Abstract
Background/Aim: The aim of the study was to investigate boost volume definition, doses, and delivery techniques for rectal cancer dose intensification. Patients and Methods: An online survey was made on 25 items (characteristics, simulation, imaging, volumes, doses, planning and treatment). Results: Thirty-eight radiation oncologists joined the study. Twenty-one delivered long-course radiotherapy with dose intensification. Boost volume was delineated on diagnostic magnetic resonance imaging (MRI) in 18 centres (85.7%), and computed tomography (CT) and/or positron emission tomography-CT in 9 (42.8%); 16 centres (76.2%) performed co-registration with CT-simulation. Boost dose was delivered on gross tumor volume in 10 centres (47.6%) and on clinical target volume in 11 (52.4%). The most common total dose was 54-55 Gy (71.4%), with moderate hypofractionation (85.7%). Intensity-modulated radiotherapy (IMRT) was used in all centres, with simultaneous integrated boost in 17 (80.8%) and image-guidance in 18 (85.7%). Conclusion: A high quality of treatment using dose escalation can be inferred by widespread multidisciplinary discussion, MRI-based treatment volume delineation, and radiation delivery relying on IMRT with accurate image-guided radiation therapy protocols.
- Rectal cancer
- dose intensification
- intensity modulated radiotherapy
- simultaneous integrated boost
- gross tumor volume
A correlation between radiation therapy (RT) doses and tumor response has been reported in rectal cancer (1). Indeed, a dose intensification strategy has been investigated to improve oncological outcomes and pathologic complete response (pCR) rate, as favourable prognostic factor (2, 3) in locally advanced rectal cancer (LARC) patients (4, 5), especially in those less likely to respond to preoperative long-course radiotherapy (LCRT) or to select patients for organ-preserving. A high rate of pCR has been reported when the administered dose was escalated up to 50-60 Gy (30% vs. 12-15% in standard treatment) (6-14).
Preoperative intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) have also resulted in a high rate of pCR with a low acute toxicity profile, excellent compliance to treatment (8-10) and effectiveness in several prospective phase II studies (15-28) and in an Italian pooled analysis (29).
Although international guidelines suggest dose intensification up to 54 Gy in cases of high risk tumor (bulky disease or circumferential resection margin involvement) (30, 31), some issues regarding boost planning and delivery (i.e. volumes definition, best imaging for delineation, and delivery technique) are still debated. Based on these considerations, a national survey was proposed by the Italian Association of Radiation and Clinical Oncology (AIRO) gastrointestinal study group aimed at evaluating the pattern of care in the setting of dose intensification at the national level.
Patients and Methods
In May 2019, an online survey was set up within www.surveymonkey.com. Members of AIRO gastrointestinal study group were individually contacted by email to request their willingness to participate in the survey. An expertise in rectal cancer treatment was required based on the professional experience and their involvement in a multidisciplinary team for rectal cancer treatment. Dose intensification was defined as a total dose up to 54 Gy (>2 Gy fraction), or more than 54 Gy.
Questionnaire. The questionnaire comprised 3 main sections and 25 items focused on: centre characteristics (5 items), simulation (3 items), imaging (4 items), volumes and doses (5 items), planning and treatment (8 items). Most of these questions were close ended questions, including quantitative and multiple-choice answers, besides the opportunity for free text comments.
Section 1: Patient care and therapeutic approach. Centre’s characteristics (public, private, university), number of LARC patients treated every year, professional members of the Interdisciplinary Group for Cancer Care, and type of diagnostic imaging were investigated.
Section 2: Simulation. Patient set-up, immobilization, and use of Iodinated contrast medium during CT simulation were explored.
Section 3: Planning and delivery. Selection criteria for dose intensification, imaging for boost delineation, boost volume definition, margins applied to generate the planning target volume (PTV), boost technique, image-guided RT (IGRT) protocols, and chemotherapy schedules were evaluated.
