Neoadjuvant Treatment Protocols Research Articles

Tumor Response and Its Impact on Treatment Failure in Rectal Cancer: Does Intensity of Neoadjuvant Treatment Matter?

Objectives: Additional adjuvant treatment in patients with rectal cancer with limited response to neoadjuvant treatment to mitigate their higher risk of treatment failure remains controversial. Methods: This is a post hoc analysis of a cohort study of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trial) that included 1948 patients with locally advanced rectal adenocarcinoma. After excluding patients with missing information, 1788 patients (1254 men and 524 women; median age: 62.6 years, age range: 19-84 years) were eligible. We analyzed the extent of tumor response and its association with the incidence of treatment failure after different neoadjuvant treatment approaches. Results: Tumor response was significantly enhanced with more intensive neoadjuvant treatment. After a median follow-up of 55 months for the entire cohort (IQR: 37 months-62 months), the incidence of treatment failure (TF) stratified by tumor response or post-neoadjuvant pathological outcome was not significantly affected by the intensity of neoadjuvant treatment, whereas the ypTNM stage was significantly associated with the risk of treatment failure. Conclusions: In this cohort study, we provide evidence that limited or no response to intensified neoadjuvant treatment protocols is not likely to be more strongly associated with an extensive risk of TF after 5-FU CRT+/- adjuvant chemotherapy.

Influence of neoadjuvant regimen on the prognosis of locally advanced gastric and gastroesophageal junction cancer with HER2 overexpression.

e16082 Background: The relative high recurrence rate in locally advanced gastric or gastroesophageal junction (G/GEJ) cancer with Her2 overexpression after surgery, along with the absence of a standard neoadjuvant treatment protocol, necessitates exploration of novel approaches for this patient population. Methods: In this study, we conducted a retrospective analysis of clinical characteristics, postoperative pathological results, and survival data for patients who underwent neoadjuvant treatment and subsequent surgery at our center from September 2020 to December 31, 2022. The inclusion criteria were as follows: 1) pathologically confirmed adenocarcinoma of the G/GEJ; 2) diagnosed as cT3-4 or N+ by enhanced CT and endoscopic ultrasound; 3) Her2 immunohistochemistry 3+ or 2+ with Fish positive in biopsy specimens; 4) discussed in a multidisciplinary team for the need for neoadjuvant treatment; 5) received 2-4 cycles of neoadjuvant therapy; 6) underwent radical D2 surgery; 7) had complete follow-up data. Results: Seventy-three patients met the inclusion criteria, with 19 receiving chemotherapy + anti-PD-1, 10 receiving chemotherapy + anti-Her2, and 44 receiving chemotherapy alone. Their pCR rates were 31.6%, 10%, and 2.3%, respectively (P = 0.003); MPR rates were 42.1%, 30%, and 11.4% (P = 0.022). As of the last follow-up on December 31, 2023, the median DFS for the chemotherapy group was 18.1 months (95% confidence interval 14.9-21.3); median DFS for the other two groups had not been reached. DFS analysis revealed differences in median DFS among different neoadjuvant treatment regimens (P = 0.025); further pairwise comparisons indicated that this difference mainly stemmed from the chemotherapy + anti-Her2 group compared to the chemotherapy group. Conclusions: In locally advanced gastric and gastroesophageal junction cancer with Her2 overexpression, neoadjuvant chemotherapy combined with anti-Her2 treatment improves the pCR rate and prolongs DFS compared to neoadjuvant chemotherapy alone.

Efficacy and safety of different regimens of neoadjuvant therapy in patients with hormone receptor-positive, her2-negative breast cancer: a network meta-analysis.

