Ines Joye

The role of diffusion-weighted MRI and 18F-FDG PET/CT in the prediction of pathologic complete response after radiochemotherapy for rectal cancer: A systematic review

After neoadjuvant radiochemotherapy (RCT) for locally advanced rectal cancer, 15-27% of the patients experience a pathological complete response (pCR). This observation raises the question as to whether invasive surgery could be avoided in a selected cohort of patients who obtain a clinical complete response after preoperative RCT. In this respect, there has been growing interest in functional imaging techniques to improve clinical response assessment. This systematic review focuses on the role of diffusion-weighted imaging (DWI) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the prediction of pCR after RCT for rectal cancer. A total of 14 publications on DWI and 25 on (18)F-FDG PET/CT were retrieved. Pooled analysis of individual patient data shows both imaging modalities have a low positive predictive value in the prediction of pCR (mean PPV of 54% and 39% for DWI- and (18)F-FDG PET/CT-based parameters respectively). Especially pre-RCT imaging is unable to predict pCR with overall accuracies of 68-72% for DWI and 44% for (18)F-FDG PET/CT. Qualitative DWI assessment 5-10weeks after the end of RCT may outperform apparent diffusion coefficient (ADC)-based DWI-parameters (overall accuracy of 87% vs. 74-78%). Although few data are available, early changes in FDG-uptake seem promising in the prediction of pCR and the role of (18)F-FDG PET/CT during RCT should be further investigated. Quantitative and qualitative (18)F-FDG PET/CT measurements are equally effective in the assessment of pCR after RCT. The major strength of DWI and (18)F-FDG PET/CT lies in the identification of non-responders who are not candidates for organ preservation. Up to now, DWI and (18)F-FDG PET/CT are not accurate enough to safely select patients for organ-sparing strategies. Future research must focus on the integration of functional imaging with clinical data and molecular biomarkers.

International consensus guidelines on Clinical Target Volume delineation in rectal cancer

INTRODUCTION The delineation of Clinical Target Volume (CTV) is a critical step in radiotherapy. Several guidelines suggest different subvolumes and anatomical boundaries in rectal cancer (RC), potentially leading to a misunderstanding in the CTV definition. International consensus guidelines (CG) are needed to improve uniformity in RC CTV delineation. MATERIAL AND METHODS The 7 radiation oncologist experts defined a roadmap to produce RC CG. Step 1: revision of the published guidelines. Step 2: selection of RC cases with different clinical stages. Step 3: delineation of cases using Falcon following previously published guidelines. Step 4: meeting in person to discuss the initial delineation outcome, followed by a CTV proposal based on revised and if needed, adapted anatomical boundaries. Step 5: peer review of the agreed consensus. Step 6: peer review meeting to validate the final outcome. Step 7: completion of RC delineation atlases. RESULTS A new ontology of structure sets was defined and the related table of anatomical boundaries was generated. The major modifications were about the lateral lymph nodes and the ischio-rectal fossa delineation. Seven RC cases were made available online as consultation atlases. CONCLUSION The definition of international CG for RC delineation endorsed by international experts might support a future homogeneous comparison between clinical trial outcomes.

Early and late toxicity of radiotherapy for rectal cancer.

With the implementation of total mesorectal excision surgery and neoadjuvant (chemo) radiotherapy, the outcome of rectal cancer patients has improved and a substantial proportion of them have become long-term survivors. These advances come at the expense of radiation- and chemotherapy-related toxicity which remains an underestimated problem. Radiation-induced early toxicity in rectal cancer treatment mainly includes diarrhea, cystitis, and perineal dermatitis, while bowel dysfunction, fecal incontinence, bleeding, and perforation, genitourinary dysfunction, and pelvic fractures constitute the majority of late toxicity. It is now generally accepted that short-course radiotherapy (SCRT) and immediate surgery is associated with less early toxicity compared to conventionally fractionated chemoradiotherapy with delayed surgery. There are no significant differences in late toxicity between both treatment regimens. While there is hardly an increase in early toxicity after preoperative SCRT with immediate surgery, late toxicity is substantial compared to surgery alone. Early toxicity is more frequent when a longer interval between SCRT and surgery is used and is comparable to the toxicity observed with conventionally fractionated radiotherapy except that it occurs after the end of the radiotherapy. So far, randomized phase III trials failed to demonstrate a substantial gain in tumoural response when oxaliplatin or molecular agents are added to the multimodality treatment. Moreover, the addition of these drugs increases toxicity and remains therefore experimental.

