Prediction of pathological complete response and prognosis in locally advanced rectal cancer

BACKGROUND Colorectal cancer is currently the third most common malignant tumor and the second leading cause of cancer-related death worldwide.Neoadjuvant chemoradiotherapy(nCRT)is standard for locally advanced rectal cancer(LARC).Except for pathological examination after resection,it is not known exactly whether LARC patients have achieved pathological complete response(pCR)before surgery.To date,there are no clear clinical indicators that can predict the efficacy of nCRT and patient outcomes.AIM To investigate the indicators that can predict pCR and long-term outcomes following nCRT in patients with LARC.METHODS Clinical data of 128 LARC patients admitted to our hospital between September 2013 and November 2022 were retrospectively analyzed.Patients were categorized into pCR and non-pCR groups.Univariate analysis(using the χ^(2) test or Fisher’s exact test)and logistic multivariate regression analysis were used to study clinical predictors affecting pCR.The 5-year disease-free survival(DFS)and overall survival(OS)rates were calculated using Kaplan-Meier analysis,and differences in survival curves were assessed with the log-rank test.RESULTS Univariate analysis showed that pretreatment carcinoembryonic antigen(CEA)level,lymphocyte-monocyte ratio(LMR),time interval between neoadjuvant therapy completion and total mesorectal excision,and tumor size were correlated with pCR.Multivariate results showed that CEA≤5 ng/mL(P=0.039),LMR>2.73(P=0.023),and time interval>10 wk(P=0.039)were independent predictors for pCR.Survival analysis demonstrated that patients in the pCR group had significantly higher 5-year DFS rates(94.7%vs 59.7%,P=0.002)and 5-year OS rates(95.8%vs 80.1%,P=0.019)compared to the non-pCR group.Tumor deposits(TDs)were significantly correlated with shorter DFS(P=0.002)and OS(P<0.001).CONCLUSION Pretreatment CEA,LMR,and time interval contribute to predicting nCRT efficacy in LARC patients.Achieving pCR demonstrates longer DFS and OS.TDs correlate with poor prognosis.

Correlation and predictive value of pathological complete response and ultrasound characteristic parameters in neoadjuvant chemotherapy for breast

BACKGROUND Breast cancer ranks as one of the most prevalent malignant tumors among women,significantly endangering their health and lives.While radical surgery has been a pivotal method for halting disease progression,it alone is insufficient for enhancing the quality of life for patients.AIM To investigate the correlation between ultrasound characteristic parameters of breast cancer lesions and clinical efficacy in patients undergoing neoadjuvant chemotherapy(NAC).METHODS Employing a case-control study design,this research involved 178 breast cancer patients treated with NAC at our hospital from July 2019 to June 2022.According to the Miller-Payne grading system,the pathological response,i.e.efficacy,of the NAC in the initial breast lesion after NAC was evaluated.Of these,59 patients achieved a pathological complete response(PCR),while 119 did not(non-PCR group).Ultrasound characteristics prior to NAC were compared between these groups,and the association of various factors with NAC efficacy was analyzed using univariate and multivariate approaches.RESULTS In the PCR group,the incidence of posterior echo attenuation,lesion diameter≥2.0 cm,and Alder blood flow grade≥II were significantly lower compared to the non-PCR group(P<0.05).The area under the curve values for predicting NAC efficacy using posterior echo attenuation,lesion diameter,and Alder grade were 0.604,0.603,and 0.583,respectively.Also,rates of pathological stage II,lymph node metastasis,vascular invasion,and positive Ki-67 expression were significantly lower in the PCR group(P<0.05).Logistic regression analysis identified posterior echo attenuation,lesion diameter≥2.0 cm,Alder blood flow grade≥II,pathological stage III,vascular invasion,and positive Ki-67 expression as independent predictors of poor response to NAC in breast cancer patients(P<0.05).CONCLUSION While ultrasound characteristics such as posterior echo attenuation,lesion diameter≥2.0 cm,and Alder blood flow grade≥II exhibit limited predictive value for NAC efficacy,they are significantly associated with poor response to NAC in breast cancer patients.

