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The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy

The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical... Background: To analyze the prognostic factors associated with stage IB‑IVA cervical cancer in patients who under ‑ went concurrent chemoradiation therapy (CCRT ) and to compare the clinical toxicities and dosimetric parameters of organs at risk between the different radiotherapy techniques. Methods: This retrospective study enrolled 93 patients with stage IB‑IVA cervical cancer who underwent definitive CCRT between April 2009 and December 2017. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy, and all of them followed by brachytherapy using a 2D planning technique. The treatment outcomes and related prognostic factors were analyzed. We also compared the clinical toxicities and dosimetric parameters between the different techniques used for the last 30 patients. Results: With a median follow‑up of 52.0 months, the 5‑ year overall survival (OS), progression‑free survival (PFS), locoregional recurrence–free survival (LRRFS), and distant metastases–free survival (DMFS) were analyzed. In a Cox proportional hazards regression model, pretreatment SCC Ag > 10 ng/mL was a significant prognostic factor for PFS (hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.03–4.70; P = 0.041), LRRFS (HR, 3.48; 95% CI 1.07–11.26; P = 0.038), and DMFS (HR 2.80; 95% CI 1.02–7.67; P = 0.045). Increasing the rectal volume receiving a radiation dose exceeding 30 Gy ( V of rectum; odds ratio [OR] 1.15; 95% CI 1.10–1.30; P = 0.03) was associated with a higher pos‑ sibility of ≥ Grade 2 acute radiation therapy (RT )‑related diarrhea. The median rectal V values were 56.4%, 97.5%, and 86.5% for tomotherapy, 3‑ dimensional conformal radiation therapy (3DCRT ), and volumetric modulated arc therapy *Correspondence: miyihu@gmail.com Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung 80708, Taiwan 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. Cheng et al. Radiation Oncology (2022) 17:91 Page 2 of 17 ( VMAT ), respectively (P < 0.001). In addition, the chance of experiencing ≥ Grade 2 acute diarrhea were 10.0%, 66.7%, and 54.5% for tomotherapy, 3DCRT, and VMAT, respectively (P = 0.029). Conclusions: Patients with pretreatment SCC Ag ≤ 10 ng/mL have better PFS, LRRFS, and DMFS than those with pretreatment SCC Ag > 10 ng/mL. The rectal V is a significant predictor of severe acute diarrhea. Tomotherapy signifi‑ cantly decreased the rectal V , reducing the severity of acute RT‑related diarrhea during external beam RT. Trial registration This study was approved by the institutional review board at Kaohsiung Medical University Hospital. The registration number is KMUHIRB‑E(I)‑20190054 and retrospectively registered on 2019/3. Keywords: Cervical cancer, SCC Ag, Volumetric modulated arc therapy, Tomotherapy, Diarrhea, Rectum Background of prior malignancy before treatment, any history of prior Cervical cancer is the fourth most common cancer type radiotherapy, and Eastern Cooperative Oncology Group among women [1]. Despite the development of prophy- (ECOG) performance status > 2. lactic vaccines, cervical cancer remains a major cause of All patients underwent pretreatment workup and can- mortality worldwide, particularly in low socioeconomic cer staging using modern approaches, including a physi- regions [2]. Concurrent chemoradiation therapy (CCRT) cal examination by a gynecologic oncologist, a tumor for non-surgical patients with cervical cancer plays an biopsy, a history review, chest X-ray, abdominal and important role in radical therapy. External beam radia- pelvic computed tomography (CT,) or pelvic magnetic tion therapy (EBRT) administered using 3-dimensional resonance imaging (MRI). Cystoscopy or sigmoidoscopy conformal radiation therapy (3DCRT) is a commonly was performed by a specialist to exclude adjacent organ used cervical cancer treatment method. However, radia- invasion for patients with locally advanced disease. In tion therapy (RT)-related acute and late toxicities are addition, routine laboratory biomarker studies, includ- well-known issues, including the development of coli- ing squamous cell carcinoma antigen (SCC Ag), carci- tis, diarrhea, cystitis, frequent urination, dysuria, and noembryonic antigen (CEA), and cancer antigen 125 proctitis. (CA125), were measured among the cohort. The median Increasingly, intensity-modulated radiotherapy follow-up was 52  months (range 6–137  months). The (IMRT), volumetric modulated arc therapy (VMAT), cancer stage was classified according to the seventh edi - and tomotherapy have become more commonly used tion of the American Joint Committee on Cancer (AJCC) RT methods over the past few decades. Comparisons TNM classification and the 2008 International FIGO of clinical results between 3DCRT, VMAT, and tomo- staging system for cervical cancer. The retrospective therapy among patients with head and neck cancer have study (KMUHIRB-E(I)-20190054) was approved by the been well described [3, 4]. Considerable studies have also Institutional Review Board (IRB) of Kaohsiung Medical examined the dosimetric differences among 3DCRT, University Hospital, and the need for informed consent VMAT, and tomotherapy in patients with cervical cancer. was waived by the IRB due to the nature of this study as a Some single-center and multi-center series examining chart review. postoperative RT have described favorable toxicity pro- files associated with the use of IMRT [5, 6]. However, dis- Radiotherapy parities in the clinical results among these techniques are All patients received a consultation with a radiation rarely reported. Thus, we compared the clinical outcomes oncologist and underwent an evaluation of clinical sta- across various techniques applied to patients with non‐ tus to ensure the necessity and safety of radiotherapy. distant metastatic cervical cancer who underwent defini - Following bladder preparation, patients were placed in a tive CCRT and examined prognostic factors. supine position with cast or cushion immobilization and underwent CT simulation, using a 3–5  mm slice thick- Methods ness, from the upper edge of the lumbar spine to 5  cm Patients below the lower border of the obturator foramen. For We enrolled patients diagnosed with cervical cancer, 3DCRT, a four-field box technique was planned using classified as stages IB to IVA according to the Interna - corner shielding in anteroposterior/posteroanterior (AP/ tional Federation of Gynecology and Obstetrics (FIGO) PA) portals. The radiation portal fields were designed staging system, between April 2009 and December 2017. as follows: (1) superior border: L4–5 interspace, which None of the enrolled patients had distant metastases at covers the common iliac lymph nodes; (2) inferior bor- treatment onset, and all patients received radical CCRT. der: 3  cm below the most inferior vaginal involvement, The exclusion criteria for this study included any history which is often below the inferior obturator foramen and Cheng  et al. Radiation Oncology (2022) 17:91 Page 3 of 17 can be as low as the introitus in cases of vaginal tumor block was the midsacroiliac joint, and the width was extension; and (3) lateral border: 1.5–2 cm outside of the 4 cm. If a parametrial tumor persists after 50–54 Gy, the pelvic rim. For the lateral fields, the superior and infe - side wall or parametrium may receive up to 60  Gy. For rior borders were consistent with the design of the AP/ VMAT or tomotherapy, the clinical target volume (CTV) PA portals. The anterior border covered the front of the was defined as the gross tumor plus microscopic disease, pubic symphysis, and the posterior edge included the including the cervix, uterus, upper third of the vagina (or entire sacrum. Pelvic radiotherapy was delivered at 1.8– upper half of the vagina, if a gross tumor is involved), the 2.0 Gy per fraction, 1–5 days each week, for a total of 25 parametrium, and the pelvic nodal drainage. The patients fractions comprising 45–50  Gy, followed by the delivery were treated with simultaneous integrated boost doses of 5.4–9 Gy in 3–5 fractions delivered by AP/PA portals of 48.6–50.4 Gy, delivered in 1.8 to 2-Gy fractions, to the using a midline block. The superior border of the midline primary tumor, 54–60  Gy delivered to the pelvic nodal Table 1 Patient and tumor characteristics for all 93 patients Characteristics 3DCRT (n = 9) VMAT (n = 43) Tomotherapy (n = 41) P value Age in years, median (range) 48 (34–66) 62 (38–84) 63 (34–89) 0.01 Age (years) < 60 8 20 17 0.034 ≥ 60 1 23 24 OTT of RT (days) ≤ 61 6 21 13 0.091 > 61 3 22 28 FIGO stage I 1 10 3 0.081 II 4 25 22 III 1 4 11 IV 3 4 5 T classification T1/T2 6 35 25 0.114 T3/T4 3 8 16 Nodal classification N0 2 32 25 0.011 N1 7 11 16 Histological type Squamous cell carcinoma 8 40 39 0.607 Adenocarcinoma 1 3 1 Others 0 0 1 Mean EBRT dose (Gy) 55.1 54.1 54.2 0.516 Mean EQD2 of brachytherapy (Gy) 28.1 29.9 29.8 0.696 EQD2 of Point A (Gy) < 81 8 27 32 0.147 ≥ 81 1 16 9 Pretreatment SCC Ag (ng/mL) ≤ 10 4 23 24 0.722 > 10 5 20 17 Post‑treatment SCC Ag (ng/mL) ≤ 1.5 8 38 32 0.399 > 1.5 1 5 9 Median follow‑up (months) 43 54 52 0.123 3DCRT three-dimensional conformal radiation therapy, VMAT volumetric modulated arc therapy, OTT overall treatment time, RT radiation therapy, FIGO the international federation of gynaecology and obstetrics, EBRT external beam radiation therapy, EQD2 equivalent dose in 2-Gy fractions, SCC Ag squamous cell carcinoma antigen Cheng et al. Radiation Oncology (2022) 17:91 Page 4 of 17 drainage, including parametrial, obturator, internal iliac, VERSION 4.03 [28]. Using these criteria, acute compli- external iliac, common iliac and gross lymph nodes, and cations were defined as those with onset during RT and 45–48  Gy, delivered in 1.6 to 1.8-Gy fractions, to elec- were assessed once per week during EBRT. Chronic com- tive nodal regions, such as presacral and paraaortic area. plications were scored retrospectively based on chart The planning target volume (PTV) was defined as the records. The overall treatment time (OTT) of RT was 8–10  mm margin around the CTV and could be modi- defined as the time interval between the first and last fied according to the clinical condition. Target planning date of RT. The primary endpoints were locoregional constraints were standardized as follows: (1) the PTV in recurrence–free survival (LRRFS), progression-free sur- all directions to receive > 95% of the prescribed dose; (2) vival (PFS), distant metastasis–free survival (DMFS), and volumes receiving more than 110% of the dose prescribed overall survival (OS). The length of follow-up was defined to the PTV were minimized. The typical organs at risk as the time from CCRT to the date of death or the last (OARs) included the rectum, bladder, intestine, large follow-up. Locoregional failure was defined as any recur - bowel, peritoneum, bilateral femoral heads, and the pel- rent or persistent disease involving the pelvis. Any dis- vic bone marrow [7]. The external contours of all bones ease failure outside of the pelvis was defined as a distant within the pelvis were delineated on the planning CT failure. Pathological reports, including those associated images, as surrogates for the bone marrow, to enhance with surgical intervention, biopsy, and cytology, in addi- the reproducibility and consistency of the contours. tion to radiology reports from radiology examinations, The intestine and large bowel contours consisted of the including chest radiography, CT, MRI, technetium-99 bowel loops from 3  cm superior to the upper border of bone scintigraphy, or positron emission tomography the PTV to its lowest extent in the pelvis. The dosimetric (PET), were reviewed to determine disease status. parameters for OARs were recorded as Vx, which repre- sented the percentage of the organ volume that received Statistical analysis X Gy or higher. For the individual patients, the selection Data were analyzed using SPSS 22.0 software (IBM Corp., of respective EBRT technique was decided by radiation Armonk, NY, USA). Dose-volume histograms (DVHs) of oncologist on the basis of clinical scenario. the PTVs and the OARs were analyzed accordingly. For PTV, the goal is to encompass the PTV in all directions Brachytherapy and concurrent chemotherapy with the 95% isodose line. To reduce toxicity and opti- After EBRT, all patients underwent afterloading brachy- mize OAR doses, DVH constraint was applied to limit therapy, which consisted of high-dose-rate Ir intracavi- maximum dose and dose-volume parameters. OS was tary brachytherapy intended to deliver a dose of 4–5 Gy/ defined as the time from primary treatment to the date time to Point A twice per week, with 5 to 6 total treat- of death from any cause or the date of the last follow-up. ments. During RT, chemotherapy was concurrently pre- PFS was defined as the time from primary treatment to scribed, consisting of weekly cisplatin for 6  weeks. The the date of disease failure at any site or to the date of the regimen was shifted to carboplatin for those patients last follow-up. LRRFS was defined as the time from pri - with impaired renal function and paclitaxel-based treat- mary treatment to the date of locoregional failure or to ment for prescribed for patients with locally advanced the date of the last follow-up. DMFS was defined as the disease. time from primary treatment to the date of distal failure or to the date of the last follow-up. LRRFS, PFS, DMFS, Follow‑up and evaluation OS, and the treatment-related toxicity were analyzed In general, the patients returned for a first follow-up using the Kaplan–Meier method, and the log-rank test visit one month after the completion of treatment, fol- was used to calculate differences between groups. Signifi - lowed by every 2–3  months during the first year and cance was defined as P < 0.05. every 3–6  months thereafter. Physical examination including pelvic examination was performed at every Results follow-up visit. Patients should have follow-up imaging, Patients either abdominal and pelvic CT or pelvic MRI, at least A total of 93 patients diagnosed with stage IB-IVA cer- every 3–6  months after the completion of treatment. vical cancer were enrolled in this retrospective study. Chest X-ray is acquired annually at least after treatment. The median age of the retrospective cohort was 61 years A serum test for tumor markers was performed every (range 34–93  years). Table  1 summarizes the patients’ 3–6  months after the completion of CCRT. The gyneco - clinical baseline characteristics, grouped according to logic oncologists and radiation oncologists recorded the three radiotherapy techniques. Nine patients (9.7%) treatment-related toxicity events according to the Com- received 3DCRT, 43 patients (46.2%) underwent VMAT, mon Terminology