胃癌肝转移的肝切除治疗及预后分析

目的 探讨胃癌肝转移肝切除治疗的疗效以及不同临床病理因素与预后的关系.方法 回顾性总结24例胃癌肝转移行肝转移灶手术切除患者的临床资料并对预后进行单因素和多因素分析.结果 全组病例均获得随访,胃癌肝转移外科治疗后1年生存率为67%,3年生存率为21%,5年生存率为13%.单因素分析显示淋巴结转移、脉管瘤栓、R0切除、转移灶大小为重要预后因素;多因素分析显示转移灶大小、脉管瘤栓为独立预后因素.结论 严格适应证的胃癌肝转移手术切除可以改善预后.综合治疗有望进一步提高疗效.     

Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results

OBJECTIVE: To evaluate retrospectively the long-term results of an approach consisting of performing surgery in every patient in whom radical removal of all metastatic disease was technically feasible. SUMMARY BACKGROUND DATA: The indications for surgical resection for liver metastases from colorectal cancer remain controversial. Several clinical risk factors have been reported to influence survival. METHODS: Between March 1980 and December 1997, 235 patients underwent hepatic resection for metastatic colorectal cancer. Survival rates and disease-free survival as a function of clinical and pathologic determinants were examined retrospectively with univariate and multivariate analyses. RESULTS: The overall 3-, 5-, 10-, and 15-year survival rates were 51%, 38%, 26%, and 24%, respectively. The stage of the primary tumor, lymph node metastasis, and multiple nodules were significantly associated with a poor prognosis in both univariate and multivariate analyses. Disease-free survival was significantly influenced by lymph node metastasis, a short interval between treatment of the primary and metastatic tumors, and a high preoperative level of carcinoembryonic antigen. The 10-year survival rate of patients with four or more nodules (29%) was better than that of patients with two or three nodules (16%), and similar to that of patients with a solitary lesion (32%). CONCLUSIONS: Surgical resection is useful for treating liver metastases from colorectal cancer. Although multiple metastases significantly impaired the prognosis, the life expectancy of patients with four or more nodules mandates removal.     

Analysis of the prognostic factors and evaluation of surgical treatment for synchronous liver metastases from gastric cancer

Background and aims  Whether or not a synchronous resection of liver metastases from gastric cancer provides a survival benefit has been a key issue. We identify the significant prognostic factors and clarify the beneficial effect on the survival of liver surgical treatment. Materials and methods  We reviewed 72 patients who underwent a gastrectomy for gastric cancer with synchronous liver metastases and classified the liver metastases into three grades, such as H1: metastases were limited to one of the lobes, H2: there were a few scattered metastases in both lobes, and H3: there were numerous scattered metastases. Results  H1, 2 metastases, and an absence of peritoneal dissemination (P0) were significantly independent prognostic factors for liver metastases of gastric cancer. In addition, the cumulative 1 and 5-year survival rates of liver surgical treatment (hepatic resection and/or microwave coagulation therapy) were 80.0% and 60.0%, whereas the survival rates for non-hepatic surgical treatment were 36.4% and 0% in 26 patients with H1, 2, and P0. In those patients, the radical operation, the solitary metastatic liver tumor, and no-distant lymph node metastases were independent prognostic determinants of survival. Conclusion  The radical operation including the surgical treatment for metastatic liver tumors should be performed to improve the prognosis in gastric cancer patients with synchronous H1, 2, and P0.     

胃癌同时性肝转移手术患者的预后分析

目的分析经手术治疗的胃癌同时性肝转移患者的预后因素。方法回顾性分析1998年1月至2012年12月间在大连医科大学附属第一医院胃肠外科手术治疗的胃癌同时性肝转移53例患者的临床病理学资料,对单发和多发肝转移患者的生存率进行比较并进行预后分析。结果本组53例患者5年总体生存率为11．3％。单发肝脏转移患者34例,5年生存率14．7％,明显高于19例多发肝转移患者的0（P=-0．000）。单因素分析结果显示,浆膜侵犯（P=0．000）、淋巴结转移（P=0．000）、手术根治度（P=0．044）、发生肝转移数目（P=0．000）和肝转移肿瘤直径（P=0．031）是影响胃癌肝转移患者预后的因素。其中浆膜侵犯（RR：3。355,P=0．012）和肝转移数目（RR：7．664,P=0．000）是影响胃癌肝转移患者预后的独立因素。结论手术治疗可以提高无浆膜侵犯的胃癌单发肝转移患者的预后。     

