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Original Article
Colorectal cancer
 Preventive efficacy of hydrocortisone enema for radiation proctitis in rectal cancer patients undergoing short-course radiotherapy: a phase II randomized placebo-controlled clinical trial
Mohammad Mohammadianpanah1,2orcid, Maryam Tazang3orcid, Nam Phong Nguyen4orcid, Niloofar Ahmadloo2orcid, Shapour Omidvari5orcid, Ahmad Mosalaei2orcid, Mansour Ansari2orcid, Hamid Nasrollahi2orcid, Behnam Kadkhodaei2orcid, Nezhat Khanjani2orcid, Seyed Vahid Hosseini1,6orcid
Annals of Coloproctology 2024;40(5):506-514.
DOI: https://doi.org/10.3393/ac.2024.00192.0027
Published online: October 22, 2024

1Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2Department of Radiation Oncology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

4Department of Radiation Oncology, Howard University, Washington, DC, USA

5Breast Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

6Department of Colorectal Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Correspondence to: Maryam Tazang, MD Department of Radiation Oncology, Shiraz University of Medical Sciences School of Medicine, Shiraz 71936, Iran Email: maryamtazang31@gmail.com
• Received: March 14, 2024   • Revised: May 22, 2024   • Accepted: June 19, 2024

© 2024 The Korean Society of Coloproctology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Purpose
    This study aimed to investigate the efficacy of hydrocortisone enema in preventing radiation proctitis in patients with rectal cancer undergoing short-course radiotherapy (SCRT).
  • Methods
    This phase II randomized controlled trial enrolled patients with newly diagnosed locally advanced rectal cancer (clinically staged T3–4 and/or N1–2M0). Participants received a median of 4 cycles of neoadjuvant chemotherapy (capecitabine plus oxaliplatin) followed by 3-dimensional conformal SCRT (25 Gy in 5 fractions). Patients were randomly assigned to receive either a hydrocortisone enema (n=50) or a placebo (n=51) once daily for 5 consecutive days during SCRT. The primary endpoint was the incidence and severity of acute proctitis.
  • Results
    Of the 111 eligible patients, 101 were included in the study. Baseline characteristics, including sex, age, performance status, and tumor location, were comparable across the treatment arms. None of the patients experienced grade 4 acute gastrointestinal toxicity or had to discontinue treatment due to treatment-related adverse effects. Patients in the hydrocortisone arm experienced significantly less severe proctitis (P<0.001), diarrhea (P=0.023), and rectal pain (P<0.001) than those in the placebo arm. Additionally, the duration of acute gastrointestinal toxicity following SCRT was significantly shorter in patients receiving hydrocortisone (P<0.001).
  • Conclusion
    Hydrocortisone enema was associated with a significant reduction in the severity of proctitis, diarrhea, and rectal pain compared to placebo. Additionally, patients treated with hydrocortisone experienced shorter durations of gastrointestinal toxicity following SCRT. This study highlights the potential benefits of hydrocortisone enema in managing radiation-induced toxicity in rectal cancer patients undergoing radiotherapy.
  • Keywords: Rectal neoplasms; Neoadjuvant therapy; Proctitis; Hydrocortisone; Enemas
Rectal cancer ranks among the most prevalent gastrointestinal (GI) cancers worldwide [1]. The current standard treatment for locally advanced rectal cancer includes neoadjuvant therapies such as short-course radiotherapy (SCRT) or concurrent long-course chemoradiation combined with chemotherapy, often administered as part of a total neoadjuvant therapy regimen [2, 3]. Although neoadjuvant pelvic radiotherapy has its benefits, the irradiation of critical organs can present significant challenges during treatment [4–6]. Acute radiation proctitis is a common side effect experienced to a varying degree by nearly half of patients undergoing pelvic radiation, particularly with conventional radiation techniques [7–10].
The onset of radiation proctitis can significantly impact patients' quality of life and may even lead to treatment discontinuation in severe cases [11]. Hence, preventing radiation proctitis, rather than addressing it post-occurrence, could improve patients’ quality of life and prove to be cost-effective. Numerous retrospective and prospective studies have explored this issue [12–15].
Proctitis is a significant type of radiation-induced toxicity among patients with pelvic organ cancers, including prostate, bladder, and cervical cancers. These patients are often treated with moderate to high-dose external beam radiotherapy [16–18]. There are few clinical trials that investigate the effectiveness of various treatment options for radiation proctitis in cancer patients. Most research has concentrated on preventive strategies for proctitis in prostate cancer patients, rather than those with primary rectal cancer [19]. Some studies have demonstrated encouraging outcomes with the use of medications such as sucralfate or mesalazine, which have been shown to reduce symptoms and improve quality of life [15]. Other trials have assessed the effectiveness of hyperbaric oxygen therapy and endoscopic techniques, such as argon plasma coagulation or formalin application, in the management of radiation proctitis [18].