The objective of this systematic review and network meta-analysis (NMA) is to assess the effectiveness and safety of various neoadjuvant treatment protocols in individuals diagnosed with hormone receptor-positive, her2 negative(HR+/HER2-) breast cancer. A systematic search was conducted in four databases (Medline, Embase, Web of Science, and CENTRAL) from the inception of the databases to January 16, 2024, to identify randomized controlled trials (RCTs) to various neoadjuvant therapy options in patients diagnosed with hormone receptor-positive, HER2-negative breast cancer. A network meta-analysis was conducted to evaluate pathological complete response (pCR). There were 17 randomized controlled trials (RCTs) included in the analysis. These trials examined 16 different treatment regimens and involved a total of 5752 participants. The analysis revealed that the six most effective neoadjuvant treatment regimens for HR+/HER2- breast cancer were: CT(A)+olaparib (82.5%), CT(A)+nivolumab (76.5%), Com (74.9%), CT (72.1%), Mono+eribulin (72.0%), and CT(A)+pembrolizumab (70.4%).Paired meta-analysis for pathological complete response (pCR) found no statistically significant distinction between treatment regimens that included both anthracycline and immunosuppressants and regimens that relied solely on anthracycline chemotherapy(OR:1.14, 95%ci 0.79-1.64, I2 = 71%, P=0.50). Similarly, there was no significant difference between platinum-based chemotherapy and anthracycline-basedchemotherapy(OR:1.37, 95%ci 0.53- 3.56, I2 = 11%, P=0.52). With regards to safety, adverse effects of grade 3-5 were observed, which included haematological toxicity, gastrointestinal reactions, skin and mucous membrane reactions, neuropathy, hepatotoxicity, and cardiac disorders. The CT(A)+Olaparib and CT(A)+nivolumab groups demonstrated superior efficacy in neoadjuvant therapy for HR+/HER2- breast cancer. Furthermore, it is crucial to focus on effectively managing the adverse effects of the treatment plan to enhance patient's ability to tolerate it. Given the constraints of the current research, additional well-executed and suitable RCTs are necessary to validate the findings of this investigation. Although pCR is valuable in assessing the effect of neoadjuvant therapy in some cases, prognostic prediction and efficacy assessment in patients with HR+/HER2- breast cancer should be based on a combination of broader clinical and biological characteristics. PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024534539, CRD42024501740.

Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14

The inclusion of immune checkpoint inhibitors (ICIs) in the treatment of operable stage III non-small-cell lung cancer is becoming a new standard. Programmed death-ligand 1 (PD-L1) protein expression on tumor cells has emerged as the most important biomarker for sensitivity to ICIs targeting the programmed cell death protein 1 (PD-1)-PD-L1 axis. Little is known about the impact of neoadjuvant treatment on PD-L1 expression. We assessed PD-L1 expression by immunohistochemistry (Ventana SP263 assay) on tumor cells in treatment-naive diagnostic tumor samples and matched lung resections from patients with stage III non-small-cell lung cancer included in the Swiss Group for Clinical Cancer Research (SAKK) trials 16/96, 16/00, 16/01, and 16/14. All patients received neoadjuvant chemotherapy (CT) with cisplatin/docetaxel, either as single modality (CT), with sequential radiotherapy [chemoradiation therapy (CRT)] or with the PD-L1 inhibitor durvalumab (CT+ ICI). Overall, 132 paired tumor samples were analyzed from patients with neoadjuvant CT (n= 69), CRT (n= 33) and CT+ ICI (n= 30). For CT and CRT, PD-L1 expression before and after neoadjuvant treatment did not differ significantly (Wilcoxon test, P= 0.94). Likewise, no statistically significant difference was observed between CT and CRT for PD-L1 expression after neoadjuvant treatment (P= 0.97). For CT+ ICI, PD-L1 expression before and after neoadjuvant treatment also did not differ significantly (Wilcoxon test, P > 0.99). Event-free survival and overall survival for patients with downregulation or upregulation of PD-L1 expression after neoadjuvant treatment were similar. In our cohort of patients neoadjuvant treatment did not influence PD-L1 expression, irrespective of the specific neoadjuvant treatment protocol. Dynamic change of PD-L1 expression did not correlate with event-free survival or overall survival.

Towards Patient-Specific Optimization of Neoadjuvant Treatment Protocols for Breast Cancer Based on Image-Guided Fluid Dynamics.