HBsAg 对胃癌肝转移患者联合切除术后生存率的影响

目的:探讨HBsAg对胃癌肝转移患者联合切除术后生存率的影响.方法:回顾性分析近10年来采用胃和肝转移灶同期切除手术的胃癌肝转移患者31例的5年系统随访资料.采用Kaplan-Meier法绘制生存曲线,Log-rank法比较生存率差异,再采用Cox风险比例模型行多因素分析.结果:31例患者中完成系统随访29例,随访率93.5％.该29例患者中,3例生存无复发,另26例均死于术后复发和转移.全组1,3,5年累积生存率分别为62.1％,22.4％,12.1％,HBsAg阳性患者(14例)1,3,5年累积生存率分别为58.4％,18.7％,8.9％,而HBsAg阴性患者(17例)分别为69.3％,27.9％,15.7％; HBsAg阴性患者术后生存状态优于HBsAg阳性患者(x2=2.119,P=0.034).多因素分析结果显示,HBsAg阳性患者术后死亡的风险是HBsAg阴性患者的1.670倍,此外,肝转移灶的大小、胃癌的手术类型也是影响术后生存的独立危险因素(RR=2.121,95％CI=1.864-2.378; RR=2.296, 95％CI=2.001-2.591).结论:HBsAg是胃癌肝转移联合切除术后影响预后的独立危险因素.因此实施此类手术时应考虑HBsAg的影响.     

Hepatic Resection for Metastatic Tumors From Gastric Cancer

OBJECTIVE: To assess the surgical results and clinicopathologic features of hepatic metastases from gastric adenocarcinoma to identify patients with a better probability of survival. SUMMARY BACKGROUND DATA: Many studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, indications for a surgical approach for gastric adenocarcinoma involving the liver have not been clearly defined. METHODS: Ninety (11%) of 807 patients with primary gastric cancer were diagnosed with synchronous (n = 78) or metachronous (n = 12) hepatic metastases. Of these, 19 underwent 20 resections intended to cure the metastatic lesion in the liver. The clinicopathologic features of the hepatic metastases in, and the surgical results for, the 19 patients were analyzed. RESULTS: The actuarial 1-year, 3-year, and 5-year survival rates after hepatic resection were, respectively, 77%, 34%, and 34%, and three patients survived for more than 5 years after surgery. Solitary and metachronous metastases were significant determinants for a favorable prognosis after hepatic resection. Pathologically, a fibrous pseudocapsule between the tumor and surrounding hepatic parenchyma was found in 13 of the 19 patients (68%). The presence of a peritumoral fibrous pseudocapsule and a well-differentiated histologic type of metastatic nodule were significant prognostic factors. Factors associated with the primary lesion were not significant prognostic determinants in patients who underwent curative resection of the primary cancer. CONCLUSIONS: Solitary and metachronous metastases from gastric cancer should be treated by a surgical approach and confer a better prognosis. A new prognostic factor, the presence of a pseudocapsule, may be helpful in defining indications for postoperative adjuvant treatment.     

��ֱ������ת���������

??Liver metastases of colorectal cancer: a survival analysis ZHU De-xiang*??REN Li??WEI Ye??et al. *Institute of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Corresponding author??XU Jian-min??E-mail??xujmin@yahoo.com.cn
Abstract Objective To investigate survival in patients with liver metastases of colorectal cancer and identify risk factors associated with survival. Methods Clinical, pathologic, treatment and complete follow-up data of the consecutive cases of colorectal liver metastasis admitted between 2000 and 2010 in Zhongshan Hospital of Fudan University were analyzed retrospectively. The prognostic value of different factors was studied through univariate and multivariate analyses. Results The median survival was 22.0 months and 5-year survival rate was 16%. Survival of synchronous liver metastases (21.2 months and 16%) was lower than that of metachronous liver metastases (30.1 months and 23%, P<0.01). Survival after resection of liver metastases was 49.8 months and 37%, which was higher than that after chemotherapy ??22.2 months and 0??, that after intervention??19.0 months and 11%??, that after chemotherapy combined with intervention??22.8 months and 10%??and that after local regional treatment (28.5 months and 0). Five factors were found to be significant and independent predictors of poor survival by multivariate analysis: simultaneous liver metastases (P=0.005), poorly differentiated primary (P=0.005), number of liver metastases ≥ 4 (P=0.008), largest liver metastases ≥ 5 cm (P=0.007), and no surgical treatment of liver metastases (P<0.001). Conclusion Survival of synchronous liver metastases is lower than that of metachronous liver metastases. Resection of liver metastases provides good long-term survival benifit for patients with resectable and initially irresectable liver metastases. Expansion of the indications for liver resection is acceptable. Long-term survival outcome can be predicted from a risk factor scoring system.     

