Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT)... Show moreBackground: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer. Show less
Vuijk, F.A.; Shahbazi, S.F.; Noortman, W.A.; Velden, F.H.P. van; Dibbets-Schneider, P.; Marinelli, A.W.K.S.; ... ; Geus-Oei, L.F. de 2023
Objective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after... Show moreObjective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial.Methods Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [18F]FDG PET/CT before, 2 weeks into, and 6–8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P ≤ 0.2, promising predictive features for response were selected.Results Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features.Conclusion Both multiparametric MRI and [18F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT. Show less
Vuijk, F.A.; Shahbazi, S.F.; Noortman, W.A.; Velden, F.H.P. van; Dibbets-Schneider, P.; Marinelli, A.W.K.S.; ... ; Geus-Oei, L.F. de 2023
ObjectiveIn this pilot study, we investigated the feasibility of response prediction using digital [F-18]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after... Show moreObjectiveIn this pilot study, we investigated the feasibility of response prediction using digital [F-18]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. MethodsRectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [F-18]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P <= 0.2, promising predictive features for response were selected. ResultsNineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Delta maximum standardized uptake value, Delta peak standardized uptake value corrected for lean body mass), were promising features. ConclusionBoth multiparametric MRI and [F-18]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT. Show less
BackgroundNeoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates.... Show moreBackgroundNeoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking.Patients and methodsIn OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery.ResultsThe median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response.ConclusionsUpdated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome. Show less
Objectives: To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer. Summary of... Show moreObjectives: To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer. Summary of Background Data: Preoperative chemoradiotherapy is increasingly used in patients with (borderline-)resectable pancreatic cancer. concerns have been raised about the potential harmful effect of any preoperative therapy on the surgical complication rate after pancreatic resection. Methods: An observational analysis was performed within the multicenter randomized controlled PREOPANC trial (April 2013-July 2017). The trial randomly assigned (1:1) patients to preoperative chemoradiotherapy followed by surgery and the remaining adjuvant chemotherapy or to immediate surgery, followed by adjuvant chemotherapy. The main analysis consisted of a per-protocol approach. The endpoints of the present analyses were the rate of postoperative complications. Results: This study included 246 patients from 16 centers, of whom 66 patients underwent resection after preoperative therapy and 98 patients after immediate surgery. No differences were found regarding major complications (37.9% vs 30.6%, P=0.400), postpancreatectomy hemorrhage (9.1% vs 5.1%, P=0.352), delayed gastric emptying (21.2% vs 22.4%, P=0.930), bile leakage (4.5% vs 3.1%, P=0.686), intra-abdominal infections (12.1% vs 10.2%, P=0.800), and mortality (3.0% vs 4.1%, P=1.000). There was a significant lower incidence of postoperative pancreatic fistula in patients who received preoperative chemoradiotherapy (0% vs 9.2%, P=0.011). Conclusions: Preoperative chemoradiotherapy did not increase the incidence of surgical complications or mortality and reduced the rate of postoperative pancreatic fistula after resection in patients with (borderline-)resectable pancreatic cancer. Show less
Simple Summary Patients diagnosed with pancreatic cancer have a poor prognosis at time of diagnosis, with a 5-year survival rate of merely 10%. The only treatment with curative intent is surgical... Show moreSimple Summary Patients diagnosed with pancreatic cancer have a poor prognosis at time of diagnosis, with a 5-year survival rate of merely 10%. The only treatment with curative intent is surgical resection of the tumor and adjacent tumor-containing lymph nodes. To improve surgical outcome and survival, additional (imaging) tools are needed that support complete surgical tumor resection. Firstly, more accurate monitoring of tumor response to neoadjuvant treatment and subsequent determination of resectability is needed. Secondly, an imaging tool is needed for intraoperative guidance allowing accurate identification, delineation, and complete resection of the tumor and suspected lymph nodes. Therefore, both tumor-targeted PET/CT before surgery and real time fluorescence-guidance during surgery could be helpful to improve patient outcome. This review focusses on literature considering tumor-targeted PET/CT and near-infrared fluorescence (NIRF) imaging. Several tumor-targeted agents are under clinical evaluation, and several other promising agents are currently tested preclinically, both with promising results. Their additional diagnostic value and feasibility for future implementation in standard clinical care of PDAC has yet to be established in phase III clinical trials. Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patient's treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins.Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers. Show less