Tumor recurrence after pathological complete response in locally advanced gastric cancer after neoadjuvant therapy:Two case reports

BACKGROUND The pathological complete response(ypCR)rate following neoadjuvant chemotherapy for advanced gastric cancer remains low and lacks a universally accepted treatment protocol.Immunotherapy has achieved breakthrough progress.CASE SUMMARY We report two female patients with gastric cancer defined as clinical stage cT4N1-2M0.Detection of mismatch repair protein showed mismatch repair function defect,and perioperative treatment with programmed death protein 1 inhibitor combined with S-1+oxaliplatin achieved ypCR.Surprisingly,the patients underwent clinical observation after surgery but developed different degrees of metastasis at~6 mo after surgery.CONCLUSION PD-1 inhibitor combined with chemotherapy provides a more strategic choice for comprehensive perioperative treatment of gastric cancer.

Pathologic complete response confirmed by surgical resection for liver metastases of gastrointestinal stromal tumor after treatment with imatinib mesylate

A 39-year-old male underwent distal gastrectomy for a high grade gastrointestinal stromal tumor(GIST) . Computed tomography(CT) and magnetic resonance imaging(MRI) 107 mo after the operation,revealed a cystic mass(14 cm in diameter) and a solid mass(9 cm in diameter) in the right and left lobes of the liver,respectively. A biopsy specimen of the solid mass showed a liver metastasis of GIST. The patient received imatinib mesylate(IM) treatment,400 mg/day orally. Following the IM treatment for a period of 35 mo,the patient underwent partial hepatectomy(S4 + S5) . The effect of IM on the metastatic lesions was interpreted as pathologic complete response(CR) . Pathologically verified cases showing therapeutic efficacy of IM have been rarely reported.

Nomogram for predicting pathological complete response to neoadjuvant chemotherapy in patients with advanced gastric cancer

BACKGROUND Survival benefit of neoadjuvant chemotherapy(NAC)for advanced gastric cancer(AGC)is a debatable issue.Studies have shown that the survival benefit of NAC is dependent on the pathological response to chemotherapy drugs.For those who achieve pathological complete response(pCR),NAC significantly prolonged prolapsed-free survival and overall survival.For those with poor response,NAC yielded no survival benefit,only toxicity and increased risk for tumor progression during chemotherapy,which may hinder surgical resection.Thus,predicting pCR to NAC is of great clinical significance and can help achieve individualized treatment in AGC patients.AIM To establish a nomogram for predicting pCR to NAC for AGC patients.METHODS Two-hundred and eight patients diagnosed with AGC who received NAC followed by resection surgery from March 2012 to July 2019 were enrolled in this study.Their clinical data were retrospectively analyzed by logistic regression analysis to determine the possible predictors for pCR.Based on these predictors,a nomogram model was developed and internally validated using the bootstrap method.RESULTS pCR was confirmed in 27 patients(27/208,13.0%).Multivariate logistic regression analysis showed that higher carcinoembryonic antigen level,lymphocyte ratio,lower monocyte count and tumor differentiation grade were associated with higher pCR.Concordance statistic of the established nomogram was 0.767.CONCLUSION A nomogram predicting pCR to NAC was established.Since this nomogram exhibited satisfactory predictive power despite utilizing easily available pretreatment parameters,it can be inferred that this nomogram is practical for the development of personalized treatment strategy for AGC patients.

Complete response to sorafenib in a patient with recurrent hepatocellular carcinoma

Partial hepatectomy is still the treatment of choice aiming at a cure for patients with hepatocellular carcinoma(HCC), provided that the patient can tolerate the treatment. For patients with multiple recurrent HCC after partial hepatectomy which cannot be treated by re-hepatectomy or local ablative therapy, the prognosis is extremely poor. sorafenib is a molecular-targeted agent which has been demonstrated in two global phase III randomized controlled trials to show survival benefit for advanced HCC. Here, we present a 56-yearold patient with HCC who showed complete clinical response after sorafenib was used for tumor recurrence which developed 3 mo after partial hepatectomy. There was no evidence of progression of disease for 60 mo till now after continuous treatment with sorafenib.

