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Radiotherapy & total neoadjuvant therapy for recurrent rectal cancer in previously irradiated patients, (RETRY): a multicenter prospective observational study

Radiation Oncology volume 19, Article number: 174 (2024) Cite this article

Abstract

Background

Local recurrence of rectal cancer (LRRC) previously treated with radiotherapy is associated with a poor prognosis. Historically, the integration of radiotherapy (RT) with surgery has improved the likelihood of complete resections (R0) and, consequently, enhanced survival. Unfortunately, many LRRC cases are not amenable to surgical intervention. The inclusion of chemotherapy (CHT) alongside advanced RT techniques including proton and carbon ion RT (CIRT) and stereotactic body radiation therapy (SBRT), has generated new treatment options. Therefore, there is a need for improved stratification of LRRC patients to enhance treatment outcomes. The RETRY is an integrated trial with the primary aim to explore if combining CHT with RT in all available modalities can enhance local control (LC) in LRRC patients, consequently improving survival.

Methods

Experts from Italian centers specializing in rectal cancer and LRRC management collaborated to design a prospective multicenter observational study within the AIRO group for gastrointestinal malignancies. Eligible participants are adult LRRC patients who previously had pelvic RT, meet specific criteria, and are affiliated with the participating Italian centers. Specific criteria must be met for CIRT referral. A total of 88 patients will be enrolled over three years. The primary objective is to determine the 3-year LC rate. Secondary outcomes include assessing survival, quality of life, and R0 resection rates in surgery cases. A minimum dose of 40 Gy, conventional fractionation with concomitant fluoropyrimidine—with/without oxaliplatin-based CHT (CRT) is prescribed in neoadjuvant setting. Alternatively, the dose will vary from 35 to 40 Gy in 5 fractions based on clinical judgment, by SBRT. Both proton and photon therapies will be evaluated in these approaches. Surgery will be considered if deemed operable. In inoperable cases, CIRT with a dose of 40–60 Gy relative biological effectiveness (RBE) will be administered with a daily dose fraction ranging between 3 and 4.8 Gy RBE.

Discussion

The RETRY trial aims to investigate the combined effects of RT and CHT and when feasible the addition of surgery, to determine whether this comprehensive approach can result in improved survival and quality of life for LRRC patients.

Trial registration number ClinicalTrials.gov (No. NCT05984576).

Background

Local recurrence of rectal cancer (LRRC) is a rare condition, accounting for 4–8% of cases [1,2,3].

Approximately one-third of LRRC are asymptomatic and are diagnosed during a follow-up evaluation, while the others present for clinical observation because of rectal bleeding, change in bowel habits, pain (more likely related to involvement/compression of other organs, bones or nerves), nonhealing perineal wound (especially after abdominoperineal resection), perineal mass, bowel obstruction, etc.

Surgery for local recurrence without residual disease (R0) is the most important factor associated with survival, and a negative resection margin is the most important predictor of disease-specific survival [4]. In fact, LRRC surgery is very complex because of the change in anatomical planes due to previous medical and surgical treatment.

An alternative non-surgical approach is represented relapse reirradiation, which can increase the rate of optimal resection (R0) and provide symptomatic relief for unresectable disease with a symptom relief rates of 82–100%, an acute toxicity rates of 9–20%, and lack of data on chronic toxicity [5,6,7,8]. Re-irradiation is also challenging due to the need to balance the doses to previously received organs at risk (OARs) and deliver an effective dose to the disease. However, when successful, reirradiation can lead recurrence to surgery with a high resectability rate [6, 9] or potentially provide better disease control if surgery is not feasible [10].

Therefore, several strategies can be employed to enhance the effect of radiotherapy (RT), such as the addition of radiosensitizing chemotherapy (CHT), the administration of adjuvant CT, or the use of advanced RT techniques such as stereotactic body radiation therapy (SBRT) or proton/carbon ion therapy (PT/CIRT). As per SBRT retrospective studies have shown median progression free survival (PFS) rates of 12.1 months and overall survival (OS) rates ranging from 28.3 to 38.7 months, respectively, with acceptable toxicity rates, providing encouraging data in a population that is ineligible for or refuses surgery [11, 12]. As per PT, it is intriguing for its excellent sparing of healthy tissue, providing a dosimetric advantage with a steep dose gradient and a consistent reduction in the bath dose, which should be reflected in reduced acute and late toxicity [13,14,15]. For this reason PT is included in the current Levels of Essential Care (LEAs) in Italy in case of reirradiation.

