Can lymphocytes serve as a predictor of response to preoperative chemoradiation therapy for locally advanced rectal cancer?

Introduction: The aim of this study is to identify factors that may predict the response of locally advanced rectal cancer tumors (LARC) to neoadjuvant chemoradiotherapy (CRT) and to evaluate the effect of circulating lymphocytes on pathological tumor response. Methods: This retrospective study included neoadjuvant CRT-treated, LARC-diagnosed patients at the Rambam Health Care Campus in Haifa, Israel. CHAID analysis, t-test, χ2 test, and ROC curve analyses were performed to explore the association between pathological complete response (pCR) and several factors including patient demographics, tumor characteristics, type of treatment, and levels of circulating lymphocytes measured on a weekly basis. Results: Out of 198 patients enrolled in the study, pCR was achieved in 50 patients (25%). ROC curve and CHAID analyses showed that absolute lymphopenia was significantly associated with lower pCR rates (p=0.046 and p=0.001, respectively). Other factors that were found to have a significant impact were radiation therapy type (p=0.033) and tumor distance from the anal verge (p= 0.041). Conclusion: An absolute decrease in the level of circulating lymphocytes during preoperative CRT to LARC is associated with poorer tumor response to treatment and thus may serve as a predictive biomarker for treatment resistance.

Physical aspects of a spatially fractionated radiotherapy technique for large soft tissue sarcomas.

This work demonstrates the safety and feasibility of Lattice Radiotherapy (LRT) for large soft tissue sarcoma in neoadjuvant radiotherapy. The treatment consisted of two courses: the LRT course with a single fraction of 20 Gy delivered to high dose nuclei (HDN) regions and the conventional course with 25 fractions of 2 Gy delivered to the planning target volume. HDN shaped as cylinders with a 1 cm diameter and 1 cm height were placed within the gross tumour volume. The number of HDNs and their position were determined based on tumor size and proximity to organs at risk. Three patients were irradiated using the LRT technique.

Rapid Initiation of Neoadjuvant Chemoradiotherapy After Diagnosis is Associated With Improved Pathologic Response in Locally Advanced Rectal Cancer.

INTRODUCTION: In rectal cancer, neoadjuvant chemoradiation (NCRT) is preferred because of toxicity profile, improved resectability and sphincter preservation, although with no impact on overall survival. Pathologic complete response (pCR) to NCRT has been linked with longer disease-free survival (DFS). The study purpose was to evaluate an association between clinical factors and treatment schedule with tumor response and treatment outcome, among patients with locally advanced rectal cancer. PATIENTS AND METHODS: In this single-center retrospective study, conducted over 9 years (2011 to 2020), patients with stage II to III rectal cancer who had received NCRT were enrolled. The standard radiotherapy was 45 Gy to the pelvis, with a simultaneous integrated 50 Gy boost to the primary tumor. Continuous 5-Fluorouracil or oral capecitabine was administered concurrently. Surgery was preplanned within 6 to 8 weeks. Multinomial logistic regressions for evaluation of clinical factors, Kaplan-Meier method for DFS estimation, and receiver operating characteristic analysis for determination of the optimal timeframe were used. RESULTS: Of 279 cases, pCR was observed in 72 (25.8%). In 207 cases, pTis-4N-negative was obtained in 137 (66.2%), pT0N-positive in 6 (2.9%), and pTis-4N-positive in 64 (30.9%). The pCR group had shorter diagnosis-NCRT time (P<0.01) and on-treatment time (P=0.05). DFS was longer for pCR and partial responders with clinical stage II and III (P<0.0001). Diagnosis-NCRT time was shown different between pCR and non-pCR groups. receiver operating characteristic analysis (P<0.01) showed that a diagnosis-NCRT time of <4.5 weeks predicts pCR with a sensitivity of 88% and specificity of 81% accuracy. CONCLUSION: The time elapsed between rectal cancer diagnosis and NCRT initiation is significantly associated with pCR. Reducing this time may increase the probability of achieving pCR.

Complete Pathologic Response Prediction by Radiomics Wavelets Features of Unenhanced CT Simulation Images in Locally Advanced Rectal Cancer Patients after Neoadjuvant Chemoradiation.

