1 INTRODUCTION

Colorectal cancer (CRC) is the third most prevalent cancer worldwide and the second leading cause of cancer-related deaths. In 2020, Global Cancer Observatory (GLOBOCAN) reported 1.9316 million new CRC cases and 935,000 deaths globally, accounting for 10.0% and 9.4% of total cancer incidence and cancer-related mortality, respectively. Of these, 732,000 new cases were rectal cancer.¹ Neoadjuvant chemoradiotherapy (NCRT) is currently the standard treatment for locally advanced rectal cancer.

Several challenges exist in treating locally advanced rectal cancer. Liao et al. reported a pathological complete response (pCR) rate of 22.7% with total neoadjuvant therapy (TNT),² indicating that many patients have residual tumors after external beam radiation in neoadjuvant therapy. Brachytherapy is commonly used to enhance the local tumor dose in the curative treatment of cervical cancer. In some parts of Europe, it is used for rectal cancer patients with residual tumors, those who cannot undergo surgery, or those unwilling to do so. Therefore, brachytherapy can be considered as a viable treatment option to improve local tumor control.

Brachytherapy involves placing a source applicator near or within the tumor or postoperative tumor bed. A key advantage of brachytherapy is its ability to deliver high radiation doses to the tumor while minimizing exposure to the surrounding normal tissues.³ The physical properties of radioactive isotopes determine their dose rates. These include high dose rate (HDR, >12 Gy/h), medium dose rate (MDR, 2 Gy/h–12 Gy/h), low dose rate (LDR, 0.4–2 Gy/h), or very low dose rate (vLDR, <0.4 Gy/h). Currently, the most commonly used radioactive isotope is high-dose-rate iridium-192.⁴ HDR brachytherapy offers the advantage of shorter treatment duration than LDRs. Common applications of brachytherapy include treating skin, cervical, endometrial, prostate, breast, and rectal cancers. Although brachytherapy for rectal cancer is less common in China and the United States, its use is increasing in Europe.⁵ Brachytherapy can be used as a standalone treatment, typically administered at 26 Gy in four fractions. When used as an adjunct to or following external beam radiation, it is generally administered at 5–10 Gy.

In 2017, Buckley⁶ published a systematic review of HDR-EBT for operable rectal cancer. This review, published in the International Journal of Biological Physics, included clinical studies published between January 1990 and December 2016. It reported the pCR rate, overall survival (OS), progression-free survival (PFS), surgical complications, and adverse effects of HDR treatment. Its limitations include the lack of detailed toxicity reports, variations in clinical endpoints across trial groups, and the predominance of single-arm, single-center, and small-scale studies. Heterogeneities were observed in patient selection, dose and fractionation of HDR-EBT, combination with CRT, chemotherapy regimens, and the interval between radiation and surgery. Additionally, the review included studies on HDR-EBT for operable rectal cancer between January 2017 and December 2023, which offer insights into current treatment approaches.

2 METHODS AND MATERIALS

2.2 Search strategy

Following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, computerized searches were conducted in PubMed, Embase, and Web of Science for studies on HDR brachytherapy for rectal cancer.⁷ The search terms included rectal cancer, brachytherapy, HDR, and high-dose-rate, with studies published between January 2000 and December 2023. Relevant references, systematic reviews, meta-analyses, and related studies were also examined. The search strategy, with PubMed as an example, is illustrated in Figure 1.

The patient populations included stagesT2–T4, with T3 being the predominant stage, and sample sizes ranged 17–483. Considering that only four randomized controlled trials (RCTs) with inconsistent control methods were available, only studies in which the intervention involved HDR-EBT were included. In the intervention group, standalone HDREBT was typically administered at 26 Gy/4 fractions, although one study used doses ranging 16–80 Gy/4 fractions.⁸ For HDR-EBT combined with long-term chemoradiotherapy, doses of 45–60 Gy were administered in 25–30 fractions, followed by 5–10 Gy in 1–2 fractions. Table 1 presents the characteristics of the included studies, whereas Tables 2 and 3 detail the risk of bias results.