Therefore, there is a paucity of data in the literature regarding radiation proctitis in rectal cancer patients. In a preliminary randomized, placebo-controlled clinical trial, Sahebnasagh et al. [20] explored the effectiveness of aloe vera in preventing acute radiation proctitis in patients with colorectal cancer receiving radiation therapy. Their findings indicated that rectal 3% aloe vera significantly improved symptoms of proctitis (diarrhea) compared to the placebo (P=0.028). Additionally, they observed that rectal 3% aloe vera could improve quality of life (P=0.004) and psychosocial status (P=0.008). Accordingly, our study aimed to investigate the preventive efficacy of hydrocortisone enema in alleviating radiation proctitis in patients with rectal cancer undergoing SCRT.
Ethics statement
The study protocol was approved by the Research Ethics Committee of Shiraz University of Medical Sciences (No. IR.SUMS.MED.REC.1400.369). Written informed consent was obtained from all patients or their legal guardians. The trial was registered in the Iranian Registry of Clinical Trials (IRCT.ir identifier: IRCT20230122057175N1). The trial was conducted in accordance with the CONSORT (Consolidated Standards of Reporting Trials) statement [21].
Study design and participants
In this single-center, phase II, randomized, triple-blind, placebo-controlled trial, patients with newly diagnosed locally advanced rectal cancer undergoing SCRT were randomly assigned to receive either a hydrocortisone enema or a placebo once daily for 5 consecutive days during their SCRT regimen.
Eligible patients were aged ≥18 years and had newly pathologically confirmed locally advanced rectal cancer, clinically staged as T3–4 and/or N1–2M0. They also required an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1. Exclusion criteria included lack of consent, severe comorbidities such as chronic liver disease, heart failure, and chronic kidney diseases, a history of another malignancy, previous pelvic radiation therapy, metastasis at presentation, synchronous colorectal cancer, colon obstruction or perforation, and concurrent participation in another trial.
Initial evaluation
Before treatment initiation, patients underwent a comprehensive initial assessment. This included taking medical histories, performing clinical examinations, conducting biochemical laboratory tests, and obtaining spiral computed tomography scans of the chest, abdomen, and pelvis, as well as pelvic magnetic resonance imaging for clinical staging.
Neoadjuvant treatments
Following clinical staging, all patients underwent a median of 4 cycles (range, 2–6 cycles) of neoadjuvant chemotherapy using the XELOX regimen, which consists of capecitabine (Xeloda, Cheplapharm Arzneimittel GmbH) and oxaliplatin. The regimen included an intravenous dose of oxaliplatin at 130 mg/m2 on day 1, followed by oral capecitabine at 1,000 mg/m2 orally twice daily from days 1 to 14 [22]. Before each chemotherapy cycle, a comprehensive assessment was conducted, which included taking the patient's history, performing a clinical examination, and conducting biochemical laboratory tests. Only those with satisfactory results and no significant chemotherapy-related complications, especially hematologic and GI issues, were permitted to continue with the chemotherapy. Three weeks after completing the final cycle of neoadjuvant chemotherapy, patients who did not experience significant chemotherapy-induced GI issues were randomly assigned to receive either a hydrocortisone or placebo enema. Following this, all patients received neoadjuvant SCRT, administered at a total dose of 25 Gy in 5 fractions over 5 consecutive days, without concurrent chemotherapy. The radiotherapy was delivered using an ONCOR Expression high-energy linear accelerator (Siemens) and employed a 3-dimensional conformal radiotherapy (3DCRT) technique. The delineation of target volumes and organs at risk was guided by the radiation therapy oncology group anorectal contouring atlas [23]. The gross tumor volume included the primary tumor and all visible regional lymph nodes. The clinical target volume (CTV) encompassed the gross tumor volume, a 15- to 20-mm circumferential margin, and the entire rectum, mesorectum, and presacral soft tissue space. Internal iliac nodes were routinely included in the CTV for all cases, whereas external iliac nodes were included only in cases with T4 lesions [24]. A planning target volume was created by adding a 7-mm margin to the CTV.
Randomization and allocation concealment
The study consecutively enrolled patients and randomly assigned them at a 1:1 ratio to receive either a daily 100-mg hydrocortisone enema or a placebo. Each patient was provided with a set of 5 enemas and instructed to use 1 daily for 5 consecutive days during the radiotherapy period, with no additional enemas permitted. Randomization was conducted in blocks of 4. To maintain the integrity of the blinding, both hydrocortisone and placebo enemas were dispensed in identical containers, labeled A and B, to all participants, clinicians, data collectors, outcome adjudicators, and data analysts (Fig. 1).
Trial procedure
