MRI tumor volume reduction rate vs tumor regression grade in the pre-operative re-staging of locally advanced rectal cancer after chemo-radiotherapy

doi:10.1016/j.ejrad.2015.08.008

European Journal of Radiology

Volume 84, Issue 12, December 2015, Pages 2438-2443

https://doi.org/10.1016/j.ejrad.2015.08.008 Get rights and content

Highlights

•
The study compared the tumor volume reduction rate vs tumor regression grade.
•
A statistically significant correlation is found between the tumor volume reduction rate and the tumor regression grade after chemo-radiotherapy.
•
When the tumor volume reduction rate is superior to 85% no residual tumor is found in the pathologic specimen, that means a complete response to chemo-radiation therapy.
•
The tumor volume reduction rate is a valid parameter of treatment response that should be included in the wider spectrum of quantitative imaging biomarkers already considered in the staging and re-staging of locally advanced rectal cancer.

Abstract

Objective

To compare tumor volume reduction rate (TVRR) measured by MR volumetry after preoperative chemoradiotherapy (CRT) and pathological tumor regression grade (TRG) in locally advanced rectal cancer (LARC).

Material and methods

In total, 20 patients with LARC (cT3-T4) treated with CRT followed by Total Mesorectal Excision (TME) between April 2011 and April 2013 were analyzed retrospectively.

Pre- and post- CRT tumor volumes (MR volumetry) were measured on 3D MR sequences. TVRR was determined using the equation TVRR (%) = (pre-CRT tumor volume—post-CRT tumor volume) × 100/pre-CRT tumor volume. The downstaging (defined as ypT0-T2) of tumor mass was evaluated and the correlation between TVRR and TRG was calculated with the method proposed by Dworak using the Spearman rank test.

Results

The median TVRR was 77.3% (range, 26.4–99.3%); TVRR was >60% in 18 cases (90%) and in 8 of these patients (44.4 %) it was >80%. Downstaging of tumor lesions was obtained in 15 patients (75%). In 4 cases there was a complete tumor regression (TRG4) at histological examination and in the same patients there was also a TVRR > 80% measured by MR volumetry. A statistically significant correlation between TVRR and TRG (r_s = 0.5466, p = 0.0126) was observed.

Conclusion

TVRR after preoperative CRT correlates with TRG in LARC. The MR volumetry is a prognostic factor to estimate the tumor response after preoperative CRT. TVRR data may be an useful biomarker for tailoring surgery and postoperative adjuvant chemotherapy.

Introduction

In patients with locally advanced rectal cancer (LARC) who undergo combined treatments, consisting of preoperative chemo-radiotherapy (CRT), surgery, and post-operative adjuvant chemotherapy, the earlier prediction of CRT responses is critical for tailoring subsequent treatments and increase the chance of a cure in an individual patient.

Since post-CRT tumor downstaging is one of the most important prognostic factors in LARC with preoperative CRT, it’s necessary to understand the best strategy to evaluate and possibly quantify with measurable biomarkers the degree of tumor downstaging [1].

The currently accepted downstaging criteria consist in the measurement of two-dimensional (WHO, world health organization) or only one-dimensional (RECIST, response evaluation criteria in solid tumors) tumor diameters.

The estimation of pre- and post-treatment tumor size represents one important criterion to quantify the response to treatments, but the two-dimensional measurements are subject to intrinsic errors, due to an irregular tumor shape, a non uniform treatment-related shrinkage, and the variability of manual measurements performed by the radiologist, that make it difficult to identify all subtle tumor size changes induced by CRT [2].

The pathological tumor regression grade (TRG), is based on a semi-quantitative scale (from 0, no response, to 4, complete pathological response), and is commonly used to estimate response to CRT in the surgical specimen [3], [4], [5].

