Complete clinical response after neoadjuvant chemoradiation for distal rectal cancer

Multimodality treatment of rectal cancer, with the combination of radiation therapy, chemotherapy, and surgery has become the preferred approach to locally advanced rectal cancer. The use of neoadjuvant chemoradiation therapy (CRT) has resulted in reduced toxicity rates, significant tumor downsizing and downstaging, better chance of sphincter preservation, and improved functional results. A proportion of patients treated with neoadjuvant CRT may ultimately develop complete clinical response. Management of these patients with complete clinical response remains controversial and approaches including radical resection, transanal local excision, and observation alone without immediate surgery have been proposed. The use of strict selection criteria of patients after neoadjuvant CRT has resulted in excellent long-term results with no oncological compromise after observation alone in patients with complete clinical response. Recurrences are detectable by clinical assessment and frequently amenable to salvage procedures.     

Nonoperative approaches to rectal cancer: a critical evaluation

A neoadjuvant multimodality approach with chemoradiation therapy (CRT) is the preferred treatment strategy for most distal rectal cancers. Significant downstaging and complete pathologic response may develop after this strategy, and there is still controversy regarding the management of these patients. In this setting, a nonoperative approach has been suggested in select patients with complete clinical response after thorough clinical, endoscopic, and radiologic assessment. However, the assessment of these patients is not straightforward and remains complex. Available data regarding this approach are limited to a single institution's experience from retrospective analyses. Standardization of the assessment of tumor response and the development of radiological/molecular tools may clarify the role of no immediate surgery in patients with complete clinical response after neoadjuvant CRT. Advances in radiation and medical oncology could potentially lead to significant improvements in complete tumor regression rates, leading to an increase in importance of a minimally invasive approach in patients with rectal cancer.     

Comparison of pathological complete response rates after neoadjuvant short-course radiotherapy or chemoradiation followed by delayed surgery in locally advanced rectal cancer

Introduction

Patients with locally advanced rectal cancer (LARC) who are unfit for chemoradiation (CRT), are often offered short-course radiotherapy followed by delayed surgery (SCRT-delay). This entails a lower radiation dose, no chemotherapy and a shorter treatment period. This may lower their chances for complete tumor response and, as such, organ-sparing approaches. The purpose of this study was to compare the pathological complete response (pCR) rates between neoadjuvant CRT and SCRT-delay in patients with LARC in a nationwide database from the Netherlands.

Neoadjuvant Chemotherapy With mFOLFOXIRI Without Routine Use of Radiotherapy for Locally Advanced Rectal Cancer

IntroductionAlthough neoadjuvant chemo-radiotherapy (CRT) achieves low local recurrence rates in locally advanced rectal cancer (LARC), it raises a lot of concerns about long-term anal and sexual functions. We explored the efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC.Patients and MethodsPatients with LARC evaluated by pelvic magnetic resonance imaging (MRI) were enrolled in this trial. All received 4 to 6 cycles of mFOLFOXIRI. MRI was performed to assess clinical response after chemotherapy. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation would receive radiation before surgery, whereas responders would have immediate total mesorectal excision (TME). Adjuvant chemotherapy with mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) was recommended. The primary endpoint was the proportion of tumor downstaging to ypT_0-2N₀M₀. The secondary endpoints were pathologic complete response rate (pCR), 3-year disease-free survival rate, and safety.ResultsOverall, 106 patients were enrolled and received neoadjuvant mFOLFOXIRI chemotherapy. A total of 103 participants underwent TME surgery. Among 103 patients who completed at least 4 cycles of preoperative chemotherapy, 2 received short-term radiation before TME, and 12 underwent long-term CRT after MRI evaluation. The pCR rate was 20.4%, and the tumor downstaging rate was 42.7%. Among patients without preoperative long-term radiotherapy, the pCR rate and tumor downstaging rate were 17.4% and 41.3%, respectively. Among the per-protocol population, the tumor downstaging rate was 48.1%, and the pCR rate was 20.3%. The chemotherapy-related toxicity was well-tolerated.ConclusionNeoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. It could be a reasonable alternative to CRT in previously untreated patients with LARC.     

Interval Between Surgery and Neoadjuvant Chemoradiation Therapy for Distal Rectal Cancer: Does Delayed Surgery Have an Impact on Outcome?

