TURKISH JOURNAL OF ONCOLOGY

Summary

The management of locally advanced rectal cancer has progressively evolved from a surgery-oriented model toward response-adapted strategies that prioritize organ preservation, functional outcomes, and quality of life. Within this framework, radiotherapy-based dose escalation has gained increasing interest as a means of enhancing tumor regression beyond that achieved with standard chemoradiotherapy alone. Contact X-ray brachytherapy (CXB) and endoluminal high-dose-rate (HDR) brachytherapy represent two localized radiation techniques with distinct physical and dosimetric characteristics. CXB delivers extremely high surface doses with limited tissue penetration, whereas HDR endorectal brachytherapy provides greater depth-dose distribution and the potential to deliver dose not only to the mucosal tumor surface but also to tissues adjacent to the rectal wall, including limited intramesorectal extensions. Contemporary ASTRO and ESMO guidelines support multidisciplinary, MRI-based, risk-adapted treatment selection and recognize the importance of sequencing within total neoadjuvant treatment (TNT), particularly when organ preservation or non-operative management is a therapeutic goal. Evidence from recent trials suggests that localized dose escalation may improve complete response and organ preservation.

Summary

Introduction

INTRODUCTION

The management of localized rectal cancer has undergone major changes over the past two decades with the widespread adoption of multimodal treatment strategies combining surgery, radiotherapy, and systemic therapy. Total mesorectal excision (TME) markedly reduced local recurrence rates, and neoadjuvant radiotherapy or chemoradiotherapy further improved local control. At the same time, it became increasingly clear that radical rectal surgery and pelvic irradiation may lead to substantial long-term morbidity, including anorectal dysfunction, urinary and sexual complications, and deterioration in quality of life.[1]

Consequently, contemporary treatment strategies increasingly aim not only to maximize oncologic control but also to individualize therapy according to tumor extent, MRI-defined risk factors, and treatment response. Organ-preserving approaches have therefore become an important component of modern rectal cancer management, particularly in patients with distal tumors in whom radical surgery may require permanent colostomy or lead to significant functional impairment. Current international guidelines emphasize multidisciplinary management, MRI-based risk stratification, and tailored treatment strategies when preservation of function or avoidance of radical surgery is an important therapeutic objective.[2,3]

Within this evolving treatment paradigm, local dose escalation has emerged as a promising strategy to increase tumor regression beyond that achieved with standard chemoradiotherapy alone. Techniques capable of delivering highly localized radiation doses are particularly attractive in this context, as they can intensify treatment at the residual tumor bed while minimizing radiation exposure to surrounding pelvic structures. Endoluminal radiation techniques such as contact X-ray brachytherapy (CXB) and endorectal high-dose-rate (HDR) brachytherapy have therefore gained increasing attention as potential tools for response-adapted treatment intensification.[4,5]

Tumor location within the rectum also plays a critical role in determining both therapeutic strategy and functional outcomes. Distal rectal cancers, in particular, present unique challenges because radical surgery frequently involves abdominoperineal resection with permanent stoma formation. In this setting, even modest improvements in tumor regression may translate into meaningful gains in sphincter preservation or rectal organ preservation. Consequently, localized dose-escalation techniques such as CXB and HDR endorectal brachytherapy are increasingly explored in response-adapted treatment strategies aimed at maximizing tumor response while maintaining acceptable toxicity.[6,7]

In this narrative review, we summarize the current role of contact X-ray brachytherapy and endoluminal HDR brachytherapy in the management of rectal cancer, with particular emphasis on dose escalation, organ preservation, and non-operative management strategies. In addition, we illustrate these concepts with an illustrative case of residual distal rectal cancer successfully treated with salvage endoluminal HDR brachytherapy following neoadjuvant chemoradiotherapy.

CONTEMPORARY GUIDELINE PERSPECTIVE ON RADIOTHERAPY AND ORGAN PRESERVATION

Current guideline documents continue to place radiotherapy at the center of multimodal treatment for stage II–III rectal cancer. The ASTRO focused update strongly recommends neoadjuvant radiotherapy for most stage II–III patients, while also recognizing that sequencing within total neoadjuvant therapy (TNT) and consideration of selective omission of surgery in complete responders have become increasingly relevant. For patients in whom non-operative management is a priority, ASTRO specifically favors chemoradiation followed by consolidation chemotherapy.[2]

Similarly, the ESMO 2025 guideline emphasizes MRI-based risk assessment and multidisciplinary discussion from diagnosis onward. High-risk MRI features such as threatened mesorectal fascia, cT4 disease, cN2 status, extramural venous invasion, and lateral lymph node enlargement are recommended for treatment stratification, including identification of patients most likely to benefit from intensified neoadjuvant.[8] These recommendations support a risk-adapted framework in which dose intensification may be considered as part of a broader organ-preserving strategy in selected patients.