Before each radiotherapy session, patients were administered a daily enema containing either hydrocortisone (100 mg) or placebo (normal saline) for 5 consecutive days. Both the hydrocortisone and placebo enemas were supplied in 60-mL containers, each equipped with a lubricated rectal applicator tip. The patients were advised not to dilute the enema solution with any other liquids. The containers were identical in terms of shape, color, and volume, distinguished only by labels marked A or B. Patients were instructed to administer the enema before bedtime and after bowel evacuation, adopting either a left-side lying or knee-chest position. Weekly examinations and assessments were conducted throughout the SCRT and continued for up to 5 weeks after the completion of radiotherapy treatment.
Primary and secondary outcomes
The primary endpoint of the study was the frequency and severity of radiation proctitis, while the secondary endpoint focused on the duration of GI toxicity. Adverse event classification and severity grading adhered to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0 [25]. We categorized proctitis based on severity levels: grade 1 for asymptomatic patients, grade 2 for patients experiencing abdominal pain accompanied by mucus or blood in their stool, grade 3 for patients with severe abdominal pain and peritoneal signs, and grade 4 for patients facing life-threatening consequences that required immediate intervention.
Outcome measurement
Patients were assessed weekly for the rate and severity of proctitis during and up to 5 weeks after completing SCRT. Each assessment included a physical examination and an evaluation of the patients' complaints, which covered abdominal pain, diarrhea, cramps, tenesmus, urgency, and the presence of mucus and blood in the stool. Consequently, the severity of proctitis was graded according to CTCAE ver. 5.0. Patients were also monitored for any treatment-related toxicity and received appropriate management as needed. In this study, the highest prevalence of grade 3 for each GI toxicity was considered the peak of GI toxicity. The trial design and study timeline are depicted in Fig. 2.
Statistical analysis
The sample size calculation was based on the cumulative incidence of grade 2 or higher proctitis at the conclusion of radiotherapy. Referencing the study by Sanguineti et al. [15], which reported cumulative incidences proctitis at 87.5% with preventive treatment using mesalazine enema and 52.4% with hydrocortisone, the sample size was estimated using a formula designed to compare 2 proportions, with α set at 0.05 and a power of 90%. The study aimed to enroll at least 50 patients in each arm, factoring in a 10% dropout rate to increase statistical power. Data analysis was conducted using SPSS ver. 16 (SPSS Inc), and comparisons were made at a significance level of P<0.05, employing the chi-square test and t-test.
Out of the 111 patients initially assessed for rectal cancer, 101 eligible individuals were enrolled and randomly assigned to either the hydrocortisone group (n=50) or the placebo group (n=51) to receive a hydrocortisone enema or a placebo (Fig. 1). Both groups showed similar distributions regarding sex, age, body mass index, ECOG performance score, clinical stage, comorbidities, and tumor location (Table 1).
All patients in both treatment arms experienced some degree of GI toxicity. There were no instances of grade 4 toxicity or treatment discontinuation due to adverse effects. The severity of proctitis (P<0.001), diarrhea (P=0.023), tenesmus (P<0.001), and rectal pain (P<0.001) was significantly lower in the hydrocortisone arm compared to the placebo arm. Additionally, there was no significant difference in hematologic toxicity between the hydrocortisone and placebo arms. Table 2 compares the frequency and severity of GI and hematologic toxicities between the 2 arms. Patients receiving hydrocortisone had significantly shorter durations of acute GI toxicity after SCRT (2.1±0.76 weeks vs. 2.8±0.52 weeks, P<0.001). The peak of grade 3 GI toxicity occurred primarily in the first and second weeks of SCRT. As illustrated in Fig. 3, the use of hydrocortisone enema delayed the peak prevalence of GI toxicity in the hydrocortisone arm by 1 week. Moreover, as shown in Fig. 4, the mean duration of grade 3 GI toxic­ity was significantly shorter in the hydrocortisone arm compared to the placebo arm (1.4±0.74 weeks vs. 2.9±1.35 weeks, P<0.001).
We found no significant associations between proctitis severity and patients' age, sex, ECOG performance score, comorbidities, or tumor location; however, there was a significant correlation between the planning target volume and proctitis (P=0.038), as well as a notable trend for a relationship between CTV and proctitis severity (P=0.089) (Table 3). Ultimately, multivariable logistic regression analysis identified hydrocortisone as the only independent variable affecting the severity of proctitis (Table 4).
In this randomized clinical trial, patients with rectal cancer were administered either a hydrocortisone enema or a placebo during neoadjuvant SCRT with 3DCRT. The findings indicate that the hydrocortisone enema not only effectively alleviated the severity of proctitis, diarrhea, and rectal pain but also reduced the duration of these symptoms following the completion of treatment.
To manage radiation-induced proctitis, a range of topical and systemic medications have been proposed, including corticosteroids, 5-aminosalicylic acid derivatives, formaldehyde, sucralfate, short-chain fatty acids, and antibiotics. However, there is currently no definitive recommendation that yields satisfactory outcomes [26, 27].