The value of MRI in the assessment of TRG has been evaluated in a subgroup analysis (92 patients with pre- and post-treatment MR studies) of the MERCURY trial (magnetic resonance imaging in rectal cancer european equivalence study) [6]. The study showed that MRI predicts the disease free survival and overall survival of patients that undergo neoadjuvant therapy for rectal cancer. A further study of the same author showed that MRI correlates also with a favorable and unfavorable histopathological TRG [7].

Tumor volumetric reduction has been also addressed as a valuable prognostic biomarker of response to CRT; it can be measured in vivo by three-dimensional (3D) region-of-interest volumetry (MR Volumetry) since MRI is the unique, “in vivo”, imaging tool that allows to precisely differentiate tumor borders from normal soft tissue, and therefore estimate tumor extent [8], [9].

Therefore the so called “tumor volume reduction rate” (TVRR) after preoperative CRT, measured with MR volumetry, has been investigated as a predictive factor of response to treatment and a biomarker of patient’s prognosis, and in patients with LARC, a correlation between high TVRR and favorable pathologic CRT responses was reported [10], [11], [12], [13].

The objective of the present study was to investigate the correlation between TVRR and TRG after preoperative CRT, as a predictive factor of response to treatment in LARC.

Section snippets

Patients

This is a single institution prospective cohort study that included twenty patients, 13 male and 7 female, with mean age 62 years (range, 34–75 years), with locally advanced rectal cancer.

The inclusion criteria were histologically confirmed rectal adenocarcinoma, distal end of tumor located within 15 cm from the anal verge, locally advanced disease (cT3–4), tumor involvement of the mesorectal fascia, and/or positive nodal status evaluated with MR imaging with or without transrectal

Results

A T-downstaging of tumor (defined as ypT0-T2) was obtained in 15 patients (75%); including 4 patients (20%) with pathologic complete regression (TRG4) at histological examination, that showed a TVRR > 80% measured by MR volumetry.

Particularly TRG0 was observed in 1 patients (5%), TRG1 in 3 patients (15%), TRG2 in 5 patients (25%), TRG3 in 7 patients (35%) and TRG4 in 4 patients (20%).

By splitting the patients according to the TRG obtained at the histological examination, the mean volumes pre-CRT

Discussion

In the present study the TVRR has been investigated as potential biomarker of tumor response to CRT. Although volume measurement is operator-dependent and time-consuming, the TVRR > 82% (observed in 8 patients) correlated with TRG 3 and 4, which means a clear threshold of the TVRR, addressing an almost partial (TRG3) to complete (TRG4) response to CRT. Among these, in 4 patients with pathologic complete response (TRG4) the TVRR was above 86%; the more is the tumor volume reduction the most

Conclusion

Preoperative CRT has been recommended in T3 and T4 stage cancers, and in those that infiltrate the upper portion of anal canal, with the aim to obtain downstaging of rectal tumour and follow the most conservative treatment in patients with complete pathologic response, from surgery to a “wait and watch” approach [26]. However the individual response to preoperative CRT changes significantly among patients, and in this clinical setting a reliable parameter/biomarker needs to be established in

Confilcts of interests

Authors declare that there are no conflicts of interests.

References (28)

V. Valentini et al.
Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients
Int. J. Radiat. Oncol. Biol. Phys.
(2002)
E.A. Eisenhauer et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur. J. Cancer
(2009)
S.G. Yeo et al.
Tumor volume reduction rate after preoperative chemoradiotherapy as a prognostic factor in locally advanced rectal cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2012)
N.K. Kim et al.
A comparative study of volumetric analysis, histopathologic downstaging, and tumor regression grade in evaluating tumor response in locally advanced rectal cancer following preoperative chemoradiation
Int. J. Radiat. Oncol. Biol. Phys.
(2007)
Y.H. Kim et al.
Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with resectable rectal cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2005)
A. Habr-Gama et al.
Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control
Int. J. Radiat. Oncol. Biol. Phys.
(2014)
P. Chatterjee et al.
Radiologic and pathological correlation of staging of rectal cancer with 3 Tesla magnetic resonance imaging
Can. Assoc. Radiol. J.
(2011)
J.J. Fütterer et al.
Preoperative 3T MR imaging of rectal cancer: local staging accuracy using a two-dimensional and three-dimensional T2-weighted turbo spin echo sequence
Eur. J. Radiol.
(2008)
N.A. Janjan et al.
Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M.D. Anderson cancer center experience
Int. J. Radiat. Oncol. Biol. Phys.
(1999)
O. Dworak et al.
Pathological features of rectal cancer after preoperative radiochemotherapy
Int. J. Colorectal Dis.
(1997)