Criteria of Adverse Events (CTCAE), and 41 patients (44.1%) received tomotherapy. The Cheng  et al. Radiation Oncology (2022) 17:91 Page 5 of 17 (a) (b) (c) (d) (e) Fig. 1 The Kaplan–Meier survival curve of overall survival. Overall survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), and e post ‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 6 of 17 Table 2 Cox proportional hazards regression analysis for overall pretreatment SCC Ag, and post-treatment SCC Ag were survival significant factors (P = 0.01, 0.001, 0.006, 0.034, and 0.018, respectively). Table 2 presents a multivariate analy- Variable HR 95% CI P value sis of these characteristics. Only an OTT of RT > 61 days Age ≥ 60 years 1.91 0.78–4.67 0.156 and T3/T4 disease were significant factors associ - OTT of RT > 61 days 2.99 1.03–8.70 0.045 ated with OS in the Cox proportional hazards regres- T3 or T4 disease 2.97 1.24–7.11 0.015 sion analysis (hazard ratio [HR] 2.99, 95% confidence N1 or N2 disease 2.11 0.87–5.13 0.098 interval [CI] 1.03–8.70, P = 0.045; and HR 2.97, 95% CI Pretreatment SCC Ag > 10 ng/mL 1.72 0.71–4.17 0.232 1.24–7.11, P = 0.015, respectively). A post-treatment SCC Post‑treatment SCC Ag > 1.5 ng/mL 2.42 0.93–6.26 0.069 Ag > 1.5  ng/mL was associated with a lower OS, but did EQD2 of Point A ≥ 81 Gy 0.82 0.34–1.99 0.666 not achieve significance (P = 0.069). RT technique 0.621 In the PFS analysis using the Kaplan–Meier method VMAT 0.44 0.08–2.39 0.341 (Fig.  2), T classification, N classification, and pretreat - Tomotherapy 0.59 0.12–2.90 0.518 ment SCC Ag were significant factors (P ≤ 0.001, 0.004, HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation and 0.005, respectively). The OTT of RT showed an therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy effect on PFS by the log-rank test, but did not achieve fractions, VMAT volumetric modulated arc therapy significance (P = 0.071). Table  3 presents the multivari- Reference category: 3DCRT, three-dimensional conformal radiation therapy ate analysis of these characteristics. T3/T4 disease, nodal positive, and pretreatment SCC Ag > 10 ng/mL remained median EBRT dose was 54  Gy (range 45–64  Gy), and significant factors affecting PFS in the Cox proportional the median equivalent dose in 2-Gy fractions (EQD2) of hazards regression analysis (HR 2.72, 95% CI 1.30–5.71, Point A was 79.8 Gy (range 49.1–93.1 Gy). No significant P = 0.008; HR 2.55, 95% CI 1.15–5.63, P = 0.021; and HR differences were observed for OTT of RT, clinical T clas - 2.20, 95% CI 1.03–4.71, P = 0.041, respectively). sification, histological type, mean EBRT dose, EQD2 of In the LRRFS analysis using the Kaplan–Meier method Point A, pre- and post-treatment SCC Ag, or follow-up (Fig.  3), only T classification and pretreatment SCC Ag duration between the three techniques. One patient in were significant factors (P = 0.032 and 0.038, respec- the 3DCRT group and one patient in the VMAT group tively). Table 4 presents the multivariate analysis of these were lost to follow-up. characteristics. Only pretreatment SCC Ag > 10  ng/ mL remained significant in the Cox proportional haz - Clinical outcomes and failure patterns ards regression analysis (HR 3.48, 95% CI 1.07–11.26, With a median follow-up of 52  months (range P = 0.038). The T3/T4 classification showed an effect on 6–137  months), the 5-year OS, PFS, LRRFS, and DMFS LRRFS but failed to reach significance (P = 0.082). were 75.2%, 65.8%, 82.2%, and 74.7% (P = 0.07, 0.06, In the DMFS analysis using the Kaplan–Meier method 0.36, and 0.23), respectively. No significant differences (Fig.  4), T classification, N classification, and pretreat - in survival outcomes were observed between the three ment SCC Ag were significant factors (P = 0.001, < 0.001, groups. The overall locoregional recurrence rate was and 0.001, respectively). The OTT of RT showed an effect 16.1% (15/93), and the majority recurrence pattern was on DMFS by the log-rank test but failed to reach signifi - local recurrence (11 patients with local recurrence and 4 cance (P = 0.071). Table 5 presents the multivariate analy- patients with regional nodal failure). The distant failure sis of these characteristics. All three factors remained rate was 23.7% (22/93), and the major recurrence sites significant in the Cox proportional hazards regression included the non-regional lymph nodes (7/22), the lung analysis (HR 2.88, 95% CI 1.01–8.22, P = 0.048; HR 6.17, (5/22), and the liver (5/22), with other sites observed less 95% CI 2.01–18.89, P = 0.001; and HR 2.80, 95% CI 1.02– frequently. 7.67, P = 0.045, respectively). OTT of RT > 61  days failed We further investigated clinical outcomes based on dif- to demonstrate significance following after covariate ferent patient and tumor characteristics, including age adjustment (P = 0.161). (≥ 60 vs. < 60 years), OTT of RT (> 61 days vs. ≤ 61 days), In the T1/T2N0 subgroup analysis using the Kaplan– T classification (T1/T2 vs. T3/T4), N classification Meier method (Fig. 5), pretreatment SCC Ag > 10 ng/mL (nodal negative vs. nodal positive), pretreatment SCC trended toward worse DMFS but not OS, PFS, or LRRFS. Ag (≤ 10 vs. > 10  ng/mL), post-treatment SCC Ag (≤ 1.5 The 5-year DMFS was 93.8% for the group with pretreat - vs. > 1.5 ng/mL), the EQD2 of Point A (≥ 81 vs. < 81  Gy), ment SCC Ag ≤ 10  ng/mL, compared with 79.4% for the and the RT technique (3DCRT vs. VMAT vs. Tomother- group with pretreatment SCC Ag > 10 ng/mL (P = 0.057). apy). In the OS analysis, using the Kaplan–Meier method Furthermore, in the Cox proportional hazards regres- (Fig.  1), the OTT of RT, T classification, N classification, sion analysis (Table  6), pretreatment SCC Ag > 10  ng/ Cheng  et al. Radiation Oncology (2022) 17:91 Page 7 of 17 (a) (b) (c) (d) (e) Fig. 2 The Kaplan–Meier survival curve of progression‑free survival. Progression‑free survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), and e post ‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 8 of 17 Table 3 Cox proportional hazards regression analysis for the occurrence of Grade 2 or worse colitis. However, we progression‑free survival found a trend toward the increased likelihood of Grade 2 or worse colitis correlated with an increasing rectum V Variable HR 95% CI P value value (OR 1.14, 95% CI 0.99–1.33, P = 0.073), although Age ≥ 60 years 1.90 0.84–4.28 0.122 this did not achieve significance. Except for the rectum OTT of RT > 61 days 1.61 0.69–3.78 0.273 V value, the occurrence of Grade 2 or worse colitis was T3 or T4 disease 2.72 1.30–5.71 0.008 not correlated with any other dosimetric parameters for N1 or N2 disease 2.55 1.15–5.63 0.021 the rectum. Pretreatment SCC Ag > 10 ng/mL 2.20 1.03–4.71 0.041 Post‑treatment SCC Ag > 1.5 ng/mL 2.01 0.82–4.96 0.129 Dosimetric parameters of organs at risk and RT technique EQD2 of Point A ≥ 81 Gy 1.39 0.65–2.97 0.403 a To compare differences in the radiation exposure for RT technique 0.423 OARs between the 3 treatment plans, the last 30 patients VMAT 0.53 0.13–2.08 0.359 were analyzed, including 9 patients (30%) in the 3DCRT Tomotherapy 0.91 0.25–3.33 0.889 group, 11 patients (36.7%) in the VMAT group, and 10 HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation patients (33.3%) in the tomotherapy group. Since we were therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy fractions, VMAT volumetric modulated arc therapy also interested in OARs and toxicity difference between Reference category: 3DCRT, three-dimensional conformal radiation therapy the 3 treatment plans, our group initiated the compari- son of dosimetric outcomes and clinical toxicities in the mid-term of study and led to only the last 30 patients mL suggested an increased risk of distant metastasis and were included. Furthermore, the improved conformality nearly reached a significant effect on DMFS (HR 12.4, achievable with IMRT can potentially mitigate adverse 95% CI 0.85–181.4, P = 0.066). However, all other factors, effects and contribute to the low utilization of 3DCRT. such as age, OTT of RT, post-treatment SCC Ag, EQD2 Table  8 presents the dosimetric comparisons for OARs of Point A, and RT technique, failed to show significant across the 3 treatment plans. Three dosimetric param - effects after covariate adjustment (P = 0.161, 0.767, 0.863, eters were analyzed for the colon, including the V , 0.921, and 0.991, respectively). V , and V values. 3DCRT was associated with higher 25 15 colon V and V values than VMAT and tomotherapy Dosimetric parameters for organs at risk and toxicity 35 25 (P = 0.002 and 0.020, respectively). However, the colon The dosimetric parameters and RT-related toxicity are V values were similar across the three groups. In addi- summarized in Table 7. The relationships between toxic - tion, no dosimetric differences for the colon were found ity and OAR doses were analyzed by logistic regression. between VMAT and tomotherapy groups. Four dosimet- Due to clinical limitations, only the last 30 patients were ric parameters were analyzed for the peritoneum, includ- able to be analyzed. ing the V, V, V and V values. We also found that The dose delivered to the colon did not affect the like - 50.4 40 30, 25 the 3DCRT group had higher peritoneum V , V , and lihood of experience Grade 2 or worse acute diarrhea. 50.4 40 V values than the VMAT and tomotherapy groups The colon V, V , and V values were analyzed, and 35 25 15 (P = 0.001, 0.002, and 0.013, respectively). In the analy- no correlation was observed between these dosimet- sis of peritoneum V values, the 3DCRT values were ric parameters and the occurrence of Grade 2 or worse higher than those for the other two techniques, but this acute diarrhea. We also analyzed the dosimetric param- difference did not achieve significance (P = 0. 147). No eters for the peritoneum and noted a trend toward the significant differences in the dosimetric parameters for increased occurrence of Grade 2 or worse acute diarrhea the peritoneum were observed between the VMAT and with an increasing peritoneum V value (odds ratio [OR] tomotherapy groups. Three dosimetric parameters were 1.62, 95% CI 0.97–2.71, P = 0.068) but not for the peri- analyzed for the rectum, including the V, V , and V toneum V, V , or V values. The dosimetric param - 50.4 40 30 50.4 30 25 values. All three of these parameters were much higher eters for the rectum showed a significant increase in the for the 3DCRT group than for the VMAT and tomother- occurrence of Grade 2 or worse acute diarrhea with an apy groups (P = 0. 003, < 0.001, and < 0.001, respectively). increasing rectum V value (OR 1.15, 95% CI 1.10–1.30, More importantly, the median rectum V values were P = 0.030) but not for the rectum V and V values. 50.4 40 56.4% and 86.5% in the tomotherapy and VMAT groups, The doses delivered to the colon and peritoneum did respectively. Tomotherapy further reduced the V not affect the likelihood of Grade 2 or worse colitis. The value for the rectum compared with VMAT (P < 0.005). colon V, V , and V and the peritoneum V , V , 35 25 15 50.4 40 Figure  6 presents the isodose distributions in a repre- V , and V values were analyzed, and no correlations 30 25 sentative T2N0 patient treated with VMAT and a T3N0 were observed between these dosimetric parameters and Cheng  et al. Radiation Oncology (2022) 17:91 Page 9 of 17 Fig. 3 The Kaplan–Meier survival curve of locoregional recurrence‑free survival. Locoregional recurrence ‑free survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), e and post‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 10 of 17 Table 4 Cox proportional hazards regression analysis for or worse chronic colitis occurred in 22.2% (2/9) of the locoregional recurrence–free survival 3DCRT group, 18.2% (2/11) of the VMAT group, and 20.0% (2/10) of the tomotherapy group, with no sig- Variable HR 95% CI P value nificant differences noted between the three groups. For Age ≥ 60 years 1.18 0.39–3.59 0.775 Grade 2 or worse acute cystitis, the incidences for the OTT of RT > 61 days 1.32 0.41–4.29 0.641 3DCRT, VMAT, and tomotherapy groups were 33.3% T3 or T4 disease 2.64 0.88–7.86 0.082 (3/9), 63.6% (7/11), and 30.0% (3/10), with no significant N1 or N2 disease 0.78 0.24–2.58 0.688 difference noted between groups. Pretreatment SCC Ag > 10 ng/mL 3.48 1.07–11.26 0.038 Post‑treatment SCC Ag > 1.5 ng/mL 0.71 0.15–3.35 0.667 Discussion EQD2 of Point A ≥ 81 Gy 1.16 0.35–3.82 0.804 Our study focused on the prognostic factors among RT technique 0.389 non‐distant metastatic cervical cancer patients treated VMAT 0.87 0.09–8.26 0.905 with definitive CCRT and compared RT-related toxicity Tomotherapy 2.10 0.24–18.58 0.504 among three different RT modalities. HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation Several studies examining the prognostic factors asso- therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy ciated with cervical cancer have been published world- fractions, VMAT volumetric modulated arc therapy wide. The major identified prognostic factors include Reference category: 3DCRT, three-dimensional conformal radiation therapy tumor size; pattern of invasion; tumor grade; pelvic nodal metastasis; age; race; socioeconomic status; sever- patient treated with tomotherapy, showing that the spi- ity of anemia; OTT; and the levels of biomarkers, such as ral delivery pattern associated with tomotherapy reduced hypoxia-inducible factor 1α (HIF-1α), vascular endothe- the unnecessary dosing of the rectum. Three dosimetric lial growth factor (VEGF), SCC Ag, and CEA. Huang parameters were analyzed for the bladder, including the et  al. suggested that pretreatment SCC Ag > 40  ng/mL V, V , and V values. The median V, V , and V 50.4 40 30 50.4 40 30 was an independent factor associated with para-aortic values for the bladder in the 3DCRT group were 40.7%, lymph node relapse, and pretreatment CEA levels have 100%, and 100%, respectively. By contrast, the VMAT been identified as a risk factor for para-aortic lymph values were 2.0%, 28.0%, and 59.5%, respectively, and the node recurrence, in addition to SCC Ag. Hong et  al. tomotherapy values were 5.7%, 28.6%, and 50.5%. For also reviewed 401 patients with cervical cancer primar- all three parameters, the values for the 3DCRT group ily treated with RT and concluded that pretreatment were much higher than for the VMAT and tomotherapy SCC Ag > 10  ng/mL was an independent predictor of groups (P = 0. 