Cloos-van Balen, M.; Portier, E.S.H.; Fiocco, M.; Hartgrink, H.H.; Langers, A.M.J.; Neelis, K.J.; ... ; Slingerland, M. 2021
Background and objectives Since the first results of the Dutch randomized CROSS-trial, neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel followed by resection for primary... Show moreBackground and objectives Since the first results of the Dutch randomized CROSS-trial, neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel followed by resection for primary resectable nonmetastatic esophageal cancer (EC) has been implemented as standard curative treatment in the Netherlands. The purpose of this retrospective study is to evaluate the clinical outcomes of this treatment in daily practice in a large academic hospital. Methods Medical records of patients treated for primary resectable nonmetastatic EC between May 2010 and December 2015 at our institution were reviewed. Treatment consisted of five weekly courses of carboplatin (area under the curve 2) and paclitaxel (50 mg/m(2)) with concurrent external beam radiotherapy (23 fractions of 1.8 Gy), followed by transthoracic or transhiatal resection. Data on survival, progression, acute and late toxicity were recorded. Results A total of 145 patients were included. Median follow-up was 43 months. Median overall survival (OS) and progression-free survival (PFS) were 35 (95% confidence interval [CI] 29.8-40.2) and 30 (95% CI 19.7-40.3) months, respectively, with corresponding 3-year OS and PFS of 49.6% (95% CI 40.4-58.8) and 45.6% (95% CI 36.6-54.6). Acute toxicity grade >= 3 was observed in 25.5% of patients. Late adverse events grade >= 3 were seen in 24.8%, mostly esophageal stenosis. Conclusion Neoadjuvant CRT followed by resection for primary resectable nonmetastatic EC in daily practice results in a 3-year OS of 49.6% (95% CI 40.4-58.8) and PFS of 45.6% (95% CI 36.6-54.6), compared with 58% (51-65%) and 51% (43-58%) within the CROSS-trial. The slightly poorer survival in our daily practice group might be due to the presence of less favorable patient and tumor characteristics in daily practice, as is to be expected in daily practice. Toxicity was comparable with that in the CROSS-trial and considered acceptable. Show less
Cloos-van Balen, M.; Portier, E.S.H.; Fiocco, M.; Hartgrink, H.H.; Langers, A.M.J.; Neelis, K.J.; ... ; Slingerland, M. 2021
Background and objectivesSince the first results of the Dutch randomized CROSS-trial, neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel followed by resection for primary... Show moreBackground and objectivesSince the first results of the Dutch randomized CROSS-trial, neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel followed by resection for primary resectable nonmetastatic esophageal cancer (EC) has been implemented as standard curative treatment in the Netherlands. The purpose of this retrospective study is to evaluate the clinical outcomes of this treatment in daily practice in a large academic hospital.MethodsMedical records of patients treated for primary resectable nonmetastatic EC between May 2010 and December 2015 at our institution were reviewed. Treatment consisted of five weekly courses of carboplatin (area under the curve 2) and paclitaxel (50 mg/m2) with concurrent external beam radiotherapy (23 fractions of 1.8 Gy), followed by transthoracic or transhiatal resection. Data on survival, progression, acute and late toxicity were recorded.ResultsA total of 145 patients were included. Median follow-up was 43 months. Median overall survival (OS) and progression-free survival (PFS) were 35 (95% confidence interval [CI] 29.8–40.2) and 30 (95% CI 19.7–40.3) months, respectively, with corresponding 3-year OS and PFS of 49.6% (95% CI 40.4–58.8) and 45.6% (95% CI 36.6–54.6). Acute toxicity grade ≥3 was observed in 25.5% of patients. Late adverse events grade ≥3 were seen in 24.8%, mostly esophageal stenosis.ConclusionNeoadjuvant CRT followed by resection for primary resectable nonmetastatic EC in daily practice results in a 3-year OS of 49.6% (95% CI 40.4–58.8) and PFS of 45.6% (95% CI 36.6–54.6), compared with 58% (51–65%) and 51% (43–58%) within the CROSS-trial. The slightly poorer survival in our daily practice group might be due to the presence of less favorable patient and tumor characteristics in daily practice, as is to be expected in daily practice. Toxicity was comparable with that in the CROSS-trial and considered acceptable. Show less
