G.J. Meijer

Imaging strategies in the management of oesophageal cancer: what’s the role of MRI?

ObjectivesTo outline the current role and future potential of magnetic resonance imaging (MRI) in the management of oesophageal cancer regarding T-staging, N-staging, tumour delineation for radiotherapy (RT) and treatment response assessment.MethodsPubMed, Embase and the Cochrane library were searched identifying all articles related to the use of MRI in oesophageal cancer. Data regarding the value of MRI in the areas of interest were extracted in order to calculate sensitivity, specificity, predictive values and accuracy for group-related outcome measures.ResultsAlthough historically poor, recent improvements in MRI protocols and techniques have resulted in better imaging quality and the valuable addition of functional information. In recent studies, similar or even better results have been achieved using optimised MRI compared with other imaging strategies for T- and N-staging. No studies clearly report on the role of MRI in oesophageal tumour delineation and real-time guidance for RT so far. Recent pilot studies showed that functional MRI might be capable of predicting pathological response to treatment and patient prognosis.ConclusionsIn the near future MRI has the potential to bring improvement in staging, tumour delineation and real-time guidance for RT and assessment of treatment response, thereby complementing the limitations of currently used imaging strategies.Key Points• MRI’s role in oesophageal cancer has been somewhat limited to date.• However MRI’s ability to depict oesophageal cancer is continuously improving.• Optimising TN-staging, radiotherapy planning and response assessment ultimately improves individualised cancer care.• MRI potentially complements the limitations of other imaging strategies regarding these points.

Diffusion-weighted magnetic resonance imaging for the prediction of pathologic response to neoadjuvant chemoradiotherapy in esophageal cancer

PURPOSE To explore the value of diffusion-weighted magnetic resonance imaging (DW-MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer. MATERIAL AND METHODS In 20 patients receiving nCRT for esophageal cancer DW-MRI scanning was performed before nCRT, after 8-13 fractions, and before surgery. The median tumor apparent diffusion coefficient (ADC) was determined at these three time points. The predictive potential of initial tumor ADC, and change in ADC (ΔADC) during and after treatment for pathologic complete response (pathCR) and good response were assessed. Good response was defined as pathCR or near-pathCR (tumor regression grade [TRG] 1 or 2). RESULTS A pathCR after nCRT was found in 4 of 20 patients (20%), and 8 patients (40%) showed a good response to nCRT. The ΔADCduring was significantly higher in pathCR vs. non-pathCR patients (34.6%±10.7% [mean±SD] vs. 14.0%±13.1%, p=0.016), as well as in good vs. poor responders (30.5%±8.3% vs. 9.5%±12.5%, p=0.002). The ΔADCduring was predictive of residual cancer at a threshold of 29% (sensitivity of 100%, specificity of 75%, PPV of 94%, and NPV of 100%), and for poor pathologic response at a threshold of 21% (sensitivity of 82%, specificity of 100%, PPV of 100%, and NPV of 80%). CONCLUSIONS In this exploratory study, the treatment-induced change in ADC during the first 2-3weeks of nCRT for esophageal cancer seemed highly predictive of histopathologic response. Larger series are warranted to verify these results.

MRI-based tumor motion characterization and gating schemes for radiation therapy of pancreatic cancer

BACKGROUND AND PURPOSE To characterize pancreatic tumor motion and to develop a gating scheme for radiotherapy in pancreatic cancer. MATERIALS AND METHODS Two cine MRIs of 60s each were performed in fifteen pancreatic cancer patients, one in sagittal direction and one in coronal direction. A Minimum Output Sum of Squared Error (MOSSE) adaptive correlation filter was used to quantify tumor motion in craniocaudal, lateral and anteroposterior directions. To develop a gating scheme, stability of the breathing phases was examined and a gating window assessment was created, incorporating tumor motion, treatment time and motion margins. RESULTS The largest tumor motion was found in craniocaudal direction, with an average peak-to-peak amplitude of 15mm (range 6-34mm). Amplitude of the tumor in the anteroposterior direction was on average 5mm (range 1-13mm). The least motion was seen in lateral direction (average 3mm, range 2-5mm). The end exhale position was the most stable position in the breathing cycle and tumors spent more time closer to the end exhale position than to the end inhale position. On average, a margin of 25% of the maximum craniocaudal breathing amplitude was needed to achieve full target coverage with a duty cycle of 50%. When reducing the duty cycle to 50%, a margin of 5mm was sufficient to cover the target in 11 out of 15 patients. CONCLUSION Gated delivery for radiotherapy of pancreatic cancer is best performed around the end exhale position as this is the most stable position in the breathing cycle. Considerable margin reduction can be established at moderate duty cycles, yielding acceptable treatment efficiency. However, motion patterns and amplitude do substantially differ between individual patients. Therefore, individual treatment strategies should be considered for radiotherapy in pancreatic cancer.