This study establishes a fluid dynamics model personalized with patient-specific imaging data to optimize neoadjuvant therapy (i.e., doxorubicin) protocols for breast cancers. Ten patients recruited at the University of Chicago were included in this study. Quantitative dynamic contrast-enhanced and diffusion weighted magnetic resonance imaging data are leveraged to estimate patient-specific hemodynamic properties, which are then used to constrain the mechanism-based drug delivery model. Then, computer simulations of this model yield the subsequent drug distribution throughout the breast. By systematically varying the dosing schedule, we identify an optimized regimen for each patient using the maximum safe therapeutic duration (MSTD), which is a metric balancing treatment efficacy and toxicity. With an individually optimized dose (range = 12.11-15.11 mg/m2 per injection), a 3-week regimen consisting of a uniform daily injection significantly outperforms all other scheduling strategies (P < 0.001). In particular, the optimal protocol is predicted to significantly outperform the standard protocol (P < 0.001), improving the MSTD by an average factor of 9.93 (range = 6.63 to 14.17). A clinical-mathematical framework was developed by integrating quantitative MRI data, advanced image processing, and computational fluid dynamics to predict the efficacy and toxicity of neoadjuvant therapy protocols, thus enabling the rational identification of an optimal therapeutic regimen on a patient-specific basis. Our clinical-computational approach has the potential to enable optimization of therapeutic regimens on a patient-specific basis and provide guidance for prospective clinical trials aimed at refining neoadjuvant therapy protocols for breast cancers.

Personalized total neoadjuvant therapy (pTNT) for advanced rectal cancer with tailored treatment sequencing based on clinical stage at presentation.

This study aimed to assess short-term outcomes of a personalized total neoadjuvant treatment (pTNT) protocol, with treatment sequencing based on clinical stage at presentation. A multidisciplinary pTNT protocol was implemented across two metropolitan hospitals. This consists of two-schema based on clinical stage: patients with distant failure risk were offered induction chemotherapy before chemoradiation (nCRT), and patients with locoregional failure risk received nCRT followed by consolidation chemotherapy. Patients underwent surgical resection unless a complete clinical response (cCR) was achieved, in which case non-operative management (NOM) was offered. A prospective cohort analysis of all patients with rectal cancer who underwent pTNT with curative intent between Jan 2019 and Aug 2022 was performed. Of 270 patients referred with rectal cancer, 102 received pTNT with curative intent and 79 have completed their treatment thus far. Thirty-three patients (41.8%) received induction chemotherapy and 46 (58.2%) received consolidation chemotherapy per protocol. The percentage of patients with EMVI, resectable M1 disease, cT4 disease, and positive lateral lymph nodes were 54.4%, 36.7%, 27.8% and 15.2%, respectively. Overall, 32 (40.5%) patients had cCR and 4 (5.1%) pCR, and 40 (50.6%) patients had non-operative management. Grade 3 toxicity was reported in 10.1% of patients and only three patients (3.8%) experienced Grade 4 chemotherapy-related toxicity, with no treatment related mortality. Early results with a defined two-schema pTNT protocol are encouraging and suggest that tailoring sequencing to disease risk at presentation may represent the optimal balance between local and distant disease control, as well as treatment toxicity.

Current status of liver transplantation for cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.

Recent Progress in the Neoadjuvant Treatment Strategy for Locally Advanced Esophageal Cancer.

