Anal Canal-Sparing Technique During Postoperative Pelvic Radiation Therapy for Cervical Cancer Patients to Reduce Hemorrhoids-related Symptoms: A Multicenter Randomized Clinical Trial
Phase: NA
Conditions: Hemorrhoidal Disease, Cervical Cancer Radiation Complications
Sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

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CLINICAL STUDY PROTOCOL 
Anal Canal-Sparing Technique During Postoperative Pelvic 
Radiation Therapy for Cervical Cancer Patients to Reduce 
Hemorrhoids-related Symptoms （ACS-RT） 
A Multicenter Randomized Clinical Trial 
 
For any communications regarding this protocol, 
please call the protocol resource person on the following page. 
Coordinating Center: NA 
*Principal Investigator (PI):  
Yong Liu, MD, PhD* 
Shanghai General Hospital, Shanghai Jiaotong University School of Medicine 
100, Haining Road, Hongkou District 
Shanghai, China 200080 
Telephone (86 21) 36123575 
Telefax (86 21) 36126254 
email yong.liu2@shgh.cn 
 
Other Key Investigators:  
Xiumei Ma, MD, PhD 
Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine 
160, Pujian Road, Pudong District 
Shanghai, China 200127 
Telephone (86 21) 68383283 
Telefax (86 21) 68383282 
email sallyma1201@163.com 
 

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Jingping Yu, MD, PhD 
Changzhou Cancer Hospital 
68, Honghe Road, Xinbei District, Changzhou, Jiangsu province, China, 213000 
Telephone（86 519）69807678 
Telefax （86 519）69807251 
email yujingping700420@sina.com 
 
Jing Xue, MD, PhD 
Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, 
Gusu School, Nanjing Medical University 
No.16 West of Baita Road, Gusu District, Suzhou, China, 215001 
Telephone (86 512) 62364043  
Telefax (86 512) 67294553 
Email jxue@njmu.edu.cn 
 
Hao Wang, MD, PhD  
First Affiliated Hospital of Anhui Medical University  
No.218 Jixi Road, Shushan District, Hefei City, Anhui province, China, 230022 
Telephone (86 551) 65908776 
Telefax (86 551) 63633742 
email wanghao@ahmu.edu.cn 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Index 
SCHEMA……………...……………………………………………………………………………5 
1. INTRODUCTION ........................................................................................................................ 6 
2. OBJECTIVES and ENDPOINTS ............................................................................................... 10 
2.1 Primary Research Objective ...................................................................................................... 10 
2.2 Research Endpoints / Observation Indicators ........................................................................... 10 
2.2.1 Primary Endpoint / Primary Observation Indicator ............................................................... 10 
2.2.2 Secondary Endpoints / Secondary Observation Indicators .................................................... 10 
2.2.3 Exploratory Endpoints / Exploratory Observation Metrics .................................................... 11 
3. STUDY POPULATION AND SAMPLE SIZE .......................................................................... 12 
3.1 Eligibility Criteria ..................................................................................................................... 12 
3.2 Ineligibility Criteria................................................................................................................... 13 
3.3 Withdrawal/Termination Criteria .............................................................................................. 14 
3.4 Sample Size ............................................................................................................................... 14 
4. RESEARCH METHODOLOGY ................................................................................................ 15 
4.1 Study Design ............................................................................................................................. 15 
4.2 Randomization and Blinding .................................................................................................... 15 
4.2.1 Randomization ....................................................................................................................... 15 
4.2.2 Blinding……………. ............................................................................................................. 16 
4.2.3 Unblinding Procedure ............................................................................................................ 16 
4.3 Statistical Analysis .................................................................................................................... 17 
5. RADIATION TREATMENT PLAN .......................................................................................... 17 
5.1 CT Simulation ........................................................................................................................... 18 
5.2 Pelvic Radiation Therapy .......................................................................................................... 18 
5.2.1 Technical Factors ................................................................................................................... 18 
5.2.2 Clinical Target Volume (CTV) .............................................................................................. 19 
5.2.3 Plan Target Volume (PTV) .................................................................................................... 19 
5.2.4 Dose Prescription ................................................................................................................... 20 
5.2.5 OAR Delineation and Dose Constraints................................................................................. 20 
5.2.5.1 Delineation of OAR ............................................................................................................ 20 

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5.2.5.2 OAR Dose Constraints ........................................................................................................ 21 
5.3 Anal Canal-Sparing Technique ................................................................................................. 21 
5.3.1 Anatomy of Anal Canal ......................................................................................................... 21 
5.3.2 Magnetic Resonance Imaging (MRI) of Anal Canal.............................................................. 22 
5.3.3 OAR Delineation and Dose Constraints................................................................................. 23 
5.4 Treatment Planning ................................................................................................................... 25 
5.4.1 Treatment Technique ............................................................................................................. 25 
5.4.2 Dose Calculation .................................................................................................................... 25 
5.5 Chemotherapy Regimens Concurrent with Radiotherapy ......................................................... 26 
5.6 Brachytherapy after EBRT ........................................................................................................ 26 
5.6.1 Indications for BT after EBRT ............................................................................................... 26 
5.6.2 Dose Calculation .................................................................................................................... 27 
5.6.3 OAR Dose Constraints ........................................................................................................... 27 
5.7 Quality Assurance (QA) in Radiotherapy ................................................................................. 27 
6 OUTCOME AND INDICATOR EVALUATION ...................................................................... 28 
6.1 Evaluation of Primary Observation Indicators .......................................................................... 28 
6.2 Evaluation of Secondary Observational Indicators ................................................................... 29 
6.3 Evaluation of Exploratory Observation Metrics ....................................................................... 30 
7. INTERRUPTION OF RADIOTHERAPY AND MANAGEMENT OF UNTOWARD 
REACTION………. ....................................................................................................................... 30 
7.1 Interruption of radiotherapy ...................................................................................................... 30 
7.2 Treatment related adverse events (AE) ..................................................................................... 31 
8. CONCOMITANT MEDICATIONS ........................................................................................... 32 
8.1 Permitted Medications and Therapies ....................................................................................... 32 
8.2 Prohibited Medications and Therapies ...................................................................................... 33 
9. TREATMENT COMPLIANCE.................................................................................................. 33 
10. TISSUE/SPECIMEN SUBMISSION ....................................................................................... 34 
11. APPENDIX ……………………………………………………………………………………34 
Reference…………… .................................................................................................................... 35 
Appendix 1…… .............................................................................................................................. 37 
Appendix 2……. ............................................................................................................................. 39 

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SCHEMA 
 
 
 
 
 
-Treated with hysterectomy  
- Requirement for adjuvant CCRT 
-Age > 18 years. 
-History of hemorrhoids  
-Eligible as per criteria 
-Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1:1 
Anal Canal-Sparing Technique 
Conventional pelvic radiation 
therapy 

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1. INTRODUCTION 
Radiation therapy (RT) is a main treatment method to improves local control and 
overall survival for cervical cancer patients with high-risk factors. External beam 
radiation therapy (EBRT) is particularly important, which plays a crucial role for 
patients either after surgery or for those ineligible for surgery [1,2]. In recent decades, 
intensity-modulated radiation therapy (IMRT) has become the mainstream of treatment 
for cancer patients. Although radiation techniques have improved over the last years, 
pelvic radiation therapy still causes adverse effects on surrounding normal tissues and 
organs regularly [3,4], which includes rectum, sigmoid colon, pelvic small bowel loops 
and ileocecal region. Studies show that 90-95% of patients with pelvic malignancies—
including gynecological tumors, urological tumors, colorectal cancer and anal canal 
cancer—develop varying degrees of radiation-induced intestinal injury. Radiation-
induced rectal injury (RRI) is still one of the most common complications of radiation 
to the pelvis, but which is also the most difficult to treat [5,6]. 
Radiation-induced rectal injury refers to damage to the rectum caused by radiation 
exposure, with radiotherapy dosage being the primary contributing factor. RRI can be 
classified into radiation-induced acute rectal injury (RARI) and radiation-induced late 
rectal injury (RLRI), clinically demarcated at the 3-month point [7,8]. Typically, the 
emergence of acute gastrointestinal symptoms is an independent risk factor for the 
subsequent development of RLRI [9]. RARI patients exhibit diverse and non-specific 
clinical symptoms that may appear shortly after radiotherapy initiation. These 
symptoms include increased bowel frequency, urgency, hematochezia, diarrhea, anal 
pain or tenesmus. Therefore, RARI is required close monitoring, although the 
symptoms of RARI could always be recovered spontaneously within 3 months after 
radiation therapy.  
However, whether from the symptoms or the pelvic radiation therapy plans, 
current studies on RARI generally combine the rectum and anal canal. Therefore, the 
so-called "Radiation-induced rectal injury" is not purely "rectal injury," but includes 
"radiation-induced rectal and anal canal injury." In addition, the radiation of perianal 
muscles can also lead to symptoms related to the rectum during pelvic radiation therapy 
[10,11]. According to current contouring guidelines, whether for gynecologic tumors or 

