRT, HR = 3.23, p < 0.001) age (< 50  years old vs. 50+ years old, HR = 2.17, p = 0.022), recurrent disease (recurrent disease vs. newly diag- nosed, HR 3.53, p = 0.007), prior pelvic RT (yes vs. no, HR = 10.50, p = 0.035), and prior systemic therapy (yes vs. no, HR 6.12, p < 0.001) were significantly associated with time to bleeding cessation. However, in the final multivariable cox proportional hazards model, only RT type (HFRT vs. CFRT) was significantly associated with time to bleeding cessation (HR 3.26, p = 0.008). To further investigate the effect of more hypofraction - Fig. 2 The effect of radiation type on time to bleeding cessation. ated RT courses (with increasing dose-per-fraction) on Time to bleeding cessation from initiation of first fraction of time to bleeding cessation, we performed a subset analy- radiation is presented via Kaplan–Meier analysis for patients receiving conventionally fractionated radiation therapy (CFRT ) and sis of time to bleeding cessation where the HFRT group hypofractionated radiation therapy (HFRT ). Log-rank p value was was further divided based on dose-per-fraction (2.0– used to compare time-to-bleeding cessation between the groups 2.5  Gy/fraction vs. > 2.5  Gy/fraction). The Kaplan–Meier (p < 0.001). Median time to bleeding cessation was 16 days and 5 days results of this analysis are shown in Fig.  3 and shows an for CFRT and HFRT, respectively apparent dose response effect with rapid bleeding ces - sation for the highest dose cohort (> 2.5  Gy/fraction). In fact, all patients receiving more than 2.5  Gy/fraction cessation was 5 days for those receiving HFRT compared had bleeding cessation within 4  days of initiation of RT to 16  days for those receiving CFRT. Log-rank testing and median time to bleeding cessation of 1  day. Over- confirmed more rapid time to bleeding cessation for the all, median time to bleeding cessation decreased with patients receiving HFRT compared to those receiving increasing dose-per-fraction with median values of CFRT (log rank p < 0.001). 16  days, 6  days, and 1  day for dose-per-fraction values To identify other factors that might contribute to dif- of ≤ 2.0  Gy, 2.1–2.5  Gy, and > 2.5  Gy, respectively. Lin- ferences in time to bleeding cessation, cox univariable ear regression analysis of time to bleeding cessation ver- regression was performed (Table  3) with a pre-deter- sus dose-per-fraction demonstrated a significant inverse mined p-value cut point of p < 0.2 set for inclusion in correlation (Additional file  1: Figure S1, r = − 0.4684, a final multivariable model. On univariable analysis, p = 0.0015). Moradi et al. Radiation Oncology (2022) 17:34 Page 6 of 9 Table 3 Univariable and multivariable cox proportional hazards analysis of the association of listed dichotomized variables with time to bleeding cessation Variable Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value CFRT 3.23 1.65–6.32 0.001 3.26 1.37–7.80 0.008 Age 50+ 2.17 1.11–4.22 0.022 0.74 0.28–1.96 0.543 Concurrent chemo 0.54 0.29–1.02 0.057 0.76 0.31–1.88 0.550 Non-White 0.97 0.53–1.80 0.941 AC or AP use 0.62 0.22–1.77 0.373 Non-cervical primary 1.20 0.62–2.33 0.581 Pre-menopausal 0.70 0.38–1.29 0.259 Transfusion required 1.14 0.60–2.21 0.680 Metastatic 1.15 0.60–2.20 0.669 Recurrence 3.53 1.42–8.82 0.007 1.96 0.51–7.54 0.326 Prior pelvic RT 10.50 1.17–93.9 0.035 2.06 0.16–27.00 0.582 Prior pelvic surgery 1.87 0.93–3.77 0.080 1.76 0.68–4.57 0.243 Prior systemic therapy 6.12 2.30–16.33 < 0.001 2.17 0.64–7.28 0.211 Pretreatment Hgb (continuous) 0.96 0.82–1.12 0.597 Pre-specified criteria for inclusion in a final multivariable model was p < 0.2 on univariable analysis compared to 25.5  Gy for CFRT (p = 0.041). We also cal- culated BED (biologically effective dose at α/β = 2) dose delivered at the time of bleeding cessation to estimate the biologically effective dose to tumor-associated endothe - lial cells (assuming normal endothelial tissue α/β = 2). For the entire cohort, the median BED dose at time of bleeding cessation was 37.6  Gy. While the median BED dose at time of bleeding cessation was lower for HFRT compared to CFRT (28.1 Gy vs. 41.0 Gy), this difference was not statistically significant (p = 0.269). We additionally looked at