肾细胞癌靶向治疗预后相关因素研究进展

肾细胞癌（RCC）是泌尿系统常见的恶性肿瘤之一。分子靶向治疗是通过干预肿瘤细胞信号传导通路,抑制肿瘤的生长。相比于传统的细胞冈子治疗手段．肾癌靶向治疗效果更好。但是目前对肾癌靶向治疗的预后仍缺乏有效判断手段,本文结合最新研究综述了RCC靶向治疗预后密切相关的影响冈素研究现状及进展。     

Pre‐surgical targeted molecular therapy in renal cell carcinoma

Pre‐surgical systemic therapy with targeted molecular agents is an attractive option as an approach to the treatment of patients with renal cell carcinoma. This treatment strategy offers a rational approach for selecting patients with metastatic disease who are most likely to benefit from cytoreductive nephrectomy, but also allows access to treated tumour tissue to study the molecular mechanisms of response and resistance. In patients with locally advanced disease, this strategy offers the potential for improved resectability and timely delivery of systemic therapy to treat subclinical metastatic disease. Preliminary evidence indicates that the use of targeted therapies before nephrectomy is safe. Reliable therapy‐specific prognostic biomarkers are needed for the optimal integration of aggressive surgical intervention and systemic therapy to maximize the oncological benefits for the patient.     

Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma

Background

In patients with metastatic renal cell carcinoma (mRCC), the timing of systemic targeted therapy in relation to cytoreductive nephrectomy (CN) is under investigation.

Objective

To evaluate postoperative complications after the use of presurgical targeted therapy prior to CN.

Design, setting, and participants

A retrospective review of all patients who underwent a CN at The University of Texas M.D. Anderson Cancer Center from 2004 to 2010 was performed. Inclusion in this study required documented evidence of mRCC, with treatment incorporating CN.

Interventions

Patients receiving presurgical systemic targeted therapy prior to CN were compared to those undergoing immediate CN.

Measurements

Complications were assessed using the modified Clavien system for a period of 12 mo postoperatively.

Results and limitations

Presurgical therapy was administered to 70 patients prior to CN (presurgical), while 103 patients had an immediate CN (immediate). A total of 232 complications occurred in 57% of patients (99 of 173). Use of presurgical systemic targeted therapy was predictive of having a complication > 90 d postoperatively (p = 0.002) and having multiple complications (p = 0.013), and it was predictive of having a wound complication (p < 0.001). Despite these specific complications, presurgical systemic targeted therapy was not associated with an increased overall complication risk on univariable or multivariate analysis (p = 0.064 and p = 0.237) and was not predictive for severe (Clavien ≥3) complications (p = 0.625). This study is limited by its retrospective nature. As is inherent to any retrospective study reporting on complications, we are limited by reporting bias and the potential for misclassification of specific complications.

Conclusions

Despite an increased risk for specific wound-related complications, overall surgical complications and the risk of severe complications (Clavien ≥3) are not greater after presurgical targeted therapy in comparison to upfront cytoreductive surgery.     

Recent advances in molecular targeted therapy for metastatic renal cell carcinoma

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15–20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.     

肾细胞癌的靶向治疗现状

随着对肿瘤新生血管生成机制的了解,一系列针对肿瘤血管生成的抗肿瘤分子靶向药物在晚期肾细胞癌的治疗方面取得了长足的进展。与传统的免疫治疗（细胞因子治疗）相比,接受靶向药物治疗患者的无进展生存期和总生存期都获得显著提高。靶向药物引起的毒副反应特点与传统化疗药物有所不同,但均处于可接受程度。由于靶向药物在治疗晚期肾癌方面取得的良好结果,新的治疗领域研究正在进行中,如高危局限性肾癌根治性肾切除术后的辅助治疗。应用足够剂量、维持治疗和正确处理毒副反应是获得临床疗效的三个基本条件。     