Various mechanisms of action have been proposed to explain the potential effects of steroids (prednisone, betamethasone, hydrocortisone) on radiation proctitis. These mechanisms range from stabilizing lysosomes in neutrophils to upregulating anti-inflammatory genes through glucocorticoid receptor binding [28]. Kochhar et al. [29] demonstrated that a rectal prednisolone enema, either alone or combined with sulfasalazine, can alleviate symptoms of radiation-induced proctosigmoiditis, with the combination treatments showing greater effectiveness.
In another study by Cavcić et al. [30], the use of betamethasone enemas combined with oral metronidazole and mesalazine significantly reduced rectal bleeding, diarrhea, and ulcers. Sanguineti et al. [15] demonstrated in a clinical trial that while topical mesalazine should not be administered during radiotherapy, hydrocortisone enemas, and topical sucralfate are equally effective in reducing acute rectal toxicity. Prescribing steroid enemas can alleviate symptoms in patients with proctitis across various clinical scenarios, not just radiation proctitis. Steroid enemas have been recognized as one of the most effective treatments for managing ulcerative proctitis [31].
In addition to treating radiation proctitis, oral corticosteroids have been suggested for managing radiation-induced oral mucositis and radiation dermatitis [32, 33]. The commonly used "magic mouthwash," a mouth rinse containing corticosteroids, antihistamines, and antacids, is a staple in routine clinical practice [34]. A randomized clinical trial conducted by Agha-Hosseini et al. [35] demonstrated that triamcinolone acetonide, when used with vitamin E and hyaluronic acid, can reduce the severity of radiation-induced oral mucositis in patients with head and neck cancers.
On the contrary, systemic prednisone has been reported not to decrease the intensity or duration of mucositis; however, it may reduce treatment interruptions [36]. After radiation exposure, normal bowel tissue undergoes a series of complex processes that involve both direct mechanisms, such as macromolecule breakage, and indirect mechanisms, including the generation of reactive free radicals and interference with mitochondrial functions, ultimately leading to a redox imbalance [37].
Furthermore, the recruitment of various immune system components contributes to perpetuating the imbalance and continues to induce damage [38]. This leads to the destruction of DNA, proteins, and lipids, resulting in necrosis and ischemia [37]. Given the anti-inflammatory properties of topical steroids, it is reasonable to infer that their localized effect can alleviate inflammation in the distal colon and rectum with minimal systemic exposure in patients with radiation proctitis [39].
This study investigated the acute effects of hydrocortisone enema, which restricts the ability to generalize the findings to chronic radiotherapy-induced proctitis. Additional evaluations involving colonoscopic images and pathological confirmations could yield further insights. The findings are particularly relevant for developing countries where advanced radiotherapy techniques, such as intensity-modulated radiotherapy, may not be available.
Steroid enemas used in conjunction with SCRT for locally advanced rectal cancer may be both cost-effective and enhance patient compliance. As the use of stereotactic body radiation therapy for prostate cancer becomes more widespread in Western countries, the application of steroid enemas could reduce the incidence of grade 1–2 proctitis and enhance patient quality of life [17, 40, 41]. The occurrence of grade 2 acute GI toxicity varies between 23% and 29% and may sometimes necessitate the injection of a space tracer to increase the separation between the prostate and rectum, thereby minimizing toxicity [40].
One limitation of the current study is that it was conducted at a single center. Additional constraints include the subjective nature of the primary outcomes and the lack of objective tools such as sigmoidoscopic assessment. Furthermore, the absence of extended follow-up and the potential impact of hydrocortisone enema on long-term outcomes, such as chronic proctitis, also limit this research. Due to these limitations, the generalizability of the findings may be restricted. Future research should aim to replicate these results in larger, more diverse populations and incorporate objective measures to strengthen the validity of the conclusions.
In conclusion, the study demonstrated that prescribing hydrocortisone enema concurrently with preoperative SCRT using 3DCRT in rectal cancer patients was associated with a reduction in the severity of irritative toxicities, including proctitis, diarrhea, rectal pain, and tenesmus. Importantly, no cases of grade 4 toxicity or treatment discontinuation were observed, and patients who received the hydrocortisone enema experienced shorter durations of irritative toxicity. These findings suggest that the use of hydrocortisone enema alongside radiotherapy may beneficially impact the incidence and severity of GI toxicity in rectal cancer patients. The preventive effect of hydrocortisone enema on GI toxicity may be partially attributed to the systemic absorption of the enema, which helps prevent enteritis. Further research and clinical trials are warranted to confirm these results and to investigate the potential benefits of this treatment approach in a broader patient population.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Funding

