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 [^18F]-fluorodeoxyglucose-positron emission tomography（FDGPET） 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.

Neoadjuvant chemoradiation therapy and pathological complete response in rectal cancer

The management of rectal cancer has evolved significantly in the last few decades.Significant improvements in local disease control were achieved in the 1990s,with the introduction of total mesorectal excision and neoadjuvant radiotherapy.Level 1 evidence has shown that,with neoadjuvant chemoradiation therapy(CRT)the rates of local recurrence can be lower than 6%and,as a result,neoadjuvant CRT currently represents the accepted standard of care.This approach has led to reliable tumor down-staging,with 15–27%patients with a pathological complete response(pCR)—defined as no residual cancer found on histological examination of the specimen.Patients who achieve pCR after CRT have better long-term outcomes,less risk of developing local or distal recurrence and improved survival.For all these reasons,sphincter-preserving procedures or organ-preserving options have been suggested,such as local excision of residual tumor or the omission of surgery altogether.Although local recurrence rate has been stable at 5–6%with this multidisciplinary management method,distal recurrence rates for locally-advanced rectal cancers remain in excess of 25%and represent the main cause of death in these patients.For this reason,more recent trials have been looking at the administration of full-dose systemic chemotherapy in the neoadjuvant setting(in order to offer early treatment of disseminated micrometastases,thus improving control of systemic disease)and selective use of radiotherapy only in non-responders or for low rectal tumors smaller than 5 cm.

Association of tumor differentiation and prognosis in patients with rectal cancer undergoing neoadjuvant chemoradiation therapy

Background and objective:Neoadjuvant chemoradiation therapy(NCRT)followed by radical resection has been a common practice for patients with locally advanced rectal cancer.This study aimed to analyse the association of tumor differentiation and prognosis in rectal-cancer patients undergoing NCRT.Methods:Patients with locally advanced,non-mucinous rectal cancer who underwent NCRT followed by radical resection between 2007 and 2017 were identified from an electronic health record system at the Sixth Affiliated Hospital of Sun Yatsen University(Guangzhou,China).Multivariable logistic regression and multivariate Cox regression were performed to analyse the association of response to NCRT and survival with clinicopathological characteristics of all these patients.Results:We identified 325 patients(241 males and 84 females;mean age,54.4611.2 years)who underwent NCRT followed by radical resection,including 26(8.0%)with poorly-differentiated rectal cancer,182(56.0%)with moderately-differentiated cancer and 117(36.0%)with well differentiated cancer.Propensity score matching analysis and multivariable logistic regression analysis results showed that tumor differentiation was significantly associated with response to NCRT.In the poor differentiation and non-poor differentiation groups,the 3-year overall survival(OS)rates were 74.6 and 93.5%,respectively,whereas the 3-year local recurrence rates were 18.6 and 3.7%,respectively.Multivariable Cox regression analyses revealed that poor differentiation was an independent risk factor for local recurrence and OS.Conclusions:Among the patients with locally advanced,non-mucinous rectal cancer,the patients with poorlydifferentiated cancer who underwent NCRT had a worse response to NCRT and poorer prognosis than those with moderately-and well-differentiated diseases.

Neoadjuvant therapy for resectable pancreatic cancer

The use of neoadjuvant therapies has played a major role for borderline resectable and locally advanced pancreatic cancers(PCs). For this group of patients, preoperative chemotherapy or chemoradiation has increased the likelihood of surgery with negative resection margins and overall survival. On the other hand, for patients with resectable PC, the main rationale for neoadjuvant therapy is that the overall survival with current strategies is unsatisfactory. There is a consensus that we need new treatments to improve the overall survival and quality of life of patients with PC. However, without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery. The focus of this paper is to provide the readers an overview of the most recent evidence on this subject.

Radiation therapy prior to a pancreaticoduodenectomy for adenocarcinoma is associated with longer operative times and higher blood loss