BACKGROUND: The optimal interval between neoadjuvant chemoradiation therapy (CRT) and surgery in the treatment of patients with distal rectal cancer is controversial. The purpose of this study is to evaluate whether this interval has an impact on survival. METHODS AND MATERIALS: Patients who underwent surgery after CRT were retrospectively reviewed. Patients with a sustained complete clinical response (cCR) 1 year after CRT were excluded from this study. Clinical and pathologic characteristics and overall and disease-free survival were compared between patients undergoing surgery 12 weeks or less from CRT and patients undergoing surgery longer than 12 weeks from CRT completion and between patients with a surgery delay caused by a suspected cCR and those with a delay for other reasons. RESULTS: Two hundred fifty patients underwent surgery, and 48.4% had CRT-to-surgery intervals of 12 weeks or less. There were no statistical differences in overall survival (86% vs. 81.6%) or disease-free survival rates (56.5% and 58.9%) between patients according to interval (< or =12 vs. >12 weeks). Patients with intervals of 12 weeks or less had significantly higher rates of Stage III disease (34% vs. 20%; p = 0.009). The delay in surgery was caused by a suspected cCR in 23 patients (interval, 48 +/- 10.3 weeks). Five-year overall and disease-free survival rates for this subset were 84.9% and 51.6%, not significantly different compared with the remaining group (84%; p = 0.96 and 57.8%; p = 0.76, respectively). CONCLUSIONS: Delay in surgery for the evaluation of tumor response after neoadjuvant CRT is safe and does not negatively affect survival. These results support the hypothesis that shorter intervals may interrupt ongoing tumor necrosis.     

Application of neoadjuvant chemoendocrine therapy for operable breast carcinomas

The use of neoadjuvant chemotherapy in primary breast cancer is based on sound theoretical, experimental and clinical principles. Higher objective response rates have been seen in patients with locally advanced breast carcinoma. Furthermore, when used in patients with operable breast carcinomas, sufficient downstaging has been achieved to allow for breast conservation surgery in patients who would otherwise require a mastectomy. This has been achieved without an increase in local recurrence. The anthracenedione mitoxantrone was used as part of the 3M/2M regimen in the neoadjuvant trial at the Royal Marsden Hospital, which was the first to establish within the setting of a clinical trial, the reduction in mastectomy requirements. This regimen combined high objective response rate with low symptomatic toxicity. An important benefit of neoadjuvant therapy is the opportunity to study in vivo the effects of treatment in primary breast carcinomas. The use of the primary tumour as a marker of response prior to surgery may, in the future, allow for the optimization of therapy for individual patients.     

Clinical parameters predicting pathologic tumor response after preoperative chemoradiotherapy for rectal cancer

PURPOSE: To identify pretreatment clinical parameters that could predict pathologic tumor response to preoperative chemoradiotherapy (CRT) for rectal cancer. METHODS AND MATERIALS: The study involved 351 patients who underwent preoperative CRT followed by surgery between October 2001 and July 2006. Tumor responses to preoperative CRT were assessed in terms of tumor downstaging and tumor regression. Statistical analyses were performed to identify clinical factors associated with pathologic tumor response. RESULTS: Tumor downstaging (defined as ypT2 or less) was observed in 167 patients (47.6%), whereas tumor regression (defined as Dworak's Regression Grades 3 or 4) was observed in 103 patients (29.3%) and complete regression in 51 patients (14.5%). Multivariate analysis found that predictors of downstaging were pretreatment hemoglobin level (p = 0.045), cN0 classification (p < 0.001), and serum carcinoembryonic antigen (CEA) level (p < 0.001), that predictors of tumor regression were cN0 classification (p = 0.044) and CEA level (p < 0.001), and that the predictor of complete regression was CEA level (p = 0.004). CONCLUSIONS: The data suggest that pretreatment CEA level is the most important clinical predictor of pathologic tumor response. It may be of benefit in the selection of treatment options as well as the assessment of individual prognosis.     