The clinical trial was supported by Shiraz University of Medical Sciences (Shiraz, Iran).

Author contributions

Conceptualization: MM, MT, NPN, SVH; Data curation: MM, MT; Formal analysis: MM; Funding acquisition: MM; Investigation: MM, MT, NA, SO, AM, MA, HN, BK, NK, SVH; Methodology: MM, MT, NPN, SVH; Project administration: MM, MT; Supervision: MM, MT; Validation: MM, MT; Visualization: all authors; Writing–original draft: all authors; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Additional information

This manuscript was partially written as part of Maryam Tazang’s thesis for the fulfillment of a Doctor of Medicine (MD) degree at Shiraz University of Medical Sciences (Shiraz, Iran).

Fig. 1.
CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the study. SCRT, short-course radiotherapy.
ac-2024-00192-0027f1.jpg
Fig. 2.
The trial design and study timeline. NACT, neoadjuvant chemotherapy; SCRT, short-course radiotherapy.
ac-2024-00192-0027f2.jpg
Fig. 3.
The peak of grade 3 gastrointestinal (GI) toxicity between the hydrocortisone and placebo arms. SCRT, short-course radiotherapy.
ac-2024-00192-0027f3.jpg
Fig. 4.
Duration of radiation proctitis in the enrolled patients.
ac-2024-00192-0027f4.jpg
Table 1.
Distribution of baseline clinical characteristics among the patients (n=101)
Characteristic Treatment
 P-value
Hydrocortisone (n=50) Placebo (n=51)
Age (yr) 54.38±8.35 54.12±9.90 0.886
Sex 0.654
 Male 38 (76.0) 36 (70.6)
 Female 12 (24.0) 15 (29.4)
Body mass index (kg/m2) 26.04±3.57 26.26±2.63 0.719
Tumor location 0.560
 Upper 30 (60.0) 29 (56.9)
 Middle 14 (28.0) 12 (23.5)
 Lower 6 (12.0) 10 (19.6)
Clinical T category 0.702
 T2 12 (24.0) 10 (19.6)
 T3 33 (66.0) 34 (66.7)
 T4 5 (10.0) 7 (13.7)
Clinical N category 0.824
 N0 7 (14.0) 4 (7.8)
 N1 26 (52.0) 27 (53.0)
 N2 17 (34.0) 20 (39.2)
ECOG performance score 0.828
 0 35 (70.0) 37 (72.5)
 1 15 (30.0) 14 (27.5)
Target volume (mL)
 Clinical target volume 693±140 702±160 0.768
 Planning target volume 1,265±176 1,238±173 0.445
Underlying comorbidity 0.961
 None 12 (24.0) 11 (21.6)
 Diabetes mellitus 20 (40.0) 19 (37.2)
 Hypertension 11 (22.0) 13 (25.5)
 Other 7 (14.0) 8 (15.7)

Values are presented as mean±standard deviation or number (%).