Furthermore, CIRT is a promising treatment option for patients with LRRC who are not candidates for resection [16]. Due to its radiobiological properties and the relative biological effectiveness that is 2–4 times higher than that of photons, CIRT may be more advantageous in a setting that is biased by radioresistance, hypoxia, and proximity to already irradiated intestinal loops.

Based on the radioresistance of LRRC either for their histology, are mostly adenocarcinoma, either for the high proportion of hypoxic cells and because of their typical location near the gastrointestinal tract, heavy ion beams could be advantageous both for the physical selectivity of particles with the high dose gradient and for the effectiveness of their radiobiology, with an RBE reported between 2 and 4 times higher than photons. Yamada et al. [16]in a recent update on CIRT experience in the treatment of gastrointestinal disease describes excellent results for patients re-irradiated for LRRC with a three-year local control (LC) rate of 85.9% with a three-year OS rate of 64.5%, results comparable to series of resected patients.

The rationale for the RETRY trial is based on the hypothesis that total neoadjuvant therapy (TNT) with re-irradiation, based on the most advanced RT techniques, followed by consolidation CHT, is an effective method to improve outcomes in LRRC patients previously irradiated to the pelvis.

The objective of this multicenter, prospective, observational study is to evaluate the efficacy in terms of local control and safety of TNT. Highlights of this study include the high degree of treatment individualization through both accurate selection and highly conformal RT planning.

Materials and methods

Study design

RETRY is a multicenter prospective observational study. Figure 1 describes the proposed treatment algorithm.

Fig. 1
figure 1

RETRY protocol workflow. Surgery is considered if R0 resection could be achieved. Operable patients may be high-risk resectable or borderline resectable, with treatment options including chemoradiotherapy (CRT), stereotactic body radiation therapy (SBRT) (photons or protons), followed by chemotherapy (CHT). In cases of inoperability, carbon ion radiation therapy (CIRT) is the preferred choice, followed by CHT if criteria are met. If not, SBRT may be considered, and if both CIRT and SBRT are not feasible, CRT followed by CHT is an option. CRT chemoradiotherapy; SBRT stereotactic body radiation therapy: CIRT carbon ion radiation therapy; CHT chemotherapy; FUP follow-up; BSC: best supportive care

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Study objectives

The study will enroll adult patients with LRRC who have previously undergone pelvic RT, according to the inclusion and exclusion criteria, afferent to the Italian centers partecipating in the study.

The primary endpoint of this study is to assess the 3-years LC rate. Secondary objectives are to evaluate the response rate (partial response rate + complete response rate); complete response (CR) (both pathological and clinical); PFS, distant metastasis free survival (DMFS) and OS rate; bleeding control (rate and time); pain control (rate and time); toxicity (assessed by CTCAE scale 5.0 version); quality of life (QLQ-C30, QLQ-CR29 and LARS in patients without stoma [17, 18]). For operable and resectable/marginally resectable patients, we will also evaluate: R0-RR (number of R0 resections/total of patients); R0-R1 RR (number of R0-R1 resections/total of patients); resectability Rate (number of resections/total of patients), disease free survival (DFS) rate.

Ethics informed consent and safety

The final protocol was approved by the Ethics Committee of Fondazione Policlinico Universitario “A. Gemelli”, IRCCS of Rome, Italy (ethics committee identifier code 5579). Any change in the protocol that may affect the conduct of the trial, potential patient benefit, or safety, such as changes in the trial objectives, trial design, patient population, sample size, study procedures, or significant administrative aspects, will require a formal protocol amendment. This amendment must be approved by the Ethics Committee. Patient recruitment will be extended to the other affiliated Italian hospitals (“SS Annunziata” Hospital, “G. d’Annunzio” University, Chieti; Responsible Research Hospital, Campobasso; Azienda Ospedaliera Universitaria delle Marche, Ancona; CNAO, National Center of Oncological Hadrontherapy, Pavia; IEO European Institute of Oncology, IRCCS, Milan) and any other centers that wish to participate, after approval of the protocol by their respective Ethics Committees.