Simple SummaryNeoadjuvant therapy is recommended as standard care for patients with locally advanced resectable esophageal cancer. Neoadjuvant chemotherapy (nCT) and chemoradiotherapy (nCRT) have convincingly been shown to improve the survival rate compared with surgery alone based on the results of several randomized clinical trials. Immunotherapy has become a new research direction in the field of EC research due to its great curative effects. However, controversies still remain in regard to identifying the most appropriate combination of nCT, nCRT, immunotherapy, and surgery, optimizing more effective neoadjuvant treatment protocols and surveillance strategies. This review comprehensively summarizes the research progress and describes and discusses the outcomes, pros, and cons of current trials. We believe our work has great academic value and will be of great help for researchers to understand the domestic and foreign research status in the field of neoadjuvant therapy in EC.Neoadjuvant therapies, primarily chemotherapy and chemoradiotherapy, are able to improve the overall survival (OS) in patients with locally advanced resectable esophageal cancer (EC) based on the results of several randomized clinical trials. The advantage of neoadjuvant therapy is chiefly attributed to the decreased risk of local–regional recurrence and distant metastasis. Thus, it has been recommended as standard treatment for patients with resectable EC. However, several fundamental problems remain. First, the combination of neoadjuvant chemotherapy (nCT), neoadjuvant chemoradiotherapy (nCRT), and surgery for EC patients with different histological types remain controversial. Furthermore, to reduce the toxicity of preoperative chemotherapy and the risk of complications caused by preoperative radiation therapy, the treatment protocols of nCT and nCRT still need to be investigated and optimized by prospective trials. Moreover, for patients with complete clinical response following neoadjuvant therapy, it is worth ascertaining whether a “watch and wait” surveillance plus surgery-as-needed policy is more favorable, as well as, in addition to preoperative chemoradiotherapy, whether immunotherapy, especially when combined with the traditional neoadjuvant therapy regimens, brings new prospects for EC treatment. In this review, we summarize the recent insights into the research progress and existing problems of neoadjuvant therapy for locally advanced resectable EC.

Abstract 222: Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics

Abstract Introduction: Standard-of-care neoadjuvant therapeutic regimens are based on clinical trials designed to identify treatment protocols at the population level, which cannot capture the unique characteristics of individual patients. Moreover, it is impossible for clinical trials to experimentally evaluate all the possible treatment combinations and dosing strategies. Mechanism-based, mathematical modeling can potentially address this critical barrier to achieving truly personalized treatment. In this contribution, we present preliminary results using a fluid dynamics model personalized with a patient's imaging data to optimize a drug injection protocol in breast cancer. Methods: Nine breast cancer patients are included in this study. MRI data are acquired, processed, and used to estimate hemodynamics and imported to our drug delivery model. By varying the dosing schedule, the model predicts varying dynamics of drug distribution throughout the breast. We define an objective function, MSTD, balancing the treatment efficacy and toxicity, and use it to optimize the injection protocol for each patient. The injection schedules tested include: (a) single injection on day 1 of each 3-week cycle; double injections of half the total dose each at (b) day 1 and 2, (c) day 1 and 3, (d) day 1 and 5, and (e) day 1 and 8 within each 3-week cycle. The doses tested vary from 0 to 100 μg/ml of maximal plasma concentration. Improvement ratio of the optimal protocol to a standard protocol, 10 μg/ml via schedule (a), is measured. Results: The optimal protocol and improvement are reported for each patient in Table 1. Conclusion: Our modeling system can efficiently solve the personalization of drug injection protocol as an optimal control problem. Different patients have different optimal treatment protocols, each of which is predicted to outperform the standard protocol. Table 1.Optimal injection protocol for individual patientsPatientOptimal scheduleOptimal dose (μg/ml)Improvement ratio1(e)8.891.492(e)6.071.823(e)5.882.124(e)7.362.415(e)5.193.266(e)5.203.377(e)5.703.598(e)4.103.079(e)4.593.49NCI U01CA142565, U01CA174706, R01CA218700, R01CA172801, U24CA226110, P30CA014599. CPRIT RR160005. Citation Format: Chengyue Wu, David A. Hormuth, Federico Pineda, Gregory S. Karczmar, Thomas E. Yankeelov. Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 222.

Post-Neoadjuvant Surveillance and Surgery as Needed Compared with Post-Neoadjuvant Surgery on Principle in Multimodal Treatment for Esophageal Cancer: A Scoping Review.