7 
 
other pelvic malignancies, the anal canal is regarded together with the rectum as the 
same organ at risk (OAR) when formulating pelvic EBRT plans, and a unified dose 
constraint standard is applied. The anal canal and its surrounding muscles are not 
assessed separately. The possible reason is, firstly, that when the prescribed dose of 
pelvic EBRT is 45-55 Gy (with a fraction size of 1.8-2 Gy), it is considered safe for the 
anal canal and its surrounding muscles [12]. Secondly, from the perspective of managing 
radiation-induced toxicities, distinguishing the anal canal, perianal muscles, and rectum 
may be limited clinical relevance when if symptoms are mild [13]. Thirdly, relying solely 
on planning CT (Computed Tomography) and pelvic MRI (Magnetic Resonance 
Imaging) makes it challenging to accurately delineate the anatomical boundaries 
between the anal canal and rectum, as well as the extent of the perianal musculature [14]. 
Lastly, there is no promising technique to reduce irradiated dose to the anal canal.  
The tolerance dose of the rectum is generally considered to be around 50 Gy[12], 
however, anal canal–related symptoms may occur at lower doses, particularly in 
patients with a history of hemorrhoids[15]. During the early phase of radiotherapy, 
hemorrhoids-associated symptoms such as perianal pain, hemorrhoidal prolapse, 
rectal bleeding, and perianal skin breakdown may occur. These symptoms are more 
likely attributable to the aggravation of pre-existing hemorrhoids rather than radiation-
induced rectal injury. A study reported that, during external beam radiation therapy 
for pelvic malignancies, the median induction dose for acute anal canal symptoms was 
34.1 Gy (range: 28.8 Gy-50.4 Gy), with a median onset time at 24 days (range: 21-36 
days). Patients receiving postoperative adjuvant radiotherapy were more prone to 
develop acute anal canal reactions compared to those undergoing definitive 
radiotherapy without surgery (P = 0.04). Among the dosimetric parameters, V10 
showed a potential association with the occurrence of acute anal canal symptoms (P = 
0.08)[16], which may suggest that the anal canal deserves more attention during pelvic 
radiation therapy. 
Hemorrhoidal disease (HD) is a common anorectal disorder in adults, arising from 
increased pressure and abnormal dilation of the hemorrhoidal vascular cushions [17]. 
The exact incidence of hemorrhoidal disease in the general population remains unclear 
and may vary across countries and regions [18]. In the United States, it is the third most 
common gastrointestinal disorder managed in outpatient clinics, affecting up to 75% 

8 
 
of American adults to varying degrees [19]. In China, the saying "nine out of ten people 
have hemorrhoids" is often used to describe its high prevalence. The main symptoms 
caused by hemorrhoids include prolapse, local burning, bleeding, perianal pain, and 
other perianal discomforts [20]. Although it is not a life-threatening condition, it can 
persistently and severely impact quality of life and increase the healthcare burden on 
society. In the United States, approximately 4 million medical consultations for 
hemorrhoidal disease occur each year, with estimated costs exceeding $770 million 
[21]. 
Anal canal toxicity should not be a neglected side-effect of pelvic radiation therapy, 
and greater attention need to be paid to the occurrence of acute hemorrhoids-related 
symptoms, particularly for cervical cancer patients with hemorrhoids. Female patients, 
especially those with a history of childbirth, have a markedly higher incidence of 
hemorrhoids and relatively reduced pelvic tolerance, making the protection of the anal 
canal especially important. Hemorrhoids-related symptoms can cause varying degrees 
of local discomfort and psychological stress in patients. Notably, as these symptoms 
may occur in the early to middle stages of pelvic EBRT, they can compromise patients' 
adherence to and completion of radiotherapy, while also increase the likelihood of 
prescriptions for hemorrhoids-related medications. Moreover, for cervical cancer 
patients, whether undergoing adjuvant radiotherapy or radical radiotherapy, EBRT 
combined with high-dose rate brachytherapy (BT) is often adopted. If anal canal 
protection is provided during EBRT, patients will definitely have better tolerance 
during BT, and the incidence and severity of anal canal-related symptoms will also 
decrease accordingly.  
However, the aggravation of hemorrhoids caused by pelvic radiation therapy has 
not yet attracted radiation oncologists' attention, and a significant proportion of such 
hemorrhoidal aggravations are attributed to radiation proctitis. Actually, pelvic normal 
tissue contouring guidelines for radiation therapy[22] has suggested when treating 
gynecologic tumors, the acute toxicities and quality of life (QoL) concerns are 
different for anal canal and rectum. However, because there are no specific dose 
constraints for anal canal at present, it is contoured as part of the AnoRectum. It also 
hoped future research may help define anal dose constraints, which may require 
contouring anal canal and rectum separately. However, there were very limited studies 

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about the relationship between hemorrhoids aggravation and pelvic radiation therapy, 
most of which were only retrospective research. 
Some studies showed that postoperative pelvic RT may aggravate acute 
hemorrhoids-related symptoms in patients with hemorrhoids in the era of two/three-
dimensional radiation, increasing by 50~70%[13,16]. Although the advent of the IMRT 
era has improved treatment precision and reduced the radiation dose to the OARs, the 
incidence of acute anal canal-related symptoms remains relatively high, as these 
symptoms can occur even at relatively low radiation doses. We have reviewed 15 
cervical cancer patients with hemorrhoids who accepted postoperative pelvic RT in 
2023 in our center, 9 patients developed acute hemorrhoids-related symptoms, with an 
incidence rate remaining as high as approximately 60%. For this reason, it remains of 
significant value to protect anal canal during pelvic radiation therapy in IMRT era, in 
which separate dose delivery for anal canal and rectum could be achieved. 
We tried to develop anal canal-sparing technique to reduce the irradiated dose to 
anal canal for cervical cancer patients with hemorrhoids who needed postoperative 
pelvic radiation therapy. Compared with standard pelvic RT plan, the irradiated doses 
of anal canal and perianal muscles were significantly reduced. The mean doses (Dmean) 
was reduced from 40 Gy to 30 Gy and the percentage volumes of them that received 20 
Gy (V20) was reduced by 15%. A study demonstrated the association between pelvic 
floor muscle and anorectal injury and radiation dose following prostate cancer 
radiotherapy, based on dose–response fitting curve, for every 1% reduction in V20, the 
risk of severe acute anal canal reactions decreased by 2.4% [23]. Correspondingly, our 
group also evaluated 15 postoperative cervical cancer patients with hemorrhoids and 
found that, after reducing the deliver dose to the anal canal, only 20.0% (3/15) 
developed hemorrhoids-related symptoms from the initiation of radiotherapy to four 
weeks after completion. This incidence was markedly lower compared with patients 
whose anal canal was not specifically protected. 
Minimizing acute toxic effects is of considerable importance to improve quality 
of life because it has been correlated with late toxic effects in patients with pelvic 
radiation therapy[9]. Currently, there is no prospective studies about anal canal 
protection to reduce the incidence of acute anal canal-related symptoms for cervical 

10 
 
cancer patients with hemorrhoids. Herein, we design a multicenter, double-blind RCT 
in which cervical cancer patients with hemorrhoids were randomly assigned to receive 
anal canal-sparing or standard postoperative pelvic radiation therapy, in either 
combined with brachytherapy or not. 
 