A simplified schematic overview of this risk-adapted management framework is presented in Figure 1a and b. These diagrams summarize the initial risk stratification and the response-adapted treatment pathways following neoadjuvant therapy, including organ-preservation strategies such as watch-and-wait, local excision, and localized dose-escalation approaches.

After neoadjuvant therapy, response assessment using MRI, endoscopy, and digital rectal examination guides subsequent management. Patients achieving clinical complete response may undergo watch-and-wait surveillance. Selected patients with near-complete response may be considered for local excision, whereas persistent disease generally requires radical surgery. In selected cases with limited residual tumor, localized dose-escalation strategies such as contact X-ray brachytherapy or HDR endorectal brachytherapy may also be considered.

Fig 1: Response-adapted treatment algorithm for localized rectal cancer. (a) Initial diagnostic evaluation and risk stratification. Staging is performed with pelvic MRI, endoscopy with biopsy, and cross-sectional imaging. Patients are stratified according to tumor stage and risk features to guide selection of local therapy, neoadjuvant chemoradiotherapy, or total neoadjuvant treatment. (b) Response-adapted management following neoadjuvant therapy. Restaging with MRI, endoscopy, and digital rectal examination (DRE) guides subsequent treatment decisions. Patients achieving clinical complete response may undergo watch-and-wait surveillance. Selected patients with near-complete response may be considered for local excision, whereas persistent disease generally requires radical surgery (total mesorectal excision, TME). In selected cases with limited residual disease, localized dose-escalation strategies such as contact X-ray brachytherapy (CXB) or HDR endorectal brachytherapy may also be considered.

DISTINGUISHING SPHINCTER PRESERVATION, RECTAL ORGAN PRESERVATION, AND NON-OPERATIVE MANAGEMENT

For conceptual clarity, three related but distinct clinical endpoints should be differentiated in the context of modern rectal cancer management: Sphincter preservation, rectal organ preservation, and non-operative management (NOM).

Sphincter preservation refers specifically to avoidance of abdominoperineal resection (Miles procedure) and permanent colostomy. In such cases, restorative procedures such as low anterior resection or coloanal anastomosis can be performed instead of permanent stoma creation. Historically, early treatment intensification strategies in distal rectal cancer were often evaluated primarily according to their ability to increase sphincter preservation rates rather than complete avoidance of surgery. The Lyon R96-02 randomized trial demonstrated that local dose escalation with contact radiotherapy could significantly increase long-term sphincter preservation without compromising oncological outcomes.[9]

Rectal organ preservation represents a broader concept referring to avoidance of radical rectal resection itself. This approach may include strategies such as local excision following neoadjuvant therapy or complete omission of surgery in selected patients. Over the past two decades, increasing attention has been directed toward organ preservation because of the functional consequences associated with total mesorectal excision, including bowel dysfunction, sexual dysfunction, and impaired quality of life.[1,2] Consequently, modern treatment paradigms increasingly emphasize treatment individualization based on tumor response and patient preference.

Non-operative management (NOM) represents a specific subset of organ-preserving strategies in which surgery is intentionally omitted in patients achieving a clinical complete response after neoadjuvant therapy. In this strategy, patients undergo structured surveillance with regular clinical examination, endoscopy, and imaging, and salvage surgery is performed if local regrowth occurs. The feasibility of this approach was first described in the pioneering Brazilian experience reported by Habr-Gama and colleagues, who demonstrated that selected patients with complete clinical response after chemoradiotherapy could be managed safely with a watch-and-wait strategy, achieving long-term survival outcomes comparable to those undergoing immediate surgery.[10] Subsequent studies and international registries have confirmed that most local regrowths occur within the first two years and can often be successfully treated with salvage surgery when detected early.[11]

Importantly, sphincter preservation does not necessarily imply rectal preservation. A patient may avoid a Miles procedure yet still undergo radical rectal surgery, thereby preserving the sphincter but not the rectum itself. Conversely, patients treated with a watch-and-wait strategy achieve both rectal preservation and avoidance of surgery. For this reason, recent clinical trials evaluating organ-preserving strategies increasingly report endpoints such as TME-free survival, which more accurately reflects avoidance of radical rectal resection.

The sequencing of systemic therapy and radiotherapy also plays an important role in determining the likelihood of achieving complete response and enabling NOM. Within the framework of total neoadjuvant therapy (TNT), the OPRA trial demonstrated that treatment sequencing influences organ preservation outcomes. In this study, patients receiving chemoradiotherapy followed by consolidation chemotherapy achieved higher rates of organ preservation compared with those receiving induction chemotherapy followed by chemoradiotherapy, without compromising disease-free survival.[12] These findings suggest that prolonged tumor regression during consolidation therapy may increase the probability of clinical complete response and thereby expand the pool of patients eligible for NOM strategies.