overall bleeding control and Fig. 3 The effect of radiation dose per fraction on time to bleeding rates of rebleeding in our patient population. All patients cessation. Time to bleeding cessation is presented for patients in the study had cessation of bleeding with bleeding receiving less than 2.0 Gy per fraction (≤ 2.0 Gy/fx), 2.1–2.5 Gy per control rates of 100%, irrespective of RT type (CFRT vs. fraction (2.1–2.5 Gy/fx) and more than 2.5 Gy per fraction (> 2.5 Gy/ fx). Log-rank p value was calculated at p < 0.001. Log-rank p testing HFRT). In all cases, bleeding cessation was achieved with between each individual group pairing was tested and yielded external beam RT and prior to initiation of any brachy- p = 0.2457 for the low dose compared to intermediate dose per therapy. A total of 4 patients (9.3%) within the cohort fraction (≤ 2.0 Gy/fx vs. 2.1–2.5 Gy/fx) but comparison of high dose experienced rebleeding after initial bleeding resolution per fraction (> 2.5 Gy/fx) with the other two groups yielded p < 0.001 with a median time to rebleeding of 128  days (range on log-rank p-testing 48–216 days). Of those four patients, two received HFRT and 2 received CFRT, resulting in rebleeding rates of 7.7% and 11.4%, respectively (χ p = 0.653). The rate of acute To investigate the relationship between BED dose 10 grade 2+ toxicity was higher in patients receiving CFRT delivered to the tumor and bleeding cessation, we plotted compared to HFRT (61.5% vs. 23.5%, p = 0.027) with histograms of the cumulative BED dose delivered at the 10 upper GI (nausea), lower GI (diarrhea), and GU (dysuria) time of bleeding cessation for individual patients in each the most common toxicities observed (Additional file  2: group (Fig.  4). For the whole cohort, the median BED 10 Table  S2). Grade 3+ toxicity was rare with two patients delivered at the time of bleeding cessation was 21.9  Gy. experiencing Grade 3 upper GI toxicity in the CFRT Patients receiving HFRT had bleeding cessation at lower group and one patient experiencing Grade 3 bladder total delivered BE D doses compared to those in the 10 outlet obstruction (secondary to blood clot from tumor CFRT group with median values of 15.2  Gy for HFRT invasion of the bladder) in the HFRT group. Pre- and M oradi et al. Radiation Oncology (2022) 17:34 Page 7 of 9 Fig. 4 Histogram showing the cumulative dose in A BED10 or B BED2 delivered at the time bleeding cessation was documented for patients receiving CFRT (white bars) and HFRT (black bars). Median BED10 at time of bleeding cessation was 25.5 Gy and 15.2 Gy for CFRT and HFRT, respectively (p = 0.041 by Mann–Whitney test). Median BED2 at time of bleeding cessation was 41.0 Gy and 28.1 Gy for CFRT and HFRT, respectively (p = 0.269 by Mann–Whitney test) post-RT hemoglobin and platelet counts for patients on incurable, palliative intent patients and in many cases, with available data, as well as the lowest hemoglobin level very hypofractionated RT regimens (e.g., 10 Gy in a sin- recorded during RT treatment are shown in Additional gle fraction) [2, 3, 5, 6]. Further, most of these studies file  1: Figure S1. There was a trend towards a lower pre- reported only overall response rates but no information RT hemoglobin for patients receiving HFRT compared to regarding how quickly bleeding cessation was achieved. CFRT (10.00 vs. 8.57, p = 0.084), but, otherwise, no dif- Other studies lumped patients with bleeding GYN malig- ference in any of the other parameters. nancies together with other bleeding tumor sites (e.g., bladder/hematuria, lung/hematemesis, etc.), making Discussion interpretation of the combined results challenging [4]. Despite being a common issue encountered in radiation One of the few contemporary studies that focused spe- oncology, the optimal RT regimen for palliation of VB cifically on patients with bleeding GYN malignancies fol - and implications of RT fractionation scheme on time to lowing palliative RT reported similar overall findings to bleeding cessation are not well defined. We found that those reported here [8]. While they did not find a statisti - women receiving HFRT had significantly decreased time cally significant difference in the time to bleeding cessa - to bleeding cessation