001, < 0.001, and < 0.001, respectively). poor disease-specific survival (DFS) [8–17]. Our study Similar to the finding for the colon and peritoneum, no showed that patients with pretreatment SCC Ag > 10 ng/ significant differences were observed among the dosi - mL had worse PFS (HR 2.2, P = 0.041), LRRFS (HR 3.48, metric parameters of the bladder between the VMAT P = 0.038), and DMFS (HR 2.8, P = 0.045). In addition, and tomotherapy groups. Finally, five dosimetric param - the subgroup analysis in our study showed that pretreat- eters were analyzed for the bone marrow, including the ment SCC Ag > 10  ng/mL was an effective predictor for V, V, V, V , and V values. Compared with VMAT 50 40 30 20 10 DMFS in T1N0/T2N0 patients (HR 12.4, P = 0.066). and tomotherapy, we found that 3DCRT results in higher These results suggest that even among patients with marrow V, V, V , and V values (P < 0.001, < 0.001, 50 40 30 20 early-stage cervical cancer primarily treated with defini - < 0.001, and = 0.002, respectively) but not marrow V tive CCRT, pretreatment SCC Ag might serve as a pre- values. Similarly, no significant differences in dosimetric dictor for distant metastasis, which can aid clinicians in parameters for the bone marrow were observed between designing an effective treatment plan. VMAT and tomotherapy. Radiotherapy combined with concurrent chemother- apy provides excellent curative effectiveness for patients RT‑related toxicity and RT techniques with cervical cancer; however, RT-related toxicities are Table  9 presents the percentages of gastrointestinal (GI) well known and can affect quality of life. RT-associ - and genitourinary complications associated with 3DCRT, ated toxicity can occur at any time during treatment or VMAT, and tomotherapy. Acute Grade 2 or worse diar- even several months to years later. Acute complications rhea for 3DCRT, VMAT, and tomotherapy occurred in can include diarrhea, desquamation, cystitis, nausea, 66.7% (6/9), 54.5% (6/11), and 10.0% (1/10) of patients, and vaginitis, which may lead to the interruption of RT respectively. Tomotherapy substantially and significantly [18]. Late complications of radiotherapy may arise sev- reduced the severity of acute diarrhea (P = 0.029). None eral months to years after pelvic irradiation, which can of the patients suffered from Grade 4 diarrhea. Grade 2 include radiation colitis, intestinal perforation, bowel Cheng  et al. Radiation Oncology (2022) 17:91 Page 11 of 17 Fig. 4 The Kaplan–Meier survival curve of distant metastases‑free survival. Distant metastases‑free survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), and e post ‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 12 of 17 Table 5 Cox proportional hazards regression analysis for distant patients are generally accepted, little research has focused metastases–free survival on dosimetric comparisons for OARs between these two plans. Our results suggested that even compared with Variable HR 95% CI P value VMAT, tomotherapy resulted in a significant reduction Age ≥ 60 years 1.32 0.47–3.65 0.599 in the rectum V value, and was further reduced com- OTT of RT > 61 days 2.27 0.72–7.14 0.161 pared with 3DCRT. In addition to dosimetric parameters T3 or T4 disease 2.88 1.01–8.22 0.048 for the rectum, we also analyzed the bladder (V, V , 50.4 40 N1 or N2 disease 6.17 2.01–18.89 0.001 V ), peritoneum ( V, V, V, V ), colon ( V, V , 30 50.4 40 30 25 35 25 Pretreatment SCC Ag > 10 ng/mL 2.80 1.02–7.67 0.045 V ), and bone marrow (V, V, V, V, V ); in addi- 15 50 40 30 20 10 Post‑treatment SCC Ag > 1.5 ng/mL 0.94 0.27–3.34 0.926 tion to a reduction in the rectum V value, tomotherapy EQD2 of Point A ≥ 81 Gy 1.32 0.47–3.68 0.601 resulted in a reduced mean bladder V value, which may RT technique 0.662 indicate a lower dose delivered to the bladder. Ultimately, VMAT 0.67 0.15–2.96 0.596 these results indicated that the implementation of VMAT Tomotherapy 0.51 0.12–2.19 0.368 or tomotherapy reduced the delivery of high-dose radia- HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation tion to normal tissues outside of the target volume, which therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy was more apparent at higher radiation doses, which likely fractions, VMAT volumetric modulated arc therapy benefits adjacent OARs. Reference category: 3DCRT, three-dimensional conformal radiation therapy To date, few studies have examined the effects of small intestine volume in gynecological IMRT patients, and obstruction, and vaginal stenosis, with profound effects only one study has reported the rectal dosimetry asso- on quality of life [19]. To reduce RT-associated side ciated with acute GI toxicity. Although the contribution effects, fixed-field IMRT, VMAT, and tomotherapy have of rectal dose parameters to acute radiation-induced widely been used for pelvic irradiation, enhancing tar- GI toxicity remains a concern in patients treated for get dose conformity while reducing high-dose delivery gynecological malignancies, most studies have primar- to target-surrounding OARs [20]. However, few com- ily focused on the postoperative population. Therefore, parisons of dosimetric parameters and clinical outcomes the current study aimed to analyze the acute toxicities have been reported among these various RT modalities. and rectal doses received by patients with cervical can- Lin et al. demonstrated a meta-analysis that combines six cer treated with definitive CCRT. Roeske et  al. analyzed studies regarding a total of 1008 patients with cervical 50 patients with gynecological malignancies who were cancer to compare the efficacies and toxicities of IMRT treated with pelvic IMRT, approximately two-thirds of with 3DCRT or conventional two-dimensional radio- whom had received hysterectomies, and concluded that therapy. And concluded that IMRT significantly reduced rectal dosimetry (range 35–49  Gy) was not a signifi - acute gastrointestinal and genitourinary toxicities as well cant factor in acute GI toxicity. In that study, only half as chronic genitourinary toxicity [29]. Guo et  al. [21] of patients (26/50) received concomitant chemother- reported that VMAT plans provided better protection of apy, which might contribute to reduced radiosensitivity the rectum and bladder compared with fixed-field IMRT, [23]. Deville et  al. studied 67 patients undergoing post- but no significant differences were observed in the sever - prostatectomy IMRT and noted that the minimum dose ity of complications. Our dosimetric data for the rectum (D ) delivered to the rectum was marginally associated min in the VMAT group were similar to those reported by with acute Grade ≥ 2 GI toxicity (P = 0.05) [24]. Huang Guo et  al. The rectum V and V values in their study 40 30 et  al. examined the association between rectal dose and were 47.39% and 82.12%, respectively, whereas, in our acute diarrhea in patients with gynecologic malignan- study, these values were 37.0% and 86.5%. However, the cies undergoing postoperative pelvic IMRT and showed bladder V and V values in our study were lower than 30 40 that a mean rectal dose ≥ 32.75 Gy is an independent fac- those reported by Guo et  al., which may be due to dif- tor for the occurrence of Grade 2 or worse diarrhea [25]. ferences in bladder preparation and target delineation. The present study included patients with cervical cancer Hsieh et  al. examined RT delivered by tomotherapy to undergoing definitive CCRT using various RT treatment the whole-pelvic area in 28 fractions totaling 50.4  Gy, plans to study the dosimetric factors associated with followed by intracavitary brachytherapy, to treat locally acute radiation-induced GI toxicity and compared OAR advanced cervical cancer and reported decreased mean dosimetry values between the 3 RT plans. Based on our doses delivered to the rectum, bladder, and intestines study, the rectum V value is a meaningful predictor compared with a conventional 4-field box plan [22]. for the occurrence of acute diarrhea and chronic colitis, Although the benefits of VMAT and tomotherapy for the especially for acute Grade 2 or worse diarrhea. treatment of patients with non-operative cervical cancer Cheng  et al. Radiation Oncology (2022) 17:91 Page 13 of 17 Fig. 5 Analysis of the association between survival outcomes and pre‑treatment serum SCC in T1/T2N0 subgroup. Pretreatment serum squamous cell carcinoma antigen (SCC Ag) correlated with a overall survival, b progression‑free survival, c locoregional recurrence ‑free survival, d and distant metastasis‑free survival in the T1/T2N0 subgroup The importance of the small bowel in acute GI toxicity showed that the cumulative incidence of Grade 2–3 diar- is difficult to disregard, and a higher incidence of acute rhea among patients treated with 39.6  Gy delivered to Grade 2 or worse diarrhea is generally considered to be small bowel volume < 60 mL and ≥ 60 mL were 33.3% and caused by the increased irradiation of the small bowel 63.4% (P = 0.001), respectively, and suggested that a small among patients who receive whole-pelvic RT. However, bowel volume of 39.6 Gy delivered to < 60 mL should be studies examining the correlation between the volume used as a constraint to alleviate acute RT-related diarrhea of irradiation received by the small bowel and the inci- [23, 25, 26]. Our study used the peritoneum as a surrogate dence of acute RT-related diarrhea in gynecological for the small bowel, which revealed that the peritoneum IMRT patients are extremely rare. Roeske et al. reported V has the potential to be used as a predictor for acute a high-dose small bowel volume effect among pelvic Grade 2 or worse diarrhea (OR 1.62, 95% CI 0.97–2.71, IMRT patients (n = 50); Chi et al. found a high-dose ( V ) P = 0.068). A larger sample size remains necessary to small bowel volume effect among IMRT-treated patients verify the effectiveness of peritoneum V as a predictor 4o (n = 32) with endometrial cancer. Huang et  al. (n = 108) of diarrhea. We attempted to use the peritoneum instead Cheng et al. Radiation Oncology (2022) 17:91 Page 14 of 17 Table 6 Cox proportional hazards regression analysis for distant can further reduce the severity of RT-related toxicities is metastases–free survival in the T1/T2 N0 subgroup still debated. Few studies have compared clinical compli- cations between fixed-field IMRT and VMAT or tomo - Variable HR 95% CI P value therapy. Guo et  al. compared the clinical toxicities and Age ≥ 60 years 5.94 0.49–71.71 0.161 dosimetric parameters of VMAT and fixed-field IMRT OTT of RT > 61 days 1.48 0.11–19.78 0.767 in patients (n = 84) with cervical cancer who underwent Pretreatment SCC Ag > 10 ng/mL 12.40 0.85–181.40 0.066 radical CCRT and concluded that VMAT plans were Post‑treatment SCC Ag > 1.5 ng/mL 0.001 0.00–1.078E33 0.863 superior to fixed-field IMRT plans in terms of the dosim - EQD2 of Point A ≥ 81 Gy 1.15 0.077–16.98 0.921 etry values recorded for the V of the rectum and the RT technique 0.991 V of the bladder, although no significant differences in VMAT 227.32 0.00–2.350E178 0.979 acute and chronic complications were observed clinically Tomotherapy 192.6 0.00–1.995E178 0.980 [21]. Impressively, our study indicated that tomotherapy HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation reduced not only the rectum V but also the severity therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy of acute diarrhea compared with VMAT, indicating the fractions, VMAT volumetric modulated arc therapy potential to translate a dosimetric advantage into clini- Reference category: 3DCRT, three-dimensional conformal radiation therapy cal benefits. Since we analyzed the acute diarrhea during EBRT rather than brachytherapy, the EQD2 of brachy- therapy might not be an interference factor of acute diar- of the small loop for dosimetric evaluations because the rhea. In addition, there’s no significant difference in mean bowel wall is sometimes ill-defined and easily mobilized EQD2 of brachytherapy among three subgroups as shown during non-enhanced CT simulations, making the con- in Table  1. The difference observed between the rectum tour process difficult and leading to low reproducibility. V values between techniques in our study (tomotherapy The major toxicities associated with pelvic radiother - vs. VMAT: 56.4% vs. 86.5%, P < 0.05) was larger than the apy for gynecologic malignancies include complications difference reported in Guo’s study (VMAT vs. fix-field involving the rectum, bladder, and bone marrow, leading IMRT: 82.12% vs. 91.33%, P = 0.002), which may have to diarrhea, colitis, cystitis, and bone marrow suppres- contributed to the divergence in clinical outcomes. By sion, which are categorized as acute or chronic toxicities contrast, no significant differences were observed among depending on the time of onset. RT techniques continue the 3 treatment plans for the occurrence of acute cystitis to evolve, from 3DCRT to IMRT, and IMRT is considered and chronic colitis. The bladder may not be as sensitive to be an effective technique with a low incidence of acute to radiation as the rectum, and a higher tolerance may toxicity [27]. However, whether VMAT or tomotherapy reduce the occurrence of acute complications. Besides, Table 7 Acute and chronic gastrointestinal toxicity by dosimetric parameters CTCAE Grade 2 + acute diarrhea CTCAE Grade 2 + chronic colitis Odds ratio 95% CI P Odds ratio 95% CI P Colon V 0.88 0.73–1.06 0.182 1.10 0.86–1.41 0.451 V 1.14 0.93–1.40 0.202 0.82 0.60–1.13 0.224 V 0.93 0.83–1.04 0.186 1.05 0.93–1.18 0.448 Peritoneum V 0.80 0.57–1.12 0.198 1.09 0.76–1.56 0.629 50.4 V 1.62 0.97–2.71 0.068 0.93 0.63–1.36 0.698 V 0.80 0.54–1.18 0.250 1.25 0.83–1.87 0.287 V 0.99 0.83–1.17 0.892 1.02 0.89–1.16 0.792 Rectum V 1.01 0.92–1.11 0.863 0.97 0.87–1.08 0.576 50.4 V 0.92 0.83–1.02 0.116 0.84 0.67–1.06 0.147 V 1.15 1.10–1.30 0.030* 1.14 0.99–1.33 0.073 CTCAE common terminology criteria for adverse events, CI confidence interval, V, V, V, V, V, V = volume receiving ≥ 50.4, ≥ 40, ≥ 35, ≥ 30, ≥ 25, ≥ 15 Gy, 50.4 40 35 30 25 15 respectively *Statistically significant Cheng  et al. Radiation Oncology (2022) 17:91 Page 15 of 17 Table 8 Dosimetric comparison of organs at risk (OARs) for the 3 treatment plans 3DCRT (n = 9) VMAT (n = 11) Tomotherapy (n = 10) P value Colon dose (%) V 34.7 [23.9–66.1] 13.0 [7.0–29.3]* 10.6 [3.5–17.1]* 0.002 V 50.3 [41.2–74.3] 30.0 [18.5–53.0] 30.4 [10.8–37.4]* 0.020 V 64.9 [51.2–81.0] 68.0 [52.0–73.2] 57.1 [33.8–80.6] 0.796 Peritoneum dose (%) V 35.8 [18.0–50.0] 3.6 [1.0–5.0]* 2.7 [0.5–5.2]* 0.001 50.4 V 51.7 [28.0–73.0] 12.0 [7.0–21.0]* * 0.002 V 58.7 [35.2–79.7] 27.0 [20.0–37.0]* 23.6 [17.5–34.6]* 0.013 V 66.7 [32.5–83.0] 45.0 [33.7–52.0] 36.6 [30.4–45.5] 0.147 Rectum dose (%) V 24.4 [15.6,–52.6] 2.2 [0.0–13.4]* 5.3 [0.3–7.4]* 0.003 50.4 V 97.5 [94.2–100.0] 37.0 [26.0–68.4]* 34.1[26.2–40.6]* < 0.001 V 97.5 [96.3–100.0] 86.5 [69.3–90.0] 56.4 [49.3–66.0]* < 0.001 Bladder dose (%) V 40.7 [31.2–46.7] 2.0 [1.0–14.0]* 5.7 [0.7–13.3]* 0.001 50.4 V 100.0 [99.8–100.0] 28.0 [23.3–34.1]* 28.6 [21.3–46.1]* < 0.001 V 100.0 [100.0–100.0] 59.5 [52.0–71.0]* 50.5 [43.2–73.6]* < 0.001 Bone marrow dose (%) V 27.8 [24.1–29.2] 4.0 [2.7–5.0]* 5.5 [3.0–8.1]* < 0.001 V 44.0 [39.7–45.5] 16.0 [13.0–17.0]* 19.6 [16.9–23.0]* < 0.001 V 58.9 [54.8–62.9] 37.0 [34.2–38.5]* 39.2 [38.0–45.8]* < 0.001 V 88.8 [81.5–91.3] 