This trial conforms to the latest version of the Declaration of Helsinki and complies with Italian laws and regulations. The protocol has been designed according to the principles of Good Clinical Practice (GCP). Patients will be fully informed of the rationale for the treatment, the potential benefits, and the possible side effects before voluntarily signing the informed consent form. No procedures are performed until the informed consent form has been properly signed.

Study duration and setting

The study will run from the approval of the present protocol by the Ethics Committee of the coordinating center and the satellite centers, and patients will be recruited for the following 3 years. A follow-up of 5 years is planned, for an overall study duration of 8 years.

Stratification

Inclusion and exclusion patient characteristics are listed in Table 1.

Table 1 Inclusion and exclusion criteria
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Variables and procedures

Patients are initially evaluated by magnetic resonance imaging (MRI) (if not contraindicated) and whole body computed tomography (CT) and/or positron emission tomography (PET) scan, according to clinical judgment. Patients will be determined to be eligible for re-RT after multidisciplinary tumor board discussion (onsite/online with referral center). The recurrence will be anatomically classified according to the Royal Marsden Group classification [19] shown in Table 2, based on the location and pattern of pelvic invasion.

Table 2 Royal Marsden group classification of pelvic recurrences describing the pattern of pelvic invasion (structures with each compartment) [19]
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Surgery will be proposed if an R0 resection can be achieved. The main contraindications for surgery are extensive or multiple infiltration of the pelvic wall, extensive infiltration of the iliac vessels or the patient is unfit for extensive surgery [20]. In this setting, the patient may be referred for chemoradiotherapy (CRT) and SBRT (either photon or proton) followed by CHT, at the physician’s discretion. If unresectable, CIRT will be the first choice. If the inclusion criteria for CIRT are met and a dosimetric advantage is demonstrated, the patient may proceed with CIRT followed by CHT. These criteria are shown in Table 3. Otherwise, if the inclusion criteria and/or dosimetric advantage for CIRT are not met, the patient may be evaluated for SBRT, and if neither is feasible, the patient may be referred for CRT followed by CHT.

Table 3 CIRT inclusion and exclusion criteria
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Patients will be examined by the radiation oncologist at the baseline visit, who will obtain all necessary information regarding the patient’s medical history and perform the digital rectal examination (DRE) if feasible. The presence of rectal bleeding and pain will be recorded using the visual analog scale (VAS) [21].

Unexpected serious adverse events are managed by the medical staff and recorded by the study data manager.

Quality of life questionnaires (QLQ-C30, QLQ-CR29 and LARS in patients without ostomy) [17, 18] will also be administered at subsequent follow-up visits.

Radiotherapy setting

The technological equipment and workflow of simulation and planning is at the discretion of the individual Centre and will include conventional LINACs capable of delivering IMRT/VMAT, MRI hybrid LINACs [22] and the Hadrontherapy synchrotron/cyclotron capable of delivering carbon ions or protons. Patients will be simulated in supine or prone position, using dedicated immobilization systems, at the discretion of the each center.

If hadrotherapy is to be performed, dose optimization will be facilitated by the use of an allograft mesh or omentum as spacer to protect the overlying small bowel and bladder. The need for a spacer in patients is discussed based on the patient’s history of previous radiation and surgery. Allograft mesh is a common material used in general and gynecologic surgery for tissue reinforcement; and for its desirable safety profile and relatively low risk of infection. Laparoscopic technique will be utilized given concurrent need for lysis of adhesions at the time of placement.

In case of hadrontherapy (either CIRT and protons) is to be carried out, the patient will be immobilized in the supine or prone position depending on the location of the target volume with a custom-made thermoplastic body mask (the latter is mainly used for patients treated with CIRT). A set of CT images of 2 mm thickness will be acquired for treatment planning. Contrast-enhanced MRI will be performed for accurate gross tumor volume (GTV) identification. MRI scans will be performed in the treatment position and with immobilization devices, using specific protocols. MRI scans will be rigidly registered to the planning CT.

Organ filling protocols are recommended to ensure the reproducibility of the treatment. If magnetic resonance guided RT (MRIgRT) is to be used, the simulation phase will also include the hybrid linear accelerator simulation study in order to acquire the MR scans required for planning and target motion assessment.