The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy

PURPOSE: Thoughtful integration of surgical and medical approaches to metastatic renal cell carcinoma is paramount for maximizing disease control. Accomplishing this in the current era of targeted molecular therapies presents unique challenges and opportunities. MATERIALS AND METHODS: A systematic review of the MEDLINE and PubMed databases, and relevant urological and oncological journals was performed pertaining to cytoreductive nephrectomy, metastasectomy, targeted molecular therapies for renal cell carcinoma, and neoadjuvant and adjuvant approaches to the management of advanced renal cell carcinoma. RESULTS: Cytoreductive nephrectomy provides an overall survival advantage in select patients with metastatic renal cell carcinoma who receive subsequent interferon-alpha. However, cytokine therapies are now being supplanted by targeted molecular approaches that block the effects of vascular endothelial growth factor and other molecular events. Although cytoreductive nephrectomy remains a standard of care, limited insight into the biological effects of nephrectomy on mechanisms such as immunoregulation and angiogenesis precludes definitive statements about how to integrate surgery and targeted agents. Ongoing investigation involving basic science and translational research is required to optimize the integration of these approaches. Adjuvant and neoadjuvant vascular endothelial growth factor targeted approaches to renal cell carcinoma are now also being explored and the unique side effects of these agents, including potential effects on wound healing and vascular integrity, require careful consideration. CONCLUSIONS: Integrated approaches involving surgery and vascular endothelial growth factor targeted therapies hold much promise for the management of advanced renal cell carcinoma. Prospective clinical testing with vigilant attention to the risk-benefit ratio and thoughtful evaluation of biological correlates are required to optimize these approaches.     

Prospective assessment of systemic therapy followed by surgical removal of metastases in selected patients with renal cell carcinoma

OBJECTIVE

To prospectively establish objective selection criteria for metastasectomy in patients with metastatic renal cell carcinoma (mRCC).

PATIENTS AND METHODS

Between 1991 and 1999, 38 patients with mRCC with responsive or stable disease after initial systemic therapy, and with potentially resectable disease, were enrolled. Patients had a metastasectomy with curative intent and received consolidative adjuvant systemic therapy.

RESULTS

Of the patients enrolled, 79% had stable disease after initial systemic therapy and 21% had a partial or complete response. Most (84%) had metastasectomy of one organ site. There was surgically no evidence of disease (sNED) in 76%. Operative morbidity and mortality were acceptable and 90% of the patients received adjuvant systemic therapy. The median (95% confidence interval) survival was 4.7 (3.0–7.8) years, and the median time to progression was 1.8 (0.8–3.1) years. Eight of 38 patients (21%) remained free of disease by the end of the study. Significant predictors of outcome were lack of sNED after metastasectomy, and the presence of pulmonary metastases. The median overall survival for those who had sNED was 5.6 years, vs 1.4 years for those who did not (P < 0.001).

CONCLUSIONS

Metastasectomy in patients with mRCC not progressing after systemic therapy is feasible, with acceptable morbidity. Predictive factors for long‐term outcome include pulmonary metastases and sNED. Future work evaluating treatments that can convert patients into surgical candidates will increase the cure rate of patients with mRCC.     

Therapy management of cardiovascular adverse events in the context of targeted therapy for metastatic renal cell carcinoma

Targeted agents have significantly improved outcomes in patients with metastatic renal cell carcinoma, and are changing long‐term expectations in these patients. Experience with these agents highlights a distinct safety and tolerability profile, differing from that observed with conventional chemotherapy and radiotherapy. Cardiovascular adverse events have been observed when treating with targeted agents. This is of particular importance for patients with metastatic renal cell carcinoma who are elderly and present with significant comorbidities. A multidisciplinary approach and close collaboration between oncologists and cardiologists is essential for optimal management of cardiovascular adverse events. Strategies for the management of these adverse events include assessment of cardiovascular status at baseline and at regular intervals, patient education, and the use of supportive medication. Effective therapy management allows patients with cardiovascular adverse events to receive and continue targeted therapy with careful monitoring. Implementation of therapy management measures contributes towards maximizing treatment outcomes with targeted agents in patients with metastatic renal cell carcinoma.     