compared to CFRT with median tion in their small cohort of incurable patients receiving time to bleeding cessation of 5  days versus 16  days, palliative RT, time to bleeding cessation was numerically respectively. When HFRT was further subdivided by the less with more hypofractionated RT and with similar amount of dose delivered per fraction, the data contin- times to bleeding cessation compared to those reported ued to demonstrate that increasing dose-per-fraction here. decreased time to bleeding cessation with an apparent Our study is somewhat unique in that we have included dose–response effect. On multivariable analysis, receipt both patients treated with curative and palliative intent of HFRT (as opposed to CFRT) was the only variable radiation. The data presented here provides information with a statistically significant association with time to on bleeding cessation with more protracted RT regimens bleeding cessation. Altogether, these data suggest that and gives useful insight into the relative effectiveness and in our cohort of patients, more hypofractionated radia- kinetics of bleeding cessation for more curative-intent tion regimens leads to more rapid bleeding cessation in RT compared to shorter-course hypofractionated RT. For patients with tumor-associated VB. example, this data may be helpful in the management of While the main result of this study, that higher dose- patients with newly diagnosed, curable cervical cancer per-fraction RT leads to more rapid tumor-related with severe bleeding at presentation. If a patient presents bleeding cessation, seems somewhat intuitive and is a with severe bleeding at presentation (e.g., requiring fre- commonly held belief by radiation oncologists, there is a quent transfusions), initiation of RT with a few fractions paucity of modern data supporting this point. The limited of HFRT may be warranted before switching to a more studies that have investigated the relationship between conventionally fractionated definitive RT course, as our radiation dose and GYN bleeding cessation have focused data suggests a significant reduction in median time to Moradi et al. Radiation Oncology (2022) 17:34 Page 8 of 9 bleeding cessation (5 days vs. 16 days) with HFRT. Alter- regarding the granularity of bleeding cessation data that natively, patients with less severe bleeding may be man- was obtained. Despite this, we still saw a statistically sig- aged appropriately with CFRT with expected bleeding nificant difference in time to bleeding cessation for CFRT cessation most likely within approximately 2  weeks of versus HFRT, and our median time to bleeding cessation RT initiation. Several studies have found an association and bleeding control rates were similar to those reported between anemia and worse oncologic outcomes in cervi- in contemporary studies as discussed above. Addition- cal cancer patients receiving radiation, possibly related ally, assessment of bleeding cessation was reliant on the to tumor hypoxia leading to increased radioresistance somewhat subjective measure of physician documen- [9–12]. While the exact mechanism for this association tation of bleeding cessation. While we did collect more is not well understood, these data suggest that more rapid objective data related to bleeding, such as hemoglobin cessation of bleeding may limit or prevent anemia and in levels and need for blood transfusion, being a retrospec- turn improve oncologic outcomes, which may also be a tive study, not all patients had this data available and it consideration when choosing RT dose and strategy. was also confounded by other factors, such as chemo- As we did include both curative and palliative intent therapy induced anemia. Given these limitations, it was patients with bleeding GYN malignancy, we must not feasible to use these data as a more objective end- acknowledge that patients receiving CFRT and HFRT point for bleeding cessation/control. While our cohort were inherently different. Patients being treated with size of 43 patients is quite sizeable compared to similar curative intent CFRT were more likely to be younger, analyses in the literature, from a statistical standpoint treatment naïve patients with cervical cancer and were this is a relatively