BACKGROUND Pancreatic adenocarcinoma is currently the fourth leading cause of cancer-related deaths in the United States.In patients with“borderline resectable”disease,current National Comprehensive Cancer Center guidelines recommend the use of neoadjuvant chemoradiation prior to a pancreaticoduodenectomy.Although neoadjuvant radiotherapy may improve negative margin resection rate,it is theorized that its administration increases operative times and complexity.AIM To investigate the association between neoadjuvant radiotherapy and 30-d morbidity and mortality outcomes among patients receiving a pancreaticoduodenectomy for pancreatic adenocarcinoma.METHODS Patients listed in the 2015-2019 National Surgery Quality Improvement Program data set,who received a pancreaticoduodenectomy for pancreatic adenocarcinoma,were divided into two groups based off neoadjuvant radiotherapy status.Multivariable regression was used to determine if there is a significant correlation between neoadjuvant radiotherapy,perioperative blood transfusion status,total operative time,and other perioperative outcomes.RESULTS Of the 11458 patients included in the study,1470(12.8%)underwent neoadjuvant radiotherapy.Patients who received neoadjuvant radiotherapy were significantly more likely to require a perioperative blood transfusion[adjusted odds ratio(aOR)=1.58,95%confidence interval(CI):1.37-1.82;P<0.001]and have longer surgeries(insulin receptor-related receptor=1.14,95%CI:1.11-1.16;P<0.001),while simultaneously having lower rates of organ space infections(aOR=0.80,95%CI:0.66-0.97;P=0.02)and pancreatic fistula formation(aOR=0.50,95%CI:0.40-0.63;P<0.001)compared to those who underwent surgery alone.CONCLUSION Neoadjuvant radiotherapy,while not associated with increased mortality,will impact the complexity of surgical resection in patients with pancreatic adenocarcinoma.

Endoscopic ultrasound and magnetic resonance imaging for re-staging rectal cancer after radiotherapy

AIM： To compare the sensitivity and specificity of two imaging techniques, endoscopic ultrasound （EUS） and magnetic resonance imaging （MRI）, in patients with rectal cancer after neoadjuvant chemoradiation therapy. And we compared EUS and MRI data with histological findings from surgical specimens. METHODS： Thirty-nine consecutive patients （51.3% Male; mean age： 68.2 ＋ 8.9 years） with histologically confirmed distal rectal cancer were examined for staging. All patients underwent EUS and MRI imaging before and after neoadjuvant chemoradiation therapy. RESULTS： After neoadjuvant chemoradiation, EUS and MRI correctly classified 46% （18/39） and 44% （17/39） of patients, respectively, in line with their histological T stage （P 〉 0.05）. These proportions were higher for both techniques when nodal involvement was considered： 69% （27/39） and 62% （24/39）. When patients were sorted into T and N subgroups, the diagnostic accuracy of EUS was better than MRI for patients with T0-T2 （44% vs 33%, P 〉 0.05） and NO disease （87% vs 52%, P = 0.013）. However, MRI was more accurate than EUS in T and N staging for patients with more advanced disease after radiotherapy, though these differences did not reach statistical significance. CONCLUSION： EUS and MRI are accurate imaging techniques for staging rectal cancer, However, after neoadjuvant RT-CT, the role of both methods in the assessment of residual rectal tumors remains uncertain.

Multidisciplinary treatment of rectal cancer in 2014: Where are we going?

In the present review we discuss the recent developments and future directions in the multimodal treatment of locally advanced rectal cancer, with respect to staging and re-staging modalities, to the current role of neoadjuvant chemo-radiation and to the conservative and more limited surgical approaches based on tumour response after neoadjuvant combined therapy. When initial tumor staging is considered a high accuracy has been reported for T pre-treatment staging, while preoperative lymph node mapping is still suboptimal. With respect to tumour re-staging, all the current available modalities still present a limited accuracy, in particular in defining a complete response. The role of short vs long-course radiotherapy regimens as well as the optimal time of surgery are still unclear and under investigation by means of ongoing randomized trials. Observational management or local excision following tumour complete response are promising alternatives to total mesorectal excision, but need further evaluation, and their use outside of a clinical trial is not recommended.The preoperative selection of patients who will benefit from neoadjuvant radiotherapy or not, as well as the proper identification of a clinical complete tumour response after combined treatment modalities,will influence the future directions in the treatment of locally advanced rectal cancer.

Prognostic value of changes in serum carcinoembryonic antigen levels for preoperative chemoradiotherapy response in locally advanced rectal cancer

BACKGROUND Preoperative chemoradiotherapy(CRT)is a standard treatment modality for locally advanced rectal cancer.However,CRT alone cannot improve overall survival.Approximately 20%of patients with CRT-resistant tumors show disease progression.Therefore,predictive factors for treatment response are needed to identify patients who will benefit from CRT.We theorized that the prognosis may vary if patients are classified according to pre-to post-CRT changes in carcinoembryonic antigen(CEA)levels.AIM To identify patients with locally advanced rectal cancer for preoperative chemoradiotherapy based on carcinoembryonic antigen levels.METHODS We retrospectively included locally advanced rectal cancer patients who underwent preoperative CRT and curative resection between 2011 and 2017.Patients were assigned to groups A,B,and C based on pre-and post-CRT serum CEA levels:Both>5;pre>5 and post≤5;and both≤5 ng/mL,respectively.We compared the response to CRT based on changes in serum CEA levels.Receiver operating characteristic curve analysis was performed to determine optimal cutoff for neutrophil–lymphocyte ratio and platelet–lymphocyte ratio.Multivariate logistic regression analysis was used to evaluate the prognostic factors for pathologic complete response(pCR)/good response.RESULTS The cohort comprised 145 patients;of them,27,43,and 65 belonged to groups A,B,and C,respectively,according to changes in serum CEA levels before and after CRT.Pre-(P<0.001)and post-CRT(P<0.001)CEA levels and the ratio of downstaging(P=0.013)were higher in Groups B and C than in Group A.The ratio of pathologic tumor regression grade 0/1 significantly differed among the groups(P=0.003).Group C had the highest number of patients showing pCR(P<0.001).Most patients with pCR showed pre-and post-CRT CEA levels<5 ng/mL(P<0.001,P=0.008).Pre-and post-CRT CEA levels were important risk factors for pCR(OR=18.71;95%CI:4.62–129.51,P<0.001)and good response(OR=5.07;95%CI:1.92–14.83,P=0.002),respectively.Pre-CRT neutrophil–lymphocyte ratio and post-CRT T≥3 stage were also prognostic factors for pCR or good response.CONCLUSION Pre-and post-CRT CEA levels,as well as change in CEA levels,were prognostic markers for treatment response to CRT and may facilitate treatment individualization for rectal cancer.