TABLE 1. Basic information of studies.

Study ID	Design	No. of patients receiving HDR, n	Treatment details	Outcome indicators
Jakobsen, et al.2006	T3Nx	48	60Gy/30f+5Gy/1f Tigafluorouracil300 mg/m2	① ④⑤⑥⑦
Jakobsen, et al.2007	T3、T4	33	60Gy/30f+5Gy/1f Tigafluorouracil300 mg/m2 +Celecoxib400mg bid	① ④⑤⑥
Jakobsen, et al.2012	T3、T4	105	50.4Gy/28f+10Gy/2f Tigafluorouracil300 mg/m2 +L-leucovorin22.5 mg/d	① ④⑤⑦
Ane L Appelt, et al. 2014	T3、T4, N0	95	50.4Gy/28f+10Gy/2f Tegafur3×100mg/m2	① ②③④⑤⑧
Tunio, et al. 2010	T3、T4 or N+	17	45Gy/25f+5.5-7Gy*2f Capecitabine825mg/m2 bid	① ⑥⑦
Sun myint, et al. 2010	-	29	45Gy/25f+10Gy/2f Capecitabine825mg/m2	①②③④⑤⑦
Arefeh, et al. 2023	-	22	50.40 Gy/28f Capecitabine825mg/m2	① ②③⑤
R. Engineer, et al.2023	-	79	50Gy/25f+8-15Gy/2-3f Capecitabine825mg/m2	① ②③⑤⑧
Breugom, et al. 2015	T3	141	26Gy/4f	② ⑤⑧
Hesselager, et al. 2013	-	316	26Gy/4f	① ④⑤⑦
Vuong, et al. 2002	T2–T4	47	26Gy/4f	① ④⑦⑧
Vuong, et al. 2007	T2–T4	96	26Gy/4f	① ②③⑤⑥
Vuong, et al. 2015	T2–T4	483	26Gy/4f	②③
Yanagi, et al. 2000	T2–T4 Nx	115	16-80Gy/4f	①⑤
Rebecca, et al. 2017	II–III	17	26Gy/4f	①
Garant, et al. 2021	T2、T3 Nx	115/60	26Gy/4f +FOLFOX x6+FOLFOX x6 postoperative 26Gy/4f + FOLFOX x12	① ②③⑥⑧

• ① pCR rate ②OS ③ DFS/PFS ④ R0 resection rate ⑤ Organ preservation rate ⑥ Adverse reaction rate of Grade 3 or above ⑦ Incidence of surgical complications ⑧Relapse and metastasis

TABLE 2. Risk of bias assessment(ROB 2.0).

Study ID	Bias arising from the randomization process	Bias from deviations from intended interventions	Bias in the measurement of the outcome	Bias from missing outcome data	Bias in the selection of the reported result	Overall bias
Jakobsen, et al.2012
Appelt, et al.2014
Tunio, et al.2010
Garant, et al.2021

• : Low risk. : Some concerns. : High risk

TABLE 3. Risk of bias in non-randomized studies of interventions(ROBINS-I).

Study ID	Bias from confounding	Bias in the selection of participants for the study	Bias in the classification of interventions	Bias from deviations from intended interventions	Bias from missing data	Bias in measurement of outcomes	Bias in selection of the reported result	Overall bios
Jakobsen, et al. 2006
Jakobsen, et al. 2007
Breugom, et al. 2015
Hesselager, et al. 2013
Sunmyint, et al. 2010
Arefeh, et al. 2023
R. Engineer, et al. 2023
Vuong, et al. 2002
Vuong, et al. 2007
Vuong, et al. 2015
Yanagi, et al. 2000
Rebecca, et al. 2017

• :Low risk :Moderate risk :Serious risk :Critical risk

3 RESULTS

3.1 Literature search results

Overall, 7,457 relevant articles were retrieved. After carefully reviewing titles, abstracts, and full texts, and removing duplicates and irrelevant papers, 24 articles were included. Among these, three articles lacked relevant data, one had population selection issues, three used targeted therapies, and one was a duplicate study. Finally, 16 studies were included in the analysis. The specific process and results of the literature screening are shown in Figure 2.