L. Losi et al.

Prognostic value of Dworak grade of regression (GR) in patients with rectal carcinoma treated with preoperative radiochemotherapy

Int. J. Colorectal Dis.

(2006)

F. Prall et al.

Tumor regression in rectal cancer after intensified neoadjuvant chemoradiation: a morphometric and clinicopathological study

World J. Surg. Oncol.

(2015)

U.B. Patel et al.

Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience

J. Clin. Oncol.

(2011)

U.B. Patel et al.

Comparison of magnetic resonance imaging and histopathological response to chemoradiotherapy in locally advanced rectal

Ann. Surg. Oncol.

(2012)

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The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer.
This open-label, single-arm, phase 2 study was done at the Sun Yat-sen University Cancer Center, Guangzhou, China. Patients aged 18–75 years with mismatch-repair deficient or microsatellite instability-high locally advanced rectal cancer were enrolled and received neoadjuvant sintilimab monotherapy (200 mg by intravenous infusion) every 21 days. After an initial four cycles of treatment, patients and clinicians could choose one of the following options: total mesorectal excision surgery, followed by four cycles of adjuvant sintilimab with or without CapeOX chemotherapy (capecitabine 1000 mg/m², orally administered twice daily on days 1–14; oxaliplatin 130 mg/m², intravenously administered on day 1 every 3 weeks), determined by clinicians; or another four cycles of sintilimab followed by radical surgery or observation (only for patients with a clinical complete response; also known as the watch and wait strategy). The primary endpoint was the complete response rate, which included both a pathological complete response after surgery and a clinical complete response after completion of sintilimab treatment. Clinical response was evaluated by digital rectal examination, MRI, and endoscopy. Response was assessed in all patients who received treatment at least until the first tumour response assessment, after the first two cycles of sintilimab. Safety was analysed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04304209).
Between Oct 19, 2019, and June 18, 2022, 17 patients were enrolled and received at least one dose of sintilimab. The median age was 50 years (IQR 35–59) and 11 (65%) of 17 patients were male. One patient was excluded from efficacy analyses because they were lost to follow-up after the first sintilimab cycle. Of the remaining 16 patients, six underwent surgery, of whom three had a pathological complete response. Nine other patients had a clinical complete response and chose the watch and wait strategy. One patient had a serious adverse event and discontinued treatment; this patient did not have a complete clinical response and refused to undergo surgery. A complete response was thus noted for 12 (75%; 95% CI 47–92) of 16 patients. One of the three patients who underwent surgery but did not have a pathological complete response showed an increase in tumour volume after the initial four cycles of sintilimab (at which point they underwent surgery); this patient was deemed to have primary resistance to immune checkpoint inhibitors. After a median follow-up of 17·2 (IQR 8·2–28·5) months, all patients were alive and none had disease recurrence. Only one (6%) patient had a grade 3–4 adverse event, which was deemed a serious adverse event (grade 3 encephalitis).
The preliminary results of this study suggest that anti-PD-1 monotherapy is effective and tolerable for patients with mismatch-repair deficient locally advanced rectal cancer and could potentially spare some patients from radical surgery. Longer treatment courses might be needed to achieve maximum effects in some patients. Longer follow-up is also needed to observe the duration of response.
The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Science and Technology Program of Guangzhou, and Innovent Biologics.
Rectal cancer response to neoadjuvant chemoradiotherapy evaluated with MRI: Development and validation of a classification algorithm
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Citation Excerpt :