2. OBJECTIVES and ENDPOINTS 
2.1 Primary Research Objective 
To compare the incidence of hemorrhoids-related symptoms between postoperative 
cervical cancer patients with a history of hemorrhoids receiving anal canal-sparing 
pelvic radiation therapy and those receiving conventional pelvic radiation therapy. 
The aim of employing the anal canal-sparing technique is to reduce the incidence of 
hemorrhoids-related symptoms in this patient population.  
2.2 Research Endpoints / Observation Indicators 
2.2.1 Primary Endpoint / Primary Observation Indicator 
 
The primary endpoint is the incidence of radiation-induced hemorrhoids-related 
symptoms occurring from the initiation of pelvic radiation therapy (including 
BT) until 4 weeks after its completion. 
 
The primary observation indicator is assessed by investigators weekly, using the 
Radiation Therapy Oncology Group (RTOG) / European Organization for 
Research and Treatment of Cancer (EORTC) Acute Radiation Morbidity 
Scoring Criteria and the Pelvic Radiation Therapy Hemorrhoids-Related 
Symptoms Assessment Scale (Shanghai General Hospital, Shanghai Jiao Tong 
University School of Medicine Version). The occurrence of any hemorrhoids-
related symptom compared to baseline will be considered an event. 
2.2.2 Secondary Endpoints / Secondary Observation Indicators 
 
The secondary endpoints include: 

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(1) 
Cumulative incidence of radiation-induced perianal musculature 
symptoms from the initiation of pelvic radiation therapy 
(including BT) until 4 weeks after its completion. 
(2) 
Comparison of patient-reported QoL from the initiation of pelvic 
radiation therapy (including BT) until 4 weeks after its 
completion. 
(3) 
Comparison of hemorrhoidal medication prescription rates from 
the initiation of pelvic radiation therapy (including BT) until 4 
weeks after its completion. 
 
The secondary observation indicators: 
(1) 
The radiation-induced perianal musculature symptoms as 
graded by patients, using the Low Anterior Resection Syndrome 
(LARS) questionnaire, with any symptom emergence from 
baseline considered an event. 
(2) 
QoL using the EORTC Core QoL Questionnaire (QLQ-C30) 
Version 3.0 and the Cervical Cancer Module (QLQ-CX24). 
Scores will be compared with baseline values. 
(3) 
Hemorrhoidal medication prescription rates: Any prescription of 
hemorrhoidal medication by the investigators recorded in the 
medical records from the start of pelvic radiation therapy until 4 
weeks after its completion will be documented as a hemorrhoidal 
medication user.  
2.2.3 Exploratory Endpoints / Exploratory Observation Metrics 
 
Exploratory Endpoints: To explore OARs delineation and dose delivery 
assessment in anal canal-sparing RT. 
 
Exploratory Observation Metrics: 
(1) Contouring methodology for the anal canal and perianal muscles 
within pelvic radiation therapy plans utilizing anal canal-sparing 

12 
 
techniques. 
(2) Dosimetric evaluation of the anal canal, including V10, V15 and 
Dmean. 
(3) Dosimetric evaluation of the perianal muscles, including V15 and 
Dmean. 
 
3. STUDY POPULATION AND SAMPLE SIZE 
3.1 Eligibility Criteria 
Participants must meet all of the following criteria on screening examination to be 
eligible for study inclusion: 
3.1.1 Treated with hysterectomy (including total abdominal hysterectomy, vaginal 
hysterectomy, radical hysterectomy, or laparoscopically assisted vaginal 
hysterectomy) within 6 weeks prior to study initiation. 
3.1.2 Histologically proven diagnosis of cervical carcinoma, including squamous cell 
carcinoma, adenocarcinoma, or adenosquamous carcinoma. 
3.1.3 Requirement for postoperative adjuvant concurrent chemoradiotherapy (CCRT), 
defined as follows: 
 
Patients who underwent radical hysterectomy require postoperative CCRT if they 
have any of the following: lymph node positivity, positive surgical margins, or 
parametrial involvement 
 
Patients with squamous cell carcinoma post-radical hysterectomy require 
postoperative CCRT if they meet Sedlis criteria (i.e., have two or more of the 
following risk factors): 
(1) Lymphovascular space invasion (LVSI) 
(2) Deep stromal invasion ≥ 1/3 
(3) Tumor diameter > 4 cm 

13 
 
(4) CCRT should be considered following multidisciplinary team 
discussion in patients with any high-risk features.  
 
Patients with postoperative pathological types of adenocarcinoma or adenosquamous 
carcinoma.  
3.1.4 Age > 18 years. 
3.1.5 Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 
1. 
3.1.6 History of hemorrhoids prior to radiotherapy, with no hemorrhoids-related 
symptoms for at least 4 weeks before radiation therapy initiation. 
3.1.7 Abdominal/pelvic MRI, chest CT, or PET-CT performed before surgery or 
study enrollment to confirm staging and exclude patients with distant metastasis. 
3.1.8 Adequate bone marrow, renal, and hepatic function (all laboratory tests must be 
completed within 14 days before starting chemoradiotherapy), defined as:  
 
Hemoglobin ≥ 9.0 g/dL; 
 
Absolute neutrophil count (ANC) > 1.5 × 10⁹/L;  
 
Platelet count ≥ 100 × 10⁹/L;  
 
Serum albumin ≥ 2.5 g/dL;  
 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN); 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN;  
 
Serum creatinine < 1.5 × ULN. 
3.1.9 Agreement to undergo anal canal MRI before radiation therapy initiation. 
3.1.10 Patient must provide study-specific informed consent form (ICF) prior to study 
entry. 
3.2 Ineligibility Criteria 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study: 

14 
 
3.2.1 Cervical cancer patients who do not meet the criteria for adjuvant radiation 
therapy. 
3.2.2 Without a confirmed history of hemorrhoids. 
3.2.3 Patients contraindicated for MRI (e.g., due to incompatible metallic implants, 
claustrophobic syndrome, or other contraindications). 
3.2.4 Patients who refuse to undergo anal canal MRI. 
3.2.5 Patients with radiographically visible residual disease post-surgery requiring 
boost during the pelvic EBRT. 
3.2.6 History of other malignancies. 
3.2.7 Prior pelvic radiotherapy resulting in overlapping radiation fields. 
3.2.8 History of allergic reaction to platinum-based chemotherapy agents. 
3.2.9 Severe and/or active comorbidities precluding tolerance of concurrent 
chemoradiotherapy. 
3.3 Withdrawal/Termination Criteria 
3.3.1 Voluntary Withdrawal: Participant decides to discontinue study participation. 
3.3.2 Loss to Follow-up: Participant becomes unreachable, leading to withdrawal. 
3.3.3 Adverse Event: Occurrence of a Serious Adverse Event (SAE) or significant 
health problem during treatment necessitating discontinuation of participation. 
3.3.4 Failure to Meet Eligibility: Participant no longer satisfies the study's inclusion 
criteria. 
3.3.5 Disease Progression or Death: Participant experiences disease progression or 
dies during the study period. 
3.4 Sample Size 
Based on reported studies[14,16,23] and preliminary findings from our group, the 
anticipated incidence of hemorrhoids-related symptoms was estimated at 60% in the 
conventional radiotherapy group and 45% in the anal canal-sparing group. A sample 
size calculation was performed using NCSS PASS software with the following 
parameters: significance level (α) = 0.05, statistical power (1-β) = 80%, single-sided 
testing, and a 1:1 allocation ratio. This yielded a requirement of 136 participants per 

15 
 
group. Accounting for an estimated 10% loss of follow-up, a total of 300 participants 
(150 per group) will effectively test the primary hypothesis. 
 