4 DISCUSSION

According to the 2023 Chinese Guidelines for the Diagnosis and Treatment of CRC, neoadjuvant therapy for rectal cancer is primarily suitable for patients with resectable T3, N+, or T4 rectal cancer with the main methods being chemoradiotherapy (CRT), short-course radiotherapy combined with consolidation chemotherapy (SCRT+CCT), and TNT. Brachytherapy has not been previously described.²⁴ This systematic review mainly investigated the application of HDR-EBT in the neoadjuvant treatment of rectal cancer.

This systematic review included studies that used HDR-EBT as neoadjuvant therapy for rectal cancer. The results of two meta-analyses from the Cochrane Library were compared to determine the direct differences between HDR-EBT and conventional CRT.^{2, 25} Table 6 presents the results.

The results indicate that HDR-EBT provides better surgical outcomes than traditional NCRT. Specifically, for the pCR rate, the odds ratios (OR) for radiotherapy combined with HDR-EBT versus traditional CRT and TNT were 2.28 and 1.37, respectively. Regarding the anal preservation rate, the OR for radiotherapy combined with HDR-EBT versus traditional CRT was 1.85. Relevant RCTs from studies by Jakobsen¹⁵ and Appelt¹⁷ have confirmed these findings. However, owing to limitations in sample sizes and variations in chemotherapy regimens, meta-analyses have not yielded consistent results. In studies using different dosing separation schemes, we conducted further research on CRT combined with HDR-EBT based on the equivalent biological dose of different radiotherapy schemes. This study showed that an increase in the equivalent biological dose did not lead to an improvement in the pCR rate (p = 0.685). This may have been due to the small sample size. Therefore, we look forward to further studies that provide suitable brachytherapy schemes. Currently, observation and watchful waiting are options for some patients who meet the clinical complete response (cCR) criteria after NCRT, thus avoiding surgery. We hope to achieve cCR with HDR-EBT in patients who do not meet the CR criteria, thereby avoiding surgery and reducing postoperative complications, such as wound infections, anastomotic leaks, and bladder dysfunction.

In the present study, patients treated with HDR-EBT had a higher rate of anal preservation than those treated with CRT. Anal preservation helps improve the quality of life of patients with rectal cancer. Given that the included studies ranged from 2000 to 2023, some did not describe the distance of the tumor from the anal margin, and considering the increasing emphasis on anal preservation by surgeons and patients, these benefits should be considered as references. Additionally, the ongoing optimization of chemotherapy drugs has improved tumor regression and increased anal preservation rates.

In the OPERA trial conducted by Gerard et al.,²⁶ the addition of contact X-ray brachytherapy significantly improved cCR and anal preservation rates for early cT2-cT3 patients, with anal preservation rates exceeding 90% for tumors less than 3 cm in diameter. Contact X-ray brachytherapy (Papillon technique) delivers surface 50 kV photons directly to the tumor to increase the dose around the tumor. However, this treatment mode has a rapid dose fall-off; while the dose at the tumor surface is 100%, it drops to 45% at 5 mm and 20% at 10 mm. Therefore, the Papillon technique is not suitable for deeply infiltrated bulky residual tumors but is better suited for small exophytic residual tumors. HDR-EBT, particularly three-dimensional image-guided brachytherapy, can increase the radiation dose to the residual primary tumors, covering more than 80% of the tumor after external beam radiotherapy. If residual tumors deeper than 10 mm are detected on rectal ultrasonography or posttreatment MRI, CT within the planned treatment area is recommended for adequate tumor coverage.

These results confirm that HDR-EBT improves local control, but has no significant impact on distant metastasis rates. We believe that TNT can be widely used for the treatment of locally advanced rectal cancer. We recommend performing close-range radiotherapy during consolidation chemotherapy, although this depends on the patient's tumor regression and tolerance.