BACKGROUND: For locally advanced rectal cancer patients a watch-and-wait strategy is an acceptable treatment option in cases of complete tumor response. Clinicians need robust methods of patient selection after neoadjuvant chemoradiation. OBJECTIVES: To predict pathologic complete response (pCR) using computer vision. To analyze radiomic wavelet transform to predict pCR. METHODS: Neoadjuvant chemoradiation for patients with locally advanced rectal adenocarcinoma who passed computed tomography (CT)-based simulation procedures were examined. Gross tumor volume was examind on the set of CT simulation images. The volume has been analyzed using radiomics software package with wavelets feature extraction module. Statistical analysis using descriptive statistics and logistic regression was performed was used. For prediction evaluation a multilayer perceptron algorithm and Random Forest model were used. RESULTS: In the study 140 patients with II-III stage cancer were included. After a long course of chemoradiation and further surgery the pathology examination showed pCR in 38 (27.1%) of the patients. CT-simulation images of tumor volume were extracted with 850 parameters (119,000 total features). Logistic regression showed high value of wavelet contribution to model. A multilayer perceptron model showed high predictive importance of wavelet. We applied random forest analysis for classifying the texture and predominant features of wavelet parameters. Importance was assigned to wavelets. CONCLUSIONS: We evaluated the feasibility of using non-diagnostic CT images as a data source for texture analysis combined with wavelets feature analysis for predicting pCR in locally advanced rectal cancer patients. The model performance showed the importance of including wavelets features in radiomics analysis.

Initial Experience with Transition from Open to Robotic-assisted Proctectomy for Patients with Rectal Cancer.

BACKGROUND: The learning curve for transition from open to laparoscopic proctectomies is difficult. Most surgeons have considerable laparoscopic experience prior to performing robotic-assisted procedures. There are data regarding the transition from open to robotic proctectomies. Minimally invasive anterior resection for rectal cancer has gained widespread popularity in recent years, especially when using a robotic platform. OBJECTIVES: To analyze the experience to the transition from open to robotic anterior resection for rectal cancer. METHODS: We performed a retrospective analysis of a computerized database. All patients who had a robotic-assisted proctectomy between December 2016 and March 2019 were included and were compared to patients who underwent an open anterior resection in the same time period. A single experienced colorectal surgeon with no prior experience in colorectal laparoscopic surgery performed the procedures. RESULTS: During the study period, 55 patients underwent robotic-assisted proctectomy and 55 had an open proctectomy. Patients had similar pre-operative demographic and clinical characteristics with the majority of patients receiving neoadjuvant chemoradiation. The surgical time was significantly lower in the open surgery group (168 minutes vs. 310 minutes, P = 0.005). Both the surgical and pathological outcomes did not differ significantly between the two groups, with good short-term oncologic outcomes and low complication rates. CONCLUSIONS: The transition from open to robotic-assisted proctectomy is feasible and safe and provides a good alternative for undertaking a minimally invasive surgery for the experienced open colorectal surgeon.

Tumor Volume as Predictor of Pathologic Complete Response Following Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer.