4. RESEARCH METHODOLOGY 
4.1 Study Design 
A multicenter RCT double-blinded trail is proposed by the Department of Radiation 
Oncology at Shanghai General Hospital, Shanghai Jiao Tong University School of 
Medicine. Collaborating institutions include Suzhou Municipal Hospital, Changzhou 
Cancer Hospital, and Renji Hospital Affiliated to Shanghai Jiao Tong University 
School of Medicine. 
The study population consists of postoperative cervical cancer patients with a 
documented history of hemorrhoids requiring adjuvant pelvic radiation therapy. 
Eligible participants will be randomly allocated to one of two arms: 
1. Experimental Arm (i.e. Anal Canal-Sparing Arm): Participants will receive 
pelvic radiation therapy using anal canal-sparing techniques. 
2. Control Arm (i.e. Conventional Radiotherapy Arm): Participants will receive 
pelvic radiation therapy using standard techniques. 
The primary objectives are to compare the incidence of hemorrhoidal symptoms and 
differences in QoL scores during radiation therapy between the two arms. Concurrently, 
the study will explore the practical implementation methodology of the anal canal-
sparing technique. 
4.2 Randomization and Blinding 
4.2.1 Randomization 
Participants across all centers will be randomized in a 1:1 ratio to either the 
experimental or control arm using Interactive Web Response System (IWRS) in our 

16 
 
institution. The stratification factor is whether the participants need brachytherapy after 
EBRT. 
4.2.2 Blinding 
This study employs a double-blind design. The whole process includes screening, 
stratification and randomization, target and organ-at-risk delineation, radiotherapy 
planning evaluation and quality control and participants’ symptoms assessment. The 
treatment allocation will remain blinded from both participants and the outcome 
assessors (including statisticians). However, the investigators responsible for screening, 
enrollment and radiotherapy planning/evaluation/quality control will remain unblinded. 
Bias Mitigation Strategies: 
 Strict Adherence to Blinding: Investigators will rigorously maintain blinding 
protocols where applicable. 
 Centralized Randomization: The IWRS will manage group allocation to ensure 
randomization integrity and consistency, minimizing selection bias. 
 Standardized Training and Procedures: All investigators from every center will 
receive comprehensive training on study objectives and protocols. Standardized 
operating procedures (SOPs) will be implemented across all centers to reduce 
procedural variations and potential biases. 
 Blind Data Review: Following study completion, data will be formally locked 
and subjected to blind review prior to analysis to prevent potential biases. 
4.2.3 Unblinding Procedure 
Following the completion of the study, all research data will be entered into the database. 
After verification for accuracy and subsequent database locking, the designated 
unblinding personnel will perform the unblinding for all blinded investigators and 
subjects. Unblinding personnel must be fully trained in and strictly adhere to this 
operational procedure. Relevant records must be maintained to ensure the trace ability 
of the unblinding process. 
Emergency Unblinding Protocol: This clinical trial employs a double-blind design and 
is a study focused on reducing adverse effects compared to conventional radiotherapy. 
Consequently, the probability of requiring emergency unblinding is relatively low. If 

17 
 
an emergency occurs during the clinical trial requiring urgent medical intervention for 
a specific subject, emergency unblinding will be performed immediately. This will 
involve promptly informing the patient of the specific pelvic radiation therapy regimen 
they received to ensure they receive timely and targeted medical care. 
4.3 Statistical Analysis 
An electronic database was established for this study, including the following patient 
data: name, age, sex, weight, height, ECOG performance status, admission date, 
surgery date, enrollment date, histologic type, pre- and post-operative staging, follow-
up dates, complete blood count, blood biochemistry, tumor markers, anal canal MRI 
findings, pelvic radiotherapy target doses and organ-at-risk doses, time of onset and 
severity of hemorrhoids-related symptoms, as well as weekly assessment timelines and 
findings after symptom appearance. 
Descriptive statistics were used to summarize all variables. All statistical analyses 
were performed using SPSS 20.0 (Version 20.0; Chicago, IL, USA). Continuous 
variables of enrolled patients, including gender, age, FIGO stage, incidence of related 
symptoms, and prescription rates of hemorrhoidal medications, were analyzed using 
the Mann-Whitney U test or Kruskal-Wallis test as appropriate. Categorical data 
including symptom scores and quality of life scores were analyzed using chi-square 
tests (χ²). When less than 20% of cells had expected frequencies <5, Pearson's chi-
square values and two-sided asymptotic significance (P-values) were selected. When 
more than 20% of cells had expected frequencies <5 or any cell had expected frequency 
<1, Fisher's exact test values and two-sided exact significance (P values) were applied. 
A two-tailed P-value <0.05 was considered statistically significant. 
 
5. RADIATION TREATMENT PLAN 
Patients enrolled are randomized to either conventional arm or anal canal-sparing arm 
for treatment with concurrent chemotherapy.  
 
Experimental Arm: Anal canal-sparing RT. Patients in this arm will receive pelvic 
radiation therapy with sparing of the anal canal. 

18 
 
 
Control Arm: Conventional RT. Patients in this arm will receive standard pelvic 
radiation therapy.  
 
Platinum-containing concurrent chemoradiotherapy utilizes cisplatin as a single 
agent (or carboplatin if cisplatin intolerant). Simultaneously, symptomatic 
treatment will be given to reduce the chemotherapy-associated adverse reactions. 
5.1 CT Simulation 
In order to avoid artifacts and fill organs and obtain accurate image information before 
CT scan simulation, necessary pre-scanning preparations should be made. It is 
necessary to empty the rectum before CT simulation, which can not only ensure the 
stability of the target volume position, but also avoid the increase of the volume of the 
rectum entering the high-dose area, the increase of irradiation dose, and the aggravation 
of radiotherapy toxicities. Therefore, it is recommended that patients should not start 
the simulation scan until they have defecated on the same day. A full bladder can reduce 
the radiation volume of bladder and small bowel. It is recommended that patients drink 
700 to 800ml of water and wait for 45-50 minutes before CT simulation to ensure 
bladder is comfortably full. The specific steps are as follows: (1) Patient positioning 
and immobilization: Patients lied on the baseplate in the supine position with 
thermoplastic trunk mask, vacuum cushion, foaming agent, shaping cushion or a prone 
positioning board immobilization. For post-operative patients or obese patients where 
a significant amount of small bowel enters the pelvic cavity, the prone position can be 
used. (2) CT scan range: The CT scans are obtained from the upper border of L3 
vertebral body or T10 vertebral body (if extended coverage is needed) to 5 cm below 
the ischial tuberosities. If including inguinal lymph nodes, extend inferiorly to 10 cm 
below the ischial tuberosity. (3) CT scan slice thickness: 3-5 mm.  
5.2 Pelvic Radiation Therapy 
5.2.1 Technical Factors 
Radiation therapy for all enrolled patients may employ IMRT, Volumetric Modulated 
Arc Therapy (VMAT), or Tomotherapy. Target volume delineation and OAR radiation 
dose constraints shall comply with RTOG 0418[1] and the NRG Oncology/RTOG 

19 
 
Consensus Guidelines[24]. Pelvic radiation therapy commences 6-8 weeks 
postoperatively, extendable to 12 weeks under special circumstances. 
5.2.2 Clinical Target Volume (CTV)  
5.2.2.1 Coverage 
CTV should encompass the lymphatic drainage regions of the involved site and 
adjacent perinodal soft tissues. For patients without lymph node metastasis identified 
by surgery or imaging, coverage must include the internal iliac, external iliac, obturator, 
and presacral nodal regions. For patients with heightened risk of nodal metastasis (e.g., 
large primary tumors, confirmed or suspected pelvic lymph node metastasis), the 
common iliac nodal region must additionally be covered. For patients with confirmed 
common iliac and/or para-aortic nodal involvement, extended-field radiotherapy 
covering both pelvic and para-aortic regions is required, with the superior border 
reaching the level of the renal vessels (or higher, depending on involved node 
distribution). For patients with invasion of the lower one-third of the vagina, bilateral 
inguinal nodal regions must be covered. The vaginal and parametrial CTV should 
include the proximal vagina and any visible paravaginal or retracted parametrial tissue 
on CT simulation images. The Internal Target Volume (ITV), accounting for internal 
organ motion, must also be considered. 
5.2.2.2 Delineation Strategy 
The iliac vessels are usually used as anatomic markers for initial delineation. 
CTV should include the blood vessels themselves, perinodal soft tissues (requiring 
lateral expansion towards the pelvic sidewall while avoiding the psoas and piriformis 
muscles), surgical clips (if present). 
5.2.2.3 Excluded Structures 
In a CTV volume, the bone, intraperitoneal small bowel and iliopsoas muscle adjacent 
to clinically negative lymph nodes should be avoided. At the same time, the most 
anterolateral external iliac lymph nodes near the proximal inguinal canal should also be 
excluded from CTV (i.e. CTV terminates at the level of the femoral heads). 
5.2.3 Plan Target Volume (PTV)  