Does a central review platform improve the quality of radiotherapy for rectal cancer? Results of a national quality assurance project

BACKGROUND AND PURPOSE Quality assurance (QA) for radiation treatment has become a priority since poorly delivered radiotherapy can negatively influence patient outcome. Within a national project we evaluated the feasibility of a central review platform and its role in improving uniformity of clinical target volume (CTV) delineation in daily practice. MATERIAL AND METHODS All Belgian radiotherapy departments were invited to participate and were asked to upload CTVs for rectal cancer treatment onto a secured server. These were centrally reviewed and feedback was given per e-mail. For each five consecutive patients per centre, the overlap parameter dice coefficient (DC) and the volumetric parameters volumetric ratio (RV) and commonly contoured volume (VCC) were calculated. RESULTS Twenty departments submitted 1224 eligible cases of which 909 were modified (74.3%). There was a significant increase in RV and VCC between the first ten patients per centre and the others. This was not seen for DC. Statistical analysis did not show a further significant improvement in delineation over the entire review period. CONCLUSION Central review was feasible and increased the uniformity in CTV delineation in the first ten rectal cancer patients per centre. The observations in this study can be used to optimize future QA initiatives.

Clinical target volume delineation for rectal cancer radiation therapy: time for updated guidelines?

Our group previously defined delineation guidelines for rectal cancer radiation therapy (1). These guidelines are based on the incidence and the predominant location of local recurrences and on the distribution of lymphatic spread before the widespread implementation of total mesorectal excision (TME). Given that changes in surgical techniques and preoperative treatment may influence not only the likelihood of local recurrences but also the pelvic pattern of recurrence itself, we searched MEDLINE to investigate whether our previously published delineation guidelines should be adjusted according to the current patterns of pelvic recurrence and lymph node spread. Although the recurrence risk has dropped for all pelvic subregions with the implementation of TME, a literature review shows that the patterns of local recurrences and lymph node spread have not changed. One could therefore argue that major modifications to our previously published guidelines cannot be recommended. However, during our literature search we found several articles in which slight adjustments to our previous guidelines were suggested (Table 1). One of the commonly discussed issues in clinical target volume (CTV) delineation for rectal cancer is the level of the cranial border. Accurate definition of the cranial border is of utmost importance because it affects the volume of small bowel that is irradiated. We previously defined the cranial border as the level of the bifurcation of the common iliac arteries into the external and internal iliacs (1). This level correlates approximately to the level of the sacral promontory.

Implementation of volumetric modulated arc therapy for rectal cancer: Pitfalls and challenges

the standard treatment for locally advanced rectal cancer is radio(chemo)therapy (rCt) followed by total mesorectal excision (tmE) surgery [1]. this preoperative treatment is associated with gastrointestinal morbidity, such as diarrhea, fecal incontinence, bowel dysfunction, obstruction and perforation [2]. radiation-induced gastrointestinal toxicity is primarily dependent on the small bowel volume receiving 15 gy (v15) and 45 gy (v45) [3–5]. Highly conformal radiation techniques, such as intensitymodulated radiotherapy (imrt) and volumetric modulated arc therapy (vmAt) effectively decrease the dose to the small bowel, thereby reducing the radiation-induced bowel toxicity [6]. mechanical small bowel displacement techniques, including prone positioning on a bellyboard, also reduce the dose to the bowel [7–9]. However, bellyboards have been associated with patient discomfort and reduced position reproducibility [10,11]. there is a substantial interand intra-fractional rectal motion, especially in the anterior direction. therefore, the precise irradiation with imrt or vmAt increases the risk to miss the tumor. Larger

Quantitative imaging outperforms molecular markers when predicting response to chemoradiotherapy for rectal cancer

BACKGROUND AND PURPOSE To explore the integration of imaging and molecular data for response prediction to chemoradiotherapy (CRT) for rectal cancer. MATERIAL AND METHODS Eighty-five rectal cancer patients underwent preoperative CRT. 18F-FDG PET/CT and diffusion-weighted imaging (DWI) were acquired before (TP1) and during CRT (TP2) and prior to surgery (TP3). Inflammatory cytokines and gene expression were analysed. Tumour response was defined as ypT0-1N0. Multivariate models were built combining the obtained parameters. Final models were calculated on the data combination with the highest AUC. RESULTS Twenty-two patients (26%) achieved ypT0-1N0 response. 18F-FDG PET/CT had worse predictive performance than DWI and T2-volumetry (AUC 0.61±0.04, 0.72±0.03, and 0.72±0.02, respectively). Combining all imaging parameters increased the AUC to 0.81±0.03. Adding cytokines or gene expression did not improve the AUC (AUC of 0.72±0.06 and 0.79±0.04 respectively). Final models combining 18F-FDG PET/CT, DWI, and T2-weighted volumetry at all TPs and using only TP1 and TP3, allowed ypT0-1N0 prediction with a 75% sensitivity, 94% specificity and PPV of 80%. CONCLUSIONS Combining 18F-FDG PET/CT, DWI, and T2-weighted MRI volumetry obtained before CRT and prior to surgery may help physicians in selecting rectal cancer patients for organ-preservation.