Long-term outcomes after surgical resection for gastric cancer liver metastasis: an analysis of 64 macroscopically complete resections

Purpose

The indication for hepatectomy in cases of gastric cancer liver metastases (GLM) remains unclear and it remains controversial whether surgical resection is beneficial for GLM. The objective of this retrospective study was to clarify the indications for and benefit of hepatectomy for GLM.

Methods

Seventy-three patients underwent hepatectomies for GLM from January 1993 to January 2011. Macroscopically complete (R0 or R1) resection was achieved in 64 patients. Among them, 32 patients underwent synchronous hepatectomy with gastrectomy and the remaining 32 patients underwent metachronous hepatectomy. Repeat hepatectomy was done in 14 patients for resectable intrahepatic recurrences. Clinicopathological factors were evaluated by univariate and multivariate analyses among patients who received macroscopically complete resection for those affecting survival.

Results

The overall 1-, 3-, and 5-year survival rates after macroscopically complete (R0 or R1) liver resection (n?=?64) for GLM were 84, 50, and 37?%, respectively, with a median survival of 34?months. Univariate analysis identified serosal invasion of the primary gastric cancer and blood transfusions during surgery as poor prognosis indicators. By multivariate analysis, serosal invasion of the primary gastric cancer and larger hepatic tumor (>5?cm in diameter) were found to be independent indicators of poor prognosis.

Conclusions

GLM patients with the maximum diameter of hepatic tumors of <5?cm and without serosal invasion of the primary gastric cancer are the best candidate for hepatectomy.     

Surgical outcomes in patients with T4 gastric carcinoma

BACKGROUND: There is controversy about the best therapeutic surgical approach for treatment of patients with T4 gastric cancer. STUDY DESIGN: We used univariate and multivariate analyses to review the surgical outcomes and prognostic factors of 117 patients who underwent surgery for T4 gastric carcinoma. RESULTS: Curative resection was performed in 38 (32.4%) patients, with the pancreas being the most frequently resected organ. The 5-year survival rate was 16.0% and the median survival time (MST) was 11 months for all 117 registered patients. The 5-year survival rates and MSTs in patients after curative and noncurative resection were 32.2% versus 9.5% and 20 months versus 8 months, respectively. These values differed considerably between the two groups (p < 0.0001). Curability was an independent prognostic factor among all registered patients, including those who underwent noncurative resection. A relatively small tumor diameter (< 100 mm) and few lymph node metastases (six or fewer metastatic lymph nodes) were independent prognostic factors when curative resection could be performed. Postoperative morbidity and mortality were acceptable after curative combined resection. CONCLUSIONS: We recommend the use of aggressive combined resection of adjacent organs, with extended lymph node dissection, for patients with T4 gastric carcinoma in whom curative resection can be used; that is, those with few metastatic lymph nodes (six or less) and a relatively small tumor diameter (100 mm). But noncurative resection should be avoided in patients with T4 gastric cancer.     

Outcome of hepatic resection for metastatic gastric cancer

The role of hepatic resection for metastatic gastric cancer is less well defined due to the tendency of gastric cancer to widely metastasize. The purpose of this study is to examine the beneficial effect of hepatic resection in patients with metastatic gastric cancer. The clinicopathologic features and long-term results of 11 patients who underwent hepatic resection for metastatic gastric cancer from January 1988 to December 1996 at Seoul National University Hospital were analyzed retrospectively. All resected hepatic metastases were solitary lesions. Among eight patients with synchronous hepatic metastases, one patient with early gastric cancer and lymph node metastases (T1N2M1) remained alive for 8 years 6 months after hepatic resection without recurrence. Among three patients with metachronous hepatic metastases, two patients with advanced gastric cancer and lymph node metastases (T3N2MO, T2N1MO at the initial operation, respectively) survived 8 years 6 months and 3 years after hepatic resection, respectively. Median survival times of synchronous and metachronous hepatic metastases were 13.0 and 74.3 months, respectively. In solitary hepatic metastatic lesions from gastric cancer, surgical resection should be considered as one of the treatment options.     