Taken together, these observations highlight that sphincter preservation, rectal preservation, and non-operative management represent related but distinct treatment goals. Clarifying these endpoints is essential when interpreting outcomes from studies evaluating radiotherapy dose escalation, local brachytherapy techniques, or total neoadjuvant therapy approaches in rectal cancer.

EXTERNAL BEAM RADIOTHERAPY AND THE RATIONALE FOR DOSE ESCALATION

Neoadjuvant radiotherapy or chemoradiotherapy remains a cornerstone of treatment for patients with stage II–III rectal cancer. According to the recent ASTRO clinical practice guideline, long-course chemoradiotherapy using approximately 45–50.4 Gy in conventional fractionation continues to represent a standard approach for tumors requiring downstaging or margin improvement prior to surgery.[2] Although this treatment strategy significantly improves local control and facilitates tumor regression, complete clinical response rates after standard chemoradiotherapy remain relatively limited, generally ranging between 15% and 25%.[1] This observation has stimulated interest in treatment intensification strategies designed to deepen tumor response and potentially increase the probability of organ preservation.

Dose escalation using external beam radiotherapy has been explored in several studies. One approach involves the use of simultaneous integrated boost (SIB) techniques within intensity-modulated radiotherapy (IMRT) planning in order to deliver higher doses to the primary tumor while maintaining standard doses to the surrounding pelvic targets. Valentini and colleagues demonstrated the feasibility of this strategy using IMRT with SIB to escalate tumor dose beyond conventional levels while maintaining acceptable toxicity profiles.[13] However, further dose intensification using external beam radiotherapy alone remains constrained by the tolerance of surrounding pelvic organs at risk, particularly the small bowel, bladder, and uninvolved rectal wall.

For this reason, current guideline discussions increasingly highlight the potential role of highly localized radiation techniques that can intensify dose delivery directly at the tumor site without substantially increasing exposure to adjacent normal tissues. In this context, endoluminal boost techniques such as contact X-ray brachytherapy and endorectal HDR brachytherapy represent attractive approaches. Rather than expanding the treated pelvic volume, these techniques modify the spatial distribution of radiation dose by concentrating high-dose regions at the residual tumor bed. This geometry of dose delivery allows substantial local dose escalation while maintaining steep dose fall-off toward surrounding organs, thereby potentially increasing tumor regression while limiting treatment-related toxicity.[2,14]

CONTACT X-RAY BRACHYTHERAPY IN RECTAL CANCER

Contact X-ray brachytherapy (CXB), also known as the Papillon technique, delivers very high radiation doses directly to the tumor surface using low-energy 50 kV photons. Because kilovoltage radiation produces an extremely steep dose gradient, very high surface doses can be delivered while limiting dose penetration to deeper tissues. This physical characteristic allows CXB to intensify treatment to superficial tumor layers while minimizing radiation exposure to surrounding pelvic structures.[4]

Early clinical evidence supporting CXB was provided by the Lyon R96-02 randomized trial, which compared conventional preoperative radiotherapy alone with radiotherapy combined with contact X-ray therapy boost in patients with distal rectal cancer. The addition of contact radiotherapy resulted in significantly improved tumor regression and increased rates of sphincter-preserving surgery without compromising local control or survival outcomes.[9,15] These findings provided an early proof-of-concept that localized dose escalation could influence surgical outcomes in rectal cancer.

More recently, the OPERA trial provided high-level evidence supporting CXB as a strategy for organ preservation. In this phase III randomized study, the addition of CXB boost after standard neoadjuvant chemoradiotherapy significantly increased clinical response and organ preservation rates compared with external beam boost alone. Early complete or near-complete response rates exceeded 90%, and long-term organ preservation rates reached approximately 75–80% in selected patients with small distal rectal tumors.[6,16,17]

Reported toxicities in CXB series have generally been limited to low-grade rectal bleeding, transient mucosal ulceration, and mild proctitis. Importantly, long-term functional outcomes have remained favorable, with no major deterioration in bowel function reported in long-term follow-up of modern series.[6,16,17] These findings support CXB as an effective localized dose-escalation strategy in carefully selected patients, particularly for small superficial tumors in the distal rectum.

Although CXB provides very high surface dose escalation, its limited depth of penetration represents an important distinction compared with Ir-192 HDR endorectal brachytherapy, which may provide greater dose coverage for deeper tumor extensions.