PURPOSE: Neoadjuvant chemoradiation followed by surgery is the current standard of care in the treatment of locally advanced rectal cancer. Those who achieved pathologic complete response, following this standard of care, complete pathologic response (pCR) had better outcome. Until now there are no reliable clinical parameters to predict this response. The purpose of the study was to evaluate whether tumor volume may serve as a predictive factor in patients treated with neoadjuvant chemoradiotherapy. MATERIALS AND METHODS: Between September 2015 and September 2019, patients diagnosed with stage IIA to IIIC rectal adenocarcinoma, who were treated with neoadjuvant chemoradiation, were enrolled to this study. All patients underwent rectal ultrasound, pelvic magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography-computed tomography and the diagnosis was confirmed by pathology report. Radiation therapy was consisted of 50 Gy delivered to the tumor site, 2 Gy a day, 5 times a week and to the pelvic lymph nodes for a total of 45 Gy in 1.8 Gy a day, 5 times a week. The gross tumor volume (GTV) was contoured by radiation oncology expert, reviewed by radiology and nuclear medicine expert and approved by radiation therapy tumor board. Chemotherapy was consisted of either capecitabine 875 mg/m2 twice a day or continuous. IV infusion of 5 fluorouracil 375 mg/m2 for 4 consecutive days in a 3 weeks apart. Operation, either low anterior or abdominoperineal resection was carried out 6 to 8 weeks following completion of treatment. Patients were assigned to either complete pathologic response (pCR) or non-pCR groups. GTV, among other clinical and treatment parameters, were evaluated for prediction of pCR. Statistical methods included independent t test, logistic regression, area under the curve-receiver operating characteristic, Bayesian independent statistics and multilayer perceptron model. RESULTS: One hundred ninety-three patients were enrolled to this study, 6 were excluded due to metastatic disease detected at the time of operation. Seventy had stage II and 117 had stage III. Forty-four of 187 (23.5%) patients achieved pCR and 143 patients had either partial or no response/progressive disease. Among the 44 pCR group, 21 had stage II and 23 had stage III disease. Treatment interruption, defined as either a delay of up to 1 week in radiation, and a dose reduction to 75%, was occurred in 42 patients. Sex, ethnicity, distance from anal verge to tumor, height, weight, age, delivered radiation dose, radiotherapy techniques, clinical T and N stage and GTV were evaluated for prediction of pCR. GTV at the volume of <39.5 cm3 was the only significant predictive factor to detect pCR by logistic regression model (P<0.01) and by Bayesian independent test (P=0.026). Area under the receiver operating characteristic curve of GTV <39.5 cm3 showed area under the curve of 0.715 (P=0.009) for stage II and area under the curve of 0.62 (P>0.05) for stage III. CONCLUSION: GTV may serve as a predictive factor for achieving pCR in locally advanced rectal cancer after neoadjuvant chemoradiotherapy.

Postoperative Radiation Therapy in Patients with Extracranial Chondrosarcoma: A Joint Study of the French Sarcoma Group and Rare Cancer Network.

PURPOSE: Postoperative radiation therapy (poRT) of intracranial/skull base chondrosarcomas (CHSs) is standard treatment. However, consensus is lacking for poRT in extracranial CHS (eCHS) owing to their easier resectability and intrinsic radioresistance. We assessed the practice and efficacy of poRT in eCHS. METHODS AND MATERIALS: This multicentric retrospective study of the French Sarcoma Group/Rare Cancer Network included patients with eCHS who were operated on between 1985 and 2015. Inverse propensity score weighting (IPTW) was used to minimize poRT allocation biases. RESULTS: Of 182 patients, 60.4% had bone and 39.6% had soft-tissue eCHS. eCHS were of conventional (31.9%), myxoid (28.6%; 41 extraskeletal, 11 skeletal), mesenchymal (9.9%), or other subtypes. En-bloc surgery with complete resection was performed in 52.6% and poRT in 36.8% of patients (median dose, 54 Gy). Irradiated patients had unfavorable initial characteristics, with higher grade and incomplete resection. Median follow-up time was 61 months. Five-year incidence of local relapse was 10% with poRT versus 21.6% without (P = .050). Using the IPTW method, poRT reduced the local relapse risk (hazard ratio, 0.27; 95% confidence interval, 0.14-0.52; P < .001). Five-year disease-free survival (DFS) was 71.8% with poRT and 64.2% without (P = .680). Using the IPTW method, poRT improved DFS (hazard ratio, 0.51; 95% confidence interval, 0.30-0.85; P = .010). The benefit of poRT on local relapse and DFS was confirmed after exclusion of the extraskeletal subtype. There was no difference in overall survival. Prognostic factors of poorer DFS in multivariate analysis were deeper location, higher grade, incomplete resection, and no poRT. CONCLUSIONS: poRT should be offered in patients with eCHS and high-grade or incomplete resection, regardless of the histologic subtype.

Radiotherapy in the treatment of extracranial hemangiopericytoma/solitary fibrous tumor: Study from the Rare Cancer Network.