The Incremental Value of Subjective and Quantitative Assessment of 18F-FDG PET for the Prediction of Pathologic Complete Response to Preoperative Chemoradiotherapy in Esophageal Cancer

A reliable prediction of a pathologic complete response (pathCR) to chemoradiotherapy before surgery for esophageal cancer would enable investigators to study the feasibility and outcome of an organ-preserving strategy after chemoradiotherapy. So far no clinical parameters or diagnostic studies are able to accurately predict which patients will achieve a pathCR. The aim of this study was to determine whether subjective and quantitative assessment of baseline and postchemoradiation 18F-FDG PET can improve the accuracy of predicting pathCR to preoperative chemoradiotherapy in esophageal cancer beyond clinical predictors. Methods: This retrospective study was approved by the institutional review board, and the need for written informed consent was waived. Clinical parameters along with subjective and quantitative parameters from baseline and postchemoradiation 18F-FDG PET were derived from 217 esophageal adenocarcinoma patients who underwent chemoradiotherapy followed by surgery. The associations between these parameters and pathCR were studied in univariable and multivariable logistic regression analysis. Four prediction models were constructed and internally validated using bootstrapping to study the incremental predictive values of subjective assessment of 18F-FDG PET, conventional quantitative metabolic features, and comprehensive 18F-FDG PET texture/geometry features, respectively. The clinical benefit of 18F-FDG PET was determined using decision-curve analysis. Results: A pathCR was found in 59 (27%) patients. A clinical prediction model (corrected c-index, 0.67) was improved by adding 18F-FDG PET–based subjective assessment of response (corrected c-index, 0.72). This latter model was slightly improved by the addition of 1 conventional quantitative metabolic feature only (i.e., postchemoradiation total lesion glycolysis; corrected c-index, 0.73), and even more by subsequently adding 4 comprehensive 18F-FDG PET texture/geometry features (corrected c-index, 0.77). However, at a decision threshold of 0.9 or higher, representing a clinically relevant predictive value for pathCR at which one may be willing to omit surgery, there was no clear incremental value. Conclusion: Subjective and quantitative assessment of 18F-FDG PET provides statistical incremental value for predicting pathCR after preoperative chemoradiotherapy in esophageal cancer. However, the discriminatory improvement beyond clinical predictors does not translate into a clinically relevant benefit that could change decision making.

Residual esophageal cancer after neoadjuvant chemoradiotherapy frequently involves the mucosa and submucosa

Objectives: To gain insight into the exact location of residual esophageal cancer in the esophageal wall and regional lymph nodes after neoadjuvant chemoradiotherapy (nCRT) and to determine the pattern of regression. Background: Data from the recently published chemoradiotherapy for oesophageal cancer followed by surgery study trial showed that 49% of squamous cell carcinomas and 23% of adenocarcinomas had a pathologically complete response (pCR) in the resection specimen after nCRT. These results impose the ethical imperative to reconsider the necessity of esophagectomy with its substantial morbidity and mortality in patients with pCR. However, it remains challenging to accurately identify these patients before resection. Methods: Between January 2003 and July 2011, all patients with esophageal cancer in a tertiary referral center, who underwent nCRT (5 weekly courses of carboplatin and paclitaxel plus 41.4 Gy concurrent radiotherapy) and surgical resection, were analyzed. The resection specimens were carefully re-evaluated by an experienced gastrointestinal pathologist. Tumor regression grade (TRG) was meticulously scored for each specific layer of the esophageal wall and for all removed lymph nodes. Results: One hundred two consecutive patients were included. Seventy-one (70%) of 102 patients were noncomplete responders (≥TRG2) and in 63 of these patients (89%), residual tumor cells were seen in the mucosa and/or submucosa. Five of 8 patients without involvement of the mucosa and the submucosa had isolated remnants in the muscle layer (5/102 = 5%); the other 3 patients had tumor cells only in a single lymph node (3/102 = 3%). The surrounding stroma showed the highest percentage of TRG1 (= pCR: 47%). In patients with pretreatment lymph node positivity, the percentage of TRG1 in all lymph nodes was also favorable (52%). Overall regression showed a nonrandom mixed pattern of both concentric regression and regression toward the lumen. Conclusions: After nCRT for esophageal cancer, both the mucosa and the submucosa show frequent residual malignant involvement. The surrounding stroma and the regional lymph nodes show the highest percentage of pCR and the overall regression pattern is most frequently a mixed pattern of both concentric regression and regression toward the lumen. This overall regression pattern lends support to careful testing of a wait-and-see approach in a subgroup of patients with esophageal cancer after nCRT.