Simple SummaryA substantial fraction of patients with esophageal cancer show post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients, including those with pCR. Surveillance and surgery as needed may be a treatment alternative for these patients. We performed a scoping review and described all relevant clinical studies addressing these two treatment approaches. We identified three completed randomized controlled trials (RCTs) including 468 participants, three planned/ongoing RCTs with a planned sample size of 752 participants, one non-randomized controlled study with 53 participants, ten retrospective cohort studies (2228 participants) and one survey on patients’ preferences (100 participants). The current scoping review reveals that although surveillance and surgery as needed has been investigated within different study designs, the available study pool show methodological limitations and clinical results are heterogeneous. A thoroughly planned RCT considering these limitations will be of great importance to provide these patients with the best treatment.Background: A substantial fraction of patients with esophageal cancer show post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients, although surveillance and surgery as needed in case of local recurrence may be a treatment alternative for patients with complete response (CR). Methods: We performed a scoping review to describe key characteristics of relevant clinical studies including adults with non-metastatic esophageal cancer receiving multimodal treatment. Until September 2020, relevant studies were identified through systematic searches in the bibliographic databases Medline, Web of Science, Cochrane Library, Science Direct, ClinicalTrials, the German study register, and the WHO registry platform. Results: In total, three completed randomized controlled trials (RCTs, with 468 participants), three planned/ongoing RCTs (with a planned sample size of 752 participants), one non-randomized controlled study (NRS, with 53 participants), ten retrospective cohort studies (with 2228 participants), and one survey on patients’ preferences (with 100 participants) were identified. All studies applied neoadjuvant chemoradiation protocols. None of the studies examined neoadjuvant chemotherapeutic protocols. Studies investigated patient populations with esophageal squamous cell carcinoma, adenocarcinoma, and mixed cohorts. Important outcomes reported were overall, disease-free and local recurrence-free survival. Limitations of the currently available study pool include heterogeneous chemoradiation protocols, a lack of modern neoadjuvant treatment protocols in RCTs, short follow-up times, the use of heterogeneous diagnostic methods, and different definitions of clinical CR. Conclusion: Although post-neoadjuvant surveillance and surgery as needed compared with post-neoadjuvant surgery on principle has been investigated within different study designs, the currently available results are based on a wide variation of diagnostic tools to identify patients with pCR, short follow-up times, small sample sizes, and variations in therapeutic procedures. A thoroughly planned RCT considering the limitations in the currently available literature will be of great importance to provide patients with CR with the best and less harmful treatment.

Recent developments and ongoing trials in transplant oncology.

Over the past two decades since the introduction of the Milan criteria, the field of transplant oncology has undergone a rapid development with a rising proportion of liver transplantations being performed for oncological indications. For many patients with liver tumours, transplantation represents the only chance for cure. However, many challenges remain, such as the adequate patient selection, management of post-transplant recurrence and refinement of neoadjuvant treatment protocols. This review provides an overview of the current state of the art of liver transplantation for oncological indications such as hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastasis and metastatic neuroendocrine tumours. We also summarize the ongoing research and explore future trends. Clinical trials are currently studying new diagnostic modalities, innovative pharmacological treatments, novel surgical techniques, downstaging regimens and new indications for liver transplantation. These emerging results will continue to shape the field of transplant oncology and provide us with the necessary tools to better select, treat and follow patients with liver tumours qualifying for liver transplantation.

Circulating Biomarkers for Response Prediction of Rectal Cancer to Neoadjuvant Chemoradiotherapy.

Rectal cancer response to neoadjuvant Chemoradiotherapy (pCRT) is highly variable. In fact, it has been estimated that only about 21 % of patients show pathologic Complete Response (pCR) after therapy, while in most of the patients a partial or incomplete tumour regression is observed. Consequently, patients with a priori chemoradioresistant tumour should not receive the treatment, which is associated with substantial adverse effects and does not guarantee any clinical benefit. For Locally Advanced Rectal Cancer Patients (LARC), a standardized neoadjuvant treatment protocol is applied, the identification and the usefulness of prognostic or predictive biomarkers can improve the antitumoural treatment strategy, modifying the sequence, dose, and combination of radiotherapy, chemotherapy and surgical resection. For these reasons, a growing number of studies are actually focussed on the discovery and investigation of new predictive biomarkers of response to pCRT. In this review, we have selected the most recent literature (2012-2017) regarding the employment of blood-based biomarkers potentially predicting pCR in LARC patients and we have critically discussed them to highlight their real clinical benefit and the current limitations of the proposed methodological approaches.