70.0 [63.0–75.4]* 70.4 [67.1–73.3]* 0.002 V 91.9 [84.4–95.6] 89.8 [87.0–94.0] 90.2 [87.1–92.7] 0.936 3DCRT three-dimensional conformal radiation therapy, VMAT volumetric modulated arc therapy, V, V, V, V, V, V = volume receiving ≥ 50.4, ≥ 40, ≥ 35, ≥ 30, 50.4 40 35 30 25 15 ≥ 25, ≥ 15 Gy, respectively Differences were compared using the Kruskal–Wallis tests for continuous variables Data are presented as the median [interquartile range] *P < 0.05 versus 3DCRT in the Bonferroni post hoc test P < 0.05 versus VMAT in the Bonferroni post hoc test P = 0.09 versus 3DCRT in the Bonferroni post hoc chronic colitis might also be affected by brachytherapy the midterm of the study, although we did not artificially and chemotherapy. Furthermore, the small sample size intervene in the case selection process. may not have been sufficiently powered to detect a differ - ence between the groups. Conclusion Our study involved some limitations. First, this study Pretreatment SCC Ag ≤ 10  ng/mL were associated with was performed as a retrospective study. Unlike a prospec- better PFS, LRRFS, and DMFS in patients with stage IB- tive study, the present study inevitably includes a degree IVA cervical cancer treated by radical CCRT and might of selection bias, recall bias, and confounding effects, serve as an effective predictor for DMFS in the T1N0/ leading to a finite level of evidence. Second, the limited T2N0 subgroup. The V value of the rectum is an impor- case number makes the results relatively tentative, and tant dosimetric factor for acute diarrhea during pelvic these findings must be confirmed in a larger sample. EBRT. Compared with VMAT, tomotherapy reduced the Third, only 30 of the 93 patients completed a dosimetric V value for the rectum and consequently alleviated the analysis because we initiated the dosimetric evaluation in severity of acute diarrhea. Cheng et al. Radiation Oncology (2022) 17:91 Page 16 of 17 Fig. 6 The isodose distributions of patients with cervical cancer treated by VAMT and Tomotherapy. The isodose distributions for a a T2N0 patient treated with volumetric modulated arc therapy and b a T3N0 patient treated with tomotherapy. The thick brown and light blue lines represented the border of rectum and bladder, respectively. The thin red, pink, light blue, orange, green lines represented the dose curves of 54, 50.4, 48, 43.2 and 37.8 Gy, respectively. Tomotherapy provided significantly less rectal volume exposed to 37.8 Gy factor; SCC Ag: Squamous cell carcinoma antigen; DFS: Disease‑specific Table 9 The gastrointestinal and genitourinary toxicity of 3DCRT, survival. VMAT, and tomotherapy Acknowledgements 3DCRT (n = 9) VMAT (n = 11) Tomotherapy P value We wish to express our gratitude to all who contributed their time and exper‑ (n = 10) tise to this study. Diarrhea Author contributions Gr. 0/1 3 (33.3) 5 (45.5) 9 (90.0) 0.029 MYH conceived the study. YKC performed the statistical analysis, participated in the interpretation of data, and wrote and revised the manuscript. JHW, YCC, Gr. ≥ 2 6 (66.7) 6 (54.5) 1 (10.0) and MYH recruited patients to the study and treated them. MYH and YKC are Colitis radiation oncologists who contributed to provide RT. SHK and HHY created Gr. 0/1 7 (77.8) 9 (81.8) 8 (80.0) 0.975 the treatment plans. All authors read and approved the final manuscript. Gr. ≥ 2 2 (22.2) 2 (18.2) 2 (20.0) Funding Cystitis This work was partly supported by funds of the Ministry of Science and Tech‑ Gr. 0/1 6 (66.7) 4 (36.4) 7 (70.0) 0.230 nology (MOST 108‑2314‑B‑037‑021‑MY3; MOST 110‑2314‑B‑037‑075‑MY2), the Kaohsiung Medical University (S110002), and the Kaohsiung Medical Gr. ≥ 2 3 (33.3) 7 (63.6) 3 (30.0) University Hospital (KMUH107‑7M31). 3DCRT three-dimensional conformal radiation therapy, VMAT volumetric modulated arc therapy, Gr. grade Availability of data and materials All data and materials have been presented in the manuscript. Data are presented as n (%) Declarations Abbreviations CCRT : Concurrent chemoradiation therapy; EBRT: External beam radiation Ethics approval and consent to participate therapy; 3DCRT : 3‑Dimensional conformal radiation therapy; IMRT: Intensity‑ This present study was approved by the Institutional Review Board in Kaohsi‑ modulated radiotherapy; VMAT: Volumetric modulated arc therapy; RT: Radia‑ ung Medical University Hospital [KMUHIRB‑E(I)‑20190054]. tion therapy; FIGO: International Federation of Gynecology and Obstetrics; ECOG: Eastern Cooperative Oncology Group; CT: Computed tomography; Consent for publication MRI: Magnetic resonance imaging; SCC: Squamous cell carcinoma; CEA: Not applicable. Carcinoembryonic antigen; CA125: Cancer antigen 125; AJCC: American Joint Committee on Cancer; IRB: Internal Review Board; AP: Anteroposterior; PA: Competing interests Posteroanterior; CTV: Clinical target volume; PTV: Planning target volume; The authors declare that they have no competing interests. OAR: Organ at risks; CTCAE: Common Terminology Criteria of Adverse Events; OTT: Overall treatment time; LRRFS: Locoregional recurrence–free survival; PFS: Author details Progression‑free survival; DMFS: Distant metastasis–free survival; OS: Overall Department of Radiation Oncology, Kaohsiung Medical University Hospital, survival; PET: Positron emission tomography; EQD2: Equivalent dose in 2‑ Gy Kaohsiung, Taiwan. Cancer Center, Kaohsiung Medical University Hospital, fractions; HR: Hazard ratio; CI: Confidence interval; OR: Odds ratio; HIF‑1α: Kaohsiung, Taiwan. Department of Radiation Oncology, Faculty of Medi‑ Hypoxia‑inducible factor 1α; VEGF: Expression of vascular endothelial growth cine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Obstetrics and Gynecology, Kaohsiung Medical University Cheng  et al. Radiation Oncology (2022) 17:91 Page 17 of 17 Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Depar tment 14. Jeong SY, Park H, Kim MS, Kang JH, Paik ES, Lee YY, et al. Pretreatment of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung lymph node metastasis as a prognostic significance in cervical cancer: Medical University, No. 100 Tzyou 1st Road, Kaohsiung 80708, Taiwan. comparison between disease status. Cancer Res Treat. 2020;52(2):516–23. https:// doi. org/ 10. 4143/ crt. 2019. 328. Received: 9 November 2021 Accepted: 2 May 2022 15. Kawanaka T, Kubo A, Ikushima H, Sano T, Takegawa Y, Nishitani H. Prognos‑ tic significance of HIF2alpha expr ‑ ession on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. J Med Investig. 2008;55(1–2):78–86. https:// doi. org/ 10. 2152/ jmi. 55. 78. 16. Loncaster JA, Cooper RA, Logue JP, Davidson SE, Hunter RD, West CM. Vascular endothelial growth factor ( VEGF) expression is a prognostic References factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J 1. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, et al. Esti‑ Cancer. 2000;83(5):620–5. https:// doi. org/ 10. 1054/ bjoc. 2000. 1319. mates of incidence and mortality of cervical cancer in 2018: a worldwide 17. Hong JH, Tsai CS, Chang JT, Wang CC, Lai CH, Lee SP, et al. The prognos‑ analysis. Lancet Glob Health. 2020;8(2):e191–203. https:// doi. org/ 10. 1016/ tic significance of pre ‑ and post ‑treatment SCC levels in patients with S2214‑ 109X(19) 30482‑6. squamous cell carcinoma of the cervix treated by radiotherapy. Int J 2. Akinyemiju T, Ogunsina K, Sakhuja S, Ogbhodo V, Braithwaite D. Life‑ Radiat Oncol Biol Phys. 1998;41(4):823–30. https:// doi. org/ 10. 1016/ s0360‑ course socioeconomic status and breast and cervical cancer screen‑ 3016(98) 00147‑3. ing: analysis of the WHO’s Study on Global Ageing and Adult Health 18. Lee J, Lin JB, Chang CL, Sun FJ, Wu MH, Jan Y T, et al. Impact of para‑aortic (SAGE). BMJ Open. 2016;6(11):e012753. https:// doi. org/ 10. 1136/ bmjop recurrence risk‑ guided intensity‑modulated radiotherapy in locally en‑ 2016‑ 012753. advanced cervical cancer with positive pelvic lymph nodes. Gynecol 3. De Felice F, Pranno N, Papi P, Brugnoletti O, Tombolini V, Polimeni A. Xeros‑ Oncol. 2018;148(2):291–8. https:// doi. org/ 10. 1016/j. ygyno. 2017. 12. 003. tomia and clinical outcomes in definitive intensity modulated radiother ‑ 19. Dang YZ, Li P, Li JP, Bai F, Zhang Y, Mu YF, et al. The efficacy and late apy (IMRT ) versus three‑ dimensional conformal radiotherapy (3D‑ CRT ) for toxicities of computed tomography‑based brachytherapy with intra‑ head and neck squamous cell carcinoma: a metaanalysis ‑ . In vivo (Athens, cavitary and interstitial technique in advanced cervical cancer. J Cancer. Greece). 2020;34(2):623–9. https:// doi. org/ 10. 21873/ invivo. 11816. 2018;9(9):1635–41. https:// doi. org/ 10. 7150/ jca. 23974. 4. Marta GN, Weltman E, Ferrigno R. Intensity‑modulated radiation therapy 20. Hansen H, Høgdall C, Engelholm S. Radiation therapy without cisplatin for (IMRT ) versus 3‑ dimensional conformal radiation therapy (3D‑ CRT ) for elderly cervical cancer patients. Int J Radiat Oncol Biol Phys. 2014;90:S484‑ head and neck cancer: cost‑ effectiveness analysis. Rev Assoc Med Bras. 85. https:// doi. org/ 10. 1016/j. ijrobp. 2014. 05. 1499. 2018;64(4):318–23. https:// doi. org/ 10. 1590/ 1806‑ 9282. 64. 04. 318. 21. Guo M, Huang E, Liu X, Tang Y. Volumetric modulated arc therapy versus 5. Mell LK, Sirák I, Wei L, Tarnawski R, Mahantshetty U, Yashar CM, et al. Bone fixed‑field intensity‑modulated radiotherapy in radical irradiation for marrow‑sparing intensity modulated radiation therapy with concur ‑ cervical cancer without lymphadenectasis: dosimetric and clinical results. rent cisplatin for stage IB‑IVA cervical cancer: an international multi‑ Oncol Res Treat. 2018;41(3):105–9. https:// doi. org/ 10. 1159/ 00048 4608. center phase II clinical trial (INTERTECC‑2). Int J Radiat Oncol Biol Phys. 22. Hsieh CH, Wei MC, Lee HY, Hsiao SM, Chen CA, Wang LY, et al. Whole 2017;97(3):536–45. https:// doi. org/ 10. 1016/j. ijrobp. 2016. 11. 027. pelvic helical tomotherapy for locally advanced cervical cancer: technical 6. Wang X, Shen Y, Zhao Y, Li Z, Gou H, Cao D, et al. Adjuvant intensity‑ implementation of IMRT with helical tomotherapy. Radiat Oncol (London, modulated radiotherapy (IMRT ) with concurrent paclitaxel and cisplatin England). 2009;4:62. https:// doi. org/ 10. 1186/ 1748‑ 717X‑4‑ 62. in cervical cancer patients with high risk factors: a phase II trial. Eur J 23. Roeske JC, Bonta D, Mell LK, Lujan AE, Mundt AJ. A dosimetric analysis of Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 2015;41(8):1082–8. acute gastrointestinal toxicity in women receiving intensity‑modulated https:// doi. org/ 10. 1016/j. ejso. 2015. 04. 018. whole‑pelvic radiation therapy. Radiother Oncol J Eur Soc Ther Radiol 7. Mell LK, Kochanski JD, Roeske JC, Haslam JJ, Mehta N, Yamada SD, et al. Oncol. 2003;69(2):201–7. https:// doi. org/ 10. 1016/j. radonc. 2003. 05. 001. Dosimetric predictors of acute hematologic toxicity in cervical cancer 24. Deville C, Vapiwala N, Hwang WT, Lin H, Ad VB, Tochner Z, et al. Com‑ patients treated with concurrent cisplatin and intensity‑modulated pelvic parative toxicity and dosimetric profile of whole ‑pelvis versus prostate radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(5):1356–65. https:// doi. bed‑ only intensity‑modulated radiation therapy after prostatectomy. Int org/ 10. 1016/j. ijrobp. 2006. 03. 018. J Radiat Oncol Biol Phys. 2012;82(4):1389–96. https:// doi. org/ 10. 1016/j. 8. Rutledge FN, Mitchell MF, Munsell M, Bass S, McGuffee V, Atkinson EN. ijrobp. 2011. 04. 041. Youth as a prognostic factor in carcinoma of the cervix: a matched 25. Huang EY, Wang YM, Chang SC, Liu SY, Chou MC. Rectal dose is the other analysis. Gynecol Oncol. 1992;44(2):123–30. https:// doi. org/ 10. 1016/ 0090‑ dosimetric factor in addition to small bowel for prediction of acute diar‑ 8258(92) 90027‑g. rhea during postoperative whole‑pelvic intensity‑modulated radiother ‑ 9. Katz A, Eifel PJ, Moughan J, Owen JB, Mahon I, Hanks GE. Socioeconomic apy in gynecologic patients. Cancers. 2021;13(3):497. https:// doi. org/ 10. characteristics of patients with squamous cell carcinoma of the uterine 3390/ cance rs130 30497. cervix treated with radiotherapy in the 1992 to 1994 patterns of care 26. Chi A, Nguyen NP, Xu J, Ji M, Tang J, Jin J, et al. Correlation of three differ ‑ study. Int J Radiat Oncol Biol Phys. 2000;47(2):443–50. https:// doi. org/ 10. ent approaches of small bowel delineation and acute lower gastrointes‑ 1016/ s0360‑ 3016(00) 00417‑x. tinal toxicity in adjuvant pelvic intensity‑modulated radiation therapy for 10. Shaverdian N, Gondi V, Sklenar KL, Dunn EF, Petereit DG, Straub MR, endometrial cancer. Technol Cancer Res Treat. 2012;11(4):353–9. https:// et al. Eec ff ts of treatment duration during concomitant chemoradiation doi. org/ 10. 7785/ tcrt. 2012. 500283. therapy for cervical cancer. Int J Radiat Oncol Biol Phys. 2013;86(3):562–8. 27. Salama JK, Mundt AJ, Roeske J, Mehta N. Preliminary outcome and toxic‑ https:// doi. org/ 10. 1016/j. ijrobp. 2013. 01. 037. ity report of extended‑field, intensity‑modulated radiation therapy for 11. Hong JH, Tsai CS, Lai CH, Chang TC, Wang CC, Chou HH, et al. Risk gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2006;65(4):1170– stratification of patients with advanced squamous cell carcinoma 6. https:// doi. org/ 10. 1016/j. ijrobp. 2006. 02. 041. of cervix treated by radiotherapy alone. Int J Radiat Oncol Biol Phys. 28. National Institutes of Health (NIH). Common terminology criteria for adverse 2005;63(2):492–9. https:// doi. org/ 10. 1016/j. ijrobp. 2005. 02. 012. events (CTCAE) v4.03. https:// ctep. cancer. gov/ proto colde velop ment/ elect 12. Huang EY, Huang YJ, Chanchien CC, Lin H, Wang CJ, Sun LM, et al. Pre‑ ronic_ appli catio ns/ docs/ CTCAE_4. 03. xlsx. Accessed 14 June 2010. treatment carcinoembryonic antigen level is a risk factor for para‑aortic 29. Lin YZ, Chen K, Lu ZY, Zhao L, Tao YL, Ouyang Y, et al. Intensity‑mod‑ lymph node recurrence in addition to squamous cell carcinoma antigen ulated radiation therapy for definitive treatment of cervical cancer: a following definitive concurrent chemoradiotherapy for squamous meta‑analysis. Radiat Oncol. 2018;13(1):177. https:// doi. org/ 10. 1186/ cell carcinoma of the uterine cervix. Radiat Oncol (London, England). s13014‑ 018‑ 1126‑7. 2012;7:13. https:// doi. org/ 10. 1186/ 1748‑ 717X‑7‑ 13. 13. Huang EY, Wang CJ, Chen HC, Fang FM, Huang YJ, Wang CY, et al. Mul‑ tivariate analysis of para‑aortic lymph node recurrence after definitive Publisher’s Note radiotherapy for stage IB‑IVA squamous cell carcinoma of uterine cervix. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ Int J Radiat Oncol Biol Phys. 2008;72(3):834–42. https:// doi. org/ 10. 1016/j. lished maps and institutional affiliations. ijrobp. 2008. 01. 035. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy

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Abstract