ENDOLUMINAL HDR BRACHYTHERAPY IN RECTAL CANCER

Endoluminal high-dose-rate (HDR) brachytherapy using Ir-192 represents an important localized radiation technique capable of delivering high radiation doses directly to the rectal tumor bed while minimizing irradiation of surrounding pelvic structures. Compared with contact X-ray brachytherapy, HDR brachytherapy provides greater tissue penetration due to the higher energy of Ir-192 photons. As a result, therapeutic dose levels can extend beyond the mucosal surface into the submucosa and tissues immediately adjacent to the rectal wall, potentially allowing improved coverage of residual tumor beds and limited perirectal tumor extensions.[5]

In the technique developed at McGill University by Vuong and colleagues, treatment planning is performed using a combination of pelvic MRI and CT-based imaging to accurately define the target volume. The clinical target volume (CTV) may include the gross tumor volume together with intramesorectal tumor deposits or perirectal tissue extensions visualized on pre-treatment MRI. This MRI-guided approach enables dose delivery not only to the visible tumor but also to adjacent mesorectal tissues that may harbor microscopic disease, while maintaining a steep dose fall-off toward surrounding organs such as the bladder and uninvolved rectum.[5,18]

A key technical component of this approach is the use of dedicated endorectal applicators specifically designed for HDR brachytherapy. In the system described by Vuong et al.,[5] the applicator incorporates a semicylindrical treatment channel combined with an inflatable balloon that functions both as a stabilizing device and as a spacer. Inflation of the balloon improves contact between the applicator surface and the rectal mucosa while simultaneously increasing the distance between the treated tumor surface and the contralateral rectal wall. This geometric configuration reduces radiation exposure to uninvolved rectal mucosa and nearby pelvic organs while improving the therapeutic ratio of treatment.[18] In addition, the balloon system stabilizes the applicator during treatment delivery, thereby enhancing reproducibility and consistency of dose distribution.

Dedicated rectum-specific applicators may further improve the therapeutic ratio of HDR brachytherapy by optimizing target–tissue apposition and maintaining stable applicator positioning during treatment delivery. Balloon-assisted systems create separation between the treated rectal wall and the contralateral mucosa, thereby reducing unnecessary irradiation of uninvolved tissues and helping maintain acceptable dose constraints to surrounding organs such as the bladder and uninvolved rectum.

HDR endorectal brachytherapy has been investigated both as a primary neoadjuvant treatment and as a boost following external beam radiotherapy. In early studies from the McGill group, HDR brachytherapy was delivered as neoadjuvant monotherapy using a total dose of approximately 26 Gy in four fractions, resulting in substantial tumor regression and high rates of downstaging prior to surgery.[18] Subsequently, HDR brachytherapy has also been used as a boost after conventional external beam chemoradiotherapy, with total boost doses typically ranging between 10 and 20 Gy delivered in multiple fractions.[5]

Clinical studies evaluating HDR brachytherapy boost have demonstrated encouraging tumor response rates with acceptable toxicity profiles. In prospective series, localized HDR boost following external beam radiotherapy has been associated with improved tumor regression and higher rates of clinical complete response compared with conventional chemoradiotherapy alone.[19] Reported toxicities have generally been limited to mild rectal bleeding, mucosal irritation, or transient proctitis, with low rates of severe complications when appropriate patient selection and applicator positioning are used.

An additional theoretical advantage of HDR brachytherapy is its potential to deliver radiation not only to the tumor surface but also to tissues immediately adjacent to the rectal wall. Because microscopic spread of rectal cancer frequently occurs within mesorectal fat and along perirectal lymphatic pathways, the ability of HDR brachytherapy to deposit dose beyond the mucosal surface may contribute to improved control of limited intramesorectal disease.[5] Although HDR brachytherapy cannot replace elective pelvic nodal irradiation delivered with external beam radiotherapy, this localized mesorectal dose contribution may be clinically relevant in selected patients with limited residual disease.

Taken together, these findings suggest that endoluminal HDR brachytherapy represents an effective method of localized dose escalation in rectal cancer. By combining precise image-guided target definition with dedicated applicator technology, HDR brachytherapy can intensify treatment to the tumor bed while limiting radiation exposure to surrounding normal tissues. This characteristic makes HDR brachytherapy particularly attractive in response-adapted treatment strategies aimed at organ preservation or non-operative management.

DOSE PENETRATION AND MESORECTAL COVERAGE

A fundamental physical difference between contact X-ray brachytherapy (CXB) and endoluminal HDR brachytherapy lies in their dose penetration characteristics and surface dose distribution. CXB uses low-energy kilovoltage photons (approximately 50 kV), which produce extremely high surface doses with a very steep dose fall-off. In typical Papillon contact therapy treatments, surface doses of approximately 30 Gy per fraction may be delivered directly to the tumor surface. However, because of the rapid attenuation of kilovoltage photons in tissue, the dose decreases sharply with depth. The dose typically falls to approximately 50% of the prescribed surface dose at a depth of about 4–5 mm, and continues to decline rapidly beyond this level. As a result, the effective treatment depth of CXB is limited to superficial tumor layers, making this technique particularly suitable for lesions confined to the mucosa or superficial submucosa.[4,7]