Neoadjuvant treatment for early-stage breast cancer: opportunities to assess tumour response

Primary, preoperative, or neoadjuvant chemotherapy was introduced in the early 1970s as part of an integrated therapeutic approach to treat inoperable locally advanced breast cancer. The approach resulted in high responses, and sufficient downstaging to allow mastectomy in some patients. In addition, a small number of pathological complete responders were reported. Gradually, the idea of preoperative chemotherapy was extended to include patients with large but operable early-stage breast cancer, with the possibility in some cases of downstaging the primary tumour to avoid mastectomy, and to allow breast-conserving surgery to be done. This approach allows the tumour to be used as a measure of treatment response in vivo. More recently, the possibility has opened up for neoadjuvant chemotherapy to provide information on the use of clinical, pathological, and molecular endpoints, which can be used as surrogate markers to predict long-term outcome in the adjuvant setting. In addition, the anatomical accessibility of the breast provides the potential for serial biopsies to investigate molecular changes during treatment.     

Primary chemotherapy in the treatment of breast cancer: the University of Texas M. D. Anderson Cancer Center experience

The use of primary systemic (neoadjuvant) therapy has become widespread in the treatment of patients with locally advanced and operable breast cancer. The utilization of this therapeutic approach provides several advantages. By monitoring changes in the dimension of the tumor, efficacy can be evaluated or assessed in vivo; unnecessary toxicity can be avoided by allowing the physician to discontinue ineffective therapy. Furthermore, downstaging of a tumor through primary therapy may allow for breast-conserving surgery in patients with large operable breast cancer and render inoperable tumors resectable. Also, the use of primary therapy can provide a pathological complete response, which correlates with prolonged periods of remission. Treatment with FAC (5-fluorouracil/doxorubicin/cyclophosphamide) has proven to be effective as neoadjuvant therapy in locally advanced breast cancer in several trials. More recently, the integration of taxanes into primary therapy regimens has been explored with promising results. Studies have suggested that the use of primary therapy, particularly the use of FAC, should perhaps become the standard in patients with locally advanced disease. The history of clinical trials focusing on primary therapy in breast cancer at the M. D. Anderson Cancer Center will be reviewed.     

Super high-dose intraarterial cisplatin infusion under percutaneous pelvic perfusion with extracorporeal chemofiltration for advanced uterine cervical carcinoma: II. Its impact on clinical response and subsequent surgery

The present pilot study was conducted to investigate the clinical efficacy of super high-dose intraarterial cisplatin infusion with percutaneous pelvic perfusion under extracorporeal chemofiltration (PPPEC) for locally advanced uterine cervical carcinoma. Cisplatin (140-240 mg/m2) was infused in uterine arteries in a neoadjuvant setting in 20 patients under the PPPEC system twice during a 2-week interval. Fourteen of 17 patients in whom reduction of the disease (tumor downstaging) was confirmed underwent radical surgery. Despite the tumor downstaging, the remaining three patients had poor PS and the other three showed insufficient stage regression. Clinical responses, histologic responses, and surgical review were studied. The rate of overall tumor response (complete response plus partial response), tumor downstaging, overall histologic response, and radical surgery performance after the second course of PPPEC were 95.0%, 85.0%, 95.0%, and 70.0%, respectively. Curative surgery, defined as negative carcinoma cells in surgical margins, was achieved in 85.7% of the cases, whereas the rate of complete surgery defined as negative carcinoma cells both in surgical margins and regional lymph nodes was 42.9%. With 42 months of median follow-up time, 3 of the 14 surgical patients died of the original disease, and the remaining 9 patients are in recurrence-free survival, whereas 2 patients are alive with disease. PPPEC achieved a high frequency of rapid tumor downstaging of locally advanced uterine cervical carcinoma without severe adverse effects and resulted in the favorable performance of the subsequent radical surgery and prognosis.     

Chemoradiation therapy for esophageal cancer

The current status and future prospects of chemoradiation therapy (CRT) for esophageal cancer are reviewed herein. In Western countries, CRT is performed for every stage of esophageal cancer and it has been reported that in definitive CRT series the complete response rate is 30 to 50%, the mean survival rate more than twelve months, and the in 2-year survival rate about 30%, while in neoadjuvant CRT series the pathological response rate is 20 to 50%, the mean survival period more than twenty months, and the 3-year survival 30 to 40%. On the other hand, as esophageal cancer is treated mainly by surgery in Japan, CRT is applied in patients with tumors invading adjacent organs, and a high pathological complete response rate is reported in some neoadjuvant studies. Although both definitive and neoadjuvant CRT increases the response rate and improves local tumor control, CRT is associated with substantial mortality and morbidity, especially in neoadjuvant series. More effective and less toxic CRT regimens, using new chemotherapeutic agents such as nedaplatin and paclitaxel and new irradiation protocol such as accelerated hyperfractionation, are needed to improve the prognosis of patients with advanced esophageal cancer.     