ECOG, Eastern Cooperative Oncology Group.

Table 2.
Comparison of the frequency and severity of radiation-related gastrointestinal toxicity between the hydrocortisone and placebo groups during SCRT and up to 5 weeks after completion of radiotherapy (n=101)
Complication Treatment
 P-value
Hydrocortisone (n=50) Placebo (n=51)
Proctitis <0.001
 Grade 1–2 42 (84.0) 20 (39.2)
 Grade 3 8 (16.0) 31 (60.8)
Diarrhea 0.023
 Grade 1–2 45 (90.0) 36 (70.6)
 Grade 3 5 (10.0) 15 (29.4)
Rectal pain <0.001
 Grade 1–2 43 (86.0) 21 (41.2)
 Grade 3 7 (14.0) 30 (58.8)
Tenesmus <0.001
 Grade 1–2 44 (88.0) 21 (41.2)
 Grade 3 6 (12.0) 30 (58.8)
Rectal hemorrhage 0.427
 Grade 1 25 (50.0) 21 (41.2)
 Grade 2 25 (50.0) 30 (58.8)
Anemia 0.777
 Grade 1–2 35 (70.0) 34 (66.7)
 Grade 3 3 (6.0) 5 (9.8)
Neutropenia 0.376
 Grade 1–2 16 (32.0) 19 (37.3)
 Grade 3 2 (4.0) 5 (9.8)
Thrombocytopenia 0.159
 Grade 1–2 3 (6.0) 8 (15.7)
 Grade 3 1 (2.0) 3 (5.9)

Values are presented as number (%).

SCRT, short-course radiotherapy.

Table 3.
Correlation between clinical characteristics and the severity of proctitis (n=101)
Characteristic Proctitis
 P-value
Grade 1–2 (n=62) Grade 3 (n=39)
Age (yr) 54.66±8.67 53.59±9.89 0.568
Sex 0.654
 Male 46 (74.2) 28 (71.8)
 Female 16 (25.8) 11 (28.2)
Body mass index (kg/m2) 25.97±3.18 26.45±3.01 0.453
Tumor location 0.895
 Upper 37 (59.7) 22 (56.4)
 Middle 16 (25.8) 10 (25.6)
 Lower 9 (14.5) 7 (17.9)
Clinical T category 0.503
 T2 12 (19.4) 10 (25.6)
 T3 41 (66.1) 26 (66.7)
 T4 9 (14.5) 3 (7.7)
Clinical N category 0.824
 N0 7 (11.3) 4 (10.3)
 N1 33 (53.2) 20 (51.3)
 N2 22 (35.5) 15 (38.5)
ECOG performance score 0.656
 0 43 (69.4) 29 (74.4)
 1 19 (30.6) 10 (25.6)
Target volume (mL)
 Clinical target volume 678±121 724±144 0.089
 Planning target volume 1,226±170 1,299±166 0.038
Underlying comorbidity 0.339
 None 15 (24.2) 7 (19.9)
 Diabetes mellitus 25 (40.3) 14 (35.9)
 Hypertension 11 (17.7) 13 (33.3)
 Other 11 (17.7) 5 (12.8)

Values are presented as mean±standard deviation or number (%). Percentages may not total 100 due to rounding.

ECOG, Eastern Cooperative Oncology Group.