20 
 
PTV entails a margin that accounts for variations in treatment delivery, including 
variations in organ motion and set-up errors. It is generally suggested that the CTV 
expands 5-10 mm into the PTV (the margin applied at each treatment center should be 
based on their measured set-up errors). 
5.2.4 Dose Prescription 
All patients received conventional fractionation radiotherapy as follows: 1.8-2.0 Gy/ 
fraction, five times a week, the prescription dose is 45.0-50.4 Gy in 5-5.5 weeks. 
5.2.5 OAR Delineation and Dose Constraints 
5.2.5.1 Delineation of OAR  
Normal tissue structures should also be delineated on CT simulation images. Referring 
to guidelines [1, 22], the rectum, bladder, small bowel, and femoral heads are defined as 
OARs on pelvic radiotherapy for cervical cancer. Their specific delineation boundaries 
are as follows. All centers are advised to adhere to these specifications. 
 
AnoRectum: The rectal contour is delineated on each axial slice of the CT images. 
The inferior border is the anal verge. The superior border is defined as the level 
where the rectal shape on axial images transitions from circular and before it curves 
anteriorly to connect with the sigmoid colon. This definition includes part of the 
anal canal, but there is no distinguish between the rectum and anal canal for 
delineation purposes in current guidelines. 
 
Bladder: The bladder contour is delineated on each axial slice of the CT images. 
The superior border is the dome of bladder, and the inferior border is the fundus of 
bladder. 
 
Bowel Bag: The bowel bag contour is delineated on each axial slice of the CT 
images. It encompasses the space surrounding small bowel loops up to the 
peritoneal edge, as the bowel may move in this space throughout the course of 
treatment. The inferior border starts from the large bowel loops or the end of small 
bowel loops, or from the superior border of the AnoRectum structure. The superior 

21 
 
border extends at least 2 cm above the PTV. If the inferior border is defined based 
on bowel loops, the anorectum is also shown in the CT axial images and should be 
considered as part of the bowel bag. Otherwise, it should be excluded. 
 
Proximal Femurs: The superior border is the top of the femoral head, including 
the greater trochanter. The inferior border is the lowest point of the ischial 
tuberosity (right or left). 
 
Delineation Validation: Following the delineation of the above OARs, slice-by-
slice validation must be performed by an experienced radiation oncology medical 
physicist and a radiation oncologist. 
5.2.5.2 OAR Dose Constraints 
It is recommended that all centers adhere to the following dose constraints. The specific 
constraints are: 
 
AnoRectum: V30 < 60%, the minimum acceptable range V50 = 35%. 
 
Bladder: V45 < 35%, the minimum acceptable range V50 = 35%. 
 
Bowel Bag: V40 < 30%, the minimum acceptable range V40 = 35%. 
 
Proximal Femurs: V30 < 15%, the minimum acceptable range V30 = 20%. 
5.3 Anal Canal-Sparing Technique 
The conventionally contoured "AnoRectum" organ-at-risk (OAR) is separated into two 
independent structures: the rectum and the anal canal. During pelvic radiotherapy 
treatment planning, different dose planning objectives are applied to the rectum and the 
anal canal. The rectum receives doses according to the standard constraint requirements, 
while the anal canal is assigned the minimum achievable dose, provided that the PTV 
coverage and other OAR constraints still meet conventional radiotherapy standards. 
This study also focuses on protecting the perianal musculature, treating it as an 
independent OAR. 
5.3.1 Anatomy of Anal Canal 

22 
 
The anal canal is the digestive system’s endpoint, and it plays a crucial role in the 
maintenance of fecal continence and defecation. It is located in the anal triangle of the 
perineum, and positioned between the bilateral ischioanal fossae. Anatomically, the 
anal canal extends from the anal verge to the dentate line, averaging 2.5cm in length in 
adults. However, the dentate line is not definable on imaging examination [25]. The most 
clinically relevant concept is the surgical anal canal, which extends between the anal 
verge and the anorectal ring, averaging 4 cm in length in adults [26]. The surgical anal 
canal has four boundaries from inferior to superior: (1) Anal Verge (Anocutaneous line): 
The lowermost boundary of the gastrointestinal tract, commonly referred to as the anal 
orifice. (2) Intersphincteric Groove (White line): Located approximately 1 cm superior 
to the anal verge, between the anal verge and the dentate line. It corresponds internally 
to the junction between the internal and external anal sphincters. Palpable as a groove. 
(3) Dentate Line (Pectinate line): A serrated line marking the transition from squamous 
to columnar epithelium and is continuous with the skin, situated approximately 2.5 cm 
superior to the anal verge. This is the only circular line visible to the naked eye among 
the four boundaries. (4) Anorectal Ring (Hermann line): Located approximately 1.5 cm 
superior to the dentate line. The surgical anal canal is divided into three zones from 
inferior to superior: (1) Cutaneous zone: Between the anal verge and the white line. 
Lined by squamous epithelium. (2) Intermediate zone (Haemorrhoidal zone): Between 
the white line and the dentate line. (3) Columnar zone: Between the dentate line and the 
anorectal ring. Contains the anal columns, forming a 0.5-1.5cm annular region. 
The anal canal is surrounded by the internal and external anal sphincters, vital for 
maintaining continence: (1) Internal anal sphincter: Encircles the upper two-thirds of 
the anal canal. Composed of thickened, involuntary circular smooth muscle from the 
rectal wall. (2) External anal sphincter: A voluntary muscle encircling the lower two-
thirds of the anal canal (thus overlapping partially with the internal sphincter). It fuses 
superiorly with the puborectalis muscle of the pelvic floor. 
5.3.2 Magnetic Resonance Imaging (MRI) of Anal Canal 
All enrolled patients undergo non-contrast MRI of anal canal following screening. 
Scans are performed using a 3-T MRI scanner equipped with a standard body matrix 

23 
 
coil. The patient is positioned supine, with the positioning laser aligned to the superior 
border of the pubic symphysis. 
The scanning protocol is as follows: (1) High-resolution T2-weighted imaging 
(T2WI) using a fast spin-echo (FSE) sequence: Acquired in three orthogonal planes 
(axial, coronal, and sagittal). Images are obtained with a slice thickness of 2-3 mm. Fat 
suppression is typically not applied. Patients are instructed to maintain shallow, quiet 
breathing during the scan. (2) Oblique axial planes: Performed perpendicular to the long 
axis of the anal canal. (3) Oblique coronal planes: Performed parallel to the long axis 
of the anal canal. (4) T1-weighted imaging (T1WI) axial planes: Acquired with fat 
suppression [27]. 
5.3.3 OAR Delineation and Dose Constraints 
The MRI and positioning CT images of anal canal were accurately registered, and the 
rectum, anal canal and surrounding musculature separated and delineated 
independently according to the fusion images. 
5.3.3.1 Delineation of Anal Canal 
Delineate according to the definition of the surgical anal canal.  
 
The superior border: The anorectal ring (Hermann line), typically defined as the 
level of an imaginary line between the inferior margins of the sacrum and pubis on 
sagittal MRI, or the line crossing the superior border of the puborectalis sling on 
coronal images.  
 
The inferior border: The anal verge, defined as the transition between the anal canal 
epithelium and perianal skin. This is an important landmark on anal canal MRI. 
The region extending approximately ± 5mm caudally from the anal verge into the 
perianal skin is typically defined as the anal verge. 
5.3.3.2 Delineation of Key Perianal Musculature 
Delineate the perianal muscles with reference to anal canal MRI and the 2023 clinical 
recommendations from the Italian Association of Radiotherapy and Clinical Oncology 
(AIRO) for female pelvic OAR contouring [28]. 