Complete response with sorafenib and transcatheter arterial chemoembolization in unresectable hepatocellular carcinoma

Patients with advanced hepatocellular carcinoma(HCC) showing portal vein tumor thrombosis(PVTT) have an extremely poor prognosis. According to treatment guidelines, the only option for HCC patients with PVTT is sorafenib chemotherapy. However, in Asia, various treatments have been attempted and possible prolongation of overall survival has been repeatedly reported. We herein report the first case of a patient with an initially unresectable advanced HCC with PVTT who underwent curative hepatectomy after sorafenib and transcatheter arterial chemoembolization(TACE) showing complete histological response. Two months after induction with sorafenib, a significant decrease in serum alpha-fetoprotein level was observed and computed tomography imaging showed a significant decrease in tumor size. Because of remaining PVTT, TACE and curative resection were performed. The combination of sorafenib and TACE may be an effective treatment for HCC patients with PVTT.

Unfavorable Pathological Complete Response Rate of Neoadjuvant Chemotherapy Epirubicin plus Taxanes for Locally Advanced Triple-negative Breast Cancer

Anthracycline-Taxane chemotherapy is widely used in neoadjuvant treatment for breast cancers. However, there is limited data reported in patients with triple negative breast cancer （TNBC）. Here, we evaluated the pathologic responses and survival of neoadjuvant epirubicin and taxanes chemotherapy in patients with locally advanced TNBC to provide some useful information for clinical practice. A total of 43 patients with locally advanced TNBC were enrolled in this study. Patients were administered with epirubicin 75 mg/m^2 plus paclitaxel 175 mg/m^2 or docetaxel 75 mg/m^2 every 3 weeks for at least 2 cycles. The primary endpoint was pathologic complete response （pCR）, which was defined as no residual invasive cancer, or only carcinoma in situ in both the excised breast and axillary lymph node, while relapse-free survival （RFS） and overall survival （OS） were secondary endpoints. Thirty-nine （90.7%） patients were at clinical stages II B-IIIC. Thirty-seven （86%） completed 4-6 cycles of preop- erative chemotherapy, and objective response rate （ORR） was 81.4% （35/43）. Forty-two patients un- derwent radical surgery subsequently. The pCR rate was 14.3% （6/42）. The most common adverse events in neoadjuvant chemotherapy were nausea/vomiting （88.4%, 38/43） and neutropenia （88.4%）. After a median follow-up period of 34.0 months, 3-year RFS and OS rate was 53.6% and 80.1%, respectively. All events of recurrence and death occurred in non-pCR patients, in whom the 3-year RFS and OS rates were 44.3% and 76.6%, respectively. This study suggest that neoadjuvant chemotherapy with epirubicin plus taxanes has a relatively low pCR rate and high early recurrence risk in locally ad- vanced TNBC, which indicates the necessity for more efficacious treatment. Further study is needed to validate these results.