Can clinical factors be used as a selection tool for an organ-preserving strategy in rectal cancer?

Abstract Background: Rectal cancer patients who achieve a good response to chemoradiotherapy (CRT), may be offered less invasive surgery or even no surgery at all. Implementation of such a policy, however, requires precise patient selection. This study identifies pretreatment clinical factors that are associated with pathological complete response (pCR) and ypT0-1N0 and evaluates their performance as a selection tool for organ-preserving strategies. Material and methods: Patients with rectal cancer treated with CRT and total mesorectal excision between January 2000 and December 2014 were retrospectively included. Following clinical characteristics were extracted from the medical files: age, gender, body mass index, ASA score, cT-stage, cN-stage, distance from the anal verge, pretreatment carcinoembryonic antigen (CEA), pretreatment hemoglobin and distance from the mesorectal fascia. Univariable and multivariable binary logistic regression models were used to predict pCR and ypT0-1N0. The discriminative ability of the prediction models was evaluated by receiver operating characteristic analysis. Results: A total of 620 patients were included of whom 120 experienced a pCR (19%) and 170 patients achieved ypT0-1N0 response (27%). A low pretreatment CEA, a high pretreatment hemoglobin and a high cN-stage were associated with pCR in multivariable analysis. A low pretreatment CEA, a low cT-stage and a high cN-stage were associated with ypT0-1N0. After cross validation, the area under the curve for the pCR and ypT0-1N0 prediction model equaled 0.609 and 0.632, respectively. Conclusion: Despite their statistical significance, the value of pretreatment clinical variables in the prediction of pCR and ypT0-1N0 is very limited. To safely select patients for organ preservation, other strategies need to be explored.

Moderate dose escalation with volumetric modulated arc therapy improves outcome in rectal cancer

Abstract Background: Locally advanced rectal cancer is frequently treated with a long course of preoperative chemoradiotherapy. We investigated the effect of moderate dose escalation with volumetric modulated arc therapy (VMAT) up to 50 Gy in 25 fractions compared to 3D conformal radiotherapy (3D-CRT) to 45 Gy in 25 fractions in rectal cancer patients. Dose–volume parameters, acute toxicity, and complete response rates were compared. Material and Methods: For both groups, 65 patients were selected from our database through availability. Dose–volume parameters and acute toxicity data were compared using a Mann–Whitney U-test. Univariate and multivariate analyses correcting for tumor and nodal stage, distance to the mesorectal fascia and interval to surgery were used to compare complete response rates. Results: Lower mean doses to the small and large bowel were observed in the VMAT group compared to the 3D-CRT group (21 Gy vs. 29 Gy [p < .001] and 26 Gy vs. 30 Gy [p = .002], respectively). Similar beneficial dose–volume parameters were observed for the bladder, sacrum and femoral heads. Furthermore, patients receiving VMAT experienced significantly less diarrhea, flatulence, non-infective cystitis, urinary frequency, dermatitis, and fatigue. In univariate analysis, a significant increase in complete response rate after moderate dose escalation with VMAT was observed (34% vs. 15%, p = .015). However, this did not remain significant when corrected for tumor and nodal stage, distance to the mesorectal fascia, and interval to surgery. Conclusions: Moderate dose escalation with VMAT resulted in superior dose–volume parameters compared to 3D-CRT, translating into lower acute toxicity. Additionally, improved tumor response after VMAT up to 50 Gy might contribute to a higher percentage of patients achieving a complete response.

Which Patients With Rectal Cancer Do Not Need Radiotherapy

According to current guidelines, the standard treatment for locally advanced rectal cancer patients is preoperative (chemo)radiotherapy followed by total mesorectal excision surgery and adjuvant chemotherapy. Improvements in surgical techniques, imaging modalities, chemotherapy regimens, and radiotherapy delivery have reduced local recurrence rates to less than 10%. The current challenge in rectal cancer treatment lies in the prevention of distant metastases, which still occur in more than 25% of the patients. The decrease in local recurrence rates, the need for more effective systemic treatments, and the increased awareness of treatment-induced toxicity raise the question as to whether a more selective use of radiotherapy is advocated.