In contrast, HDR brachytherapy using Ir-192 produces higher-energy photons with substantially greater tissue penetration. Although the surface dose in HDR endorectal brachytherapy depends on the prescription depth and applicator geometry, surface doses are typically lower than those delivered with CXB when normalized to prescription dose. In clinical HDR endorectal brachytherapy plans, therapeutic doses can be prescribed at depths of approximately 5–10 mm from the mucosal surface, and the 50% isodose line generally extends to depths of approximately 10–15 mm depending on applicator design and source position. This deeper dose penetration allows HDR brachytherapy to treat residual tumor beds extending beyond the mucosal surface and to provide partial dose coverage to tissues immediately adjacent to the rectal wall.[5]

A fundamental physical difference between contact X-ray brachytherapy and HDR endorectal brachytherapy lies in their depth-dose characteristics. In CXB, the low-energy kilovoltage photons produce extremely high surface doses with rapid dose fall-off, resulting in effective treatment depths limited to a few millimeters. In contrast, Ir-192 HDR brachytherapy produces deeper dose penetration into tissues adjacent to the rectal wall. A simplified schematic representation of these dose distribution differences is shown in Figure 2.

Fig 2: Simplified schematic comparison of dose distribution in contact X-ray brachytherapy (CXB) and HDR endorectal brachytherapy. CXB produces extremely high surface doses with rapid dose fall-off, typically decreasing to approximately 50% of the surface dose at a depth of about 4–5 mm. In contrast, Ir-192 HDR brachytherapy provides greater depth-dose penetration, with therapeutic dose levels commonly prescribed at depths of approximately 5–10 mm from the mucosal surface. This difference allows HDR brachytherapy to deliver dose not only to the mucosal tumor surface but also to tissues adjacent to the rectal wall and limited intramesorectal regions. The depth-dose relationships illustrated in this schematic are approximate and intended to demonstrate the general differences in dose distribution between the two techniques rather than exact dosimetric measurements.

This difference in dose distribution is particularly relevant in rectal cancer because microscopic tumor spread frequently occurs within the mesorectal fat and along perirectal lymphatic pathways. While localized brachytherapy techniques cannot replace elective pelvic nodal irradiation delivered with external beam radiotherapy, the dose geometry of HDR brachytherapy allows a portion of the radiation dose to extend beyond the rectal wall into adjacent mesorectal tissues. Consequently, intramesorectal lymphatic structures located near the rectal wall may receive a partial therapeutic dose contribution. Depending on tumor location and applicator orientation, limited regions of the lateral mesorectal compartment may also fall within intermediate dose levels, which may contribute to improved control of localized residual disease.[5]

While CXB achieves extremely high mucosal surface doses with minimal penetration, HDR brachytherapy provides a broader depth-dose distribution that may be advantageous for treating residual tumor beds and limited intramesorectal extensions. The main technical and clinical differences between contact X-ray brachytherapy and HDR endorectal brachytherapy are summarized in Table 1.

Table 1: Physical and clinical characteristics of contact X-ray brachytherapy (CXB) and Ir-192 HDR endorectal brachytherapy in rectal cancer. CXB: Contact X-Ray Brachytherapy; HDR: Ir-192 HDR Endorectal Brachytherapy.

BIOLOGICAL DOSE COMPARISON OF EXTERNAL RADIOTHERAPY AND BRACHYTHERAPY BOOST

Comparison of dose-escalation strategies in rectal cancer requires careful consideration of differences in fractionation schedules and radiation delivery techniques. The biologically effective dose (BED) and equivalent dose in 2-Gy fractions (EQD2) are widely used radiobiological metrics to compare treatment regimens delivered with different fractionation schemes.

Standard long-course chemoradiotherapy typically delivers 45–50.4 Gy in 25–28 fractions, corresponding to an EQD2 of approximately 45–50 Gy for tumor tissue assuming an α/β ratio of 10 Gy.[2] Although this regimen provides effective tumor downstaging and improved local control, complete response rates remain limited, which has stimulated interest in additional strategies aimed at increasing the biologically effective tumor dose.

One such strategy involves external beam dose escalation using simultaneous integrated boost (SIB) techniques. In the study by Valentini and colleagues, intensity-modulated radiotherapy allowed delivery of approximately 54–55 Gy in 25 fractions (2.2 Gy per fraction) to the primary tumor while maintaining conventional pelvic doses to surrounding tissues. When converted using an α/β ratio of 10 Gy, this regimen corresponds to an EQD2 of approximately 56 Gy, representing a modest but clinically meaningful biological dose escalation compared with standard chemoradiotherapy.[20]

Another strategy involves localized dose intensification using brachytherapy boost following external beam radiotherapy. In published HDR endorectal brachytherapy series, boost regimens most commonly deliver 10–20 Gy in 2–4 fractions after external beam treatment.[5] For example, a regimen of 3 × 5 Gy HDR brachytherapy boost corresponds to an EQD2 of approximately 21–23 Gy, resulting in cumulative tumor EQD2 values that may exceed 65–70 Gy when combined with conventional external beam chemoradiotherapy. Because brachytherapy delivers highly localized radiation with steep dose gradients, this additional dose escalation can be achieved while maintaining acceptable toxicity levels to surrounding normal tissues.