Statistics. The statistical analysis was provided by www.surveymonkey.com and included a description of all variables. Responses were tabulated, and the percentage values are reported.
Results
Thirty-eight centres (Public=27, Private=7, University=4) of different Italian regions (northern Italy:25, center:8, south:5) joined the survey.
Section 1: Patient care and therapeutic approach. Fourteen centres (36.8%) declared to treat >30 patients per year with dose intensification preoperative LCRT, and 11 (28.9%) between 10-20 patients. All centres reported case discussion by the Interdisciplinary Group for Cancer Care, where different specialists were involved: Radiation Oncologist= 100%, Medical Oncologist=100%, Surgeon=100%, Radiologist=86.1%, Endoscopist=75%, Pathologist=69.4%, Nuclear Medicine physician=27.8%; Psychologist=11.1%, Geneticist=5.6%, Anesthesiologist=2.8%, Geriatrician=2.8%, Nutritionist=2.8%. Preliminary exams requested in all centres for diagnosis and staging are reported in Figure 1.
Preliminary exams requested in all centres for diagnosis and staging. CEA: Carcinoembryonic antigen; CT: computed tomography; MRI: magnetic resonance imaging; FDG-PET: fluorodeoxyglucose - positron emission tomography.
Section 2: Simulation. Immobilization devices were used in 35 centres (92.1%), including belly board in 47.37% of cases. Irradiation in the prone or supine position were equally preferred.
Iodinated contrast medium was administered during CT simulation in one centre; Fluorodeoxyglucose-positron emission tomography (FDG-PET) simulation (with same treatment set-up position) was routinely used in 3 centres (7.9%) and for specific indication in 8 centres (21.1%); Magnetic resonance imaging (MRI) simulation (with same treatment set-up position) was routinely used in 5 centres (13.2%) and for specific indications in 3 centres (7.9%). In 26 centres (68.4%) an empty bladder filling protocol was used.
Section 3: Planning and delivery. Twenty-one centres declared to perform dose intensified preoperative LCRT. Table I shows the selection criteria for dose intensification. Volumes delineation: Boost volume was delineated on diagnostic MRI in 18 centres (85.7%), and on CT scan and/or FDG-PET-CT in 9 centres (42.8%). Co-registration with CT simulation was always performed in 16 centres (76.2%), for selected cases in 3 centres (14.3%) and never in 2 centres (9.5%). A boost dose was delivered on the gross tumor volume (GTV) in 10 centres (47.6%), and on the clinical target volume (CTV) in 11 centres (52.4%). Detailed areas included in the boost volume are shown in Table II. PTV for the boost volume was generated as an isotropic, anisotropic and adapted margin in 16 (76.1%), 3 (14.3%) and 2 (9.5%) centres, respectively.
Selection criteria for dose intensification.
Detailed areas included in the Boost volume delivered on the gross tumor volume (GTV) and clinical target volume (CTV), respectively.
Dose and fractionation schedule. SIB is the preferred modality for boost delivery (17 centres=80.8%). Daily sequential or concomitant boost was delivered in 4 (19%) and 3 (14.3%) of the institutions, respectively. Boost was delivered up to a total dose of 54-55 Gy in15 centres (71.4%), and >55 Gy (range=56-61.6 Gy) in 6 centres (28.6%), with moderate hypofractionation in 19 centres (90.5%).
Techniques. Intensity-modulated radiotherapy (IMRT) was used for dose intensification treatment in all the centres. Three-dimensional conformal radiotherapy (3D-CRT) is alternatively used in 1 centre. Image-guided RT (IGRT) is used in 18 centres (85.7%). Modality and protocols are shown in Figure 2.
Image-guided radiation therapy (IGRT) modality (a) and protocols (b). kV EPI: kV Electronic portal imaging; MV EPI: MV electronic portal imaging; kV CBCT: kV cone-beam computer tomography; MV CBCT: MV cone-beam computer tomography.