GTV will be represented by the tumour recurrence and enlarged pelvic lymph-nodes detected on MRI and/or CT and/or PET-CT scan diagnostic images and shown on the simulation CT scan. Any area of recurrence observed on the OARs should be included. The clinical target volume (CTV) will include the GTV with a margin of at least 10 mm, adjusted for bone anatomy, if not clinically involved in disease recurrence [23]. The planning target volume (PTV) will be created from the CTV with an isotropic expansion of 5–10 mm, while, in the case of SBRT, the GTV = CTV and the GTV-PTV margins may be reduced to 3–5 mm, depending on the image guided radiotherapy (IGRT) used in the individual Centre, random and setup errors and internal organ motion, following the rule proposed by Abusaris et al. [23, 24] with minor differences, due to the nature of the study. During delivery, the application of daily IGRT protocols is strongly recommended according to the discretion of the individual center.

The OARs to be contoured are the bladder, the femoral heads, the small bowel and large bowel loops, the roots and branches of the cauda equina, the sacral plexus, the bone marrow and the anal canal.

Dose limits for OARs will be assessed according the ALARA criterion and the recommendations of the Abusaris et al. and Murray et al. studies [24, 25], according to which the maximum cumulative dose is 110 Gy3 with a maximum of 10 cc of tissue for the rectum and bowel and 120 Gy3 with a maximum of 10 cc of tissue for the bladder. In addition, Murray et al. [25] suggest subtracting the previous dose from the traditional constraint, or, if this is not possible, suggest assuming a degree of repair of up to 50% depending on the time interval before re-irradiation.

In the case of IMRT/VMAT technique or SBRT technique, the dose should be reported according to the ICRU (International Commission on Radiation Units and Measurements) Report 83 [26] and Report 91 [27], respectively. For CIRT and protons, the dose will be reported according to the ICRU report 93 and 78, respectively [28, 29].

Radiotherapy will be delivered with a dose of 40–50 Gy in 1.8–2 Gy daily fractions. SBRT can be delivered with a total doses of 35–40 Gy in 5 fractions, with respect to OARs constraints. Protontherapy can be administered with either a standard (40–50 Gy 1.8–2 Gy daily fraction) and hypofractionated (35–40 Gy in 5 fraction) schedule depending on tumor size and location. The pencil beam technique will be used and a robust plan optimization will be applied. CIRT will be delivered to the CTV including GTV plus a 0.5–1 cm margin, depending on the different sites of recurrence and the clinical situation, with a total dose ranging between 40 and 60 Gy relative biological effectiveness (RBE), in a daily dose/fraction between 3 and 4.8 Gy RBE/fraction (based on cumulative constraints on OARs evaluated with appropriate dose conversions, 4 or 5 fractions per week).

Chemotherapy setting

Concomitant chemoradiation

Concurrent CHT will be administered using 5-fluorouracil (5-FU protracted intravenous infusion, 225 mg/m2/day, 7 days per week) or capecitabine (1650 mg/m2/day bid or chronomodulated 5 days per week) + / − 4 cycles of oxaliplatin (50 mg/m2), according to medical judgment. In case the of either SBRT or CIRT, concurrent CHT will not be considered.

Consolidation/adjuvant chemotherapy

At the end of CRT, all patients will undergo further cycles of chemotherapy (at least 3 cycles), according to FOLFOX6 (racemic leucovorin 200 mg/m2 or 400 mg/m2, at the discretion of the treating investigator, oxaliplatin 85 mg/m2 in a 2 h infusion, fluorouracil bolus 400 mg/m2 on day 1, and a 46-h infusion of fluorouracil 2400 mg/m2, every 2 weeks) or, in poor clinical conditions, the de Gramont regimen (FU bolus 400 mg/m2 + FU continuous infusion 600 mg/m2 + folinic acid 100 mg/m2 on days 1 and 2, every 2 weeks). In any case all patients must be restaged (local and distant) after 3 months from the end of RT, except those deemed for resection.

If the tumor is resectable, at 12–13 weeks after the start of CRT, patients will be evaluated for tumor resectability, and, if feasible, surgical resection of the recurrence will be performed no more than 2 weeks later.

If the tumor is resectable, the patient will undergo surgery, followed by further cycles of CHT if clinically indicated, or follow-up as determined by the multidisciplinary tumor board. If the patient is considered inoperable, or if he/she has received SBRT or CIRT, he/she may receive further CHT after re-evaluation, a new line of CHT or targeted therapy if disease progression (PD), or be followed according to a follow-up plan or best supportive care (BSC), depending on the decision of the MDTB.