The role of liver transplantation for hilar cholangiocarcinoma

BACKGROUND: Hilar cholangiocarcinoma is a devastating disease. Surgery is the only potentially curative modality. However, the results of surgical resection for hilar cholangiocarcinomas are disappointing. The introduction of liver transplantation for this condition has brought new hope for the management of this disease. The aim of this review is to discuss the role of liver transplantation in this disease. DATA SOURCES: A MEDLINE search was conducted for the articles on liver transplantation for hilar cholangiocarcinoma. Their results have been compiled and compared with the existing literature on resection for this disease. RESULTS: The earlier series on liver transplantation for hilar cholangiocarcinoma were not encouraging because of poor patient selection. The Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation has shown remarkable success (survival at 1-, 3-, and 5-year post-transplantation being 92%, 82%, and 82%, respectively). With better patient selection and integration of neoadjuvant chemoradiation, the long-term survival is superior to that of the patients who undergo resection, as shown by the published literature on resection. The limitations of organ availability can be overcome by the living donor liver transplantation programme. This review article discusses the rationale, pros and cons of liver transplantation vis-à-vis resection for hilar cholangiocarcinoma.CONCLUSIONS: Liver transplantation, especially living donor liver transplantation, is a new and exciting alternative to resection for hilar cholangiocarcinoma. Integration of neoadjuvant chemoradiation has the potential to further improve the curative potential of liver transplantation. The strategy of combining neoadjuvant chemoradiation and liver transplantation brings new hope for the treatment of this difficult disease.

Predictive significance of cancer related-inflammatory markers in locally advanced rectal cancer

BACKGROUND Locally advanced rectal cancer is treated using neoadjuvant chemoradiation(nCRT),followed by total mesorectal excision(TME).Tumor regression and pathological post-treatment stage are prognostic for oncological outcomes.There is a significant correlation between markers representing cancer-related inflammation,including high neutrophil-to-lymphocyte ratio(NLR),monocyteto-lymphocyte ratio(MLR),and platelet-to-lymphocyte(MLR)and unfavorable oncological outcomes.However,the predictive role of these markers on the effect of chemoradiation is unknown.AIM To evaluate the predictive roles of NLR,MLR,and PLR in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiation.METHODS Patients(n=111)with locally advanced rectal cancer who underwent nCRT followed by TME at the Minimally Invasive Surgery Unit,Siriraj Hospital between 2012 and 2018 were retrospectively analyzed.The associations between post-treatment pathological stages,neoadjuvant rectal(NAR)score and the pretreatment ratios of markers of inflammation(NLR,MLR,and PLR)were analyzed.RESULTS Clinical stages determined using computed tomography,magnetic resonance imaging,or both were T4(n=16),T3(n=94),and T2(n=1).The NAR scores were categorized as high(score>16)in 23.4%,intermediate(score 8-16)in 41.4%,and low(score<8)in 35.2%.The mean values of the NLR,PLR,and MLR correlated with pathological tumor staging(ypT)and the NAR score.The values of NLR,PLR and MLR were higher in patients with advanced pathological stage and high NAR scores,but not statistically significant.CONCLUSION In patients with locally advanced rectal cancer,pretreatment NLR,MLR and PLR are higher in those with advanced pathological stage but the differences are not significantly different.

Neoadjuvant treatment of rectal cancer:where are we now?

Introduction Colorectal cancer is the third leading cause of cancer-related mortality in the United States[1].Of this group of patients,approximately 39000 cases of rectal cancer were reported in the US in 20151].Treatment of rectal cancer truly requires combinatorial therapy with surgery,chemotherapy and radiation(RT),which now comprise the cornerstone of treatment for rectal cancer.