Neoadjuvant Sunitinib Facilitates Nephron-Sparing Surgery and Avoids Long-Term Dialysis in a Patient With Metachronous Contralateral Renal Cell Carcinoma

Bilateral Renal Cell Carcinoma (RCC) is an uncommon clinical entity, affecting 3%-6% of patients with localized RCC. Sunitinib has proven efficacy in the management of metastatic RCC (mRCC), however, there is very limited evidence of primary tumor response. With the changing treatment paradigm, the role of sunitinib should be extended to the neoadjuvant setting, to downstage locally advanced primary renal tumors, to facilitate nephron-sparing surgery (NSS), and to select responding patients with mRCC for continuation of treatment after cytoreductive nephrectomy. The role of sunitinib in downstaging primary renal tumors to facilitate curative NSS has not been previously reported. We report the case of recurrent renal tumors in a solitary kidney, where neoadjuvant sunitinib downstaged the tumors enough to allow NSS.     

Genome-wide and size-based cell-free DNA indices as predictive biomarkers for locally advanced esophageal squamous cell carcinoma treated with preoperative or definitive chemoradiotherapy

For locally advanced esophageal cancer, concurrent chemoradiotherapy (CRT) followed by surgery has been a standard treatment, while clinical studies showed comparable survival outcomes between definitive CRT and neoadjuvant CRT followed by surgery in patients responding to CRT. Thus, biomarkers are required to predict treatment outcomes and benefit of adding surgery after CRT. This prospective biomarker study examined the role of cell-free DNA (cfDNA) fragmentation profiles and genomic copy number variations (CNVs) in predicting treatment outcomes in esophageal squamous cell carcinoma patients treated with neoadjuvant or definitive CRT. The clinical response was evaluated after induction chemotherapy and after CRT. Fragment Ratio (FR)-score and I-score were calculated from plasma cfDNA reflecting fragment lengths and CNV of cfDNA, respectively. The association between indices of cfDNA (cfDNA concentration, FR-score, and I-score) and treatment outcomes (clinical response, time to progression [TTP], and overall survival [OS]) were evaluated. Sixty-one patients were included. Thirty patients received neoadjuvant CRT followed by surgery, whereas 31 received definitive CRT. Low baseline, post-induction chemotherapy, and post-CRT FR-scores and low post-induction I-score were significantly associated with improved treatment response (P < 0.05). Additionally, patients with surgery after CRT showed significantly longer survival than patients without surgery in the FR-score-high group (median TTP, 12.7 vs 3.4 months; P = 0.011; OS, not reached vs 12.9 months; P = 0.02), while there was no survival benefit with surgery in the FR-score-low group. FR-score may be a new biomarker to predict treatment response, residual tumor burden after CRT, and consequently, survival benefit of adding morbid surgery after CRT. FR-score has strength in a relatively simple and inexpensive methodology compared to deep sequencing, resulting in high availability and accessibility, despite limited sensitivity.     

Locally advanced rectal cancer: what is the evidence for induction chemoradiation?

The concept of spatial cooperation in neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer is attractive. Chemotherapy may, as a component of CRT, not only act as a radiosensitizing agent but also potentially eradicate distant micrometastases. Recent trials have demonstrated that the addition of concurrent 5-fluorouracil (5-FU)-based chemotherapy to radiation increases the pathological complete response rate, and reduces local recurrence, but as yet, a survival advantage has not been observed. AIMS: This review aims to examine the evidence for induction CRT in locally advanced rectal cancer. The endpoints of pathological complete response, a negative circumferential margin, sphincter-sparing surgery, local control, disease-free survival (DFS), and overall survival (OS) are examined, as are acute and late morbidity, surgical complications, and late functional results. METHODS: The information to produce this review was compiled by searching PubMed and MEDLINE for English language articles published until April 2007. The search term included "induction, neoadjuvant, chemotherapy, radiotherapy, chemoradiation, combined modality" in association with rectal cancer. CONCLUSIONS: CRT in the European randomized trials of rectal cancer improves tumor downstaging, pathological complete response, and local control over radiotherapy alone, but does not translate into a benefit in terms of longer DFS or OS, or a higher chance of sphincter preservation. Metastatic disease remains a significant problem, which provides a strong rationale for the integration of a second cytotoxic drug, or biologically targeted agents.     