Background: To analyze the prognostic factors associated with stage IB‑IVA cervical cancer in patients who under ‑ went concurrent chemoradiation therapy (CCRT ) and to compare the clinical toxicities and dosimetric parameters of organs at risk between the different radiotherapy techniques. Methods: This retrospective study enrolled 93 patients with stage IB‑IVA cervical cancer who underwent definitive CCRT between April 2009 and December 2017. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy, and all of them followed by brachytherapy using a 2D planning technique. The treatment outcomes and related prognostic factors were analyzed. We also compared the clinical toxicities and dosimetric parameters between the different techniques used for the last 30 patients. Results: With a median follow‑up of 52.0 months, the 5‑ year overall survival (OS), progression‑free survival (PFS), locoregional recurrence–free survival (LRRFS), and distant metastases–free survival (DMFS) were analyzed. In a Cox proportional hazards regression model, pretreatment SCC Ag > 10 ng/mL was a significant prognostic factor for PFS (hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.03–4.70; P = 0.041), LRRFS (HR, 3.48; 95% CI 1.07–11.26; P = 0.038), and DMFS (HR 2.80; 95% CI 1.02–7.67; P = 0.045). Increasing the rectal volume receiving a radiation dose exceeding 30 Gy ( V of rectum; odds ratio [OR] 1.15; 95% CI 1.10–1.30; P = 0.03) was associated with a higher pos‑ sibility of ≥ Grade 2 acute radiation therapy (RT )‑related diarrhea. The median rectal V values were 56.4%, 97.5%, and 86.5% for tomotherapy, 3‑ dimensional conformal radiation therapy (3DCRT ), and volumetric modulated arc therapy *Correspondence: miyihu@gmail.com Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung 80708, Taiwan 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. Cheng et al. Radiation Oncology (2022) 17:91 Page 2 of 17 ( VMAT ), respectively (P < 0.001). In addition, the chance of experiencing ≥ Grade 2 acute diarrhea were 10.0%, 66.7%, and 54.5% for tomotherapy, 3DCRT, and VMAT, respectively (P = 0.029). Conclusions: Patients with pretreatment SCC Ag ≤ 10 ng/mL have better PFS, LRRFS, and DMFS than those with pretreatment SCC Ag > 10 ng/mL. The rectal V is a significant predictor of severe acute diarrhea. Tomotherapy signifi‑ cantly decreased the rectal V , reducing the severity of acute RT‑related diarrhea during external beam RT. Trial registration This study was approved by the institutional review board at Kaohsiung Medical University Hospital. The registration number is KMUHIRB‑E(I)‑20190054 and retrospectively registered on 2019/3. Keywords: Cervical cancer, SCC Ag, Volumetric modulated arc therapy, Tomotherapy, Diarrhea, Rectum Background of prior malignancy before treatment, any history of prior Cervical cancer is the fourth most common cancer type radiotherapy, and Eastern Cooperative Oncology Group among women [1]. Despite the development of prophy- (ECOG) performance status > 2. lactic vaccines, cervical cancer remains a major cause of All patients underwent pretreatment workup and can- mortality worldwide, particularly in low socioeconomic cer staging using modern approaches, including a physi- regions [2]. Concurrent chemoradiation therapy (CCRT) cal examination by a gynecologic oncologist, a tumor for non-surgical patients with cervical cancer plays an biopsy, a history review, chest X-ray, abdominal and important role in radical therapy. External beam radia- pelvic computed tomography (CT,) or pelvic magnetic tion therapy (EBRT) administered using 3-dimensional resonance imaging (MRI). Cystoscopy or sigmoidoscopy conformal radiation therapy (3DCRT) is a commonly was performed by a specialist to exclude adjacent organ used cervical cancer treatment method. However, radia- invasion for patients with locally advanced disease. In tion therapy (RT)-related acute and late toxicities are addition, routine laboratory biomarker studies, includ- well-known issues, including the development of coli- ing squamous cell carcinoma antigen (SCC Ag), carci- tis, diarrhea, cystitis, frequent urination, dysuria, and noembryonic antigen (CEA), and cancer antigen 125 proctitis. (CA125), were measured among the cohort. The median Increasingly, intensity-modulated radiotherapy follow-up was 52  months (range 6–137  months). The (IMRT), volumetric modulated arc therapy (VMAT), cancer stage was classified according to the seventh edi - and tomotherapy have become more commonly used tion of the American Joint Committee on Cancer (AJCC) RT methods over the past few decades. Comparisons TNM classification and the 2008 International FIGO of clinical results between 3DCRT, VMAT, and tomo- staging system for cervical cancer. The retrospective therapy among patients with head and neck cancer have study (KMUHIRB-E(I)-20190054) was approved by the been well described [3, 4]. Considerable studies have also Institutional Review Board (IRB) of Kaohsiung Medical examined the dosimetric differences among 3DCRT, University Hospital, and the need for informed consent VMAT, and tomotherapy in patients with cervical cancer. was waived by the IRB due to the nature of this study as a Some single-center and multi-center series examining chart review. postoperative RT have described favorable toxicity pro- files associated with the use of IMRT [5, 6]. However, dis- Radiotherapy parities in the clinical results among these techniques are All patients received a consultation with a radiation rarely reported. Thus, we compared the clinical outcomes oncologist and underwent an evaluation of clinical sta- across various techniques applied to patients with non‐ tus to ensure the necessity and safety of radiotherapy. distant metastatic cervical cancer who underwent defini - Following bladder preparation, patients were placed in a tive CCRT and examined prognostic factors. supine position with cast or cushion immobilization and underwent CT simulation, using a 3–5  mm slice thick- Methods ness, from the upper edge of the lumbar spine to 5  cm Patients below the lower border of the obturator foramen. For We enrolled patients diagnosed with cervical cancer, 3DCRT, a four-field box technique was planned using classified as stages IB to IVA according to the Interna - corner shielding in anteroposterior/posteroanterior (AP/ tional Federation of Gynecology and Obstetrics (FIGO) PA) portals. The radiation portal fields were designed staging system, between April 2009 and December 2017. as follows: (1) superior border: L4–5 interspace, which None of the enrolled patients had distant metastases at covers the common iliac lymph nodes; (2) inferior bor- treatment onset, and all patients received radical CCRT. der: 3  cm below the most inferior vaginal involvement, The exclusion criteria for this study included any history which is often below the inferior obturator foramen and Cheng  et al. Radiation Oncology (2022) 17:91 Page 3 of 17 can be as low as the introitus in cases of vaginal tumor block was the midsacroiliac joint, and the width was extension; and (3) lateral border: 1.5–2 cm outside of the 4 cm. If a parametrial tumor persists after 50–54 Gy, the pelvic rim. For the lateral fields, the superior and infe - side wall or parametrium may receive up to 60  Gy. For rior borders were consistent with the design of the AP/ VMAT or tomotherapy, the clinical target volume (CTV) PA portals. The anterior border covered the front of the was defined as the gross tumor plus microscopic disease, pubic symphysis, and the posterior edge included the including the cervix, uterus, upper third of the vagina (or entire sacrum. Pelvic radiotherapy was delivered at 1.8– upper half of the vagina, if a gross tumor is involved), the 2.0 Gy per fraction, 1–5 days each week, for a total of 25 parametrium, and the pelvic nodal drainage. The patients fractions comprising 45–50  Gy, followed by the delivery were treated with simultaneous integrated boost doses of 5.4–9 Gy in 3–5 fractions delivered by AP/PA portals of 48.6–50.4 Gy, delivered in 1.8 to 2-Gy fractions, to the using a midline block. The superior border of the midline primary tumor, 54–60  Gy delivered to the pelvic nodal Table 1 Patient and tumor characteristics for all 93 patients Characteristics 3DCRT (n = 9) VMAT (n = 43) Tomotherapy (n = 41) P value Age in years, median (range) 48 (34–66) 62 (38–84) 63 (34–89) 0.01 Age (years) < 60 8 20 17 0.034 ≥ 60 1 23 24 OTT of RT (days) ≤ 61 6 21 13 0.091 > 61 3 22 28 FIGO stage I 1 10 3 0.081 II 4 25 22 III 1 4 11 IV 3 4 5 T classification T1/T2 6 35 25 0.114 T3/T4 3 8 16 Nodal classification N0 2 32 25 0.011 N1 7 11 16 Histological type Squamous cell carcinoma 8 40 39 0.607 Adenocarcinoma 1 3 1 Others 0 0 1 Mean EBRT dose (Gy) 55.1 54.1 54.2 0.516 Mean EQD2 of brachytherapy (Gy) 28.1 29.9 29.8 0.696 EQD2 of Point A (Gy) < 81 8 27 32 0.147 ≥ 81 1 16 9 Pretreatment SCC Ag (ng/mL) ≤ 10 4 23 24 0.722 > 10 5 20 17 Post‑treatment SCC Ag (ng/mL) ≤ 1.5 8 38 32 0.399 > 1.5 1 5 9 Median follow‑up (months) 43 54 52 0.123 3DCRT three-dimensional conformal radiation therapy, VMAT volumetric modulated arc therapy, OTT overall treatment time, RT radiation therapy, FIGO the international federation of gynaecology and obstetrics, EBRT external beam radiation therapy, EQD2 equivalent dose in 2-Gy fractions, SCC Ag squamous cell carcinoma antigen Cheng et al. Radiation Oncology (2022) 17:91 Page 4 of 17 drainage, including parametrial, obturator, internal iliac, VERSION 4.03 [28]. Using these criteria, acute compli- external iliac, common iliac and gross lymph nodes, and cations were defined as those with onset during RT and 45–48  Gy, delivered in 1.6 to 1.8-Gy fractions, to elec- were assessed once per week during EBRT. Chronic com- tive nodal regions, such as presacral and paraaortic area. plications were scored retrospectively based on chart The planning target volume (PTV) was defined as the records. The overall treatment time (OTT) of RT was 8–10  mm margin around the CTV and could be modi- defined as the time interval between the first and last fied according to the clinical condition. Target planning date of RT. The primary endpoints were locoregional constraints were standardized as follows: (1) the PTV in recurrence–free survival (LRRFS), progression-free sur- all directions to receive > 95% of the prescribed dose; (2) vival (PFS), distant metastasis–free survival (DMFS), and volumes receiving more than 110% of the dose prescribed overall survival (OS). The length of follow-up was defined to the PTV were minimized. The typical organs at risk as the time from CCRT to the date of death or the last (OARs) included the rectum, bladder, intestine, large follow-up. Locoregional failure was defined as any recur - bowel, peritoneum, bilateral femoral heads, and the pel- rent or persistent disease involving the pelvis. Any dis- vic bone marrow [7]. The external contours of all bones ease failure outside of the pelvis was defined as a distant within the pelvis were delineated on the planning CT failure. Pathological reports, including those associated images, as surrogates for the bone marrow, to enhance with surgical intervention, biopsy, and cytology, in addi- the reproducibility and consistency of the contours. tion to radiology reports from radiology examinations, The intestine and large bowel contours consisted of the including chest radiography, CT, MRI, technetium-99 bowel loops from 3  cm superior to the upper border of bone scintigraphy, or positron emission tomography the PTV to its lowest extent in the pelvis. The dosimetric (PET), were reviewed to determine disease status. parameters for OARs were recorded as Vx, which repre- sented the percentage of the organ volume that received Statistical analysis X Gy or higher. For the individual patients, the selection Data were analyzed using SPSS 22.0 software (IBM Corp., of respective EBRT technique was decided by radiation Armonk, NY, USA). Dose-volume histograms (DVHs) of oncologist on the basis of clinical scenario. the PTVs and the OARs were analyzed accordingly. For PTV, the goal is to encompass the PTV in all directions Brachytherapy and concurrent chemotherapy with the 95% isodose line. To reduce toxicity and opti- After EBRT, all patients underwent afterloading brachy- mize OAR doses, DVH constraint was applied to limit therapy, which consisted of high-dose-rate Ir intracavi- maximum dose and dose-volume parameters. OS was tary brachytherapy intended to deliver a dose of 4–5 Gy/ defined as the time from primary treatment to the date time to Point A twice per week, with 5 to 6 total treat- of death from any cause or the date of the last follow-up. ments. During RT, chemotherapy was concurrently pre- PFS was defined as the time from primary treatment to scribed, consisting of weekly cisplatin for 6  weeks. The the date of disease failure at any site or to the date of the regimen was shifted to carboplatin for those patients last follow-up. LRRFS was defined as the time from pri - with impaired renal function and paclitaxel-based treat- mary treatment to the date of locoregional failure or to ment for prescribed for patients with locally advanced the date of the last follow-up. DMFS was defined as the disease. time from primary treatment to the date of distal failure or to the date of the last follow-up. LRRFS, PFS, DMFS, Follow‑up and evaluation OS, and the treatment-related toxicity were analyzed In general, the patients returned for a first follow-up using the Kaplan–Meier method, and the log-rank test visit one month after the completion of treatment, fol- was used to calculate differences between groups. Signifi - lowed by every 2–3  months during the first year and cance was defined as P < 0.05. every 3–6  months thereafter. Physical examination including pelvic examination was performed at every Results follow-up visit. Patients should have follow-up imaging, Patients either abdominal and pelvic CT or pelvic MRI, at least A total of 93 patients diagnosed with stage IB-IVA cer- every 3–6  months after the completion of treatment. vical cancer were enrolled in this retrospective study. Chest X-ray is acquired annually at least after treatment. The median age of the retrospective cohort was 61 years A serum test for tumor markers was performed every (range 34–93  years). Table  1 summarizes the patients’ 3–6  months after the completion of CCRT. The gyneco - clinical baseline characteristics, grouped according to logic oncologists and radiation oncologists recorded the three radiotherapy techniques. Nine patients (9.7%) treatment-related toxicity events according to the Com- received 3DCRT, 43 patients (46.2%) underwent VMAT, mon Terminology Criteria of Adverse Events (CTCAE), and 41 patients (44.1%) received tomotherapy. The Cheng  et al. Radiation Oncology (2022) 17:91 Page 5 of 17 (a) (b) (c) (d) (e) Fig. 1 The Kaplan–Meier survival curve of