Direct comparison between contact X-ray brachytherapy (CXB) and HDR brachytherapy dose prescriptions is not straightforward because of fundamental differences in radiation energy and dose distribution. CXB delivers extremely high surface doses using low-energy kilovoltage photons with rapid dose fall-off, whereas HDR brachytherapy provides broader dose penetration into tissues adjacent to the rectal wall. Consequently, while CXB may generate very high mucosal surface doses, HDR brachytherapy may provide more meaningful dose coverage to deeper tumor extensions and tissues immediately adjacent to the rectal wall. A simplified comparison of the biological dose characteristics of different dose-escalation strategies is presented in Table 2.

Table 2: Biological dose comparison of different dose-escalation strategies in rectal cancer. Calculations assume an α/β ratio of 10 Gy for tumor tissue. CXB produces very high surface doses but with extremely limited tissue penetration. EQD2: Equivalent dose in 2-Gy fractions; ChRT: Chemoradiotherapy; HDR: Ir-192 HDR Endorectal Brachytherapy; SIB: Simultaneous integrated boost; IMRT: Intensity-modulated radiotherapy.

SYSTEMIC THERAPY AND TOTAL NEOADJUVANT TREATMENT

Recent clinical trials have demonstrated that incorporation of systemic chemotherapy within a total neoadjuvant treatment (TNT) framework can substantially increase tumor response rates in locally advanced rectal cancer. TNT strategies aim to deliver all planned systemic therapy before surgery, thereby improving treatment compliance and potentially enhancing both local tumor regression and systemic disease control. Contemporary radiotherapy guidelines also recognize TNT as an increasingly adopted strategy for patients with locally advanced disease, particularly when tumor downstaging and organ preservation are important treatment goals.[2]

The addition of oxaliplatin-containing chemotherapy to fluoropyrimidine-based chemoradiotherapy regimens has been associated with higher rates of tumor regression and pathological complete response (pCR). Intensified neoadjuvant strategies combining radiotherapy with oxaliplatin-based systemic therapy have therefore gained increasing interest in organ-preservation oriented treatment paradigms.

Several randomized trials have evaluated different TNT strategies. In the PRODIGE-23 trial, the incorporation of induction chemotherapy using modified FOLFIRINOX before chemoradiotherapy significantly increased pathological complete response rates and improved disease-free survival compared with conventional treatment, supporting the concept that early systemic therapy may enhance tumor response while addressing micrometastatic disease.[21]

The RAPIDO trial evaluated an alternative TNT approach consisting of short-course radiotherapy followed by systemic chemotherapy. This strategy significantly increased pathological complete response rates compared with standard long-course chemoradiotherapy and demonstrated improved disease-related treatment failure outcomes.[22] However, when the primary objective is maximal tumor regression and potential organ preservation, many contemporary treatment protocols still favor long-course chemoradiotherapy, which allows more gradual tumor regression and may facilitate response-based management strategies.

An additional critical question concerns the optimal sequencing of chemotherapy and radiotherapy within TNT. Two randomized trials have specifically addressed this issue. In the OPRA trial, patients were randomized to receive either induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy followed by consolidation chemotherapy. Although disease-free survival was similar between the two approaches, consolidation chemotherapy administered after chemoradiotherapy resulted in significantly higher rates of rectal preservation, suggesting that continued tumor regression during the post-radiotherapy interval may enhance the likelihood of achieving a clinical complete response.[23]

Similarly, the German CAO/ARO/AIO-12 trial compared induction versus consolidation chemotherapy within a TNT framework. Long-term analysis demonstrated that administration of chemotherapy after chemoradiotherapy resulted in higher rates of pathological or sustained clinical complete remission while maintaining comparable oncologic outcomes, toxicity profiles, and quality of life. These findings support the strategy of initiating treatment with chemoradiotherapy followed by consolidation chemotherapy when organ preservation is an important therapeutic objective.[24,25]

Taken together, current evidence suggests that oxaliplatin-based systemic therapy integrated within TNT and delivered after initial chemoradiotherapy may represent one of the most effective strategies to increase complete response rates. In treatment paradigms aiming for organ preservation or non-operative management, many contemporary protocols therefore favor a radiotherapy-first approach followed by consolidation chemotherapy, often within a long-course chemoradiotherapy framework. Ongoing trials continue to refine the optimal sequencing and intensity of TNT regimens, but current evidence supports this strategy as a rational platform for maximizing tumor regression and expanding organ-preserving treatment options.