Delaying surgery after neoadjuvant chemoradiotherapy in rectal cancer has no influence in surgical approach or short-term clinical outcomes

Aims

In rectal cancer, increasing the interval between the end of neoadjuvant chemoradiotherapy (CRT) and surgery could improve the pathological complete response (pCR) rates, allow full-dose neoadjuvant chemotherapy, and select patients with a clinical complete response (cCR) for inclusion in a “watch & wait” program (W&W). However, controversy arises from waiting more than 8–12 weeks after CRT, as it might increase fibrosis around the total mesorectal excision (TME) plane potentially leading to technical difficulties and higher surgical morbidity. This study evaluates the type of surgical approach and short term post-operative outcomes in patients with rectal cancer that were operated before and after 12 weeks post CRT.

26例低位局部进展期直肠癌术前加量IMRT临床观察

目的 探讨低位直肠癌患者行术前同期加量IMRT联合卡培他滨化疗方案的可行性及治疗效果。方法 选取2015-2016年301医院26例局部晚期直肠癌患者,肠镜下肿瘤下缘距肛缘5 cm内。放疗剂量分割模式:直肠肿瘤及转移淋巴结为58.75 Gy分25次(2.35 Gy/次),盆腔淋巴引流区为50 Gy分25次,同步卡培他滨化疗(825 mg/m²,2 次/d,5天/周)5周。同步放化疗结束后休息1周,继续辅以1个周期卡培他滨化疗(1250 mg/m²,2 次/d,连续14 d)。同步放化疗结束后6~8周行直肠TME。研究主要终点为获得ypCR及保肛手术率,次要终点为急性放化疗反应、TN降期率及术后并发症。结果 26例患者均完成新辅助放化疗,其中25例患者已行手术治疗,1例患者因肛周水肿无法手术。术后ypCR率达32%(8/25),保肛手术率为60%(15/25);TN总降期率为92%(23/25),R0切除率为100%。放化疗期间24例患者发生1、2级不良反应,2例患者发生3级放射性皮炎,未见≥4级急性不良反应。术后输尿管损伤1例,肠梗阻1例。结论 低位直肠癌患者行术前同期加量IMRT联合卡培他滨化疗方案安全可行,ypCR、R0切除率及保肛手术率达到了预期效果,长期生存是否获益有待今后进一步研究。临床试验注册 中国临床试验注册中心,注册号:ChiCTR-ONC-12002387。     

Efficacy of neoadjuvant chemoradiotherapy in resectable esophageal squamous cell carcinoma--a single institutional study

A prospective phase II study of neoadjuvant chemoradiotherapy (CRT) for resectable esophageal squamous cell carcinoma was conducted from May 1993 to March 1996. A total of 88 patients fitted the eligibility criteria and were treated with two courses of induction chemotherapy (cisplatin 60 mg/m²/day on day 1 and 5-fluorouracil (5-FU) 1 000 mg/m²/day on days 2-6) with concurrent hyperfractionated radiotherapy (48 Gy/40 fractions/4 weeks) followed by esophagectomy or definitive CRT comprising 4 cycles of cisplatin/5-FU and hyperfractionated radiotherapy (additional 12 Gy) with intracavitary brachytherapy (9 Gy). Clinical response and downstaging were achieved in 83% and 42% of the patients, respectively. With a median follow-up of 77 months, median survival time was 18 months with a 5-year survival rate of 23%. The clinical responses to CRT and surgery were independent prognostic factors for overall survival. Among the intended surgery group (n=52), 41 (79%) patients underwent surgery and 36 had a resection with a pathologic complete response rate of 43%. When compared with a matched historical control (n=40), there was a significant survival benefit in the multimodality arm (p=0.04). This multimodality therapy was feasible and its efficacy was promising, especially when surgical resection was performed. The therapeutic benefit of neoadjuvant CRT remains to be assessed in large well-designed randomized trials, one of which is ongoing at our institution.     

