O. Reerink

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial)

BackgroundFor esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer.Methods/designThis is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥18 and ≤80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien–Dindo classification of surgical complications.DiscussionThis is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient.Trial registrationDutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790

Dynamic contrast enhanced MR imaging for rectal cancer response assessment after neo-adjuvant chemoradiation

Patient selection for organ sparing treatment after good response to neo‐adjuvant chemoradiation (CRT) for locally advanced rectal cancer is challenging as no optimal restaging modality is available after CRT. In this study, we assessed the value of dynamic contrast enhanced magnetic resonance imaging (DCE‐MRI) for rectal cancer pathological response prediction.

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.

Imaging of oesophageal cancer with FDG-PET/CT and MRI

Integrated 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) PET/CT and magnetic resonance imaging (MRI) with functional features of diffusion-weighted imaging (DWI) are advancing imaging technologies that have current and future potential to overcome important limitations of conventional staging methods in the management of patients with oesophageal cancer. PET/CT has emerged as an important part of the standard work-up of patients with oesophageal cancer. Besides its important ability to detect unsuspected metastatic disease, PET/CT may be useful in the assessment of treatment response, radiation treatment planning, and detection of recurrent disease. In addition, high-resolution T2-weighted MRI and DWI have potential complementary roles. Recent improvements in MRI protocols and techniques have resulted in better imaging quality with the potential to bring improvement in staging, radiation treatment planning, and the assessment of treatment response. Optimal use and understanding of PET/CT and MRI in oesophageal cancer will contribute to the impact of these advancing technologies in tailoring treatment to the individual patient and achieving best possible outcomes. In this article, we graphically outline the current and potential future roles of PET/CT and MRI in the multidisciplinary management of oesophageal cancer.

Combined T2w volumetry, DW-MRI and DCE-MRI for response assessment after neo-adjuvant chemoradiation in locally advanced rectal cancer.

Background. To assess the value of combined T2-weighted magnetic resonance imaging (MRI) (T2w) volumetry, diffusion-weighted (DW)-MRI and dynamic contrast enhanced (DCE)-MRI for pathological response prediction after neo-adjuvant chemoradiation (CRT) in locally advanced rectal cancer (LARC). Material and methods. MRI with DW-MRI and DCE-MRI sequences was performed before start of CRT and before surgery. After surgery, the tumor regression grade (TRG) was obtained based on the score by Mandard et al. Pathological complete responders (pCR, TRG 1), and pathological good responders (GR, TRG 1 + 2) were compared to non-pCR and non-GR patients, respectively. Results. In total 55 patients were analyzed, six had a pCR (10.9%) and 10 a GR (18.2%). Favorable responders had a larger decrease in tumor volume and Ktrans and a larger increase in apparent diffusion coefficient (ADC) values compared to non-responders. ADC change showed the best diagnostic accuracy for pCR. For GR, the model including ADC change and volume change showed the best diagnostic performance. However, this performance was not statistically better compared to the model with ADC change alone. Inclusion of Ktrans change did not increase the diagnostic accuracy for pathological favorable response. Conclusions. This explorative study showed that ADC change is a promising diagnostic tool for pCR and GR. Volume decrease showed potential limited additional diagnostic value for GR while Ktrans change showed no additional diagnostic value for pCR and GR.

RandomizEd controlled trial for pre-operAtive dose-escaLation BOOST in locally advanced rectal cancer (RECTAL BOOST study) : study protocol for a randomized controlled trial