Concurrent chemotherapy. Nineteen (90.5%) out of 21 centres offered dose intensified radiotherapy with concurrent chemotherapy: Capecitabine (17 centres=89.4%), 5-FU (1 centre=5.2%) or 5-FU plus oxaliplatin (FolOx, 2 centres= 10.5%).
Intensified treatment employing chemotherapy was also investigated. Induction chemotherapy was given in selected patients in 13 centres (42.8%). Consolidation chemotherapy (post-RT and before surgery) was administered in selected cases in 4 centres (19%). Selection criteria for patients treated with induction or consolidation chemotherapy and treatment schedules are shown in Table III. FolOx is the preferred schedule prescribed for both induction (61.5%) and consolidation (66.7%) chemotherapy.
Selection criteria for patient treated with induction or consolidation chemotherapy and treatment schedules.
Discussion
The clinical outcome of LARC patients is largely dependent on tumor response to chemo-radiotherapy (CRT) (1, 2). A pCR rate of 26.7%, with TRG1-2 rate of 41.8%, was shown in a dose intensification study of 322 patients with LARC. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively (32). Moreover, an exponential increase in pCR-rate after neoadjuvant radiation dose ≥60 Gy, has been shown by mathematical and clinical dose–response prediction models (pCR=50% with >92 Gy) (6). These data were confirmed by a systematic review and meta-analysis of 14 studies on 487 patients treated with ≥60 Gy, reporting high pCR-rates (20.4%; 95%CI=16.8-24.5%) with acceptable early toxicity (grade ≥3 toxicity in 10.3%; 95%CI=5.4-18.6%) (7). None of the studies included in this meta-analysis used IMRT. In the last two decades, a progressive increase in the use of IMRT in respect to 3D-CRT has been reported in a retrospective cohort study including a total of 1,773 patients receiving neoadjuvant chemoradiotherapy, especially in LARC patients with huge tumors (cT4) (33).
The effect of dose intensification delivered with modern radiation and/or planning techniques, has been tested in phase II studies reporting favourable results in terms of feasibility and toxicity when using IMRT with SIB intensification in combination with fluoropyrimidine-based chemotherapy (15-28). Then, outcomes within studies using modern inverse-planning techniques (IMRT, volumetric modulated arc therapy and tomotherapy) and moderate intensified schedules (54-60 Gy) have been evaluated in a recent meta-analysis (34). The estimated pooled pCR rate was 24.1% across 37 eligible studies (1,817 patients), and 25.7% when inverse-planning was delivered (17 publications, 959 patients).
Included in this metanalysis, a retrospective multicentric Italian study on 76 LARC patients was conducted, reporting a pCR rate of 27.8% for patients treated with dose ranging from 52.5 to 57.5 Gy (median 54 Gy) to the SIB boost volume. Treatment was well tolerated with grade ≥3 acute toxicity rates of 4-25% (29). The main critical issues of this study were represented by the different SIB doses employed due to the different IMRT modalities available at each participating centre and by the limited sample size, probably related to the lack of significant indication, including the RT dose level. On the contrary, since the 5 participating centres had previous collaborated in the INTERACT rectal cancer trial (14), they shared the same delineation criteria for boost volume, defined as tumour and corresponding mesorectum plus an MRI-based cranio-caudal extension of 1-2 cm.
Most of evaluated patients were staged as IIIB (64.5%) and mesorectal fascia involvement (MRF+) was documented in 45% of them. Indeed, a dose intensification strategy could be particularly demanded in locally advanced high risk tumors such as T4-tumors, those with mesorectal fascia involvement, or suspicious bulky lymph nodes, aiming to improve resectability and local control.
Based on the aforementioned critical issues and the still debated considerations regarding the setting of dose intensification, this survey was proposed by the gastrointestinal study group of Italian Association of Radiation and Clinical Oncology (AIRO) to evaluate the pattern of care at the national level.