overall survival. Overall survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), and e post ‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 6 of 17 Table 2 Cox proportional hazards regression analysis for overall pretreatment SCC Ag, and post-treatment SCC Ag were survival significant factors (P = 0.01, 0.001, 0.006, 0.034, and 0.018, respectively). Table 2 presents a multivariate analy- Variable HR 95% CI P value sis of these characteristics. Only an OTT of RT > 61 days Age ≥ 60 years 1.91 0.78–4.67 0.156 and T3/T4 disease were significant factors associ - OTT of RT > 61 days 2.99 1.03–8.70 0.045 ated with OS in the Cox proportional hazards regres- T3 or T4 disease 2.97 1.24–7.11 0.015 sion analysis (hazard ratio [HR] 2.99, 95% confidence N1 or N2 disease 2.11 0.87–5.13 0.098 interval [CI] 1.03–8.70, P = 0.045; and HR 2.97, 95% CI Pretreatment SCC Ag > 10 ng/mL 1.72 0.71–4.17 0.232 1.24–7.11, P = 0.015, respectively). A post-treatment SCC Post‑treatment SCC Ag > 1.5 ng/mL 2.42 0.93–6.26 0.069 Ag > 1.5  ng/mL was associated with a lower OS, but did EQD2 of Point A ≥ 81 Gy 0.82 0.34–1.99 0.666 not achieve significance (P = 0.069). RT technique 0.621 In the PFS analysis using the Kaplan–Meier method VMAT 0.44 0.08–2.39 0.341 (Fig.  2), T classification, N classification, and pretreat - Tomotherapy 0.59 0.12–2.90 0.518 ment SCC Ag were significant factors (P ≤ 0.001, 0.004, HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation and 0.005, respectively). The OTT of RT showed an therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy effect on PFS by the log-rank test, but did not achieve fractions, VMAT volumetric modulated arc therapy significance (P = 0.071). Table  3 presents the multivari- Reference category: 3DCRT, three-dimensional conformal radiation therapy ate analysis of these characteristics. T3/T4 disease, nodal positive, and pretreatment SCC Ag > 10 ng/mL remained median EBRT dose was 54  Gy (range 45–64  Gy), and significant factors affecting PFS in the Cox proportional the median equivalent dose in 2-Gy fractions (EQD2) of hazards regression analysis (HR 2.72, 95% CI 1.30–5.71, Point A was 79.8 Gy (range 49.1–93.1 Gy). No significant P = 0.008; HR 2.55, 95% CI 1.15–5.63, P = 0.021; and HR differences were observed for OTT of RT, clinical T clas - 2.20, 95% CI 1.03–4.71, P = 0.041, respectively). sification, histological type, mean EBRT dose, EQD2 of In the LRRFS analysis using the Kaplan–Meier method Point A, pre- and post-treatment SCC Ag, or follow-up (Fig.  3), only T classification and pretreatment SCC Ag duration between the three techniques. One patient in were significant factors (P = 0.032 and 0.038, respec- the 3DCRT group and one patient in the VMAT group tively). Table 4 presents the multivariate analysis of these were lost to follow-up. characteristics. Only pretreatment SCC Ag > 10  ng/ mL remained significant in the Cox proportional haz - Clinical outcomes and failure patterns ards regression analysis (HR 3.48, 95% CI 1.07–11.26, With a median follow-up of 52  months (range P = 0.038). The T3/T4 classification showed an effect on 6–137  months), the 5-year OS, PFS, LRRFS, and DMFS LRRFS but failed to reach significance (P = 0.082). were 75.2%, 65.8%, 82.2%, and 74.7% (P = 0.07, 0.06, In the DMFS analysis using the Kaplan–Meier method 0.36, and 0.23), respectively. No significant differences (Fig.  4), T classification, N classification, and pretreat - in survival outcomes were observed between the three ment SCC Ag were significant factors (P = 0.001, < 0.001, groups. The overall locoregional recurrence rate was and 0.001, respectively). The OTT of RT showed an effect 16.1% (15/93), and the majority recurrence pattern was on DMFS by the log-rank test but failed to reach signifi - local recurrence (11 patients with local recurrence and 4 cance (P = 0.071). Table 5 presents the multivariate analy- patients with regional nodal failure). The distant failure sis of these characteristics. All three factors remained rate was 23.7% (22/93), and the major recurrence sites significant in the Cox proportional hazards regression included the non-regional lymph nodes (7/22), the lung analysis (HR 2.88, 95% CI 1.01–8.22, P = 0.048; HR 6.17, (5/22), and the liver (5/22), with other sites observed less 95% CI 2.01–18.89, P = 0.001; and HR 2.80, 95% CI 1.02– frequently. 7.67, P = 0.045, respectively). OTT of RT > 61  days failed We further investigated clinical outcomes based on dif- to demonstrate significance following after covariate ferent patient and tumor characteristics, including age adjustment (P = 0.161). (≥ 60 vs. < 60 years), OTT of RT (> 61 days vs. ≤ 61 days), In the T1/T2N0 subgroup analysis using the Kaplan– T classification (T1/T2 vs. T3/T4), N classification Meier method (Fig. 5), pretreatment SCC Ag > 10 ng/mL (nodal negative vs. nodal positive), pretreatment SCC trended toward worse DMFS but not OS, PFS, or LRRFS. Ag (≤ 10 vs. > 10  ng/mL), post-treatment SCC Ag (≤ 1.5 The 5-year DMFS was 93.8% for the group with pretreat - vs. > 1.5 ng/mL), the EQD2 of Point A (≥ 81 vs. < 81  Gy), ment SCC Ag ≤ 10  ng/mL, compared with 79.4% for the and the RT technique (3DCRT vs. VMAT vs. Tomother- group with pretreatment SCC Ag > 10 ng/mL (P = 0.057). apy). In the OS analysis, using the Kaplan–Meier method Furthermore, in the Cox proportional hazards regres- (Fig.  1), the OTT of RT, T classification, N classification, sion analysis (Table  6), pretreatment SCC Ag > 10  ng/ Cheng  et al. Radiation Oncology (2022) 17:91 Page 7 of 17 (a) (b) (c) (d) (e) Fig. 2 The Kaplan–Meier survival curve of progression‑free survival. Progression‑free survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), and e post ‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 8 of 17 Table 3 Cox proportional hazards regression analysis for the occurrence of Grade 2 or worse colitis. However, we progression‑free survival found a trend toward the increased likelihood of Grade 2 or worse colitis correlated with an increasing rectum V Variable HR 95% CI P value value (OR 1.14, 95% CI 0.99–1.33, P = 0.073), although Age ≥ 60 years 1.90 0.84–4.28 0.122 this did not achieve significance. Except for the rectum OTT of RT > 61 days 1.61 0.69–3.78 0.273 V value, the occurrence of Grade 2 or worse colitis was T3 or T4 disease 2.72 1.30–5.71 0.008 not correlated with any other dosimetric parameters for N1 or N2 disease 2.55 1.15–5.63 0.021 the rectum. Pretreatment SCC Ag > 10 ng/mL 2.20 1.03–4.71 0.041 Post‑treatment SCC Ag > 1.5 ng/mL 2.01 0.82–4.96 0.129 Dosimetric parameters of organs at risk and RT technique EQD2 of Point A ≥ 81 Gy 1.39 0.65–2.97 0.403 a To compare differences in the radiation exposure for RT technique 0.423 OARs between the 3 treatment plans, the last 30 patients VMAT 0.53 0.13–2.08 0.359 were analyzed, including 9 patients (30%) in the 3DCRT Tomotherapy 0.91 0.25–3.33 0.889 group, 11 patients (36.7%) in the VMAT group, and 10 HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation patients (33.3%) in the tomotherapy group. Since we were therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy fractions, VMAT volumetric modulated arc therapy also interested in OARs and toxicity difference between Reference category: 3DCRT, three-dimensional conformal radiation therapy the 3 treatment plans, our group initiated the compari- son of dosimetric outcomes and clinical toxicities in the mid-term of study and led to only the last 30 patients mL suggested an increased risk of distant metastasis and were included. Furthermore, the improved conformality nearly reached a significant effect on DMFS (HR 12.4, achievable with IMRT can potentially mitigate adverse 95% CI 0.85–181.4, P = 0.066). However, all other factors, effects and contribute to the low utilization of 3DCRT. such as age, OTT of RT, post-treatment SCC Ag, EQD2 Table  8 presents the dosimetric comparisons for OARs of Point A, and RT technique, failed to show significant across the 3 treatment plans. Three dosimetric param - effects after covariate adjustment (P = 0.161, 0.767, 0.863, eters were analyzed for the colon, including the V , 0.921, and 0.991, respectively). V , and V values. 3DCRT was associated with higher 25 15 colon V and V values than VMAT and tomotherapy Dosimetric parameters for organs at risk and toxicity 35 25 (P = 0.002 and 0.020, respectively). However, the colon The dosimetric parameters and RT-related toxicity are V values were similar across the three groups. In addi- summarized in Table 7. The relationships between toxic - tion, no dosimetric differences for the colon were found ity and OAR doses were analyzed by logistic regression. between VMAT and tomotherapy groups. Four dosimet- Due to clinical limitations, only the last 30 patients were ric parameters were analyzed for the peritoneum, includ- able to be analyzed. ing the V, V, V and V values. We also found that The dose delivered to the colon did not affect the like - 50.4 40 30, 25 the 3DCRT group had higher peritoneum V , V , and lihood of experience Grade 2 or worse acute diarrhea. 50.4 40 V values than the VMAT and tomotherapy groups The colon V, V , and V values were analyzed, and 35 25 15 (P = 0.001, 0.002, and 0.013, respectively). In the analy- no correlation was observed between these dosimet- sis of peritoneum V values, the 3DCRT values were ric parameters and the occurrence of Grade 2 or worse higher than those for the other two techniques, but this acute diarrhea. We also analyzed the dosimetric param- difference did not achieve significance (P = 0. 147). No eters for the peritoneum and noted a trend toward the significant differences in the dosimetric parameters for increased occurrence of Grade 2 or worse acute diarrhea the peritoneum were observed between the VMAT and with an increasing peritoneum V value (odds ratio [OR] tomotherapy groups. Three dosimetric parameters were 1.62, 95% CI 0.97–2.71, P = 0.068) but not for the peri- analyzed for the rectum, including the V, V , and V toneum V, V , or V values. The dosimetric param - 50.4 40 30 50.4 30 25 values. All three of these parameters were much higher eters for the rectum showed a significant increase in the for the 3DCRT group than for the VMAT and tomother- occurrence of Grade 2 or worse acute diarrhea with an apy groups (P = 0. 003, < 0.001, and < 0.001, respectively). increasing rectum V value (OR 1.15, 95% CI 1.10–1.30, More importantly, the median rectum V values were P = 0.030) but not for the rectum V and V values. 50.4 40 56.4% and 86.5% in the tomotherapy and VMAT groups, The doses delivered to the colon and peritoneum did respectively. Tomotherapy further reduced the V not affect the likelihood of Grade 2 or worse colitis. The value for the rectum compared with VMAT (P < 0.005). colon V, V , and V and the peritoneum V , V , 35 25 15 50.4 40 Figure  6 presents the isodose distributions in a repre- V , and V values were analyzed, and no correlations 30 25 sentative T2N0 patient treated with VMAT and a T3N0 were observed between these dosimetric parameters and Cheng  et al. Radiation Oncology (2022) 17:91 Page 9 of 17 Fig. 3 The Kaplan–Meier survival curve of locoregional recurrence‑free survival. Locoregional recurrence ‑free survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), e and post‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 10 of 17 Table 4 Cox proportional hazards regression analysis for or worse chronic colitis occurred in 22.2% (2/9) of the locoregional recurrence–free survival 3DCRT group, 18.2% (2/11) of the VMAT group, and 20.0% (2/10) of the tomotherapy group, with no sig- Variable HR 95% CI P value nificant differences noted between the three groups. For Age ≥ 60 years 1.18 0.39–3.59 0.775 Grade 2 or worse acute cystitis, the incidences for the OTT of RT > 61 days 1.32 0.41–4.29 0.641 3DCRT, VMAT, and tomotherapy groups were 33.3% T3 or T4 disease 2.64 0.88–7.86 0.082 (3/9), 63.6% (7/11), and 30.0% (3/10), with no significant N1 or N2 disease 0.78 0.24–2.58 0.688 difference noted between groups. Pretreatment SCC Ag > 10 ng/mL 3.48 1.07–11.26 0.038 Post‑treatment SCC Ag > 1.5 ng/mL 0.71 0.15–3.35 0.667 Discussion EQD2 of Point A ≥ 81 Gy 1.16 0.35–3.82 0.804 Our study focused on the prognostic factors among RT technique 0.389 non‐distant metastatic cervical cancer patients treated VMAT 0.87 0.09–8.26 0.905 with definitive CCRT and compared RT-related toxicity Tomotherapy 2.10 0.24–18.58 0.504 among three different RT modalities. HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation Several studies examining the prognostic factors asso- therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy ciated with cervical cancer have been published world- fractions, VMAT volumetric modulated arc therapy wide. The major identified prognostic factors include Reference category: 3DCRT, three-dimensional conformal radiation therapy tumor size; pattern of invasion; tumor grade; pelvic nodal metastasis; age; race; socioeconomic status; sever- patient treated with tomotherapy, showing that the spi- ity of anemia; OTT; and the levels of biomarkers, such as ral delivery pattern associated with tomotherapy reduced hypoxia-inducible factor 1α (HIF-1α), vascular endothe- the unnecessary dosing of the rectum. Three dosimetric lial growth factor (VEGF), SCC Ag, and CEA. Huang parameters were analyzed for the bladder, including the et  al. suggested that pretreatment SCC Ag > 40  ng/mL V, V , and V values. The median V, V , and V 50.4 40 30 50.4 40 30 was an independent factor associated with para-aortic values for the bladder in the 3DCRT group were 40.7%, lymph node relapse, and pretreatment CEA levels have 100%, and 100%, respectively. By contrast, the VMAT been identified as a risk factor for para-aortic lymph values were 2.0%, 28.0%, and 59.5%, respectively, and the node recurrence, in addition to SCC Ag. Hong et  al. tomotherapy values were 5.7%, 28.6%, and 50.5%. For also reviewed 401 patients with cervical cancer primar- all three parameters, the values for the 3DCRT group ily treated with RT and concluded that pretreatment were much higher than for the VMAT and tomotherapy SCC Ag > 10  ng/mL was an independent predictor of groups (P = 0. 