Follow-up

Patients will be followed-up during RT treatment, and acute toxicities will be reported according to the CTCAE 5.0 version scale. Thereafter, they will be perform follow-up visits (see Table 4), whether they have surgery or not (bi- or tri-monthly), based on the individual Centre’s follow-up schedule, with clinical examination, DRE and MR, CT or PET imaging depending on clinical judgment.

Table 4 Follow-up schedule
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Statistical analysis plan

Sample size calculation

RC 5 years-incidence is of 150.000 cases. The overall relapse rate has been estimated as the 5%, i.e. 150 cases/year. A previous study from our group in 2006 showed a control rate of 46.6% at 3 years [6]. The recent advances in the last 15 years allow us to assume an increase in the LC rate of 15%, i.e. an expected control rate of 61.6 Assuming a power of 80% with a two-sided 95% confidence interval, with 3 years of accrual and 3 years of follow-up, 80 patients will be needed to achieve the primary outcome, with an expected number of events of 36. Assuming a drop-out rate of 10%, the sample size to be enrolled is 88 patients. The sample size calculation was performed using the PASS2022 statistical software with a two-sided one-sample log-rank test [30]. The number of patients expected to be enrolled at the promoting centre is 30.

Translational research

Radiomic analyses will be considered on staging and restaging imaging as part of the study. Biospecimens, when available, will be collected and preserved for future molecular assessments, enhancing our understanding of the underlying molecular characteristics.

Statistical analysis

The sample will be described in its clinical and demographic characteristics by descriptive statistics techniques. In depth, qualitative data will be expressed as absolute and relative percentage frequency, whilst quantitative variables either by mean and standard deviation (SD) or median and interquartile range (IQR), as appropriate. To verify the Gaussian distribution of quantitative variables, the Shapiro–Wilk test will be applied.

In the case of missing values, this will be treated by imputeRR package, using multiple imputation with Lasso Regression methods centered on the mean as for quantitative data, whilst classification trees for imputation by “rpartC” function, centered on the mode, i.e. most represented class object, will be applied on qualitative data [31].

CR will be defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis < 10 mm and PR will be defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters [32]. The 3y-LC rate will be defined as absence of tumor relapse (in resected patients) or tumor progression (in patients without resection or with macroscopic residual disease) assessed over the 3-year time interval. PFS is defined as the duration of time from start of treatment to time of distant or local progression, or death, whichever occurs first. DMFS is defined as the time from the end of RT-treatment to event of distant progression or death from any cause. OS is defined as the time from pathologic tissue diagnosis to death from any cause. Both primary endpoint (i.e. 3y-LC rate) and secondary (i.e., Response Rate, PFS,CR, DMFS, OS) will be computed by the Kaplan Meier analysis by using R package “survival” [33, 34]. Kaplan Meier curve will be further depicted by using “ggplot2” and “survminer” R packages [35, 36].

Resected is considered a patient with no residual disease (R0) or with microscopic (R1) or macroscopic (R2) residual disease after surgical excision. The target lesion’s response to treatment will be assessed by diagnostic imaging (MRI, CT or PET-CT) required during follow-up. For operable and resectable/marginally resectable patients, R0-RR, R0-R1 RR and Resectability Rate will be further computed as absolute and relative percentage frequency.

Acute and Late toxicity will be reported by descriptive statistics, as well as quality of life, in terms of QLQ-C30, QLQ-CR29 and LARS questionnaires scores [17, 18], in the overall population. Further analyses will be conducted analyzing variations over time in the QoL and in all variable measured overtime. For repeated measurement analyses, a mixed model for repeated measures will be applied, either generalized (GMMRM) or not (MMRM), according to the type of variable analyzed. In depth, correlations between repeated measures will be modelled using a repeated effect with a compound-symmetry structure. Models will be fitted with “lme4” and “lmertest” R packages [37, 38]. In order to use these models on small samples, a Bartlett-like adjustment will be made by bootstrap resampling with the “pbkrtest” R package [39]. As the chi-square distribution in large samples is not accurate on a low scale, Bartlett’s correction divides by a correction term, with the adjustment term being a first-moment estimate of the null distribution of the T-statistic.

Fluctuations of the different parameters over time wiil be further represented by “violin plots”, by using R packages “ggpubr” [40], ““ggstatsplot” [41], “ggplot2”, “ggprism” and “ggsignif” [35, 42, 43].