BackgroundTreatment for locally advanced rectal cancer (LARC) consists of chemoradiation therapy (CRT) and surgery. Approximately 15% of patients show a pathological complete response (pCR). Increased pCR-rates can be achieved through dose escalation, thereby increasing the number patients eligible for organ-preservation to improve quality of life (QoL). A randomized comparison of 65 versus 50Gy with external-beam radiation alone has not yet been performed. This trial investigates pCR rate, clinical response, toxicity, QoL and (disease-free) survival in LARC patients treated with 65Gy (boost + chemoradiation) compared with 50Gy standard chemoradiation (sCRT).Methods/designThis study follows the ‘cohort multiple randomized controlled trial’ (cmRCT) design: rectal cancer patients are included in a prospective cohort that registers clinical baseline, follow-up, survival and QoL data. At enrollment, patients are asked consent to offer them experimental interventions in the future. Eligible patients—histologically confirmed LARC (T3NxM0 <1 mm from mesorectal fascia, T4NxM0 or TxN2M0) located ≤10 cm from the anorectal transition who provided consent for experimental intervention offers—form a subcohort (n = 120). From this subcohort, a random sample is offered the boost prior to sCRT (n = 60), which they may accept or refuse. Informed consent is signed only after acceptance of the boost. Non-selected patients in the subcohort (n = 60) undergo sCRT alone and are not notified that they participate in the control arm until the trial is completed.sCRT consists of 50Gy (25 × 2Gy) with concomitant capecitabine. The boost (without chemotherapy) is given prior to sCRT and consists of 15 Gy (5 × 3Gy) delivered to the gross tumor volume (GTV). The primary endpoint is pCR (TRG 1). Secondary endpoints include acute grade 3–4 toxicity, good pathologic response (TRG 1-2), clinical response, surgical complications, QoL and (disease-free) survival. Data is analyzed by intention to treat.DiscussionThe boost is delivered prior to sCRT so that GTV adjustment for tumor shrinkage during sCRT is not necessary. Small margins also aim to limit irradiation of healthy tissue. The cmRCT design provides opportunity to overcome common shortcomings of classic RCTs, such as slow recruitment, disappointment-bias in control arm patients and poor generalizability.Trial registrationThe Netherlands Trials Register NL46051.041.13. Registered 22 August 2013. ClinicalTrials.gov NCT01951521. Registered 18 September 2013.

Repeatability of diffusion-weighted imaging in rectal cancer

Serial diffusion‐weighted MRI (DW‐MRI) measurements of the apparent diffusion coefficient (ADC) of rectal tumors are used for rectal cancer response evaluation after neo‐adjuvant treatment. In this study, we determined the repeatability of DW‐MRI to distinguish therapy‐related response from measurement variations.

Combination of biodegradable stent placement and single-dose brachytherapy is associated with an unacceptably high complication rate in the treatment of dysphagia from esophageal cancer

BACKGROUND For the palliative treatment of dysphagia, esophageal stent placement provides immediate improvement, whereas brachytherapy offers better long-term relief. OBJECTIVE To evaluate safety and efficacy of concurrent brachytherapy and biodegradable stent placement. DESIGN Prospective, single-arm study. SETTING Two tertiary-care referral centers. PATIENTS Nineteen consecutive patients with significant dysphagia resulting from unresectable esophageal cancer, with a life expectancy of more than 3 months. INTERVENTION Single-dose brachytherapy (12 Gy) on day 1 followed by biodegradable stent placement on day 2. MAIN OUTCOME MEASUREMENTS Intervention-related major complications (determined by an expert panel) and dysphagia. RESULTS Nineteen patients (13 men, median age 66 years [interquartile range (IQR) 59-71] years) were included; 7 patients (37%) also received palliative chemotherapy. After inclusion of 19 patients, the study was ended prematurely because the safety threshold was exceeded. In total, 28 major complications occurred in 17 patients (89%). In 9 patients (47%), major complications were determined intervention-related (severe retrosternal pain with or without vomiting [n = 6], hematemesis [n = 1], recurrent dysphagia [n = 2]. Dysphagia scores decreased significantly from a median of 3 (IQR 3-4) to a median of 1 (IQR 0-3) after 1 month (P < .001). Despite adequate luminal patency in 17 patients (89%), normal diet could not be tolerated in 7 patients (37%) because of retrosternal pain and vomiting. LIMITATIONS Lack of routine endoscopy or contrast esophagram to evaluate recurrent dysphagia during follow-up. CONCLUSION Despite restoration of luminal patency, a combined treatment of brachytherapy and biodegradable stent placement cannot be recommended for the palliative treatment of esophageal cancer because of an unacceptably high intervention-related major complication rate.

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.