24 
 
 
Anal Sphincter Complex (ASC) 
The Anal sphincter complex comprises the internal anal sphincter (IAS) and the 
external anal sphincter (EAS). 
The IAS is the innermost muscular layer of the anal canal and the distal 
continuation of the rectal smooth muscle layer. It is intermediate signal intensity and 
appears hypointense on T2WI sequence. On sagittal MR images, it is clearly visible 
from the anorectal junction to approximately 1 cm above the anal verge, concentrically 
surrounded by the EAS. In the proximal anal canal, the IAS appears doughnut-
shaped with a visible lumen and a thickness of 2-3 mm. Distally, the lumen is not visible, 
and the IAS surrounds the upper 2/3 of the anal canal. 
The EAS is the outermost muscular layer of the lower anal canal. It extends 
approximately 1 cm beyond the IAS, with a mean thickness of about 4 mm. It 
appears low signal intensity on T2WI, originates from the puborectalis muscle, and its 
deep portion fuses with or is tightly connected to the puborectalis, extending down to 
the anal orifice. It partially encircles the IAS, separated from it by the intersphincteric 
space. 
 
The Levator Ani Muscle (LAM) 
The LAM is a broad tendinomuscular sheet forming the majority of the pelvic floor, 
involved in urination, defecation, and maintaining continence. It is isointense to 
hypointense on T2WI. In the axial plane, it typically has a V-shaped configuration, 
extending superiorly from the anterior aspect of the pubis, medially towards the 
puborectalis and anorectum, and laterally towards the dorsal pubis, obturator fascia, 
and ischiorectal fossa. 
5.3.3.3 Delineation of Rectum (excluding anal canal) (Rectum-A)  
For the experimental arm utilizing the anal canal-sparing technique, the Rectum-A is 
defined as the structure resulting from subtracting the delineated anal canal volume 
from the conventionally defined AnoRectum. 
5.3.3.4 Delineation of Other OARs 
Other OARs include the bladder, bowel bag, and bilateral proximal femurs. For details, 
see sections 5.2.5.1. 

25 
 
5.3.3.5 Delineation Validation 
Following the delineation of the above OARs, slice-by-slice validation must be 
performed by an experienced diagnostic radiologist and an experienced radiation 
oncologist using the registered images of CT and MRI. 
5.3.3.6 Dose Constraints 
 
Anal Canal: V10 < 70%, V15 < 60%, Dmean < 30 Gy, the minimum acceptable 
range V10 < 100%, V20 < 80%. 
 
ASC and LAM: V15 Gy < 70%, Dmean < 30 Gy, the minimum acceptable range 
V15 Gy < 100%, V20 < 80%. 
5.4 Treatment Planning 
5.4.1 Treatment Technique 
Radiotherapy delivery may utilize IMRT with 5-9 fields, volumetric modulated arc 
therapy (VMAT) with 1-2 arcs or Tomotherapy. All treatment plans were created for 
6-10 MV photons beam. 
5.4.2 Dose Calculation 
The dose calculation algorithm must incorporate tissue heterogeneity correction, and 
the calculation grid size is ≤ 3 mm. The treatment plan must meet the following 
requirements: 
5.4.2.1 Target Volume Calculation: All plans achieved full prescription dose 
coverage to at least 95% of the PTV volume, and > 90% of the prescription dose 
coverage to at least 99% of the PTV volume. 
5.4.2.2 Hot Spots: Volume within the PTV receiving > 110% of the prescription dose 
should not be delivered to more than 1%. Volume outside the PTV receiving > 105% 
of the prescription dose should not be delivered to more than 10%. 
5.4.2.3 OARs: The maximum dose to any OAR must be < 110% of the prescription 
dose. Other OARs constraints detailed in Sections 5.2.5.2 and 5.3.3.6. A summary of 
all target volume and OAR constraints is provided in Table 1. 

26 
 
 
Table 1. The Target and OARs Dose Constraints 
Target volume 
PTV 
1. 95% of the PTV volume receives full prescription dose, and ≥ 99% of 
the PTV volume receives > 90% of the prescription dose. 
2. Volume within the PTV receiving > 110% of the prescription dose 
must be < 1%, and volume outside the PTV receiving > 105% of the 
prescription dose must be < 10%. 
OARs 
Bladder 
V45 < 35%, the minimum acceptable range V50 = 35% 
Rectum-A 
V30 < 60%, the minimum acceptable range V50 = 35% 
Bowel bag 
V40 < 30%, the minimum acceptable range V40 = 35% 
Proximal 
femurs 
V30 < 15%, the minimum acceptable range V30 = 20% 
Anal canal 
V10 < 70%, V15 < 60%, Dmean < 30 Gy, the minimum acceptable 
range V10 < 100%, V20 < 80%.  
ASC and 
LAM 
V15 < 70%, Dmean <30 Gy, the minimum acceptable range V15 < 
100%, V20 < 80% 
 
5.5 Chemotherapy Regimens Concurrent with Radiotherapy 
All patients received concurrent chemotherapy during radiotherapy. The specific 
regimen options are: 
5.5.1 Weekly Cisplatin Regimen: Cisplatin is administered once every 7 days with 
concurrent radiotherapy for 5 cycles at a dose of 30-40 mg/m². The single dose should 
not exceed 70 mg/m². 
5.5.2 Triweekly Cisplatin Regimen: Cisplatin is administered once every 3 weeks 
with concurrent radiotherapy for 2 cycles at a dose of 50-70 mg/m².  
5.5.3 Carboplatin Alternative: Switching cisplatin to carboplatin in concurrent 
chemotherapy for patient intolerant to cisplatin. 
5.6 Brachytherapy after EBRT 
5.6.1 Indications for BT after EBRT 
According to the NCCN 2025[29] guidelines and the ABS recommendations[30], 
postoperative brachytherapy is primarily used as an adjuvant to EBRT, mainly for 

27 
 
patients with positive or close surgical margins. In addition, patients with other high-
risk factors or severe and/or complex intermediate-risk factors may also receive 
brachytherapy. Furthermore, for patients with vaginal involvement or those who 
underwent less-than-radical surgery, brachytherapy can be considered as a 
supplemental treatment. Each center should determine, through multidisciplinary 
discussion, whether brachytherapy is required before randomization. 
5.6.2 Dose Calculation  
Based on the recommendations of ABS and NCCN, the target volume for conventional 
postoperative brachytherapy includes the proximal 3-5 cm of the vagina. For patients 
with positive vaginal margins, the recommended dose fractionation is 6 Gy × 3 fractions 
(prescription dose reference point at 5 mm beneath the vaginal mucosa), and for those 
with negative vaginal margins, the recommended dose fractionation is 6 Gy × 2 
fractions (prescription dose reference point at 5 mm beneath the vaginal mucosa). 
5.6.3 OAR Dose Constraints  
The dose constraints for organs at risk in brachytherapy are defined as the combined 
dose from external beam radiotherapy and brachytherapy, with the dose received by a 
2cc volume as the criterion. The limits are as follows: 
 
Rectum: 2cc ≤ 75 Gy (EQD2). 
 
Sigmoid colon: 2cc ≤ 75 Gy (EQD2). 
 
Bladder: 2cc ≤ 90 Gy (EQD2). 
 
Small intestine: 2cc ≤ 75 Gy (EQD2) 
5.7 Quality Assurance (QA) in Radiotherapy 
As this is a multicenter study, a multicenter QA team will be established to ensure 
quality control across all aspects of the clinical trial, particularly radiotherapy planning. 
Throughout the study duration, cross-center QA will be implemented for all stages, 
including screening, enrollment, radiotherapy planning, hemorrhoids diagnosis, and 
symptom assessment. In particular, the image-based components such as MRI of anal 
canal, OAR delineation using the anal canal-sparing technique, treatment planning and 

28 
 
dose calculation will be discussed by online video conference for QA. A standardized 
assessment review form (see Appendix 1) of anal canal-sparing strategy during 
postoperative pelvic radiotherapy for cervical cancer patients will be developed and 
provided to all participating centers for use. 
 