P-values < 0.05 will be considered statistically significant. Suggestive p values will also be reported (0.05 < p < 0.10). All analyses will be conducted with R software, version 4.2.0 (CRAN®, R Core 2022, Vienna, Austria) [44].

Discussion

The multicenter, observational RETRY study is designed to evaluate the role of various modalities of RT in combination with CHT in patients with LRRC. The study also aims to determine whether CHT, when combined with RT, provides additional value in the treatment of LRRC patients, specifically in terms of 3-year LC. Re-irradiation of LRRC in previously irradiated patients is a complex clinical challenge that requires a nuanced approach to balance therapeutic efficacy and potential toxicity in a multidisciplinary setting, as this patient population has historically had a poor prognosis.

As previously mentioned, achieving an R0 resection is pivotal for improving survival in LRRC patients [4, 45] with only a minority, around 20–30% [46], able to undergo surgery with clear margins.

This limitation is often attributed to comorbidities or the presence of disease that presents a surgical challenge to removal, influenced by factors such as location, size, and infiltration of adjacent tissues. As a result, the majority of LRRC patients require extensive surgery with a significant risk of complications to achieve a potential cure.

In this context, the combination of reirradiation with consolidation CHT in the neoadjuvant setting of LRRC offers potential benefits such as tumor size reduction, improved R0 resection rates, local disease control, symptom relief, early management of micrometastases, and improved OS. However, the associated risks of CHT-related and cumulative RT-related toxicity must be carefully weighed against the benefits of achieving curative resection and effective disease control, considering their impact on postoperative outcomes and patients’ overall quality of life.

Currently, some ongoing trials are investigating the optimal treatment for patients with LRRC. The randomized Phase III GRECCAR15 trial compares induction CHT, CRT and surgery to induction CHT and surgery in previously irradiated patients, with R0 resection rate as the primary outcome measure [47]. The PelvEx II trial is a multicenter, randomized phase III trial comparing the efficacy of induction CHT followed by neoadjuvant chemo(re)irradiation and surgery to neoadjuvant chemo(re)irradiation and surgery alone. The primary objective is to increase the rate of R0 resections [48].

The RETRY trial aims to evaluate the role of consolidation CHT after RT or CRT, in contrast to the previously mentioned trials using induction CHT. This approach is based on the recent literature TNT for locally advanced rectal cancer, which suggests better outcomes in terms of higher pathological complete response and better compliance with CRT, when utilizing consolidation CHT along with CRT instead of induction CHT [49].

Despite neoadjuvant treatment, a significant number of patients with unresectable LRRC do not undergo surgery. Therefore, the primary outcome for the entire study cohort is selected as 3-year local control (LC), emphasizing the importance of local disease control for symptom management and quality of life.

For these patients with unresectable LRRC, given the evolution of RT technologies and oncological treatments, efforts should be made to find the best integration of treatments.

Several RT options are available, including IMRT, SBRT, CIRT, PT, and MRgRT. A recent systematic review analyzed the impact of different RT techniques in the treatment of LRRC, including patients treated with IMRT, CIRT and SBRT, reporting OS rates between 90 and 73% and LC rates between 89% and 71.6%. The authors report variable toxicity rates, but higher tolerability profiles compared to 3D conformal techniques, emphasizing the need for comparative studies to determine the optimal technique, considering the site of recurrence. Comparison with surgery and exploration of combined approaches, along with ongoing research into biologic breakthroughs and non-pharmacologic therapies, highlight the evolving landscape of LRRC treatment [50].

Despite this, a lack of consensus on recommendations for indications, doses, and treatment techniques persists [50, 51].

The potential for future RT trials in the LRRC is significant and aims to address treatment heterogeneity by exploring the optimal dose, timing, volumes and RT techniques to maximize treatment efficacy and personalize care for this diverse patient population, as demonstrated by a recent survey in Italy [51].

It is expected that the results of this RETRY study, based on the collective interest of leading Italian centers specialized in the treatment of rectal cancer and LRRC, will foster collaboration and improve outcomes for LRRC patients.

The ultimate goal is to help guide clinical practice in the decision-making process.

Conclusion

In conclusion, re-irradiation for recurrent rectal cancer is a dynamic field in which integration of evidence from multiple studies is essential. Careful consideration of patient-specific factors, technological advances, and emerging molecular insights will be critical to optimizing treatment strategies and improving the overall therapeutic index in this challenging clinical scenario.