Pelvic MRI routinely performed for staging definition and risk factor identification in 97.4% of centres (Figure 1). This is in agreement with current guidelines that recognize MRI of the rectum as able to accurately predict the depth of extramural spread and the involvement of the mesorectal fascia and then recommend MRI for local staging, as well as for preoperative assessment of patients with high risk tumors, where dose intensification could be carried out (35, 36). Consequently, the selection criteria for dose intensification applied in this survey mainly included patients with high risk tumors, especially cT4 (52.4%), MRF involvement (47.6%), and/or low rectum (38%) (Table I).
The target volume delineation represents one of the major sources of uncertainty in radiotherapy and, it may have a significant impact on the delivery dose to the tumor, especially when dose intensification is planned and highly conformal techniques, such as SIB-IMRT, are used. Then, accuracy in the choice of the appropriate image for delineating volumes, in the delineation of the volume itself and image-guidance protocols is strongly recommended (37). Although many guidelines are currently available for elective CTV delineation in rectal cancer (38-40), no consensus or guideline is currently available for the definition and delineation of the boost volume.
In order to compare our results with the available data in the literature, details about prescribed doses, definition of volumes and possible margins were investigated in the 18 studies, included in the review of Burbach et al., on 649 patients treated with >60 Gy (7) (Table IV), and in 19 modern prospective and or randomized studies with boost dose/fraction between 2-2.5 Gy (Table V). Compared to historical studies using conformational technique, SIB boost is often delineated as primary tumor with corresponding mesorectum and or macroscopically suspicious lymph node, with different margins to generate the CTV.
Dose prescription and boost parameters in the 18 studies, on 649 patients treated with >60 Gy, included in the systematic review by Burbach J et al. (7).
Dose and boost volume parameters in modern prospective or randomized studies with boost dose/fraction between 2-2.5 Gy (19, on 1209 patients treated with a total accumulation of EBRT dose between 45-60 Gy). If not clearly reported, EQD2 total dose was calculated considering α/β= 10 for tumor * (7), and α/β=5.06 for rectal tumor ** (24).
The ability of modulated intensity techniques to deliver high doses sparing the organs at risk (OARs) allows to consider a margin to the GTV for tumor spread. The need to add a margin to the GTV, with the possible inclusion of the mesorectum, is related to the evidence that microscopic metastatic foci were reported within the mesorectum in up to 38.7% of patients (41) and that one of the main prognostic factors in rectal cancer is the status of the circumferential resection margin (CRM). Indeed, the CRM involvement has been associated with a poor prognosis, not only for local recurrence, but also for the development of distant metastases and patient survival (42). Location and depth of tumor invasion, nodal involvement, and tumor size >2 cm, mucinous adenocarcinomas and signet ring cell carcinomas, high grade tumors, and lymphovascular and perineural invasion have been identified as features independently associated with a positive CRM (41). Bulky lymph nodes with mesorectal fascia involvement and/or suspicious extra mesorectal nodes could then benefit of dose intensification. Finally, the inclusion of pathological lymph nodes could be individually considered based on their dimensions and the proximity of OARs and the related tolerability (i.e. bowels).
The improvement of diagnostic imaging allowed for a prediction of a potentially involved margin. Currently, preoperative MRI is considered highly accurate for the prediction of CRM involvement and represents the standard of care in assessing T-stage and margin status of tumor within a tolerance of 0.5 and 1 mm, respectively, resulting in more adequate treatment planning with a further decrease in cases of positive resection margins at surgery (43, 44). Moreover, Diffusion-weighted imaging (DWI) looks promising for delineation due to its ability to discriminate tumors from healthy tissue upon diffusion-restriction, resulting in smaller GTV compared to T2-weighted MRI and lower inter-observer variability (45-47). Fourteen of the evaluated studies (74%, Table V) specifically reported the use of MRI for GTV delineation, with DWI in two studies.