small sample size with limited power more likely to receive concurrent chemotherapy, whereas and risk of type 2 error. Despite this, we did still see sig- patients receiving HFRT were more likely to be older nificant differences in time to bleeding cessation with RT patients with non-cervical malignancy with recurrent regimen choice. However, other variables that one might disease. Further, physicians likely elected to use HFRT expect to influence bleeding cessation, such as receipt of for patients with more severe bleeding. This is consist - anticoagulant or antiplatelet medications, were not sig- ent with the lower pre-RT hemoglobin levels seen in the nificantly associated with time to bleeding cessation, pos - HFRT group compared to CFRT (10.00  g/dL vs. 8.57  g/ sibly due to the limited sample size and power. dL, p = 0.084). Taking all these facts together, patients in the HFRT group likely had more severe bleeding and more recalcitrant tumors, making the significant reduc - Conclusion tion in time to bleeding cessation between HFRT and Women with continuous VB from GYN malignancies CFRT even more meaningful. receiving HFRT experienced more rapid bleeding cessa- Another unique aspect of our study is that we calcu- tion than those receiving CFRT with an apparent dose lated the individual BED and BED doses that were response effect with increasing dose-per-fraction. For 10 2 delivered for individual patients at the time of physician- patients with severe GYN bleeding, initiation of high documented bleeding cessation. The goal of this analy - dose-per-fraction radiation to rapidly halt malignancy sis was to provide physicians a tool to estimate time to related bleeding may be warranted. bleeding cessation for various RT fractionation schemes (via calculation of BED and BED ) when considering 2 10 Abbreviations various regimens for patients with active bleeding. We VB: Vaginal bleeding; GYN: Gynecologic; RT: Radiation therapy; HFRT: Hypofrac- found that the BE D dose delivered at time of bleeding tionated radiation; CFRT: Conventionally fractionated radiation; EBRT: External beam radiation therapy; EMR: Electronic medical record; BED: Biologically cessation was statistically significantly greater for CFRT effective dose; CTCAE: Common Terminology Criteria for Adverse Events; HR: compared to HFRT. However, the BE D dose delivered Hazard ratio; IR: Interventional radiology. at time of bleeding cessation was not statistically differ - ent. This suggests that time to initial bleeding cessation Supplementary Information may be more driven by the effect of RT on tumor asso - The online version contains supplementary material available at https:// doi. ciated endothelium (with lower associated α/β) rather org/ 10. 1186/ s13014- 022- 01995-7. than on tumor cells. Indeed, there is some data to suggest that more hypofractionated RT doses may more greatly Additional file 1. Supplemental Figures: Supplemental Figure 1. Relationship between dose per day delivered and time to bleeding ces- impact/damage tumor-associated endothelium, which sation. Line shown is simple linear regression demonstrating an inverse may have led to earlier bleeding cessation for patients correlation (Pearson’s correlation r = -0.4684, p = 0.0015) receiving HFRT in this study [13–15]. Additional file 2. Supplemental Tables: Supplemental Table 1. There are several limitations to the present study. Hemoglobin and platelet levels before and after completion of radiation. Values reported are the arithmetic mean. P-values were calculated by Given the retrospective nature, there are limitations M oradi et al. Radiation Oncology (2022) 17:34 Page 9 of 9 palliative radiation therapy: less is more. J Pain Symptom Manage. Mann-Whitney test. Supplemental Table 2 Acute toxicities reported 2021;61(2):377-383.e372. by RT type received. Grade 2+ toxicities per CTCAE criteria are reported. 9. Bishop AJ, Allen PK, Klopp AH, Meyer LA, Eifel PJ. Relationship between P-values were determined via Fisher’s exact test. low hemoglobin levels and outcomes after treatment with radiation or chemoradiation in patients with cervical cancer: has the impact of ane- mia been overstated? Int J Radiat Oncol Biol Phys. 2015;91(1):196–205. Acknowledgements 10. Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensi- The authors would like to thank Hollye Kelly for her help in querying depart- tivity to radiation therapy and chemotherapy? Oncologist. 2004;9(Suppl mental databases for patient identification. 5):31–40. 11. Zayed S, Nguyen TK, Lin C, et al. Red blood cell transfusion practices Authors’ contributions for patients with cervical cancer undergoing radiotherapy. JAMA Netw CS, LM and SM devised the study. LM and RP identified eligible patients Open. 2021;4(4):e213531. and collected data. CS and AD analyzed the data. CS, LM, and AD were the 12. Moreno-Acosta P, Vallard A, Carrillo S, et al. Biomarkers of resistance to major contributors to writing of the manuscript. All authors read, edited, and radiation therapy: a prospective study in cervical carcinoma. Radiat approved the final manuscript. Oncol. 2017;12(1):120. 13. Park HJ, Griffin RJ, Hui S, Levitt SH, Song CW. Radiation-induced vascular Funding damage in tumors: implications of vascular damage in ablative hypofrac- No external funding source was utilized for the submitted research. All fund- tionated radiotherapy (SBRT and SRS). Radiat Res. 2012;177(3):311–27. ing support was from the University of Alabama Department of Radiation 14. Song CW, Kim MS, Cho LC, Dusenbery K, Sperduto PW. Radiobiological Oncology. basis of SBRT and SRS. Int J Clin Oncol. 2014;19(4):570–8. 15. Song CW, Glatstein E, Marks LB, et al. Biological principles of stereotactic Availability of data and materials body radiation therapy (SBRT ) and stereotactic radiation surgery (SRS): The datasets used and/or analysed during the current study are available from indirect cell death. Int J Radiat Oncol Biol Phys. 2021;110(1):21–34. the corresponding author on reasonable request. Publisher’s Note Declarations Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Ethics approval and consent to participate This retrospective study was performed per departmental IRB as approved by UAB’s Institutional Review Board (UAB IRB 120703005). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA. Case Western Reserve University School of Medicine, Cleveland, OH, USA. Received: 22 October 2021 Accepted: 19 January 2022 References 1. Smith SC, Koh WJ. Palliative radiation therapy for gynaecological malig- nancies. Best Pract Res Clin Obstet Gynaecol. 2001;15(2):265–78. 2. Hodson DI, Krepart GV. Once-monthly radiotherapy for the palliation of pelvic gynecological malignancy. Gynecol Oncol. 1983;16(1):112–6. 3. Spanos WJ Jr, Wasserman T, Meoz R, Sala J, Kong J, Stetz J. Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: final report of RTOG phase I/II study. Int J Radiat Oncol Biol Phys. 1987;13(10):1479–82. 4. Sapienza LG, Ning MS, Jhingran A, et al. Short-course palliative radiation Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : therapy leads to excellent bleeding control: a single centre retrospective study. Clin Transl Radiat Oncol. 2019;14:40–6. fast, convenient online submission 5. Halle JS, Rosenman JG, Varia MA, Fowler WC, Walton LA, Currie JL. 1000 thorough peer review by experienced researchers in your field cGy single dose palliation for advanced carcinoma of the cervix or endo- rapid publication on acceptance metrium. Int J Radiat Oncol Biol Phys. 1986;12(11):1947–50. 6. Yan J, Milosevic M, Fyles A, Manchul L, Kelly V, Levin W. A hypofraction- support for research data, including large and complex data types ated radiotherapy regimen (0-7-21) for advanced gynaecological cancer • gold Open Access which fosters wider collaboration and increased citations patients. Clin Oncol (R Coll Radiol). 2011;23(7):476–81. maximum visibility for your research: over 100M website views per year 7. Pereira J, Phan T. Management of bleeding in patients with advanced cancer. Oncologist. 2004;9(5):561–70. At BMC, research is always in progress. 8. Butala AA, Lee DY, Patel RR, et al. A retrospective study of rapid symptom response in bleeding gynecologic malignancies with short course Learn more biomedcentral.com/submissions

Journal

Radiation OncologySpringer Journals

Published: Feb 14, 2022

Keywords: Gynecologic cancer; Vaginal bleeding; Radiation; Cervical cancer

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