Neoadjuvant Therapy for Breast Cancer: State of the Science and Future Directions

Systemic neoadjuvant chemotherapy has long been known to confer clinical benefits for breast cancer patients by downstaging inoperable disease or providing those with operable disease the opportunity for breast conservation, without compromising risk of recurrence. In recent years, its benefits have broadened as it has become a pivotal platform for clinical research, providing new prognostic and predictive insights into in vivo response to therapy and long-term outcomes. The use of neoadjuvant chemotherapy in the research setting has expanded our knowledge of heterogeneity in tumor biology and chemosensitivity and provided insights into the relationships between molecular signatures of tumors, pathologic complete response (pCR), and long-term outcomes. This has provided opportunities to specifically select patients who might benefit from novel therapies and test these in a more efficient manner. Despite these major advancements, however, the majority of patients do not attain a pathologic complete response with systemic neoadjuvant chemotherapy. This review describes the standard of care for systemic neoadjuvant therapy for breast cancer and discusses current management controversies and ongoing clinical trials designed to increase the proportion of patients who currently achieve a pCR.     

The effectiveness of planned esophagectomy after neoadjuvant chemoradiotherapy for advanced esophageal carcinomas

BACKGROUND: The best treatment option for patients with locally advanced esophageal carcinoma has not yet been determined, especially because the benefits of esophagectomy after neoadjuvant chemoradiotherapy are still controversial. We report the results of a retrospective cohort comparison of definitive chemoradiotherapy without surgery (CRT) versus neoadjuvant chemoradiotherapy followed by planned surgery (CRTS) in patients with advanced esophageal squamous cell carcinoma (SCC). MATERIALS AND METHODS: Between January 1991 and December 2002, 67 patients were enrolled in this study. Fifty of the 67 patients were considered to have inoperable tumors due to distant organ metastasis, distant lymph node metastasis, severe organ dysfunction or rejection of surgery by the patient and received CRT, while the remaining 17 patients were treated with CRTS. The clinical responses of the primary tumors were evaluated. RESULTS: In the 50 CRT patients, the one- and 2-year survival rates were 33.8% and 20.2%, respectively, and the median survival time (MST) was 13.5 months. In the 17 CRTS patients, the response rate (CR + PR) was 76.5%, and the pathological complete response (pCR) rate was 29.4%. Their one- and 2-year survival rates were 61.6% and 35.9%, respectively, and the MST was 24.4 months. The survival rates of the CRT patients were lower than those of the CRTS patients (p = 0.1288). When the 12 patients with distant organ metastases were removed from the CRT group, the one- and 2-year survival rates of the remaining 38 patients were 36.5% and 24.1%, respectively, and the MST was 14.7 months. The survival rates of these 38 CRT patients without distant organ metastases were similar to those of the 12 CRTS patients in the pathological partial response (pPR) group (p = 0.6279). CONCLUSION: This retrospective cohort comparison of CRT versus CRTS demonstrated that there may not be any survival benefit from the addition of surgery in the pPR group for advanced esophageal carcinomas. For patients with a poor response to neoadjuvant chemoradiotherapy, we suggest that the addition of chemoradiotherapy, instead of planned esophagectomy, may show a similar survival rate to definitive CRT. Thus, a large series of a randomized control study will be required to confirm the benefit of surgery after chemoradiotherapy.     

Current Views on the Interval Between Neoadjuvant Chemoradiation and Surgery for Rectal Cancer

Neoadjuvant chemoradiation (CRT) has been established as standard treatment for stage II and III rectal cancer, and delayed interval between CRT and rectal resection has emerged as appropriate treatment due to the marked benefits associated with this approach. Despite favorable findings on downstaging and pathological complete response without increasing in morbidity and mortality, no significant improvement in sphincter preservation rate and rectal cancer overall survival has been observed with the current recommended 6–8-week interval. Trials are currently underway and may provide answers regarding the optimal interval between CRT and surgical resection, but until now, the best interval between CRT and surgery remains unclear.