Neoadjuvant and adjuvant treatment of pancreatic cancer

Resection is the only curative treatment option for pancreatic cancer patients. Adjuvant chemotherapy can improve disease-free survival and overall survival after resection. Furthermore, neoadjuvant treatment protocols are currently being investigated in alarge number of studies. Summary of the current evidence for adjuvant and neoadjuvant treatment. Review of the current scientific literature and guidelines. After resection for pancreatic cancer patients should receive intensive chemotherapy with mFOLFIRINOX, gemcitabine plus capecitabine or gemcitabine/5-fluorouracil (5-FU) monotherapy. Neoadjuvant treatment concepts are promising but have to be further evaluated in prospective studies.

Results of portosystemic shunts during extended pancreatic resections.

Patients with borderline resectable pancreatic cancer are increasingly explored after neoadjuvant treatment protocols. A complete resection, then, frequently includes the resection of the mesentericoportal axis. Portosystemic shunting for advanced tumours with infiltration of the splenic vein or cavernous transformation of the portal vein can enable complete tumour resection and prevent portovenous congestion of the intestine. The aim of this study was to report the results of this technique for selected patients. Patients operated for pancreatic cancer at our department between September 2012 and December 2017 using intraoperative portosystemic shunting were included in this retrospective analysis. Some 11 patients with pancreatectomy and simultaneous portosystemic shunting were included. The median age was 65.1years. A distal splenorenal shunt and a temporary mesocaval shunt were accomplished in 5 and 4 cases, respectively. Two patients were operated using persistent mesocaval shunts (from the coronary, splenic or inferior mesenteric veins). The median operating time was 9.43h. All but one patient were resected with tumour-negative resection margins; 5 patients had relevant complicated postoperative courses. There was one case of in-hospital mortality but no further 30- or 90-day mortality or graft-associated complications. Five patients were alive after a median follow-up of 24.6months. The median postoperative survival was 12months. Portosystemic shunting at the time of extended pancreatectomy is technically challenging but feasible and enables complete tumour resection in cases in which standard vascular reconstruction is limited by cavernous transformation or to prevent sinistral portal hypertension with acceptable morbidity in selected cases. Considering the limited overall survival, the potential individual patient benefit needs to be weighed against the considerable morbidity of advanced tumour resections.

Neoadjuvant hypofractionated chemoradiotherapy with S-1 for patients with resectable and borderline resectable pancreatic cancer

The ideal neoadjuvant treatment protocol for patients with pancreatic cancer (PDAC) remains unclear. We evaluated the efficacy and safety of neoadjuvant hypofractionated chemoradiotherapy with S-1 (NACRT) for patients with resectable (R) and borderline resectable (BR) PDAC. Methods: Eligibility criteria included patients with R and BR PDAC, performance status 0-1, and age 20-85 years. Hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m2) was delivered 5 days/week for 2 weeks prior to pancreatectomy. Results: Fifty-seven patients were enrolled, including 33 R and 24 BR patients. The total rates of protocol treatment completion and resection were 91% (50/57) and 96% (55/57). No patient experienced grade 4 toxicity. CT showed 52 (91%) with a SD, 4 (7%) with a PR, and 1 patient (2%) with PD. Pathologically negative margins (R0) were achieved in 54 of 55 patients (98%) who underwent pancreatectomy. Pathological response was classified as Evans grade I in 8 patients (15%), IIa in 31 (56%), IIb in 14 (25%), III in 1 (2%), and IV in 1 (2%). The 1-, 3- and 5-year overall survival (OS) rates were 93%, 73% and 49% in R and 75%, 47% and ND in BR patients, respectively (p=0.025). Conclusion: Present study demonstrated that hypofractionated NACRT with S-1 is well tolerated and safe. Our protocol allowed a high rate of subsequent resection, with encouraging survival data. This is the first and largest study to evaluate the safety and efficacy of hypofractionated NACRT with S-1 in patients with R and BR PDAC.

Recent Advances in Pancreatic Cancer Surgery.