6 OUTCOME AND INDICATOR EVALUATION 
6.1 Evaluation of Primary Observation Indicators 
The leading endpoint of this study was the incidence of hemorrhoids-related symptoms 
from the beginning of pelvic radiotherapy to 4 weeks after the end of radiotherapy. 
Researchers evaluated the main observation indicators referring to the "RTOG/EORTC 
Acute Radiation Injury Grading Standards" and the "Pelvic Radiotherapy Hemorrhoids-
Related Symptom Assessment Form (Shanghai General Hospital Version)" weekly. 
Any hemorrhoids-related symptoms that occur during the study observation period 
compared to baseline are considered as an event. 
The main observation indicator of this study is the incidence of hemorrhoids-
related symptoms and signs in pelvic radiotherapy, using the method of researcher 
evaluation. Since symptoms and physical symptoms related to hemorrhoids often occur 
in the middle and late stages of radiotherapy, which is an acute adverse reaction of 
radiotherapy, we will observe and evaluate them weekly from the beginning of 
radiotherapy until 4 weeks after the end of radiotherapy. The symptoms and signs 
related to hemorrhoids mainly include perianal pain, hemorrhoids prolapse, rectal 
bleeding, perianal skin damage, anal mucosal damage or ulcer, size and shape of 
hemorrhoids, etc. At present, the evaluation and grading of acute radiation injuries in 
radiotherapy mainly refer to the RTOG/EORTC Acute Radiation Injury Grading 
Standards, and researchers will also refer to the skin and lower gastrointestinal/pelvic 
parts of this standard for radiation injury grading. The size and morphology of perianal 
skin, anal mucosa, and hemorrhoids were comprehensively evaluated and recorded 
using visual examination, digital rectal examination, and anoscopy. 
However, the RTOG standard does not classify symptoms and signs related to 
hemorrhoids item by item. Meanwhile, limitations still exist in Goliger's hemorrhoids 
grading. Firstly, only internal hemorrhoids were described, while the clinical 

29 
 
manifestations of external hemorrhoids and mixed hemorrhoids are not included in the 
evaluation system. Secondly, this grading is mainly based on the degree of hemorrhoids 
prolapse, and there is insufficient evaluation of other hemorrhoids-related symptoms. 
To provide a more comprehensive and objective evaluation of hemorrhoids-related 
symptoms in radiotherapy patients, and to better quantify and compare them, this study 
will refer to the radiation injury assessment method of RTOG 1203 [31], which refers to 
the Expanded Prostate Cancer Index Composite (EPIC) Questionnaire for Intestinal 
and Adverse Events. Based on the main observed symptoms and signs in this study, a 
Pelvic Radiation Therapy Hemorrhoids-Related Symptoms Assessment Scale 
(Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine 
Version) (see Appendix 2) will be developed for researchers to evaluate. 
The above assessment includes hemorrhoids-related symptom evaluation before 
treatment, 3 to 5 radiotherapy sessions (1st week), 8 to 10 radiotherapy sessions (2nd 
week), 13 to 15 radiotherapy sessions (3rd week), 18 to 20 radiotherapy sessions (4th 
week), 23 to 25 radiotherapy sessions (5th week), 26 to 28 radiotherapy sessions (5.5 
week), the first week of BT, the second week of BT and once a week from the first 
week to the fourth week after completion of radiotherapy. 
6.2 Evaluation of Secondary Observational Indicators 
The secondary observation includes the evaluation of symptoms related to perianal 
muscle radiation injury, score of life quality, and prescription rate of hemorrhoids.  
The symptoms related to perianal muscle radiation injury mainly include changes 
in bowel habits such as impaired bowel control and increased frequency of bowel 
movements. For symptoms related to perianal muscle radiation injury, participants will 
refer to the Low Anterior Resection Syndrome (LARS) Scoring Questionnaire and 
conduct self-assessment. Symptom assessment related to perianal muscle radiation 
injury should be conducted before treatment, 3 to 5 radiotherapy sessions (1st week), 8 
to 10 radiotherapy sessions (2nd week), 13 to 15 radiotherapy sessions (3rd week), 18 
to 20 radiotherapy sessions (4th week), 23 to 25 radiotherapy sessions (5th week), 26 
to 28 radiotherapy sessions (5.5 week), the first week of BT, the second week of BT 
and once a week from the first week to the fourth week after completion of radiotherapy. 

30 
 
The QoL will be scored based on the EORTC Core QoL Questionnaire (QLQ-C30) 
Version 3.0 and the Cervical Cancer Module (QLQ-CX24), which will be self-
evaluated by participants. Assess QoL before treatment, 3 to 5 radiotherapy sessions 
(1st week), 8 to 10 radiotherapy sessions (2nd week), 13 to 15 radiotherapy sessions 
(3rd week), 18 to 20 radiotherapy sessions (4th week), 23 to 25 radiotherapy sessions 
(5th week), 26 to 28 radiotherapy sessions (5.5 week), the first week of BT and the 
second week of BT, as well as in the second and fourth weeks after completion of 
radiotherapy. 
The types of hemorrhoids drugs used are detailed in 8.1.1. From the beginning of 
radiotherapy to 4 weeks after the end of radiotherapy, any hemorrhoids drug prescribed 
by the researcher is classified as a hemorrhoid drug user. During the research process, 
researchers need to keep detailed records of the names, usage methods, and duration of 
prescription drugs. 
6.3 Evaluation of Exploratory Observation Metrics 
Exploratory observation metrics include the delineation method and projection dose of 
organs at risk using anal canal protection techniques, as described in section 5.3 of the 
anal canal protection plan. 
 
7. INTERRUPTION OF RADIOTHERAPY AND MANAGEMENT OF 
UNTOWARD REACTION 
7.1 Interruption of radiotherapy 
Uncontrollable diarrhea or other acute complications may require interruption of 
radiotherapy, and the reason and duration of such interruption must be recorded. If the 
total number of days of treatment interruption exceeds 5 days, it is considered a 
violation of the radiation therapy plan. During the research period, interruptions in 
radiation therapy should be avoid as far as possible. 
Once the radiotherapy is interrupted, synchronous chemotherapy will also be 
suspended. Chemotherapy suspended due to adverse events does not need to be 
supplemented after the end of radiation therapy, and chemotherapy will be stopped 
synchronously after the completion of radiation therapy. 

31 
 
If synchronous chemotherapy needs to be suspended due to chemotherapy related 
adverse events, radiotherapy will continue. 
7.2 Treatment related adverse events (AE) 
During the research period, the occurrence and severity of acute radiation toxicity 
should be evaluated weekly from the beginning of pelvic radiotherapy until 4 weeks 
after the end of radiotherapy. The acute adverse reactions of concurrent pelvic 
radiotherapy and chemotherapy for cervical cancer may include fatigue, decreased 
appetite, nausea, vomiting, diarrhea, constipation, rectal irritation symptoms, frequent 
urination and difficulty urinating, as well as decreased blood cell count and abnormal 
liver and kidney function indicators. 
All adverse reactions will be evaluated and graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The treatment of 
common adverse events is shown in Table 2. 
 
Table 2. The treatment of common adverse events 
Symptoms related to hemorrhoids 
(bleeding/pain): CTC grade 
Treatment 
Level 1-2 
Strengthen local hygiene and take sitz 
baths, etc. 
Level 3 or 4 
Provide symptomatic and medical 
treatment. If unrelieved, withhold 
radiotherapy and proceed with hemorrhoids 
therapy. 
Diarrhea: CTC grade 
Treatment 
Level 1-2 
Dietary modification with emphasis on 
low-fiber intake. 
Level 3 or 4 
Manage symptomatically; if unrelieved, 
withhold radiotherapy. 
Nausea and vomiting：CTC grade 
Treatment 

32 
 
Level 1-2 
Reduce the infusion rate of chemotherapy 
drugs 
Level 3 or 4 
Manage symptomatically; if unrelieved, 
withhold concurrent chemotherapy. 
Myelosuppression：CTC grade 
Treatment 
Level 1-2 
Monitor closely and adjust chemotherapy 
dosage as needed. 
Level 3 or 4 
Prompt intervention indicated, with 
emergent response to infection or bleeding. 
Symptoms related to the urinary 
tract：CTC grade 
Treatment 
Level 1-2 
Maintain adequate hydration 
Level 3 or 4 
Manage symptomatically; initiate 
antimicrobial therapy based on 
susceptibility testing if necessary. 
 