Predictors of pathologic complete response in patients with residual flat mucosal lesions after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective:The accurate prediction of tumor response to neoadjuvant chemoradiotherapy(nCRT)remains challenging.Few studies have investigated pathologic complete response(ypCR)prediction in patients with residual flat mucosal lesions after treatment.This study aimed to identify variables for predicting ypCR in patients with residual flat mucosal lesions after nCRT for locally advanced rectal cancer(LARC).Methods:Data of patients with residual flat mucosal lesions after nCRT who underwent radical resection between 2009 and 2015 were retrospectively collected from the LARC database at Peking University Cancer Hospital.Univariate and multivariate analyses of the association between clinicopathological factors and ypCR were performed,and a nomogram was constructed by incorporating the significant predictors.Results:Of the 246 patients with residual flat mucosal lesions included in the final analysis,56(22.8%)had ypCR.Univariate and multivariate analyses showed that pretreatment cT stage(pre-cT)≤T2(P=0.016),magnetic resonance tumor regression grade(MR-TRG)1-3(P=0.001)and residual mucosal lesion depth=0 mm(P<0.001)were associated with a higher rate of ypCR.A nomogram was developed with a concordance index(C-index)of0.759 and the calibration curve showed that the nomogram model had good predictive consistency.The follow-up time ranged from 3.0 to 113.3 months,with a median follow-up time of 63.77 months.The multivariate Cox regression model showed that the four variables in the nomogram model were not risk factors for disease-free survival(DFS)or overall survival(OS).Conclusions:Completely flat mucosa,early cT stage and good MR-TRG were predictive factors for ypCR instead of DFS or OS in patients with LARC with residual flat mucosal lesions after nCRT.Endoscopic mucosal re-evaluation before surgery is important,as it may contribute to decision-making and facilitate nonoperative management or organ preservation.

Potential predictive factors for pathologic complete response after the neoadjuvant treatment of rectal adenocarcinoma:a single center experience

Objective:To assess the response rate of patients with rectal adenocarcinoma to neoadjuvant therapy and to identify the predictors of histological regression after neoadjuvant radiotherapy(RT)or concurrent chemoradiotherapy(CCRT).Methods:This study recruited 64 patients.The patients had resectable cancer of the lower and the middle rectum(T3/T4 and/or N+)without distant metastasis and received neoadjuvant RT or CCRT followed by radical surgery with total mesorectal excision(TME)between January 2006 and December 2011.The patients were classified into non-response(NR),partial response(PR),and pathologic complete response(p CR)based on the Dworak tumor regression grading system.Results:The median age of patients was 57 years(ranging from 22 to 85).A total of 24 patients were treated with neoadjuvant CCRT,whereas 40 patients were treated with RT alone.Abdominoperineal resection(APR)was performed on 29 patients(45%).Anterior resection with TME was performed on 34 patients(53%).One patient had local resection.Histologically,12(19%),24(73%),and 28(44%)patients exhibited p CR,PR,and NR,respectively.Univariate analysis revealed that the predictors of tumor regression were as follows:the absence of lymph node involvement from initial imaging(c N0)(P=0.021);normal initial carcinoembryonic antigen(CEA)level(P=0.01);hemoglobin level≥12 g/dl(P=0.009);CCRT(P=0.021);and tumor downstaging in imaging(P=0.001).Multivariate analysis showed that the main predictors of p CR were CT combined with neoadjuvant RT,c N0stage,and tumor regression on imaging.Conclusions:Identifying the predictors of p CR following neoadjuvant therapy aids the selection of responsive patients for nonaggressive surgical treatment and possible surveillance.

Advanced gastrointestinal stromal tumor patients with complete response after treatment with imatinib mesylate

AIM： Most gastrointestinal stromal tumors （GISTs） express constitutively activated mutant isoforms of kit kinase or platelet-derived growth factor receptor alpha （PDGFRA）, which are potential therapeutic targets for imatinib mesylate （Glivec）. Partial response occurred in almost two thirds of GIST patients treated with Glivec. However, complete response （CR） after Glivec therapy was sporadically reported. Here we illustrated advanced GIST patients with CR after Glivec treatment. METHODS： Between January 2001 and June 2005, 42 advanced GIST patients were treated with Glivec. Patients were administered 400 mg of Glivec in 100-mg capsules, taken orally daily with food. The response of the tumor to Glivec was evaluated after one month, three months, and every three months thereafter or whenever medical need was indicated. Each tumor of patients was investigated for mutations of kit or PDGFRA. RESULTS： The median follow-up time of the 42 ad-vanced GIST patients treated with Glivec was 16.9 months （range, 1.0- 47.0 months）. Overall, 3 patients had complete response CR （7.1%）, 26 partial response （67.8%）, 5 stationary disease （11.9%）, and 3 progressive disease （11.9%）. The median duration of Glivec administration for the three patients was 36 months （range, 23-36 months）. The median time to CR after Glivec treatment was 20 months （range, 9-26 months）. Deletion and insertion mutations of c-kit exon 11 and insertion mutation of c-kit exon 9 were found in two cases and one case, respectively. CONCLUSION： Complete response （CR） can be achieved in selected advanced GIST patients treated with Glivec. The median time to CR after Glivec treatment was 20 months. Deletion and insertion mutations of kit exon 11 and insertion mutation of kit exon 9 contribute to the genetic features in these selected cases.