ILLUSTRATIVE CASE

A 54-year-old patient with biopsy-proven distal rectal adenocarcinoma was referred for multidisciplinary evaluation. Initial staging included pelvic magnetic resonance imaging and whole-body PET/CT imaging, which demonstrated a localized distal rectal tumor without distant metastasis (Fig. 3).

Fig 3: Baseline PET/CT imaging of the illustrative case. Axial fused PET/CT and CT images demonstrate focal FDG uptake corresponding to the distal rectal tumor before neoadjuvant chemoradiotherapy.

The patient underwent neoadjuvant chemoradiotherapy consisting of pelvic external beam radiotherapy delivered to 50 Gy in 25 fractions with concurrent capecitabine-based chemotherapy, in accordance with contemporary guideline-based treatment recommendations for locally advanced rectal cancer.

Clinical reassessment approximately one month after completion of chemoradiotherapy revealed persistent localized tumor residue located approximately 4 cm from the anal verge. Endoscopic examination demonstrated a residual lesion confined to the distal rectal wall without evidence of circumferential extension. Because the patient initially declined radical surgical treatment, the case was reviewed in a multidisciplinary tumor board and a decision was made to perform salvage endoluminal HDR brachytherapy as a localized dose-escalation strategy.

Prior to treatment planning, endoscopic metal clips were placed at the proximal and distal margins of the residual lesion to facilitate accurate target localization on planning CT images. CT-based treatment planning was subsequently performed, and the clinical target volume (CTV) was defined to encompass the residual lesion with an estimated depth of approximately 1 cm from the mucosal surface. The treatment planning images and corresponding dose distribution are illustrated in Figure 4.

Fig 4: CT-based treatment planning for endoluminal HDR brachytherapy. Axial, sagittal, and coronal planning images demonstrate positioning of the endorectal applicator, clinical target volume (CTV) delineation, and corresponding isodose distribution. The high-dose region is concentrated at the tumor surface with rapid dose fall-off toward surrounding normal tissues.

Approximately seven weeks after completion of external beam radiotherapy, the patient underwent endoluminal HDR brachytherapy using an Ir-192 source. A single fraction of 7 Gy was delivered to the defined target volume with a dedicated endorectal applicator designed to ensure adequate contact with the rectal wall while limiting dose exposure to surrounding tissues.

In this case, the applicator system did not incorporate an inflatable balloon spacer. Consequently, separation between the treated rectal wall and adjacent pelvic structures was limited. As a result, the mucosal surface dose was relatively high and dose reduction to the contralateral rectal wall and nearby organs could not be optimized to the same extent as with balloon-assisted applicator systems described in the literature. Nevertheless, treatment planning confirmed that dose constraints to surrounding organs remained within clinically acceptable limits, and the procedure was safely delivered with careful applicator positioning and CT-based planning.

Although a single 7 Gy fraction may appear relatively modest when compared with HDR brachytherapy boost regimens reported in the literature, treatment planning analysis suggested that this fraction resulted in an estimated surface dose of approximately 29 Gy at the tumor–mucosa interface. This level of surface dose is broadly comparable to that achieved in contact X-ray brachytherapy protocols such as the OPERA study, where approximately 30 Gy per fraction is delivered directly to the tumor surface.

Despite the different photon energies used in these techniques—kilovoltage X-rays in contact therapy versus Ir-192 gamma photons in HDR brachytherapy—the magnitude of surface dose may therefore fall within a similar range. However, the spatial dose distribution differs substantially between the two modalities. While contact X-ray brachytherapy primarily delivers very high doses to superficial mucosal layers, HDR brachytherapy provides deeper dose penetration into tissues adjacent to the rectal wall, allowing partial dose coverage of residual tumor beds and nearby perirectal tissues.

Follow-up evaluation approximately three weeks after brachytherapy demonstrated imaging and endoscopic findings consistent with complete clinical response. Despite this favorable response, surgical resection was recommended because of concerns regarding the patient's ability to comply with the intensive surveillance required for a non-operative management strategy.

Definitive surgery was performed approximately three months after completion of brachytherapy, and pathological examination revealed pathological complete response (ypT0N0) with no residual tumor identified.

Postoperatively, the patient received adjuvant capecitabine chemotherapy for three months. At the time of last follow-up, the patient remained disease-free after seven years, with no evidence of local recurrence or distant metastasis.

This case illustrates the potential role of salvage endoluminal HDR brachytherapy as a localized dose-escalation strategy in patients with residual rectal cancer following neoadjuvant chemoradiotherapy.