Hepatic Resection for Metastatic Breast Cancer: Prognostic Analysis of 34 Patients

Liver metastasis of breast cancer is considered a generalized disease, and surgical treatment is rarely discussed. Thirty-four patients who underwent 35 hepatectomies for liver metastases of breast cancer between 1985 and 2003 were analyzed. The median interval between the breast surgery and relapse in the liver was 1.9 years (0–20 years). The liver was the first site of recurrence in 25 patients. Fifteen clinicopathologic factors were evaluated using univariate and multivariate analyses to predict survival after hepatic resection. No patients died because of the surgery. The median survival was 36 months (1 month to 20 years). The overall and disease-free 5-year survival rates after hepatectomy for breast metastases were 21% and 16%, respectively. Four patients survived more than 5 years. The presence of extrahepatic recurrence prior to hepatectomy was the only significant prognostic factor according to the analyses, and the 5-year survival rate of patients without extrahepatic disease was 31%. No patient who had hilar lymph node metastasis survived more than 5 years. In the absence of extrahepatic recurrence, surgical resection of liver metastasis from breast cancer can offer an acceptable prognosis and should not be avoided in selected patients.     

Colorectal hepatic metastases: resection, local ablation, and hepatic artery infusion pump are associated with prolonged survival

BACKGROUND: Treatment of metastatic colorectal cancer to the liver is not uniform. We describe the management of metastatic colorectal cancer of the liver at a single institution during a 10-year period. METHODS: From January 1, 1990, through December 31, 1999, 174 patients were identified from the tumor registry at the University of Alabama at Birmingham with a diagnosis of metastatic colorectal cancer to the liver. Patient, tumor, laboratory, operative, and adjuvant therapy factors were analyzed, with overall survival as the endpoint. Log-rank tests were used for univariate analysis, Cox-proportional hazards model for multivariate analysis, and Kaplan-Meier curves were used for graphical representation of survival. Significance was defined as P<.05. RESULTS: Median age was 60 years (age range, 18-92 years). Seventy-nine percent of patients had synchronous liver metastases at the time of diagnosis of the primary colorectal tumor. The primary tumor was in the colon and rectum 75% and 25% of the time, respectively. Of the 89 patients who underwent operation, 73 received definitive surgical treatment for their liver metastases. Fifty-two patients underwent lobectomy or wedge resection, 5 underwent cryotherapy, and 16 had a hepatic artery infusion pump (HAIP) inserted. Median follow-up duration of surgically treated patients was 26 months. Operative mortality was 1.3%. The 3-year actuarial survivals for patients who underwent resection, HAIP, or those with unresectable disease were 70 months, 32 months, and 3 months, respectively (P<.001). By multivariate analysis, surgical intervention, a carcinoembryonic antigen level less than 200 microg/L, or a low T stage of the primary tumor were associated with prolongation of survival. CONCLUSIONS: Surgical resection should be attempted for hepatic colorectal metastases, as this is associated with prolonged overall survival. Hepatic artery infusion pump insertion seems to prolong overall survival for those with unresectable hepatic metastases, but it is not equal to resection. Aggressive surgical management of patients with hepatic colorectal metastases is safe, may prolong overall survival, and therefore should be considered in all patients with metastases confined to the liver.     