These results are particularly important from a clinical point of view in order to reduce the risk of undertreatment when considering a patient for organ-preserving strategy. None of the previously published studies, based on a single biomarker (i.e. MR-TRG, TVRR, DSI or DWI/ADC), were able to achieve such results [7,8,10,12,16,26]. However, the proposed decision support model misclassified three of the twenty-one NCRs providing a sensitivity and NPV of 85.7% and 94.2% respectively.
The aim of this study was to develop and validate a decision support model using data mining algorithms, based on morphologic features derived from MRI images, to discriminate between complete responders (CR) and non-complete responders (NCR) patients after neoadjuvant chemoradiotherapy (CRT), in a population of patients with locally advanced rectal cancer (LARC).
Two populations were retrospectively enrolled: group A (65 patients) was used to train a data mining decision tree algorithm whereas group B (30 patients) was used to validate it. All patients underwent surgery; according to the histology evaluation, patients were divided in CR and NCR. Staging and restaging MRI examinations were retrospectively analysed and seven parameters were considered for data mining classification.
Five different classification methods were tested and evaluated in terms of sensitivity, specificity, accuracy and AUC in order to identify the classification model able to achieve the best performance.
The best classification algorithm was subsequently applied to group B for validation: sensitivity, specificity, positive and negative predictive value, accuracy and ROC curve were calculated. Inter and intra-reader agreement were calculated.
Four features were selected for the development of the classification algorithm: MRI tumor regression grade (MR-TRG), staging volume (SV), tumor volume reduction rate (TVRR) and signal intensity reduction rate (SIRR). The decision tree J48 showed the highest efficiency: when applied to group B, all the CR and 18/21 NCR were correctly classified (sensitivity 85.71%, specificity 100%, PPV 100%, NPV 94.2%, accuracy 95.7%, AUC 0.833).
Both inter- and intra-reader evaluation showed good agreement (κ > 0.6).
The proposed decision support model may help in distinguishing between CR and NCR patients with LARC after CRT.
Could early tumour volume changes assessed on morphological MRI predict the response to chemoradiation therapy in locally-advanced rectal cancer?
2018, Clinical Radiology
Citation Excerpt :
In order to increase the chance of recovery and improve oncological outcome, it is important to determine beforehand what kind of response to CRT patients will achieve, in order to assign patients to the appropriate treatment strategy. Nowadays, most clinical studies focus on the potential role of tumour reduction rate at post-treatment MRI, and they demonstrate that a higher tumour volume reduction rate on MRI after neoadjuvant therapy is associated with a better pathological response20–22 as well as a more favourable outcome12; however, this approach may fail to distinguish CR from PR, that are frequently characterised by similar ΔVpost.11,13 Therefore, in order to effectively guide patient-tailored treatments, a reliable and early assessment of the treatment response is required.
To investigate the potential role of an additional magnetic resonance imaging (MRI) examination performed during neoadjuvant chemoradiation therapy (CRT) in the prediction of pathological response in locally advanced rectal cancer (LARC).
Forty-eight consecutive patients with LARC underwent neoadjuvant CRT. MRI studies at 1.5 T, including high-resolution T2-weighted sequences that were acquired parallel and perpendicular to the main axis of the tumour were performed before (preMRI), during (midMRI), and 6–8 weeks after the end of CRT (postMRI). Cancer volumes (V_pre, V_mid, V_post) were drawn manually and the reduction rate calculated (ΔV_mid, ΔV_post). According to Rödel's pathological tumour regression grade (TRG), patients were considered non-responders (NR; TRG0-2), partial responders (PR; TRG3), and complete responders (CR; TRG4). Multivariate regression analysis was performed to identify the best MRI predictors of NR, PR, and CR.