Availability of data and materials

The datasets used analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Dr. Pia Clara Pafundi from the Gemelli Generator Facility of Epidemiology and Biostatistics at Policlinico Agostino Gemelli IRCCS Rome for assistance with statistics and sample calculation. We extend our gratitude to Dr. Elisa Meldolesi for her role in conceptualizing and providing comprehensive clinical evidence, enabling the formulation of this trial. We would like to express our sincere appreciation to the Reviewing Committee, consisting of Prof. Domenico Genovesi, Dr. Marco Lupatelli, Dr. Elisa Palazzari, Dr. Ester Orlandi, Prof. Pierfrancesco Franco, Prof. Liliana Belgioia and Prof. Stefano Pergolizzi, for their meticulous review process, which has played a crucial role in ensuring the quality and accuracy of this manuscript. We are also deeply grateful Prof. Vincenzo Valentini and Dr. Antonino De Paoli, members of the Advisory Board. Their expertise and thoughtful feedback have significantly enriched the content of this publication.

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Authors and Affiliations

  1. Department of Diagnostic Imaging, Radiation Oncology and Haematology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy

    Maria Antonietta Gambacorta, Angela Romano & Giuditta Chiloiro

  2. Radiation Oncology Unit, “SS Annunziata” Hospital, “G. d’Annunzio” University, Chieti, Italy

    Luciana Caravatta

  3. Responsible Research Hospital, Campobasso, Italy

    Gabriella Macchia

  4. Radiation Oncology Unit, Internal Medicine Department, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy

    Elena Galofaro & Giovanna Mantello

  5. Scientific Direction, CNAO, National Center of Oncological Hadrontherapy, Pavia, Italy

    Francesca Valvo

  6. Clinical Department, CNAO, National Center of Oncological Hadrontherapy, Pavia, Italy

    Viviana Vitolo

  7. Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, Milan, Italy

    Daniela Alterio

Authors
  1. Maria Antonietta Gambacorta
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  2. Angela Romano
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  3. Luciana Caravatta
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  4. Gabriella Macchia
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  5. Giuditta Chiloiro
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  6. Elena Galofaro
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  7. Francesca Valvo
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  8. Viviana Vitolo
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  9. Daniela Alterio
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  10. Giovanna Mantello
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Contributions

MAG, LC, GMac, GMan, VV, and FV contributed to the conceptualization and design of the study. AR was responsible for writing the manuscript and providing administrative and technical support. GC conducted the data analysis, with support from EG. MAG, LC, GMac, GMan, VV, FV and DA contributed to the critical revision of the manuscript. All authors participated in drafting the manuscript, approved the final version to be published, and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Angela Romano.

Ethics declarations

Ethics approval and consent to participate

The final protocol received approval from the ethics committee of Fondazione Policlinico Universitario “A. Gemelli”, IRCCS of Rome, Italy (ethics committee identifier code 5579). Any modification to the protocol that could impact the study execution, potential patient benefit, or safety, such as changes in study objectives, study design, patient population, sample size, study procedures, or significant administrative aspects, will require a formal protocol amendment. This amendment must be endorsed by the Ethics Committee. Patient recruitment will extend to the other affiliated Italian hospitals (“SS Annunziata” Hospital, “G. d’Annunzio” University, Chieti; Responsible Research Hospital, Campobasso; Azienda Ospedaliera Universitaria delle Marche, Ancona; CNAO, National Center of Oncological Hadrontherapy, Pavia; IEO European Institute of Oncology, IRCCS, Milan) and any centres that would like to participate, after approval of the protocol by their respective ethics committees. This study adheres to the latest version of the Declaration of Helsinki and complies with Italian laws and regulations. The protocol has been written according to the principles of good clinical practice (GCP). Patients are provided with comprehensive information about the rationale for the treatment, the potential benefits and the possible side effects before they voluntarily sign the informed consent form. No interventions are performed until the informed consent form has been duly signed.

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Not applicable.

Competing interests

All authors declare that they have no competing interests.

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Gambacorta, M.A., Romano, A., Caravatta, L. et al. Radiotherapy & total neoadjuvant therapy for recurrent rectal cancer in previously irradiated patients, (RETRY): a multicenter prospective observational study. Radiat Oncol 19, 174 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13014-024-02555-x

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Keywords

Radiation Oncology

ISSN: 1748-717X

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