Research has indicated that pCR after surgery predicts a better prognosis.²⁷ Several studies have shown no significant differences in the PFS or OS between patients receiving HDR-EBT and those receiving traditional long-course chemoradiotherapy or 5 × 5 Gy short-course radiotherapy. However, two studies published in 2023 found that using IMRT combined with HDR as a neoadjuvant regimen resulted in better survival rates than traditional CRT or TNT.^{20, 21} Owing to the limited number of studies and sample sizes, this regimen requires further exploration.

The incidence of grade 3 or higher adverse events with HDR-EBT combined with chemoradiotherapy was notably lower than that with traditional chemoradiotherapy or TNT. This may be due to the smaller irradiation field of HDR-EBT and differences in chemotherapy regimens, with traditional regimens like FOLFOX, FOLFIRI, and XELOX causing more hematological toxicity and diarrhea, while HDR-EBT primarily causes abdominal pain and diarrhea. In the MORPHEUS Phase II–III Study, it was shown that patients receiving brachytherapy had an improved PFS compared to those receiving EBRT.²⁸ There were no significant differences between the two groups in terms of acute toxicities, postoperative surgical complications, or medical complications within one month after surgery. Therefore, we concluded brachytherapy toxicity was within an acceptable range. Earlier studies did not report adverse events. Therefore, we hope that future studies will provide more detailed reports.

Patients receiving HDR-EBT had significantly lower local recurrence rates than those treated with traditional preoperative chemoradiotherapy. These findings suggest that HDR-EBT may enhance local disease control and potentially lead to improved patient outcomes. Despite this advantage in local recurrence, the probability of distant metastasis between the two groups showed no significant differences. This indicates that although HDR-EBT may effectively target local diseases, it does not necessarily affect systemic disease progression in the same way. Further research is needed to understand the mechanisms underlying these findings and to explore how combining HDR-EBT with other treatments could optimize overall patient outcomes. By focusing on both local control and distant metastasis, we can better tailor the treatment strategies for patients with rectal cancer.

In future research, we suggest incorporating HDR-EBT into the TNT process and conducting a randomized controlled trial (RCT) to compare this combined approach with the use of TNT alone for neoadjuvant therapy in rectal cancer. This would allow for a direct comparison of the benefits to patients with the addition of HDR-EBT. Additionally, MRI, digital rectal examination, and colonoscopy can be used to assess cCR and compare treatment efficacy.

Currently, HDR-EBT is not extensively used. It is mainly suitable for patients who are generally inoperable or unsuitable for surgery, or for those with residual tumors after external beam radiotherapy (EBRT) and chemotherapy. These patients often require additional doses to achieve tumor control, and HDR-EBT can minimize the impact on surrounding healthy tissues. Therefore, we recommend HDR-EBT for supplemental dosing.

Current research on HDR-EBT combined with long-course chemoradiotherapy lacks a standardized dosing regime, with studies ranging from 5–15 Gy. This variability highlights the urgent need to establish uniform brachytherapy dosing protocols to improve the quality of future studies and reach a consensus on minimum requirements for study endpoints. Most included studies were nonRCTs; therefore, more RCTs are required to validate these findings. Additionally, the limited sample sizes and absence of long-term follow-up data, such as five-year or ten-year prognoses, in studies combining HDR-EBT with long-course chemoradiotherapy hinder comprehensive assessment of the treatment's long-term benefits. Future research should aim to provide robust data on long-term outcomes to determine the efficacy and safety of this therapeutic approach.

Integrating HDR-EBT with traditional NCRT can improve post-surgical pCR rates. However, studies indicate this does not significantly improve OS or PFS than CRT alone. Recent studies have suggested that IMRT with HDR-EBT as a neoadjuvant therapy regimen may improve PFS and OS rates. Specifically, HDR-EBT-related adverse events, such as proctitis and grade 1 or 2 acute toxicity, remain within acceptable limits. Further clinical research is warranted to optimize the application, dosing strategies, adverse effect management, and survival outcomes associated with HDR-EBT.

CONFLICT OF INTERESTS STATEMENT

The authors declare that there is no conflict of interests.

ETHICAL STATEMENT

Not applicable.