001, < 0.001, and < 0.001, respectively). poor disease-specific survival (DFS) [8–17]. Our study Similar to the finding for the colon and peritoneum, no showed that patients with pretreatment SCC Ag > 10 ng/ significant differences were observed among the dosi - mL had worse PFS (HR 2.2, P = 0.041), LRRFS (HR 3.48, metric parameters of the bladder between the VMAT P = 0.038), and DMFS (HR 2.8, P = 0.045). In addition, and tomotherapy groups. Finally, five dosimetric param - the subgroup analysis in our study showed that pretreat- eters were analyzed for the bone marrow, including the ment SCC Ag > 10  ng/mL was an effective predictor for V, V, V, V , and V values. Compared with VMAT 50 40 30 20 10 DMFS in T1N0/T2N0 patients (HR 12.4, P = 0.066). and tomotherapy, we found that 3DCRT results in higher These results suggest that even among patients with marrow V, V, V , and V values (P < 0.001, < 0.001, 50 40 30 20 early-stage cervical cancer primarily treated with defini - < 0.001, and = 0.002, respectively) but not marrow V tive CCRT, pretreatment SCC Ag might serve as a pre- values. Similarly, no significant differences in dosimetric dictor for distant metastasis, which can aid clinicians in parameters for the bone marrow were observed between designing an effective treatment plan. VMAT and tomotherapy. Radiotherapy combined with concurrent chemother- apy provides excellent curative effectiveness for patients RT‑related toxicity and RT techniques with cervical cancer; however, RT-related toxicities are Table  9 presents the percentages of gastrointestinal (GI) well known and can affect quality of life. RT-associ - and genitourinary complications associated with 3DCRT, ated toxicity can occur at any time during treatment or VMAT, and tomotherapy. Acute Grade 2 or worse diar- even several months to years later. Acute complications rhea for 3DCRT, VMAT, and tomotherapy occurred in can include diarrhea, desquamation, cystitis, nausea, 66.7% (6/9), 54.5% (6/11), and 10.0% (1/10) of patients, and vaginitis, which may lead to the interruption of RT respectively. Tomotherapy substantially and significantly [18]. Late complications of radiotherapy may arise sev- reduced the severity of acute diarrhea (P = 0.029). None eral months to years after pelvic irradiation, which can of the patients suffered from Grade 4 diarrhea. Grade 2 include radiation colitis, intestinal perforation, bowel Cheng  et al. Radiation Oncology (2022) 17:91 Page 11 of 17 Fig. 4 The Kaplan–Meier survival curve of distant metastases‑free survival. Distant metastases‑free survival correlated with a overall treatment time of radiation therapy b T classification c N classification d pretreatment serum squamous cell carcinoma antigen (SCC Ag), and e post ‑treatment serum SCC Ag Cheng et al. Radiation Oncology (2022) 17:91 Page 12 of 17 Table 5 Cox proportional hazards regression analysis for distant patients are generally accepted, little research has focused metastases–free survival on dosimetric comparisons for OARs between these two plans. Our results suggested that even compared with Variable HR 95% CI P value VMAT, tomotherapy resulted in a significant reduction Age ≥ 60 years 1.32 0.47–3.65 0.599 in the rectum V value, and was further reduced com- OTT of RT > 61 days 2.27 0.72–7.14 0.161 pared with 3DCRT. In addition to dosimetric parameters T3 or T4 disease 2.88 1.01–8.22 0.048 for the rectum, we also analyzed the bladder (V, V , 50.4 40 N1 or N2 disease 6.17 2.01–18.89 0.001 V ), peritoneum ( V, V, V, V ), colon ( V, V , 30 50.4 40 30 25 35 25 Pretreatment SCC Ag > 10 ng/mL 2.80 1.02–7.67 0.045 V ), and bone marrow (V, V, V, V, V ); in addi- 15 50 40 30 20 10 Post‑treatment SCC Ag > 1.5 ng/mL 0.94 0.27–3.34 0.926 tion to a reduction in the rectum V value, tomotherapy EQD2 of Point A ≥ 81 Gy 1.32 0.47–3.68 0.601 resulted in a reduced mean bladder V value, which may RT technique 0.662 indicate a lower dose delivered to the bladder. Ultimately, VMAT 0.67 0.15–2.96 0.596 these results indicated that the implementation of VMAT Tomotherapy 0.51 0.12–2.19 0.368 or tomotherapy reduced the delivery of high-dose radia- HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation tion to normal tissues outside of the target volume, which therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy was more apparent at higher radiation doses, which likely fractions, VMAT volumetric modulated arc therapy benefits adjacent OARs. Reference category: 3DCRT, three-dimensional conformal radiation therapy To date, few studies have examined the effects of small intestine volume in gynecological IMRT patients, and obstruction, and vaginal stenosis, with profound effects only one study has reported the rectal dosimetry asso- on quality of life [19]. To reduce RT-associated side ciated with acute GI toxicity. Although the contribution effects, fixed-field IMRT, VMAT, and tomotherapy have of rectal dose parameters to acute radiation-induced widely been used for pelvic irradiation, enhancing tar- GI toxicity remains a concern in patients treated for get dose conformity while reducing high-dose delivery gynecological malignancies, most studies have primar- to target-surrounding OARs [20]. However, few com- ily focused on the postoperative population. Therefore, parisons of dosimetric parameters and clinical outcomes the current study aimed to analyze the acute toxicities have been reported among these various RT modalities. and rectal doses received by patients with cervical can- Lin et al. demonstrated a meta-analysis that combines six cer treated with definitive CCRT. Roeske et  al. analyzed studies regarding a total of 1008 patients with cervical 50 patients with gynecological malignancies who were cancer to compare the efficacies and toxicities of IMRT treated with pelvic IMRT, approximately two-thirds of with 3DCRT or conventional two-dimensional radio- whom had received hysterectomies, and concluded that therapy. And concluded that IMRT significantly reduced rectal dosimetry (range 35–49  Gy) was not a signifi - acute gastrointestinal and genitourinary toxicities as well cant factor in acute GI toxicity. In that study, only half as chronic genitourinary toxicity [29]. Guo et  al. [21] of patients (26/50) received concomitant chemother- reported that VMAT plans provided better protection of apy, which might contribute to reduced radiosensitivity the rectum and bladder compared with fixed-field IMRT, [23]. Deville et  al. studied 67 patients undergoing post- but no significant differences were observed in the sever - prostatectomy IMRT and noted that the minimum dose ity of complications. Our dosimetric data for the rectum (D ) delivered to the rectum was marginally associated min in the VMAT group were similar to those reported by with acute Grade ≥ 2 GI toxicity (P = 0.05) [24]. Huang Guo et  al. The rectum V and V values in their study 40 30 et  al. examined the association between rectal dose and were 47.39% and 82.12%, respectively, whereas, in our acute diarrhea in patients with gynecologic malignan- study, these values were 37.0% and 86.5%. However, the cies undergoing postoperative pelvic IMRT and showed bladder V and V values in our study were lower than 30 40 that a mean rectal dose ≥ 32.75 Gy is an independent fac- those reported by Guo et  al., which may be due to dif- tor for the occurrence of Grade 2 or worse diarrhea [25]. ferences in bladder preparation and target delineation. The present study included patients with cervical cancer Hsieh et  al. examined RT delivered by tomotherapy to undergoing definitive CCRT using various RT treatment the whole-pelvic area in 28 fractions totaling 50.4  Gy, plans to study the dosimetric factors associated with followed by intracavitary brachytherapy, to treat locally acute radiation-induced GI toxicity and compared OAR advanced cervical cancer and reported decreased mean dosimetry values between the 3 RT plans. Based on our doses delivered to the rectum, bladder, and intestines study, the rectum V value is a meaningful predictor compared with a conventional 4-field box plan [22]. for the occurrence of acute diarrhea and chronic colitis, Although the benefits of VMAT and tomotherapy for the especially for acute Grade 2 or worse diarrhea. treatment of patients with non-operative cervical cancer Cheng  et al. Radiation Oncology (2022) 17:91 Page 13 of 17 Fig. 5 Analysis of the association between survival outcomes and pre‑treatment serum SCC in T1/T2N0 subgroup. Pretreatment serum squamous cell carcinoma antigen (SCC Ag) correlated with a overall survival, b progression‑free survival, c locoregional recurrence ‑free survival, d and distant metastasis‑free survival in the T1/T2N0 subgroup The importance of the small bowel in acute GI toxicity showed that the cumulative incidence of Grade 2–3 diar- is difficult to disregard, and a higher incidence of acute rhea among patients treated with 39.6  Gy delivered to Grade 2 or worse diarrhea is generally considered to be small bowel volume < 60 mL and ≥ 60 mL were 33.3% and caused by the increased irradiation of the small bowel 63.4% (P = 0.001), respectively, and suggested that a small among patients who receive whole-pelvic RT. However, bowel volume of 39.6 Gy delivered to < 60 mL should be studies examining the correlation between the volume used as a constraint to alleviate acute RT-related diarrhea of irradiation received by the small bowel and the inci- [23, 25, 26]. Our study used the peritoneum as a surrogate dence of acute RT-related diarrhea in gynecological for the small bowel, which revealed that the peritoneum IMRT patients are extremely rare. Roeske et al. reported V has the potential to be used as a predictor for acute a high-dose small bowel volume effect among pelvic Grade 2 or worse diarrhea (OR 1.62, 95% CI 0.97–2.71, IMRT patients (n = 50); Chi et al. found a high-dose ( V ) P = 0.068). A larger sample size remains necessary to small bowel volume effect among IMRT-treated patients verify the effectiveness of peritoneum V as a predictor 4o (n = 32) with endometrial cancer. Huang et  al. (n = 108) of diarrhea. We attempted to use the peritoneum instead Cheng et al. Radiation Oncology (2022) 17:91 Page 14 of 17 Table 6 Cox proportional hazards regression analysis for distant can further reduce the severity of RT-related toxicities is metastases–free survival in the T1/T2 N0 subgroup still debated. Few studies have compared clinical compli- cations between fixed-field IMRT and VMAT or tomo - Variable HR 95% CI P value therapy. Guo et  al. compared the clinical toxicities and Age ≥ 60 years 5.94 0.49–71.71 0.161 dosimetric parameters of VMAT and fixed-field IMRT OTT of RT > 61 days 1.48 0.11–19.78 0.767 in patients (n = 84) with cervical cancer who underwent Pretreatment SCC Ag > 10 ng/mL 12.40 0.85–181.40 0.066 radical CCRT and concluded that VMAT plans were Post‑treatment SCC Ag > 1.5 ng/mL 0.001 0.00–1.078E33 0.863 superior to fixed-field IMRT plans in terms of the dosim - EQD2 of Point A ≥ 81 Gy 1.15 0.077–16.98 0.921 etry values recorded for the V of the rectum and the RT technique 0.991 V of the bladder, although no significant differences in VMAT 227.32 0.00–2.350E178 0.979 acute and chronic complications were observed clinically Tomotherapy 192.6 0.00–1.995E178 0.980 [21]. Impressively, our study indicated that tomotherapy HR hazard ratio, CI confidence interval, OTT overall treatment time, RT radiation reduced not only the rectum V but also the severity therapy, SCC Ag squamous cell carcinoma antigen, EQD2 equivalent dose in 2-Gy of acute diarrhea compared with VMAT, indicating the fractions, VMAT volumetric modulated arc therapy potential to translate a dosimetric advantage into clini- Reference category: 3DCRT, three-dimensional conformal radiation therapy cal benefits. Since we analyzed the acute diarrhea during EBRT rather than brachytherapy, the EQD2 of brachy- therapy might not be an interference factor of acute diar- of the small loop for dosimetric evaluations because the rhea. In addition, there’s no significant difference in mean bowel wall is sometimes ill-defined and easily mobilized EQD2 of brachytherapy among three subgroups as shown during non-enhanced CT simulations, making the con- in Table  1. The difference observed between the rectum tour process difficult and leading to low reproducibility. V values between techniques in our study (tomotherapy The major toxicities associated with pelvic radiother - vs. VMAT: 56.4% vs. 86.5%, P < 0.05) was larger than the apy for gynecologic malignancies include complications difference reported in Guo’s study (VMAT vs. fix-field involving the rectum, bladder, and bone marrow, leading IMRT: 82.12% vs. 91.33%, P = 0.002), which may have to diarrhea, colitis, cystitis, and bone marrow suppres- contributed to the divergence in clinical outcomes. By sion, which are categorized as acute or chronic toxicities contrast, no significant differences were observed among depending on the time of onset. RT techniques continue the 3 treatment plans for the occurrence of acute cystitis to evolve, from 3DCRT to IMRT, and IMRT is considered and chronic colitis. The bladder may not be as sensitive to be an effective technique with a low incidence of acute to radiation as the rectum, and a higher tolerance may toxicity [27]. However, whether VMAT or tomotherapy reduce the occurrence of acute complications. Besides, Table 7 Acute and chronic gastrointestinal toxicity by dosimetric parameters CTCAE Grade 2 + acute diarrhea CTCAE Grade 2 + chronic colitis Odds ratio 95% CI P Odds ratio 95% CI P Colon V 0.88 0.73–1.06 0.182 1.10 0.86–1.41 0.451 V 1.14 0.93–1.40 0.202 0.82 0.60–1.13 0.224 V 0.93 0.83–1.04 0.186 1.05 0.93–1.18 0.448 Peritoneum V 0.80 0.57–1.12 0.198 1.09 0.76–1.56 0.629 50.4 V 1.62 0.97–2.71 0.068 0.93 0.63–1.36 0.698 V 0.80 0.54–1.18 0.250 1.25 0.83–1.87 0.287 V 0.99 0.83–1.17 0.892 1.02 0.89–1.16 0.792 Rectum V 1.01 0.92–1.11 0.863 0.97 0.87–1.08 0.576 50.4 V 0.92 0.83–1.02 0.116 0.84 0.67–1.06 0.147 V 1.15 1.10–1.30 0.030* 1.14 0.99–1.33 0.073 CTCAE common terminology criteria for adverse events, CI confidence interval, V, V, V, V, V, V = volume receiving ≥ 50.4, ≥ 40, ≥ 35, ≥ 30, ≥ 25, ≥ 15 Gy, 50.4 40 35 30 25 15 respectively *Statistically significant Cheng  et al. Radiation Oncology (2022) 17:91 Page 15 of 17 Table 8 Dosimetric comparison of organs at risk (OARs) for the 3 treatment plans 3DCRT (n = 9) VMAT (n = 11) Tomotherapy (n = 10) P value Colon dose (%) V 34.7 [23.9–66.1] 13.0 [7.0–29.3]* 10.6 [3.5–17.1]* 0.002 V 50.3 [41.2–74.3] 30.0 [18.5–53.0] 30.4 [10.8–37.4]* 0.020 V 64.9 [51.2–81.0] 68.0 [52.0–73.2] 57.1 [33.8–80.6] 0.796 Peritoneum dose (%) V 35.8 [18.0–50.0] 3.6 [1.0–5.0]* 2.7 [0.5–5.2]* 0.001 50.4 V 51.7 [28.0–73.0] 12.0 [7.0–21.0]* * 0.002 V 58.7 [35.2–79.7] 27.0 [20.0–37.0]* 23.6 [17.5–34.6]* 0.013 V 66.7 [32.5–83.0] 45.0 [33.7–52.0] 36.6 [30.4–45.5] 0.147 Rectum dose (%) V 24.4 [15.6,–52.6] 2.2 [0.0–13.4]* 5.3 [0.3–7.4]* 0.003 50.4 V 97.5 [94.2–100.0] 37.0 [26.0–68.4]* 34.1[26.2–40.6]* < 0.001 V 97.5 [96.3–100.0] 86.5 [69.3–90.0] 56.4 [49.3–66.0]* < 0.001 Bladder dose (%) V 40.7 [31.2–46.7] 2.0 [1.0–14.0]* 5.7 [0.7–13.3]* 0.001 50.4 V 100.0 [99.8–100.0] 28.0 [23.3–34.1]* 28.6 [21.3–46.1]* < 0.001 V 100.0 [100.0–100.0] 59.5 [52.0–71.0]* 50.5 [43.2–73.6]* < 0.001 Bone marrow dose (%) V 27.8 [24.1–29.2] 4.0 [2.7–5.0]* 5.5 [3.0–8.1]* < 0.001 V 44.0 [39.7–45.5] 16.0 [13.0–17.0]* 19.6 [16.9–23.0]* < 0.001 V 58.9 [54.8–62.9] 37.0 [34.2–38.5]* 39.2 [38.0–45.8]* < 0.001 V 88.8 [81.5–91.3] 70.0 [63.0–75.4]* 70.4 [67.1–73.3]* 