Complete response to trastuzumab and chemotherapy in recurrent urothelial bladder carcinoma with HER2 gene amplification: A case report

BACKGROUND Targeted treatments may greatly affect the natural history of urothelial carcinoma based on their pharmacokinetics. A phase II trial has explored the combination of cytotoxic chemotherapy with the anti-HER-2 monoclonal antibody trastuzumab in selected patients with metastatic bladder cancer, but it failed.CASE SUMMARY Here, we report a case of recurrent urothelial bladder carcinoma(UBC) in a patient who has undergone three operations, and further illuminate its diagnosis and treatment. The diagnosis of UBC was rendered according to the pathological indices. Next-generation sequencing on formalin fixed paraffin-embedded(FFPE)tissue was also performed and suggested HER2 gene amplification in the FFPE tissue. Based on HER2 gene amplification in FFPE, the patient was treated with chemotherapy in combination with trastuzumab after his third surgery.Fortunately, the patient got a clinically complete remission to trastuzumab for 34 mo.CONCLUSION There is not enough clinical evidence for incorporating trastuzumab in routine treatment of UBC. This case hinted that recurrent UBC patients with HER2 gene amplification may benefit from targeted trastuzumab. Further studies are needed to further investigate the status of HER2 gene and better determine trastuzumab in the management of UBC.

Asian Case of Metastatic Melanoma in Which a Complete Response Was Maintained after Discontinuation of Dabrafenib and Trametinib

A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus trametinib after achieving CR have not been published;therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.

Sixteen Years of Trastuzumab Use： Complete Response in Lung, Bone, and CNS Metastasis from Breast Cancer

Although metastatic breast cancer is considered as an incurable disease, various biological drivers influence the outcomes. The use of trastuzumab in patients overexpressing HER（human epidermal growth factor receptor 2）-2 increases long-term survival even in those patients who developed brain metastasis. Nevertheless, special attention must be paid to the risk of cardiotoxicity. We report the case of a young woman with HER-2-positive breast cancer with bone and lung disease who developed brain metastasis during treatment with trastuzumab. The treatment has been continued and she is alive and in complete remission after 16 years.

Complete response in a patient of advanced pancreatic cancer treated with third-line sintilimab and anlotinib:a case report

The patient was a 63-year-old female,who was diagnosed with advanced pancreatic cancer with mediastinal lymph node and lung metastases and pleural effusion in June 2019.First-line treatment with 6 cycles of gemcitabine plus tegafur with best response of partial response.Second-line treatment was 4 cycles of nab-paclitaxel monotherapy ended up with disease progression.Third-line treatment was sintilimab with anlotinib for 10 cycles.The patient's condition has achieved clinical complete remission so far.

Advanced cervix cancer patient with chemotherapy-induced grade IV myelosuppression achieved complete remission with cadonilimab:A case report

BACKGROUND The prognosis for patients with advanced metastatic cervix cancer(MCC)is poor,and this disease continues to pose a considerable therapeutic challenge.Despite the administration of first-line regimens consisting of cisplatin,paclitaxel,and bevacizumab,survival rates for patients with metastasis remain poor.The emergence of bispecific antibodies(BsAbs)offers a novel treatment option for patients diagnosed with MCC.CASE SUMMARY In this report,we present a patient with MCC who was treated with cadonilimab monotherapy at a dose of 6 mg/kg every two weeks after chemotherapy was proven to be intolerable.The patient exhibited a sustained complete response for a duration of 6 months,demonstrating an optimistic outlook.CONCLUSION This case illustrates the considerable efficacy of cadonilimab for treating advanced MCC.Therefore,BsAb therapy is a promising strategy for effectively treating patients with advanced MCC and should be considered as an option when patients are intolerant to standard chemotherapy.