Benefits and limits of hepatic resection for gastric metastases

BACKGROUND: The significance of hepatic resection for gastric metastases has been controversial. METHODS: Forty consecutive patients undergoing hepatic resection for gastric metastases were reviewed to examine the benefits and the limits of hepatic resection using univariate and multivariate analyses. RESULTS: The overall survival was 27% at 2 years, 18% at 5 years, and 11% at 10 years. Six patients survived more than 5 years. All of the 6 patients underwent anatomical hepatic resection more extensive than segmentectomy, with sufficient resection margin. There were recurrences in 31 patients, and 94% of the recurrences were in the remaining liver. Univariate analysis showed time of hepatic metastases (P = 0.0078) and resection margin (P = 0.024) as significant prognostic factors. Multivariate analysis indicated that only time of hepatic metastases was an independent prognostic factor that influenced survival. CONCLUSIONS: These results suggest that in patients with synchronous metastases we should consider patient selection more strictly, and that in patients with metachronous metastases we should perform anatomical hepatic resection with sufficient resection margin.     

Hepatic resections for bilobar liver metastases from colorectal cancer

The present study was performed to assess survival benefits in patients who underwent a hepatic resection for isolated bilobar liver metastases from colorectal cancer. Thirty-eight patients underwent a curative hepatic resection for isolated colorectal liver metastasis. Among them, 11 patients had bilobar liver metastases and 19 had a solitary metastasis. The remaining 8 patients had unilobar multiple lesions. We investigated survival in two groups those with bilobar and those with solitary metastatic tumors. Survival and disease-free survival were 36% and 18% at 5 years, respectively, in the patients with bilobar liver metastases, while these survivals were 43% and 34% in the patients with solitary liver metastasis. In the 38 patients, repeated hepatic resections were performed in 15 patients with recurrent liver disease. The 5-year survival and disease-free survival rates for these patients were 38% and 27%, respectively, after the second hepatic resections. Of the 11 patients with bilobar liver metastases, 5 underwent a repeated hepatic resection, and they all survived for over 42 months. Based on our observations, a hepatic resection was thus found to be effective even in selected patients with either bilobar nodules or recurrence in the remnant liver. Received: February 7, 2000 / Accepted: April 26, 2000     

结肠癌同时性肝转移同期手术与分期手术的疗效比较

目的：对比结肠癌同时性肝转移行同期手术与分期手术切除转移灶的疗效。方法：回顾性分析36例结肠癌同时性肝转移患者的临床资料,其中16例行结肠癌根治术同时切除肝转移病灶（同期手术组）;20例先行结肠癌根治性切除、二期行肝转移病灶切除（分期手术组）。比较两组患者的1,3,5年生存率。结果：同期手术组患者1,3,5年生存率分别为87.5%,37.5%,18.8%,分期手术组患者1,3,5年生存率分别为65%,10.0%,0.0%。两组比较,1年生存率差异无统计学意义（P>0.05）,同期手术组3,5年生存率明显高于分期手术组（均P<0.05）。结论：结肠癌同时性肝转移行同期手术可延长患者生存时间。

     

胃癌肝转移外科治疗的临床分析

目的 评价胃癌肝转移的外科治疗效果及病理因素对其预后的影响。方法 本组834例胃癌患者中共有91例诊断为肝转移，其中79例为同时性肝转移，12例术后发现异时转移，共21例行胃癌肝转移灶切除术。结果 胃癌肝转移灶切除后1年、3年生存率分别为69％、30％。单转移灶及异时性转移是其有利的预后因素。13例肝转移灶有假包膜形成。结论 单转移灶及异时转移、肿瘤假包膜形成预示胃癌肝转移切除患者有较好的预后。     

Is a proliferation index of cancer cells a reliable prognostic factor after hepatectomy in patients with colorectal liver metastases?

BACKGROUND: In spite of many reports focusing on prognostic factors after hepatectomy in patients with colorectal liver metastases, few studies have investigated pathological factors, eg, fibrous pseudocapsulation, growth pattern at the tumor margin, and proliferation activity of cancer cells, other than histological type and surgical margin. The aim of the present study was to investigate whether absence of pseudocapsulation, infiltrative growth pattern of metastases, and higher proliferation of cancer cells shown by Ki-67 immunohistochemical reactivity were associated with poorer survival after hepatectomy among patients with colorectal liver metastases. METHODS: Between 1988 and 1998, 221 patients underwent hepatic resection of colorectal metastases with curative intent in our institution. Pathology analyses were focused on pseudocapsulation of liver metastases, growth pattern at the tumor edge, and Ki-67 labelling index (Ki-67 LI) of cancer cell nuclei. Univariate analyses of survival and of disease-free survival were performed for several clinicopathological factors, and multivariate analyses of survival and disease-free survival were also performed. RESULTS: The univariate survival analyses showed that pseudocapsulation, growth pattern, and Ki-67 LI were significant prognostic factors, besides synchronous versus metachronous occurrence of metastases, carcinoembryonic antigen level before hepatectomy, and number of metastases. A multivariate analysis showed that Ki-67 labeling index was the most reliable prognostic factor of survival. In addition, Ki-67 LI and microscopic growth pattern were multivariately predictive factors of disease-free survival. CONCLUSIONS: This large single-institution study showed that investigation of cancer cell proliferation and pathologic characteristics of the tumor margin are major prognostic factors.     