0.002 V 91.9 [84.4–95.6] 89.8 [87.0–94.0] 90.2 [87.1–92.7] 0.936 3DCRT three-dimensional conformal radiation therapy, VMAT volumetric modulated arc therapy, V, V, V, V, V, V = volume receiving ≥ 50.4, ≥ 40, ≥ 35, ≥ 30, 50.4 40 35 30 25 15 ≥ 25, ≥ 15 Gy, respectively Differences were compared using the Kruskal–Wallis tests for continuous variables Data are presented as the median [interquartile range] *P < 0.05 versus 3DCRT in the Bonferroni post hoc test P < 0.05 versus VMAT in the Bonferroni post hoc test P = 0.09 versus 3DCRT in the Bonferroni post hoc chronic colitis might also be affected by brachytherapy the midterm of the study, although we did not artificially and chemotherapy. Furthermore, the small sample size intervene in the case selection process. may not have been sufficiently powered to detect a differ - ence between the groups. Conclusion Our study involved some limitations. First, this study Pretreatment SCC Ag ≤ 10  ng/mL were associated with was performed as a retrospective study. Unlike a prospec- better PFS, LRRFS, and DMFS in patients with stage IB- tive study, the present study inevitably includes a degree IVA cervical cancer treated by radical CCRT and might of selection bias, recall bias, and confounding effects, serve as an effective predictor for DMFS in the T1N0/ leading to a finite level of evidence. Second, the limited T2N0 subgroup. The V value of the rectum is an impor- case number makes the results relatively tentative, and tant dosimetric factor for acute diarrhea during pelvic these findings must be confirmed in a larger sample. EBRT. Compared with VMAT, tomotherapy reduced the Third, only 30 of the 93 patients completed a dosimetric V value for the rectum and consequently alleviated the analysis because we initiated the dosimetric evaluation in severity of acute diarrhea. Cheng et al. Radiation Oncology (2022) 17:91 Page 16 of 17 Fig. 6 The isodose distributions of patients with cervical cancer treated by VAMT and Tomotherapy. The isodose distributions for a a T2N0 patient treated with volumetric modulated arc therapy and b a T3N0 patient treated with tomotherapy. The thick brown and light blue lines represented the border of rectum and bladder, respectively. The thin red, pink, light blue, orange, green lines represented the dose curves of 54, 50.4, 48, 43.2 and 37.8 Gy, respectively. Tomotherapy provided significantly less rectal volume exposed to 37.8 Gy factor; SCC Ag: Squamous cell carcinoma antigen; DFS: Disease‑specific Table 9 The gastrointestinal and genitourinary toxicity of 3DCRT, survival. VMAT, and tomotherapy Acknowledgements 3DCRT (n = 9) VMAT (n = 11) Tomotherapy P value We wish to express our gratitude to all who contributed their time and exper‑ (n = 10) tise to this study. Diarrhea Author contributions Gr. 0/1 3 (33.3) 5 (45.5) 9 (90.0) 0.029 MYH conceived the study. YKC performed the statistical analysis, participated in the interpretation of data, and wrote and revised the manuscript. JHW, YCC, Gr. ≥ 2 6 (66.7) 6 (54.5) 1 (10.0) and MYH recruited patients to the study and treated them. MYH and YKC are Colitis radiation oncologists who contributed to provide RT. SHK and HHY created Gr. 0/1 7 (77.8) 9 (81.8) 8 (80.0) 0.975 the treatment plans. All authors read and approved the final manuscript. Gr. ≥ 2 2 (22.2) 2 (18.2) 2 (20.0) Funding Cystitis This work was partly supported by funds of the Ministry of Science and Tech‑ Gr. 0/1 6 (66.7) 4 (36.4) 7 (70.0) 0.230 nology (MOST 108‑2314‑B‑037‑021‑MY3; MOST 110‑2314‑B‑037‑075‑MY2), the Kaohsiung Medical University (S110002), and the Kaohsiung Medical Gr. ≥ 2 3 (33.3) 7 (63.6) 3 (30.0) University Hospital (KMUH107‑7M31). 3DCRT three-dimensional conformal radiation therapy, VMAT volumetric modulated arc therapy, Gr. grade Availability of data and materials All data and materials have been presented in the manuscript. Data are presented as n (%) Declarations Abbreviations CCRT : Concurrent chemoradiation therapy; EBRT: External beam radiation Ethics approval and consent to participate therapy; 3DCRT : 3‑Dimensional conformal radiation therapy; IMRT: Intensity‑ This present study was approved by the Institutional Review Board in Kaohsi‑ modulated radiotherapy; VMAT: Volumetric modulated arc therapy; RT: Radia‑ ung Medical University Hospital [KMUHIRB‑E(I)‑20190054]. tion therapy; FIGO: International Federation of Gynecology and Obstetrics; ECOG: Eastern Cooperative Oncology Group; CT: Computed tomography; Consent for publication MRI: Magnetic resonance imaging; SCC: Squamous cell carcinoma; CEA: Not applicable. Carcinoembryonic antigen; CA125: Cancer antigen 125; AJCC: American Joint Committee on Cancer; IRB: Internal Review Board; AP: Anteroposterior; PA: Competing interests Posteroanterior; CTV: Clinical target volume; PTV: Planning target volume; The authors declare that they have no competing interests. OAR: Organ at risks; CTCAE: Common Terminology Criteria of Adverse Events; OTT: Overall treatment time; LRRFS: Locoregional recurrence–free survival; PFS: Author details Progression‑free survival; DMFS: Distant metastasis–free survival; OS: Overall Department of Radiation Oncology, Kaohsiung Medical University Hospital, survival; PET: Positron emission tomography; EQD2: Equivalent dose in 2‑ Gy Kaohsiung, Taiwan. Cancer Center, Kaohsiung Medical University Hospital, fractions; HR: Hazard ratio; CI: Confidence interval; OR: Odds ratio; HIF‑1α: Kaohsiung, Taiwan. Department of Radiation Oncology, Faculty of Medi‑ Hypoxia‑inducible factor 1α; VEGF: Expression of vascular endothelial growth cine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Obstetrics and Gynecology, Kaohsiung Medical University Cheng  et al. Radiation Oncology (2022) 17:91 Page 17 of 17 Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Depar tment 14. Jeong SY, Park H, Kim MS, Kang JH, Paik ES, Lee YY, et al. Pretreatment of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung lymph node metastasis as a prognostic significance in cervical cancer: Medical University, No. 100 Tzyou 1st Road, Kaohsiung 80708, Taiwan. comparison between disease status. Cancer Res Treat. 2020;52(2):516–23. https:// doi. org/ 10. 4143/ crt. 2019. 328. Received: 9 November 2021 Accepted: 2 May 2022 15. Kawanaka T, Kubo A, Ikushima H, Sano T, Takegawa Y, Nishitani H. Prognos‑ tic significance of HIF2alpha expr ‑ ession on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. J Med Investig. 2008;55(1–2):78–86. https:// doi. org/ 10. 2152/ jmi. 55. 78. 16. Loncaster JA, Cooper RA, Logue JP, Davidson SE, Hunter RD, West CM. Vascular endothelial growth factor ( VEGF) expression is a prognostic References factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J 1. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, et al. Esti‑ Cancer. 2000;83(5):620–5. https:// doi. org/ 10. 1054/ bjoc. 2000. 1319. mates of incidence and mortality of cervical cancer in 2018: a worldwide 17. Hong JH, Tsai CS, Chang JT, Wang CC, Lai CH, Lee SP, et al. The prognos‑ analysis. Lancet Glob Health. 2020;8(2):e191–203. https:// doi. org/ 10. 1016/ tic significance of pre ‑ and post ‑treatment SCC levels in patients with S2214‑ 109X(19) 30482‑6. squamous cell carcinoma of the cervix treated by radiotherapy. Int J 2. Akinyemiju T, Ogunsina K, Sakhuja S, Ogbhodo V, Braithwaite D. Life‑ Radiat Oncol Biol Phys. 1998;41(4):823–30. https:// doi. org/ 10. 1016/ s0360‑ course socioeconomic status and breast and cervical cancer screen‑ 3016(98) 00147‑3. ing: analysis of the WHO’s Study on Global Ageing and Adult Health 18. Lee J, Lin JB, Chang CL, Sun FJ, Wu MH, Jan Y T, et al. Impact of para‑aortic (SAGE). BMJ Open. 2016;6(11):e012753. https:// doi. org/ 10. 1136/ bmjop recurrence risk‑ guided intensity‑modulated radiotherapy in locally en‑ 2016‑ 012753. advanced cervical cancer with positive pelvic lymph nodes. Gynecol 3. De Felice F, Pranno N, Papi P, Brugnoletti O, Tombolini V, Polimeni A. Xeros‑ Oncol. 2018;148(2):291–8. https:// doi. org/ 10. 1016/j. ygyno. 2017. 12. 003. tomia and clinical outcomes in definitive intensity modulated radiother ‑ 19. Dang YZ, Li P, Li JP, Bai F, Zhang Y, Mu YF, et al. The efficacy and late apy (IMRT ) versus three‑ dimensional conformal radiotherapy (3D‑ CRT ) for toxicities of computed tomography‑based brachytherapy with intra‑ head and neck squamous cell carcinoma: a metaanalysis ‑ . In vivo (Athens, cavitary and interstitial technique in advanced cervical cancer. J Cancer. Greece). 2020;34(2):623–9. https:// doi. org/ 10. 21873/ invivo. 11816. 2018;9(9):1635–41. https:// doi. org/ 10. 7150/ jca. 23974. 4. Marta GN, Weltman E, Ferrigno R. Intensity‑modulated radiation therapy 20. Hansen H, Høgdall C, Engelholm S. Radiation therapy without cisplatin for (IMRT ) versus 3‑ dimensional conformal radiation therapy (3D‑ CRT ) for elderly cervical cancer patients. Int J Radiat Oncol Biol Phys. 2014;90:S484‑ head and neck cancer: cost‑ effectiveness analysis. Rev Assoc Med Bras. 85. https:// doi. org/ 10. 1016/j. ijrobp. 2014. 05. 1499. 2018;64(4):318–23. https:// doi. org/ 10. 1590/ 1806‑ 9282. 64. 04. 318. 21. Guo M, Huang E, Liu X, Tang Y. Volumetric modulated arc therapy versus 5. Mell LK, Sirák I, Wei L, Tarnawski R, Mahantshetty U, Yashar CM, et al. Bone fixed‑field intensity‑modulated radiotherapy in radical irradiation for marrow‑sparing intensity modulated radiation therapy with concur ‑ cervical cancer without lymphadenectasis: dosimetric and clinical results. rent cisplatin for stage IB‑IVA cervical cancer: an international multi‑ Oncol Res Treat. 2018;41(3):105–9. https:// doi. org/ 10. 1159/ 00048 4608. center phase II clinical trial (INTERTECC‑2). Int J Radiat Oncol Biol Phys. 22. Hsieh CH, Wei MC, Lee HY, Hsiao SM, Chen CA, Wang LY, et al. Whole 2017;97(3):536–45. https:// doi. org/ 10. 1016/j. ijrobp. 2016. 11. 027. pelvic helical tomotherapy for locally advanced cervical cancer: technical 6. Wang X, Shen Y, Zhao Y, Li Z, Gou H, Cao D, et al. Adjuvant intensity‑ implementation of IMRT with helical tomotherapy. Radiat Oncol (London, modulated radiotherapy (IMRT ) with concurrent paclitaxel and cisplatin England). 2009;4:62. https:// doi. org/ 10. 1186/ 1748‑ 717X‑4‑ 62. in cervical cancer patients with high risk factors: a phase II trial. Eur J 23. Roeske JC, Bonta D, Mell LK, Lujan AE, Mundt AJ. A dosimetric analysis of Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 2015;41(8):1082–8. acute gastrointestinal toxicity in women receiving intensity‑modulated https:// doi. org/ 10. 1016/j. ejso. 2015. 04. 018. whole‑pelvic radiation therapy. Radiother Oncol J Eur Soc Ther Radiol 7. Mell LK, Kochanski JD, Roeske JC, Haslam JJ, Mehta N, Yamada SD, et al. Oncol. 2003;69(2):201–7. https:// doi. org/ 10. 1016/j. radonc. 2003. 05. 001. Dosimetric predictors of acute hematologic toxicity in cervical cancer 24. Deville C, Vapiwala N, Hwang WT, Lin H, Ad VB, Tochner Z, et al. Com‑ patients treated with concurrent cisplatin and intensity‑modulated pelvic parative toxicity and dosimetric profile of whole ‑pelvis versus prostate radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(5):1356–65. https:// doi. bed‑ only intensity‑modulated radiation therapy after prostatectomy. Int org/ 10. 1016/j. ijrobp. 2006. 03. 018. J Radiat Oncol Biol Phys. 2012;82(4):1389–96. https:// doi. org/ 10. 1016/j. 8. Rutledge FN, Mitchell MF, Munsell M, Bass S, McGuffee V, Atkinson EN. ijrobp. 2011. 04. 041. Youth as a prognostic factor in carcinoma of the cervix: a matched 25. Huang EY, Wang YM, Chang SC, Liu SY, Chou MC. Rectal dose is the other analysis. Gynecol Oncol. 1992;44(2):123–30. https:// doi. org/ 10. 1016/ 0090‑ dosimetric factor in addition to small bowel for prediction of acute diar‑ 8258(92) 90027‑g. rhea during postoperative whole‑pelvic intensity‑modulated radiother ‑ 9. Katz A, Eifel PJ, Moughan J, Owen JB, Mahon I, Hanks GE. Socioeconomic apy in gynecologic patients. Cancers. 2021;13(3):497. https:// doi. org/ 10. characteristics of patients with squamous cell carcinoma of the uterine 3390/ cance rs130 30497. cervix treated with radiotherapy in the 1992 to 1994 patterns of care 26. Chi A, Nguyen NP, Xu J, Ji M, Tang J, Jin J, et al. Correlation of three differ ‑ study. Int J Radiat Oncol Biol Phys. 2000;47(2):443–50. https:// doi. org/ 10. ent approaches of small bowel delineation and acute lower gastrointes‑ 1016/ s0360‑ 3016(00) 00417‑x. tinal toxicity in adjuvant pelvic intensity‑modulated radiation therapy for 10. Shaverdian N, Gondi V, Sklenar KL, Dunn EF, Petereit DG, Straub MR, endometrial cancer. Technol Cancer Res Treat. 2012;11(4):353–9. https:// et al. Eec ff ts of treatment duration during concomitant chemoradiation doi. org/ 10. 7785/ tcrt. 2012. 500283. therapy for cervical cancer. Int J Radiat Oncol Biol Phys. 2013;86(3):562–8. 27. Salama JK, Mundt AJ, Roeske J, Mehta N. Preliminary outcome and toxic‑ https:// doi. org/ 10. 1016/j. ijrobp. 2013. 01. 037. ity report of extended‑field, intensity‑modulated radiation therapy for 11. Hong JH, Tsai CS, Lai CH, Chang TC, Wang CC, Chou HH, et al. Risk gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2006;65(4):1170– stratification of patients with advanced squamous cell carcinoma 6. https:// doi. org/ 10. 1016/j. ijrobp. 2006. 02. 041. of cervix treated by radiotherapy alone. Int J Radiat Oncol Biol Phys. 28. National Institutes of Health (NIH). Common terminology criteria for adverse 2005;63(2):492–9. https:// doi. org/ 10. 1016/j. ijrobp. 2005. 02. 012. events (CTCAE) v4.03. https:// ctep. cancer. gov/ proto colde velop ment/ elect 12. Huang EY, Huang YJ, Chanchien CC, Lin H, Wang CJ, Sun LM, et al. Pre‑ ronic_ appli catio ns/ docs/ CTCAE_4. 03. xlsx. Accessed 14 June 2010. treatment carcinoembryonic antigen level is a risk factor for para‑aortic 29. Lin YZ, Chen K, Lu ZY, Zhao L, Tao YL, Ouyang Y, et al. Intensity‑mod‑ lymph node recurrence in addition to squamous cell carcinoma antigen ulated radiation therapy for definitive treatment of cervical cancer: a following definitive concurrent chemoradiotherapy for squamous meta‑analysis. Radiat Oncol. 2018;13(1):177. https:// doi. org/ 10. 1186/ cell carcinoma of the uterine cervix. Radiat Oncol (London, England). s13014‑ 018‑ 1126‑7. 2012;7:13. https:// doi. org/ 10. 1186/ 1748‑ 717X‑7‑ 13. 13. Huang EY, Wang CJ, Chen HC, Fang FM, Huang YJ, Wang CY, et al. Mul‑ tivariate analysis of para‑aortic lymph node recurrence after definitive Publisher’s Note radiotherapy for stage IB‑IVA squamous cell carcinoma of uterine cervix. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ Int J Radiat Oncol Biol Phys. 2008;72(3):834–42. https:// doi. org/ 10. 1016/j. lished maps and institutional affiliations. ijrobp. 2008. 01. 035.

Journal

Radiation OncologySpringer Journals

Published: May 12, 2022

Keywords: Cervical cancer; SCC Ag; Volumetric modulated arc therapy; Tomotherapy; Diarrhea; Rectum

References