Pancreatic cancer surgery is a continuously evolving field. Despite tremendous advances in perioperative outcomes, pancreatic resection is still associated with substantial morbidity, and mortality is not nil. Institutional caseload is a well-established determinant of patient outcomes, and centralization to experienced centers is essential to the safety and oncological appropriateness of the resection. Minimally invasive approaches are increasingly applied for pancreatic resection, even in cancer patients. Nevertheless, the level of evidence in this field remains low. Minimally invasive distal pancreatectomy appears potentially beneficial towards some perioperative outcomes, although its oncological results remain incompletely studied. Data regarding perioperative and oncologic outcomes for minimally invasive pancreaticoduodenectomy (Whipple's resection) is even less mature, but suggest that similar results as the open approach can be achieved in selected, high-volume centers. Conversely, its indiscriminate adoption by inexperienced surgeons and institutions has potential deleterious effects given its steep learning curve. Newer neoadjuvant treatment protocols display enhanced ability to downstage advanced tumors, increasing candidates for potentially curative surgery. Conversely, putative benefits of neoadjuvant treatment in patients with technically resectable tumors have not been reliably demonstrated and its optimal indications remain highly controversial.

Surgery for primary liver malignancies – innovations and limitations

Primary liver malignancies mainly arise from hepatocytes or bile duct cells. They become clinically evident as hepatocellular carcinomas (HCCs) and intrahepatic or hilar cholangiocarcinoma (CC). The treatment of these tumours is based on an interdisciplinary, multimodal approach, in which surgery has a major role. As techniques have improved, more patients can undergo safe operations, including extended resections and vascular reconstructions. In the case of an expected critical liver remnant after surgery, techniques before or during surgery can be used to induce liver hypertrophy, which reduces postoperative liver failure. There is ongoing discussion about whether resection or transplantation in cirrhotic livers is preferred in patients with HCCs. Patients with cholangiocarcinomas should undergo transplantation only within clinical trials. A neoadjuvant treatment protocol (Mayo Clinic protocol) that improves surgical outcome in patients with hilar CCs has been established. Nevertheless, criteria to predict good outcome of liver transplantation in patients HCCs and CCs exist and should be respected. Recent innovations in liver surgery are minimally invasive procedures. The innovative approach of robotic-assisted operations is a technical upgrade to conventional laparoscopy. These methods enable experienced surgeons to perform nearly all types of surgery, including living donor hepatectomy for liver transplantation. The oncological outcomes after minimally invasive liver resection are comparable to those of open procedures. For most patients surgery remains the only chance for complete cure and therefore it is still the most commonly performed procedure for primary liver tumour treatment. New innovative techniques will support the impact of surgery in the future.

Abstract 571: Circulating proteins in response to combined-modality therapy in locally advanced rectal cancer identified by antibody array screening