Twenty-five patients were considered PR (52%), 13 CR (27%), and 10 NR (22%). Tumour shrinkage mainly occurred shortly after CRT (ΔV_mid: CR: 80±10% versus PR: 56±19% versus NR: 28±22%, p=2.2×10⁻¹⁶). V_mid, V_post, ΔV_mid, and ΔV_post correlated with TRG (p<0.001). At multivariate analysis, the combined assessment of V_mid and ΔV_mid was selected as the best predictor of response to CRT, in that it distinguishes CR, PR, and NR early and accurately (81.5%).
MidMRI allows final response assessment to neoadjuvant CRT earlier and better than the MRI performed after the end of CRT. MRI findings at midMRI may be useful to tailor patient treatment.
Tumor volume predicts local recurrence in early rectal cancer treated with radical resection: A retrospective observational study of 270 patients
2018, International Journal of Surgery
Citation Excerpt :
In many types of human cancers, including nasopharyngeal carcinomas, hepatocellular carcinoma and laryngeal cancer, the tumor volume has been associated with the LR and OS of patients [22,31–34]. Meanwhile, the tumor volume reduction rate (TVRR) is also a primary marker for evaluating the therapeutic effect of neoadjuvant treatment in rectal cancer [35–38]. Additionally, Tayyab et al. [12] demonstrated that the tumor volume was a main predictor of OS in low rectal cancers.
Radical resection is regarded as the primary treatment for early rectal cancer, and tumor volume is an independent predictor of many other types of cancer. The purpose of the present study is to assess the effect of tumor volume on the survival of patients with early rectal cancer treated with radical surgery.
A total of 270 patients with histologically confirmed stage T1/2 N0 rectal cancer who underwent radical resection between September 2006 and September 2014 were enrolled in this study. The tumor volume was measured based on the preoperative pelvic MRI. The clinical significance of tumor volume with respect to patients' outcomes was evaluated, and the multivariate Cox proportional regression model was used to analyse the risk factors for survival of these patients.
The median follow-up period was 57.6 months. The tumor volume was significantly correlated with preoperative Hb, CEA level and number of retrieved lymph nodes (all p < 0.05). The large tumor group had a lower disease-free survival (DFS) rate than the small tumor group (5-year DFS rate: 80.4% vs 89.6%, p = 0.042), whereas there was no difference in the overall survival rate. The 5-year local recurrence rates for patients in the large and small tumor groups were 10.5% and 3.0%, respectively (p = 0.030). Additionally, the tumor volume was an independent clinical predictor for both DFS and local recurrence-free survival (LRFS).
In conclusion, the tumor volume is significantly associated with DFS and LRFS of patients with stage T1/2 N0 rectal cancer who underwent radical resection alone. Tumor volume may be considered an important indicator for neoadjuvant or adjuvant therapeutic interventions.
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MRI tumor volume reduction rate vs tumor regression grade in the pre-operative re-staging of locally advanced rectal cancer after chemo-radiotherapy

Highlights

Abstract

Objective

Material and methods

Results

Conclusion

Introduction

Section snippets

Patients

Results

Discussion

Conclusion

Confilcts of interests

Int. J. Radiat. Oncol. Biol. Phys.

Eur. J. Cancer

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Can. Assoc. Radiol. J.

Eur. J. Radiol.

Int. J. Radiat. Oncol. Biol. Phys.

Pathological features of rectal cancer after preoperative radiochemotherapy

Int. J. Colorectal Dis.

Prognostic value of Dworak grade of regression (GR) in patients with rectal carcinoma treated with preoperative radiochemotherapy

Int. J. Colorectal Dis.

Tumor regression in rectal cancer after intensified neoadjuvant chemoradiation: a morphometric and clinicopathological study

World J. Surg. Oncol.

Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience

J. Clin. Oncol.

Comparison of magnetic resonance imaging and histopathological response to chemoradiotherapy in locally advanced rectal

Ann. Surg. Oncol.