结直肠癌肝转移患者的预后因素分析

目的：分析结直肠癌伴肝转移患者手术切除后影响术后生存率的危险因素。方法：回顾性分析54例手术治疗的结直肠癌肝转移患者的临床及随访资料,对相关因素行单因素和多因素分析。结果：单因素分析显示,原发癌分化程度、淋巴转移、肝转移灶数目、肝转移灶肿瘤大小、手术方式及是否术后进行综合治疗等为影响患者预后的因素（均P<0.05）;多因素分析表明,手术方式、淋巴结转移和原发肿瘤分化程度是主要危险因素（均P<0.05）。结论：及早发现并进行根治切除以及加强术后综合治疗是提高本病远期疗效的关键。

     

Hepatic resection for colorectal liver metastases. Influence on survival of preoperative factors and surgery for recurrences in 80 patients.

This report analyses an experience with 80 liver resections for metastatic colorectal carcinoma. Primary colorectal cancers had all been resected. Liver metastases were solitary in 44 patients, multiple in 36 patients, unilobar in 76 patients, and bilobar in 4 patients. Tumor size was less than 5 cm in 33 patients, 5-10 cm in 30 patients, and larger than 10 cm in 17 patients. There were 43 synchronous and 37 metachronous liver metastases with a delay of 2-70 months. The surgical procedures included more major liver resections (55 patients) than wedge resections (25 patients). Portal triad occlusion was used in most cases, and complete vascular exclusion of the liver was performed for resection of the larger tumors. In-hospital mortality rate was 5%. Three- and 5-year survival rates were 40.5% and 24.9%, respectively. None of the analysed criteria: size and number of liver metastases, delay after diagnosis of the primary cancer, Duke's stage, could differentiate long survivors from patients who did not benefit much from liver surgery due to early recurrence. Recurrences were observed in 51 patients during the study, two thirds occurring during the first year after liver surgery. Eight patients had resection of "secondary" metastases after a first liver resection: two patients for extrahepatic recurrences and six patients for liver recurrences. Encouraging results raise the question of how far agressive surgery for liver metastases should go.     

Surgical treatment of liver metastases from colorectal cancer

We analyze our experience over a 10-year period in the surgical treatment of liver metastases from colorectal cancer. Between 01.01.1995 and 08.31.2005 189 liver resections were performed in 171 patients with liver metastases from colorectal cancer (16 re-resections - 2 in the same patient and a "two-stage" liver resection in 2 patients). In our series there were 83 patients with synchronous liver metastases (69 simultaneous resections, 12 delayed resections and 2 "two-stage" liver resection were performed) and 88 metachronous liver metastases. Almost all types of liver resections have been performed. The morbidity and mortality rates were 17.4% and 4.7%, respectively. Median survival was 28.5 months and actuarial survival at 1-, 3- and 5-year was 78.7%, 40.4% and 32.7%, respectively. Between January 2002 and August 2005 hyperthermic ablation of colorectal cancer liver metastases has been performed in 6 patients; in other 5 patients with multiple bilobar liver metastases liver resection was associated with radiofrequency ablation and one patient underwent only radiofrequency ablation for recurrent liver metastasis. In conclusion, although the treatment of colorectal cancer liver metastases is multimodal (resection, ablation, chemotherapy and radiation therapy), liver resection is the only potential curative treatment. The quality and volume of remnant liver parenchyma is the only limitation of liver resection. The morbidity, mortality and survival rates after simultaneous liver and colorectal resection are similar with those achieved by delayed resection. Postoperative outcome of patients with major hepatic resection is correlated with the surgical team experience. The long-term survival was increased using the new multimodal treatment schemes.