Our results are comparable, showing that boost volume is delineated on diagnostic MRI in 18 centres (85.7%), and on CT scan and/or PET-CT in 9 centres (42.8%). Boost dose was delivered on the macroscopic disease (GTV) in 10 centres (47.6%), and included the macroscopic tumor, cN+, or bulky cN+ extra-mesorectum in 66.7%, 52.4% and 47.6% of the cases, respectively (Table II). Boost dose was delivered on the CTV in 11 centres (52.4%), including high-risk areas (Table II). IMRT was used for dose intensification treatment in all centres and SIB was the preferred modality for boost delivery (80.8%), with moderate hypofractionation in 19 centres (90.5%), and chemotherapy was administered concurrently to dose intensification radiotherapy in 19 of 21 (90.5%) centres.
Finally, Image-guided RT protocols were used in 18 centres (85.7%). This seems particularly relevant considering that large deformation in the shape of the mesorectum have been described and that changes in rectal filling have been found to be the major cause of changes (48-50), with significant clinical impact when modulated intensity techniques are performed (51). Based on these considerations, an individualized anisotropic margin should be evaluated and an optimal IGRT strategy (imaging modality and frequency) should be identified based on the height of the tumor and site-specific set-up calculations (52).
In conclusion, locally advanced rectal cancer patients could benefit from different radiation treatment strategies including dose modulation, appropriate volume delineation, organ motion evaluation, IGRT protocols and modern delivery techniques aimed to improve oncological outcomes. Although there is currently no consensus in the literature regarding boost volume definition and relative margins, our survey is in accordance with the main prospective and randomized studies of preoperative LCRT with dose intensification. The current status in this setting in Italy showed a high quality of treatment, as highlighted by multidisciplinary discussion in all centres, volume delineation based on MRI in the majority of centres, and SIB-IMRT for delivery in all centres, with accurate IGRT protocols. Considering the growing interest in dose intensification treatment, these requirements could therefore be considered essential when moderate escalation (54-60 Gy) with modern inverse-planning techniques is delivered.
Acknowledgements
The Authors wish to thank the Scientific Commission of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) for the revision of the manuscript and the Italian Radiation Centres who have contributed to this study providing data for standard treatment: Rosetto Maria Elena, UOC Radioterapia, Viterbo; Reso Maria, Ospedale di Circolo e Fondazione Macchi ASST-Sette Laghi, Varese; Conti Monica, AULSS 3 Serenissima Ospedale di Venezia; RuoRedda Maria Grazia, Ordine Mauriziano, Torino; Galardi Alessandra, AOU Careggi, Firenze; Dell’Acqua Veronica, Istituto Europeo di Oncologia, Milano; Bacigalupo Almalina; Policlinico San Martino, Genova; Ciabattoni Antonella, Ospedale S. Filippo Neri, Roma; Fusco Vincenzo, IRCCS CROB, Rionero in Vulture; Lucido M. Rosaria, ASL 1 Imperiese, Sanremo; Bagnoli Rita, ASL Nord-Ovest, Lucca; Leone Maria Vittoria, Ospedale S. Giovanni Calibita - FBF, Roma; Canino Paola, Multimedica Castellanza; Pittoni Patrizia, ASST-Lariana, Como; Gumina Calogero, Policlinico San Donato, San Donato Milano; Musio Daniela, Policlinico Universitario Umberto I, Roma; Maurizi Francesca, Ospedale San Salvatore Muraglia, Pesaro
Footnotes
Authors’ Contributions
LC, ML, GM, MAG and DG designed and coordinated the study and the analysis. All authors provided data. CL, CR and LG performed main data analysis, provided pictures and drafted the manuscript. ML, GM, MAG, DG, FP, and VD critically revised the study and the manuscript. All Authors reviewed and approved the final manuscript.
↵§ These Authors contributed equally to the present study.
Conflicts of Interest
The Authors report no conflicts of interest in relation to this study.
- Received February 3, 2021.
- Revision received March 1, 2021.
- Accepted March 3, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