All Grade 4/5 adverse events occurring from radiotherapy initiation to 4 weeks 
post-treatment must be reported within 5 days. Serious adverse events (SAE) needs to 
be reported to the Ethics Committee notification, typically within 24 hours of 
notification. All events must be recorded in the case report form (CRF). 
 
8. CONCOMITANT MEDICATIONS 
Concomitant medications in this study shall be documented continuously from the 
initiation of the first radiotherapy session until 4 weeks after the final radiotherapy. The 
names, usage and dosage, start and end times, and reasons for combined medication 
and treatment should be recorded. 
8.1 Permitted Medications and Therapies 

33 
 
8.1.1 Investigators may prescribe medications for hemorrhoids-related symptoms based 
on clinical evaluation, but patients are strictly prohibited from self-administering any 
hemorrhoidal treatments or other drugs that may aggravate or alleviate intestinal 
reactions. Approved symptomatic medications primarily include laxatives, venoactive 
drugs, topical agents, analgesics, and traditional Chinese medicines. 
8.1.2 Therapeutic use of recombinant human granulocyte colony-stimulating factor (G-
CSF), thrombopoietin-stimulating agents, platelet transfusion, and other interventions 
for myelosuppression may be administered by investigators based on clinical 
assessment. 
8.1.3 Appropriate symptomatic medications may be administered for adverse events 
caused by radiotherapy and/or chemotherapy drugs. 
8.1.4 Symptomatic treatment drugs may be provided when patients develop clinical 
symptoms due to non-neoplastic diseases. 
8.1.5 For subjects with comorbid conditions, relevant medications may be continued as 
needed or adjusted at any time during the study period. 
8.2 Prohibited Medications and Therapies 
8.2.1 Subjects are not permitted to concurrently participate in other clinical studies. 
8.2.2 Subjects must not receive any other anti-tumor medications (including but not 
limited to chemotherapy, immunotherapy, targeted therapy, or anti-angiogenic drugs) 
outside those specified in the study protocol. 
 
9. TREATMENT COMPLIANCE 
The treatments specified in this study shall be administered under investigator 
supervision in either inpatient or outpatient settings to monitor compliance. The timing 
and dosage of radiotherapy, as well as the dates, times, and exact doses of each 
chemotherapy infusion, must be recorded in the electronic Case Report Form (eCRF). 
Poor compliance is defined as the subject's failure to adhere to the protocol-
mandated assessments for hemorrhoids-related symptoms (including required 
examinations and/or questionnaire completion) for non-medical reasons. In such cases, 

34 
 
the investigator shall determine whether to discontinue the subject's treatment based on 
individual circumstances. 
 
10. TISSUE/SPECIMEN SUBMISSION 
NA. 
 
11. APPENDIX 
Data collection procedures are cataloged in Appendices 1-5 (complete content mapping 
available in Table 3). 
 
Table 3. Summary of Supplementary Appendices 
Appendix 
Numbering 
Appendix Titles 
Appendix 1 
Structured Audit Framework for Anal Canal-Sparing 
Protocol in Postoperative Pelvic Radiation Therapy of 
Cervical Cancer 
Appendix 2 
Shanghai General Hospital Hemorrhoids-Specific Symptom 
Scale for Pelvic Radiation Therapy 
 
 
 
 
 
 
 
 
 
 

35 
 
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37 
 
Appendix 1  
Structured Audit Framework for Anal Canal-Sparing Protocol in Postoperative Pelvic 
Radiotherapy of Cervical Cancer 
Patient Name 
  
ID 
  
Auditor 
  
Prescription 
  
Technique 
 
Date 
  
Contouring Validation 
Structure 
Approved 
Structure 
Approved 
Structure 
Approved 
Anal Canal 
  
Anal 
Sphincter 
  
Rectum 
  
Dosimetric Compliance Assessment 
Structure 
V10 
V15 
V20 
Dmean 
Approved 
Anal Canal 
  
  
  
  
  
Anal 
Sphincter 
 
 
  
  
  
Levator Ani 
 
 
  
  
  
Rectum 
V30 
V50 
  
Approved 
  
  
  
Bladder 
V45 
V50 
Approved 
  
  
  
Bowel Bag 
V40
（%） 
V45（cc） 
Approved 
  
  
  
Femoral 
Heads 
V30 
  
Approved 
  
  
  
Protocol Dose Constraints for Trial Eligibility：                 
Target Coverage： 
95% of PTV volume must receive the prescription dose 
99% of PTV volume must receive >90% of prescription dose       
Organ-at-Risk Constraints： 
Is the patient 
eligible for 
the 
experimental 
arm? 

38 
 
Rectum: 
Ideal: V30 <60%; 
Minimum acceptable: V50 =35%; 
Bladder: 
Ideal: V45 <35%; 
Minimum acceptable: V50 =35%; 
Bowel Bag: 
Ideal: V40 <30%; 
Minimum acceptable: V40 =35%; 
Femoral Heads: 
Ideal: V30 <15%; 
Minimum acceptable: V30 =20%; 
Anal Canal: 
Ideal: V10 <70%, V15 <60%, mean dose <30 Gy; 
Minimum acceptable: V10 <100%, V20 <80% 
Perianal Muscles: 
Ideal: V15 <70%, mean dose <30 Gy; 
Minimum acceptable: V15 <100%, V20 <80%. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

39 
 
Appendix 2  
Shanghai General Hospital Hemorrhoids-Specific Symptom Scale for Pelvic 
Radiation Therapy 
 
1. Blood in Stool 
a. Over the past 7 days, how frequently did you notice blood in your stool? 
Ο Never 
Ο Rarely (1-2 
days) 
Ο Occasionally 
(3-4 days) 
Ο Frequently 
(5-6 days) 
Ο Almost 
persistently 
(daily) 
b. Over the past 7 days, what was the most severe form of bleeding you experienced? 
Ο No bleeding 
Ο Minor blood on 
toilet paper 
Ο Blood dripping 
after defecation 
Ο Projective 
bleeding 
during/after 
defecation 
 
2.Hemorrhoids Prolapse 
a. Over the past 7 days, how frequently did you experience hemorrhoids prolapse 
during bowel movements? 
Ο Never 
Ο Rarely (1-2 
days) 
Ο Occasionally 
(3-4 days) 
Ο Frequently 
(5-6 days) 
Ο Almost 
persistently 
(daily) 
b. Over the past 7 days, how did the prolapsed hemorrhoids reduce? 
Ο Spontaneously reduced 
Ο Required manual 
reduction 
Ο Persistently prolapsed or 
immediately re-prolapsed 
after reduction 
Clinical Examination Documentation (Based on visual inspection/external exam and 
anoscopy) 
a. Hemorrhoids Type: Ο Internal Hemorrhoids       Ο External Hemorrhoids     
Ο Mixed Hemorrhoids 
b. Hemorrhoids Size:  
c. Additional Findings: 
 
 
3. Perianal Skin Breakdown 
a. Over the past 7 days, severity of perianal skin breakdown: 
Ο None 
Ο Follicular 
dark erythema 
Ο Focal moist 
desquamation 
Ο Confluent 
moist 
desquamation 
Ο Ulceration 
 

40 
 
4. Anal Mucosal Erosion/Ulceration 
a. Over the past 7 days, severity of anal mucosal changes: 
Ο None 
Ο Mucosal 
edema 
Ο Mucosal 
hyperemia 
Ο Punctate 
ulceration 
Ο Patchy 
ulceration 
 
5. Perianal Pain 
a. Over the past 7 days, worst perianal pain intensity: 
Visual Analogue Scale (VAS) 
Ο 0-2 (Mild) Ο 3-5 (Moderate) Ο 6-8 (Severe) 
Ο >8 (Excruciating)