Endoscopic biopsy and EUS for the detection of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer: a systematic review and meta-analysis

BACKGROUND AND AIMS Accurate determination of residual cancer status after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer could assist in selecting the optimal treatment strategy. The aim of this study was to review the evidence on the diagnostic accuracy of endoscopic biopsy and EUS after nCRT for detecting residual cancer at the primary tumor site (ypT+) and regional lymph nodes (ypN+) as opposed to a pathologic complete response (ypT0 and ypN0). METHODS PubMed/Medline, Embase, and the Cochrane library were systematically searched. The analysis included diagnostic studies reporting on the accuracy of endoscopic biopsy or EUS in detecting residual cancer versus complete response after nCRT for esophageal cancer with histopathology as the reference standard. Bivariate random-effects models were used to estimate pooled sensitivities and specificities and examine sources of heterogeneity. RESULTS Twenty-three studies comprising 12 endoscopic biopsy studies (1281 patients), 11 EUS studies reporting on ypT status (593 patients), and 10 EUS studies reporting on ypN status (602 patients), were included. Pooled estimates for sensitivity of endoscopic biopsy after nCRT for predicting ypT+ were 34.5% (95% confidence interval [CI], 26.0%-44.1%) and for specificity 91.0% (95% CI, 85.6%-94.5%). Pooled estimates for sensitivity of EUS after nCRT were 96.4% (95% CI, 91.7%-98.5%) and for specificity were 10.9% (95% CI, 3.5%-29.0%) for detecting ypT+, and 62.0% (95% CI, 46.0%-75.7%) and 56.7% (95% CI, 41.8%-70.5%) for detecting ypN+, respectively. CONCLUSIONS Endoscopic biopsy after nCRT is a specific but not sensitive method for detecting residual esophageal cancer. Although EUS after nCRT yields a high sensitivity, only a limited number of patients will have negative findings at EUS with still a substantial false-negative rate. Furthermore, EUS provides only moderate accuracy for detecting residual lymph node involvement. Based on these findings, these endoscopic modalities cannot be used to withhold surgical treatment in test-negative patients after nCRT. ( CLINICAL TRIAL REGISTRATION NUMBER CRD42015016527.).

Diagnostic Performance of F-18-FDG PET and PET/CT for the Detection of Recurrent Esophageal Cancer After Treatment with Curative Intent: A Systematic Review and Meta-Analysis

The aim of this study was to assess the diagnostic performance of 18F-FDG PET and integrated 18F-FDG PET/CT for diagnosing recurrent esophageal cancer after initial treatment with curative intent. Methods: The PubMed, Embase, and Cochrane library were systematically searched for all relevant literature using the key words “18F-FDG PET” and “esophageal cancer” and synonyms. Studies examining the diagnostic value of 18F-FDG PET or integrated 18F-FDG PET/CT, either in routine clinical follow-up or in symptomatic patients in whom recurrence of esophageal cancer was suspected, were deemed eligible for inclusion. The primary outcome was the presence of recurrent esophageal cancer as determined by histopathologic biopsy or clinical follow-up. Risk of bias and applicability concerns were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Sensitivities and specificities of individual studies were meta-analyzed using bivariate random-effects models. Results: Eight eligible studies were included for meta-analysis, comprising 486 patients with esophageal cancer who underwent 18F-FDG PET or PET/CT after previous treatment with curative intent. The quality of the included studies assessed by the QUADAS-2 tool was considered reasonable; there were few concerns with regard to the risk of bias and applicability. Integrated 18F-FDG PET/CT and standalone 18F-FDG PET were used in 4 and 3 studies, respectively. One other study analyzed both modalities separately. In 4 studies, 18F-FDG PET or PET/CT was performed as part of routine follow-up, whereas in 4 other studies the diagnostic test was performed on indication during clinical follow-up. Pooled estimates of sensitivity and specificity for 18F-FDG PET and PET/CT in diagnosing recurrent esophageal cancer were 96% (95% confidence interval, 93%–97%) and 78% (95% confidence interval, 66%–86%), respectively. Subgroup analysis revealed no statistically significant difference in diagnostic accuracy according to type of PET scanner (standalone PET vs. integrated PET/CT) or indication of scanning (routine follow-up vs. on indication). Conclusion: 18F-FDG PET and PET/CT are reliable imaging modalities with a high sensitivity and moderate specificity for detecting recurrent esophageal cancer after treatment with curative intent. The use of 18F-FDG PET or PET/CT particularly allows for a minimal false-negative rate. However, histopathologic confirmation of 18F-FDG PET– or PET/CT-suspected lesions remains required, because a considerable false-positive rate is noticed.