Abstract Background: In treatment of locally advanced rectal cancer (LARC) with chemoradiotherapy (CRT) followed by surgery, local recurrence rates are low but development of metastatic disease remains a dominant cause of failure. The attempt of improving survival outcome by increasingly complex multimodality programs is at the price of extended limits of treatment intensity and patient tolerance. Prediction biomarkers of efficacy and toxicity might therefore assist in achieving more individualized treatment in LARC. Methods: In a prospective LARC study (NCT00278694) composed of neoadjuvant chemotherapy (NACT; two cycles of the Nordic FLOX regimen) before long-course CRT in order to intensify treatment, serial serum samples were collected from 87 cases at baseline, following NACT (post-NACT), at CRT completion (post-CRT), and at evaluation of the neoadjuvant treatment 2-4 weeks before surgery. Anticipating that proteins were released into the circulation from the tumor as well as from other tissues as an adverse response to the combined-modality therapy, the serum samples were analyzed using an antibody array detecting a variety of 507 proteins (RayBiotech® AHH-BLG-1 array). Alterations in circulating protein profiles during the neoadjuvant treatment were correlated to progression-free survival (PFS) and treatment toxicities as assessed by Common Terminology Criteria for Adverse Events (CTCAE) scoring. Median follow-up was 63 months. Results: Significant changes in serum protein levels (as compared to baseline) were observed during the treatment course, with the numerically greater alterations found post-CRT. Gene ontology analysis of the altered proteins showed that the majority were involved in immune system processes and extracellular matrix organization. Interestingly, the levels of lipocalin-2 (LCN2) and matrix metalloproteinase-9 (MMP9) were significantly lowered during the entire treatment course with post-NACT median fold change decline to 0.46 and 0.38 for LCN2 and MMP9 respectively, followed by a gradual increase towards baseline values post-CRT and at evaluation before surgery. On univariate cox regression analysis, post-NACT values (fold change from baseline) of LCN2 and MMP9 were entered as continuous data, and for both factors, the lower the value the better PFS with a hazard ratio for a PFS event of 2.8 and 2.3, respectively. Both components (the Nordic FLOX regimen and pelvic CRT) of the neoadjuvant treatment protocol would cause intestinal toxicity, but the individual patient's post-NACT decline in LCN2 and MMP9 serum levels did not predict CTCAE grade 3 diarrhea at CRT completion when the highest incidence of treatment-induced enteropathy was recorded. Conclusion: Antibody array analysis of serial serum samples from the neoadjuvant treatment course represented a ‘liquid biopsy’ insight into systemic responses to intensified combined-modality therapy in LARC. Citation Format: Erta Kalanxhi, Helga Helseth Hektoen, Sebastian Meltzer, Svein Dueland, Kathrine Roe Redalen, Kjersti Flatmark, Anne Hansen Ree. Circulating proteins in response to combined-modality therapy in locally advanced rectal cancer identified by antibody array screening. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 571. doi:10.1158/1538-7445.AM2015-571

Neoadjuvant treatment for advanced esophageal cancer: response assessment before surgery and how to predict response to chemoradiation before starting treatment.

Patients with advanced esophageal cancer (T3-4, N) have a poor prognosis. Chemoradiation or chemotherapy before esophagectomy with adequate lymphadenectomy is the standard treatment for patients with resectable advanced esophageal carcinoma. However, only patients with major histopathologic response (regression to less than 10% of the primary tumor) after preoperative treatment will have a prognostic benefit of preoperative chemoradiation. Using current therapy regimens about 40% to 50% of the patients show major histopathological response. The remaining cohort does not benefit from this neoadjuvant approach but might benefit from earlier surgical resection. Therefore, it is an aim to develop tools for response prediction before starting the treatment and for early response assessment identifying responders. The current review discusses the different imaging techniques and the most recent studies about molecular markers for early response prediction. The results show that [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) has a good sensitivity but the specificity is not robust enough for routine clinical use. Newer positron emission tomography detector technology, the combination of FDG-PET with computed tomography, additional evaluation criteria and standardization of evaluation may improve the predictive value. There exist a great number of retrospective studies using molecular markers for prediction of response. Until now the clinical use is missing. But the results of first prospective studies are promising. A future perspective may be the combination of imaging technics and special molecular markers for individualized therapy. Another aspect is the response assessment after finishing neoadjuvant treatment protocol. The different clinical methods are discussed. The results show that until now no non-invasive method is valid enough to assess complete histopathological response.

Concurrent chemoradiotherapy for locally advanced breast cancer-time for a new paradigm?

In cases of locally advanced breast cancer (labc), preoperative ("neoadjuvant") therapy was traditionally reserved to render the patient operable. More recently, neoadjuvant therapy, particularly chemotherapy, is being used in patients with operable disease to increase the opportunity for breast conservation. Despite the increasing use of preoperative chemotherapy, rates of pathologic complete response, a surrogate marker for disease-free survival, remain modest in patients with locally advanced disease and particularly so when the tumour is estrogen or progesterone receptor-positive and her2-negative. A new paradigm for labc patients is needed. In other solid tumours (for example, rectal, esophageal, and lung cancers), concurrent chemoradiotherapy (ccrt) is routinely used in neoadjuvant and adjuvant treatment protocols alike. The literature suggests that ccrt in labc patients with inoperable disease is associated with response rates higher than would be anticipated with systemic therapy alone. Ongoing trials in this field are eagerly awaited to determine if ccrt should become the new paradigm.