BACKGROUND AND PURPOSE: The role of radiotherapy (RT) in the treatment of hemangiopericytoma/solitary fibrous tumor (HPC/SFT) is still under debate. We aimed at investigating whether radiotherapy can improve the results in patients operated for extracranial HPC/SFT. MATERIALS AND METHODS: Data from patients with HPC/SFT, treated from 1982 to 2012, were retrospectively reviewed within the Rare Cancer Network framework. Actuarial local control (LC), disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) were calculated with Kaplan-Meyer method. Patient and tumor parameters were analyzed by univariate and multivariate analysis. RESULTS: Of 114 HPC/SFT, 58 (50.9%) occurred in the extremities/superficial trunk and 56 (49.1%) in intra-thoracic/retroperitoneum. Seventy-eight patients (68.4%) underwent surgery only (Sx), and 36 (31.6%) Sx and RT (Sx + RT). Median RT dose was 60 Gy (range 45-68.4 Gy) in 1.6-2.2 Gy fractions. In the extremities/superficial trunk group of patients, actuarial 5-year LC rates were 50.4% after Sx and 91.6% after Sx + RT (p < 0.0001) for LC, and 50.4% after Sx and 83.1% after Sx + RT (p = 0.008) for DFS. In the intra-thoracic/retroperitoneum group of patients, actuarial 5-year rates were 89.3% after Sx and 77.8% after Sx + RT (p = 0.99) for LC, and 73.8% after Sx and 77.8% after Sx + RT (p = 0.93) for DFS. At multivariate analysis, the addition of RT resulted in better LC and DFS in the whole series. The advantage was confirmed for LC in the group of patients affected by extremity/superficial trunk tumors. CONCLUSION: Addition of RT to Sx could improve the prognosis, in terms of LC and DFS, essentially in patients with extremities/superficial trunk tumor locations.

The Role of Radiotherapy in Resected R0/R+ Pancreatic Cancer: A Real-Life Single-Institution Experience.

PURPOSE/OBJECTIVE: The purpose of this study was to evaluate the role of external radiation therapy following resection of pancreatic cancer. PATIENTS AND METHODS: Patients who underwent either Whipple procedure or distal pancreatectomy and treated with either chemo-radiotherapy (chemo-rad) or chemotherapy alone (R0 chemo) were enrolled in this study. The chemotherapy (chemo) was based on cisplatin and either gemcitabine or 5 FU/leukovorin. The total radiation dose was 50.4 Gy given in 1.8 Gy 5 times a week. Overall survival, based on resection margin, nodal status, and treatment type, was estimated in all patients. RESULTS: Of the 734 referred patients, 134 underwent either Whipple procedure or distal pancreatectomy during the years 2000 to 2018. In total, 93 had complete tumor resection (R0 group), and 41 had involved resection margins (R+ group). An overall 49 of the 93 were treated with R0 chemo, and 44 were treated with chemo-rad (R0 chemo-rad). The median overall survival for the R0 group was 28 months; for R0 chemo, it was 29 months, and, for R0 chemo-rad, it was 27 months (P-value, NS). For the 41 R+ group, it was 17 months and was significantly lower than that of R0 (P<0.001). The survival of R+ chemo-rad (26 patients) was 23 months, and, for R+ chemo (15 patients), it was 12 months (P=0.01). In total, 72 with positive nodes (N+) had shorter overall survival than those with N negative (22 and 27 mo, P=0.015). The survival of patients with N+/R0 chemo-rad and chemo was similar-31 and 27 months (P-value, NS), and, in the N+/R+ group, the survival was 22 and 16 months in the chemo-rad and chemo only groups, respectively (P=0.006). CONCLUSIONS: external radiation therapy increased significantly the overall survival of R+ resected pancreatic cancer but not N+ patients. Additional studies to delineate the role of chemo-rad in this setting are warranted.

History of the rare cancer network and past research.

Approximately, twenty years ago, the Rare Cancer Network (RCN) was formed in Lausanne, Switzerland, to support the study of rare malignancies. The RCN has grown over the years and now includes 130 investigators from twenty-four nations on six continents. The network held its first international symposium in Nice, France, on March 21-22, 2014. The proceedings of that meeting are presented in two companion papers. This manuscript reviews the history of the growth of the RCN and contains the abstracts of fourteen oral presentations made at the meeting of prior RCN studies. From 1993 to 2014, 74 RCN studies have been initiated, of which 54 were completed, 10 are in progress or under analysis, and 9 were stopped due to poor accrual. Forty-four peer reviewed publications have been written on behalf of the RCN.