Quantification of esophageal tumor motion on cine-magnetic resonance imaging

PURPOSE To quantify the movement of esophageal tumors noninvasively on cine-magnetic resonance imaging (MRI) by use of a semiautomatic method to visualize tumor movement directly throughout multiple breathing cycles. METHODS AND MATERIALS Thirty-six patients with esophageal tumors underwent MRI. Tumors were located in the upper (8), middle (7), and lower (21) esophagus. Cine-MR images were collected in the coronal and sagittal plane during 60 seconds at a rate of 2 Hz. An adaptive correlation filter was used to automatically track a previously marked reference point. Tumor movement was measured in the craniocaudal (CC), left-right (LR), and anteroposterior (AP) directions and its relationship along the longitudinal axis of the esophagus was investigated. RESULTS Tumor registration within the individual images was typically done at a millisecond time scale. The mean (SD) peak-to-peak displacements in the CC, AP, and LR directions were 13.3 (5.2) mm, 4.9 (2.5) mm, and 2.7 (1.2) mm, respectively. The bandwidth to cover 95% of excursions from the mean position (c95) was also calculated to exclude outliers caused by sporadic movements. The mean (SD) c95 values were 10.1 (3.8) mm, 3.7 (1.9) mm, and 2.0 (0.9) mm in the CC, AP, and LR dimensions. The end-exhale phase provided a stable position in the respiratory cycle, compared with more variety in the end-inhale phase. Furthermore, lower tumors showed more movement than did higher tumors in the CC and AP directions. CONCLUSIONS Intrafraction tumor movement was highly variable between patients. Tumor position proved the most stable during the respiratory cycle in the end-exhale phase. A better understanding of tumor motion makes it possible to individualize radiation delivery strategies accordingly. Cine-MRI is a successful noninvasive modality to analyze motion for this purpose in the future.

Influence of the linac design on intensity-modulated radiotherapy of head-and-neck plans

In this study, we quantify the impact of linac/MLC design parameters on IMRT treatment plans. The investigated parameters were leaf width in the MLC, leaf transmission, related to the thickness of the leaves, and penumbra related primarily to the source size. Seven head-and-neck patients with stage T1-T3N0-N2cM0 oropharyngeal cancer were studied. For each patient nine plans were made with a different set of linac/MLC parameters. The plans were optimized in Pinnacle(3) v7.6c and PLATO RTS v2.6.4, ITP v1.1.8. A hypothetical ideal linac/MLC was introduced to investigate the influence of one parameter at a time without interaction of other parameters. When any of the three parameters was increased from the ideal set-up values (leaf width 2.5 mm, transmission 0%, penumbra 3 mm), the mean dose to the parotid glands increased, given the same tumour coverage. The largest increase was found for increasing leaf transmission. The investigation showed that by changing more than one parameter of the ideal linac/MLC set-up, the increase in the mean dose was smaller than the sum of dose increments for each parameter separately. As a reference to clinical practice, we also optimized the plans of the seven patients with the clinically used Elekta SLi 15, equipped with a standard MLC with a leaf width of 10 mm. As compared to the ideal linac, this resulted in an increase of the average dose to the parotid glands of 5.8 Gy.

Dynamic contrast-enhanced MRI for treatment response assessment in patients with oesophageal cancer receiving neoadjuvant chemoradiotherapy.

PURPOSE To explore and evaluate the potential value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal cancer. MATERIAL AND METHODS Twenty-six patients underwent DCE-MRI before, during (week 2-3) and after nCRT, but before surgery (pre/per/post, respectively). Histopathologic tumour regression grade (TRG) was assessed after oesophagectomy. Tumour area-under-the-concentration time curve (AUC), time-to-peak (TTP) and slope were calculated. The ability of these DCE-parameters to distinguish good responders (GR, TRG 1-2) from poor responders (noGR, TRG⩾3), and pathologic complete responders (pCR) from no-pCR was assessed. RESULTS Twelve patients (48%) showed GR of which 8 patients (32%) pCR. Analysis of AUC change throughout treatment, AUCper-pre, was most predictive for GR, at a threshold of 22.7% resulting in a sensitivity of 92%, specificity of 77%, PPV of 79%, and a NPV of 91%. AUCpost-pre was most predictive for pCR, at a threshold of -24.6% resulting in a sensitivity of 83%, specificity of 88%, PPV of 71%, and a NPV of 93%. TTP and slope were not associated with pathologic response. CONCLUSIONS This study demonstrates that changes in AUC throughout treatment are promising for prediction of histopathologic response to nCRT for oesophageal cancer.