In this context, HDR endorectal brachytherapy should not be considered merely as a superficial "local boost" technique. Rather, it represents a spatially optimized dose-escalation strategy capable of delivering therapeutically meaningful radiation to the residual tumor bed while simultaneously depositing dose in tissues immediately adjacent to the rectal wall. This geometric dose distribution differentiates HDR brachytherapy from purely surface-based approaches and may contribute to improved control of limited residual disease located within the rectal wall or nearby mesorectal tissues. Consequently, in carefully selected patients with localized residual disease after neoadjuvant therapy, endoluminal HDR brachytherapy may serve as a valuable component of response-adapted treatment strategies aimed at maximizing tumor regression while preserving organ function.

FUTURE DIRECTIONS

Future research should focus on refining patient selection, technique standardization, and optimal sequencing of local dose escalation within modern total neoadjuvant treatment (TNT) paradigms. Advances in imaging-based response assessment—including MRI tumor regression grading, diffusion-weighted imaging, and emerging radiomic approaches—may help identify patients most likely to benefit from localized boost strategies rather than immediate radical surgery. In addition, circulating biomarkers such as circulating tumor DNA (ctDNA) may further improve risk stratification and guide individualized treatment pathways.[26]

Prospective comparative studies evaluating contact X-ray brachytherapy (CXB), HDR endorectal brachytherapy, and advanced external beam dose-escalation techniques are needed. Such studies should incorporate harmonized endpoints including clinical complete response, sustained organ preservation, non-operative management (NOM), feasibility of salvage surgery, and patient-reported functional outcomes in order to better define optimal treatment selection for different residual tumor phenotypes.[6,17]

At the technical level, further standardization of HDR brachytherapy techniques—including applicator design, spacer or balloon-assisted systems, adaptive image-guided planning, and consensus dose constraints for organs at risk—may improve treatment reproducibility across centers. Improved applicator technologies capable of optimizing tumor contact while reducing dose to the contralateral rectal wall and nearby pelvic organs may further enhance the therapeutic ratio of endoluminal brachytherapy.[5,18]

Finally, integration of localized dose-escalation strategies with intensified systemic therapy and structured surveillance protocols may expand safe organ-preserving pathways in rectal cancer. As multidisciplinary treatment strategies continue to evolve, localized brachytherapy techniques may play an increasingly important role within response-adapted management algorithms aimed at maximizing tumor regression while preserving rectal function and quality of life.[23,25]

Although organ preservation strategies were initially explored primarily in patients with cT2–T3 tumors, emerging data from total neoadjuvant therapy trials suggest that selected patients with more advanced T3–T4 or node-positive disease may also achieve clinical complete response. In such cases, a watch-and-wait strategy may be considered within structured surveillance programs and multidisciplinary decision-making. For patients with limited residual disease after neoadjuvant therapy, localized dose-escalation approaches such as contact X-ray brachytherapy or HDR endorectal brachytherapy may be considered in experienced centers before proceeding to definitive surgery.

Introduction

Conclusion

The management of rectal cancer is increasingly shifting toward response-adapted strategies that aim not only to achieve optimal oncologic control but also to preserve organ function and quality of life whenever feasible. Within this evolving paradigm, radiotherapy-based dose escalation has emerged as a promising approach to deepen tumor response beyond that achieved with conventional chemoradiotherapy alone.[2,6]

Contact X-ray brachytherapy and endoluminal HDR brachytherapy represent two complementary localized radiation techniques capable of delivering highly concentrated doses to the tumor bed while limiting exposure of surrounding pelvic structures. Although CXB produces extremely high mucosal surface doses with very limited penetration, HDR brachytherapy provides greater depth-dose distribution and may deliver therapeutically relevant doses to tissues immediately adjacent to the rectal wall, including limited intramesorectal extensions.[5,14,18] These differing physical characteristics suggest that the two modalities may serve distinct but complementary roles in response-adapted treatment strategies.

In the era of total neoadjuvant therapy, integration of systemic therapy with radiotherapy-based dose escalation may further increase complete response rates and expand opportunities for organ-preserving management.[23] Careful patient selection, accurate imaging-based response assessment, and multidisciplinary decision-making remain essential to identify patients most likely to benefit from such strategies. Response-adapted management following neoadjuvant therapy may enable organ preservation in selected patients, including watch-and-wait approaches in those achieving clinical complete response and localized dose-escalation techniques for patients with limited residual disease.

The illustrative case presented in this review demonstrates the potential role of salvage endoluminal HDR brachytherapy as a localized dose-escalation strategy in residual rectal cancer following neoadjuvant chemoradiotherapy. The achievement of pathological complete response and durable disease control in this patient highlights the capacity of targeted brachytherapy techniques to contribute meaningfully to response-adapted treatment paradigms.

As treatment strategies continue to evolve, further prospective studies are needed to clarify the optimal integration of localized brachytherapy techniques within modern multimodality treatment frameworks. Such efforts may help refine individualized therapeutic pathways aimed at maximizing tumor regression while preserving rectal function and avoiding unnecessary radical surgery.

Conclusion