Table 4.
Multivariable logistic regression analysis of independent variables influencing the severity of proctitis
Variable Odds ratio 95% CI P-value
Age (yr) 0.972 0.922–1.026 0.301
Sex 0.748 0.243–2.305 0.613
Body mass index (kg/m2) 1.085 0.919–1.282 0.337
Tumor location
 Upper Reference - -
 Middle 0.701 0.151–3.216 0.684
 Lower 1.262 0.240–6.630 0.784
Clinical T category
 T2 Reference - -
 T3 6.646 0.979–45.108 0.053
 T4 4.112 0.771–21.922 0.098
Clinical N category
 N0 Reference - -
 N1 1.040 0.186–5.805 0.964
 N2 0.883 0.273–2.857 0.835
ECOG performance score
 0 Reference - -
 1 1.175 0.361–3.824 0.788
Target volume (mL)
 Clinical target volume 1.003 0.999–1.006 0.166
 Planning target volume 1.003 1.000–1.005 0.065
Underlying comorbidity
 None Reference - -
 Diabetes mellitus 0.834 0.137–5.062 0.844
 Hypertension 1.053 0.219–5.065 0.949
 Other 3.202 0.604–16.984 0.172
Treatment
 Placebo Reference - -
 Hydrocortisone 0.122 0.047–0.320 <0.001

CI, confidence interval; ECOG, Eastern Cooperative Oncology Group.

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      Preventive efficacy of hydrocortisone enema for radiation proctitis in rectal cancer patients undergoing short-course radiotherapy: a phase II randomized placebo-controlled clinical trial
      Ann Coloproctol. 2024;40(5):506-514.   Published online October 22, 2024
      DOI: https://doi.org/10.3393/ac.2024.00192.0027
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    Preventive efficacy of hydrocortisone enema for radiation proctitis in rectal cancer patients undergoing short-course radiotherapy: a phase II randomized placebo-controlled clinical trial
    Image Image Image Image
    Fig. 1. CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the study. SCRT, short-course radiotherapy.
    Fig. 2. The trial design and study timeline. NACT, neoadjuvant chemotherapy; SCRT, short-course radiotherapy.
    Fig. 3. The peak of grade 3 gastrointestinal (GI) toxicity between the hydrocortisone and placebo arms. SCRT, short-course radiotherapy.
    Fig. 4. Duration of radiation proctitis in the enrolled patients.

    Fig. 1.

    Fig. 2.

    Fig. 3.

    Fig. 4.