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.

Nomogram for predicting pathological complete response and tumor downstaging in patients with locally advanced rectal cancer on the basis of a randomized clinical trial

Background:Preoperative fluoropyrimidine with radiotherapy was regarded as the standard of care for locally advanced rectal cancer(LARC).The model for predicting pCR in LARC patients was based on standard treatment only.This study aimed to establish a nomogramwith pretherapeutic parameters and different neoadjuvant regimens for predicting pathologic complete response(pCR)and tumor downstaging or good response(ypT0-2N0M0)after receiving neoadjuvant treatment in patients with LARC based on a randomized clinical trial.Methods:Between January 2011 and February 2015,309 patients with rectal cancer were enrolled from a prospective randomized study(NCT01211210).All pretreatment clinical parameters were collected to build a nomogram for predicting pCR and tumor downstaging.The model was subjected to bootstrap internal validation.The predictive performance of the model was assessed with concordance index(C-index)and calibration plots.Results:Of the 309 patients,53(17.2%)achieved pCR and 132(42.7%)patients were classified as tumor downstaging with ypT0-2N0M0.Based on the logistic-regression analysis and clinical consideration,tumor length(P=0.005),tumor circumferential extent(P=0.036),distance from the anal verge(P=0.019),and neoadjuvant treatment regimen(P<0.001)showed independent association with pCR following neoadjuvant treatment.The tumor length(P=0.015),tumor circumferential extent(P=0.001),distance from the anal verge(P=0.032),clinical T category(P=0.012),and neoadjuvant treatment regimen(P=0.001)were significantly associated with good tumor downstaging(ypT0-2N0M0).Nomograms were developed to predict the probability of pCR and tumor downstaging with a C-index of 0.802(95%confidential interval[CI],0.736-0.867)and 0.730(95%CI,0.672-0.784).Internal validation revealed good performance of the calibration plots.Conclusions:The nomogramprovided individual prediction responses to different preoperative treatment for patients with rectal cancer.This model might help physicians in selecting an optimized treatment,but warrants further external validation.

Sustained complete response of advanced hepatocellular carcinoma with metronomic capecitabine: a report of three cases

Background:Hepatocellular carcinoma(HCC)is one of the most frequent causes of cancer-related death.Sorafenib,a multitarget angiogenesis inhibitor,is an approved frontline treatment for advanced HCC in Western countries,although a complete response(CR)to treatment is infrequently reported.Capecitabine,an oral fluoropyrimidine,has been shown to be effect in both treatment-naïve patients and those previously treated with sorafenib.To date,how-ever,only one case of sustained CR to metronomic capecitabine has been reported.Case presentation:We describe three cases of advanced HCC treated with metronomic capecitabine where a CR was obtained.In the first case,capecitabine was administered as first line therapy;in the second case,capecitabine was used after intolerance to sorafenib;while in the third case,capecitabine was administered after sorafenib failure.Conclusion:Capecitabine is a potentially important treatment option for patients with advanced HCC and may even represent a cure in certain cases.

Advances for achieving a pathological complete response for rectal cancer after neoadjuvant therapy

Neoadjuvant therapy has become the standard of care for locally advanced mid-low rectal cancer. Pathological complete response (pCR) can be achieved in 12%e38% of patients. Patients with pCR have the most favorable long-term outcomes. Intensifying neoadjuvant therapy and extending the interval between termination of neoadjuvant treatment and surgery may in-crease the pCR rate. Growing evidence has raised the issue of whether local excision or observation rather than radical surgery is an alternative for patients who achieve a clinical complete response after neoadjuvant therapy. Herein, we highlight many of the advances and resultant controversies that are likely to dominate the research agenda for pCR of rectal cancer in the modern era.