    Preventive efficacy of hydrocortisone enema for radiation proctitis in rectal cancer patients undergoing short-course radiotherapy: a phase II randomized placebo-controlled clinical trial
    Characteristic Treatment
    		 P-value
    Hydrocortisone (n=50) Placebo (n=51)
    Age (yr) 54.38±8.35 54.12±9.90 0.886
    Sex 0.654
     Male 38 (76.0) 36 (70.6)
     Female 12 (24.0) 15 (29.4)
    Body mass index (kg/m2) 26.04±3.57 26.26±2.63 0.719
    Tumor location 0.560
     Upper 30 (60.0) 29 (56.9)
     Middle 14 (28.0) 12 (23.5)
     Lower 6 (12.0) 10 (19.6)
    Clinical T category 0.702
     T2 12 (24.0) 10 (19.6)
     T3 33 (66.0) 34 (66.7)
     T4 5 (10.0) 7 (13.7)
    Clinical N category 0.824
     N0 7 (14.0) 4 (7.8)
     N1 26 (52.0) 27 (53.0)
     N2 17 (34.0) 20 (39.2)
    ECOG performance score 0.828
     0 35 (70.0) 37 (72.5)
     1 15 (30.0) 14 (27.5)
    Target volume (mL)
     Clinical target volume 693±140 702±160 0.768
     Planning target volume 1,265±176 1,238±173 0.445
    Underlying comorbidity 0.961
     None 12 (24.0) 11 (21.6)
     Diabetes mellitus 20 (40.0) 19 (37.2)
     Hypertension 11 (22.0) 13 (25.5)
     Other 7 (14.0) 8 (15.7)
    Complication Treatment
    		 P-value
    Hydrocortisone (n=50) Placebo (n=51)
    Proctitis <0.001
     Grade 1–2 42 (84.0) 20 (39.2)
     Grade 3 8 (16.0) 31 (60.8)
    Diarrhea 0.023
     Grade 1–2 45 (90.0) 36 (70.6)
     Grade 3 5 (10.0) 15 (29.4)
    Rectal pain <0.001
     Grade 1–2 43 (86.0) 21 (41.2)
     Grade 3 7 (14.0) 30 (58.8)
    Tenesmus <0.001
     Grade 1–2 44 (88.0) 21 (41.2)
     Grade 3 6 (12.0) 30 (58.8)
    Rectal hemorrhage 0.427
     Grade 1 25 (50.0) 21 (41.2)
     Grade 2 25 (50.0) 30 (58.8)
    Anemia 0.777
     Grade 1–2 35 (70.0) 34 (66.7)
     Grade 3 3 (6.0) 5 (9.8)
    Neutropenia 0.376
     Grade 1–2 16 (32.0) 19 (37.3)
     Grade 3 2 (4.0) 5 (9.8)
    Thrombocytopenia 0.159
     Grade 1–2 3 (6.0) 8 (15.7)
     Grade 3 1 (2.0) 3 (5.9)
    Characteristic Proctitis
    		 P-value
    Grade 1–2 (n=62) Grade 3 (n=39)
    Age (yr) 54.66±8.67 53.59±9.89 0.568
    Sex 0.654
     Male 46 (74.2) 28 (71.8)
     Female 16 (25.8) 11 (28.2)
    Body mass index (kg/m2) 25.97±3.18 26.45±3.01 0.453
    Tumor location 0.895
     Upper 37 (59.7) 22 (56.4)
     Middle 16 (25.8) 10 (25.6)
     Lower 9 (14.5) 7 (17.9)
    Clinical T category 0.503
     T2 12 (19.4) 10 (25.6)
     T3 41 (66.1) 26 (66.7)
     T4 9 (14.5) 3 (7.7)
    Clinical N category 0.824
     N0 7 (11.3) 4 (10.3)
     N1 33 (53.2) 20 (51.3)
     N2 22 (35.5) 15 (38.5)
    ECOG performance score 0.656
     0 43 (69.4) 29 (74.4)
     1 19 (30.6) 10 (25.6)
    Target volume (mL)
     Clinical target volume 678±121 724±144 0.089
     Planning target volume 1,226±170 1,299±166 0.038
    Underlying comorbidity 0.339
     None 15 (24.2) 7 (19.9)
     Diabetes mellitus 25 (40.3) 14 (35.9)
     Hypertension 11 (17.7) 13 (33.3)
     Other 11 (17.7) 5 (12.8)
    Variable Odds ratio 95% CI P-value
    Age (yr) 0.972 0.922–1.026 0.301
    Sex 0.748 0.243–2.305 0.613
    Body mass index (kg/m2) 1.085 0.919–1.282 0.337
    Tumor location
     Upper Reference - -
     Middle 0.701 0.151–3.216 0.684
     Lower 1.262 0.240–6.630 0.784
    Clinical T category
     T2 Reference - -
     T3 6.646 0.979–45.108 0.053
     T4 4.112 0.771–21.922 0.098
    Clinical N category
     N0 Reference - -
     N1 1.040 0.186–5.805 0.964
     N2 0.883 0.273–2.857 0.835
    ECOG performance score
     0 Reference - -
     1 1.175 0.361–3.824 0.788
    Target volume (mL)
     Clinical target volume 1.003 0.999–1.006 0.166
     Planning target volume 1.003 1.000–1.005 0.065
    Underlying comorbidity
     None Reference - -
     Diabetes mellitus 0.834 0.137–5.062 0.844
     Hypertension 1.053 0.219–5.065 0.949
     Other 3.202 0.604–16.984 0.172
    Treatment
     Placebo Reference - -
     Hydrocortisone 0.122 0.047–0.320 <0.001
    Table 1. Distribution of baseline clinical characteristics among the patients (n=101)

    Values are presented as mean±standard deviation or number (%).

    ECOG, Eastern Cooperative Oncology Group.

    Table 2. Comparison of the frequency and severity of radiation-related gastrointestinal toxicity between the hydrocortisone and placebo groups during SCRT and up to 5 weeks after completion of radiotherapy (n=101)

    Values are presented as number (%).

    SCRT, short-course radiotherapy.

    Table 3. Correlation between clinical characteristics and the severity of proctitis (n=101)

    Values are presented as mean±standard deviation or number (%). Percentages may not total 100 due to rounding.

    ECOG, Eastern Cooperative Oncology Group.

    Table 4. Multivariable logistic regression analysis of independent variables influencing the severity of proctitis

    CI, confidence interval; ECOG, Eastern Cooperative Oncology Group.

    Table 1.

    Table 2.

    Table 3.

    Table 4.

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