The role of cytoreductive nephrectomy in the era of molecular targeted therapy

While the widespread use of imaging has resulted in an increasing number of incidentally detected renal cancers, up to one third of patients present with metastatic disease and a significant number of those with clinically localized disease subsequently develop metastasis. The prognosis for patients with metastatic disease has traditionally been poor, with a 2-year survival of only 10 to 20%. However, over the past decade a number of developments have enhanced the treatment of these patients. Phase III trials have demonstrated a significant improvement in overall survival for well-selected patients undergoing cytoreductive nephrectomy prior to immunotherapy. Meanwhile, the recent introduction of molecular targeted agents has resulted in improved response rates and tolerability compared with immunotherapy, and has prompted a re-evaluation of the role and timing of surgery in patients with advanced disease. This review examines the role of surgical therapy for patients with metastatic disease in the new era of molecular targeted therapy.     

Impact of hyponatremia on survival of patients with metastatic renal cell carcinoma treated with molecular targeted therapy

Objectives: Hyponatremia is reported to be associated with poor survival in localized renal cell carcinoma and metastatic renal cell carcinoma treated with immunotherapy. However, there are no reports on the relationship between hyponatremia and prognosis of metastatic renal cell carcinoma treated with molecular targeted therapy. We evaluated the prognostic significance of hyponatremia in metastatic renal cell carcinoma treated with molecular targeted therapy as first‐line therapy. Methods: We retrospectively analyzed a database comprising 87 patients treated from April 2008 to July 2011 with sorafenib or sunitinib as first‐line therapy for metastatic renal cell carcinoma. Patients were divided into three groups according to serum sodium level: severe hyponatremia (≤134 mEq/L), mild hyponatremia (135–137 mEq/L) and normal natremia (≥138 mEq/L). Results: Median cancer‐specific survival time was 8.8 months in the patients with severe and mild hyponatremia, and 32.6 months in the patients with normal natremia (P < 0.001). Multivariate analysis showed severe and mild hyponatremia to be significantly associated with cancer‐specific survival (hazard ratio 6.228; 95% confidence interval 2.161–17.947, P = 0.001; hazard ratio 3.374; 95% confidence interval 1.294–8.798, P = 0.013), respectively. Neutrophilia and high C‐reactive protein level (C‐reactive protein ≥1.0 mg/dL) were significant prognostic factors to predict inferior cancer‐specific survival. In Harrell's concordance index calculation, hyponatremia could significantly improve the predictive accuracy for estimation of survival probability (P = 0.028). Conclusions: Hyponatremia (<138 mEq/L), neutrophilia and high C‐reactive protein levels seem to represent significant predictive factors for cancer‐specific survival in metastatic renal cell carcinoma patients treated with molecular targeted therapy as first line therapy. Furthermore, hyponatremia might be significantly associated with chronic inflammation and tumor aggressiveness.     

Nephron‐sparing surgery for small incidental renal cell carcinoma

Background : Nephron‐sparing surgery is currently an accepted treatment for renal cell carcinomas in patients with bilateral tumours, solitary kidneys and when overall renal function is impaired or at risk from medical disease. Its role in patients with a normal contralateral kidney remains controversial. Methods : The authors’ experience in 23 patients undergoing partial nephrectomy for small peripheral lesions between 1995 and 2000 is reported here. Results : Twenty‐three patients (13 men and 10 women) with a mean age of 56 years underwent partial nephrectomy. All but three of these patients had a normal contralateral kidney. Mean operating time was 141 min with a mean reduction of haemoglobin of 28 g/dL. Three patients required transfusion. Serum creatinine did not change significantly between preoperative and postoperative values. Two JJ stents were placed prophylactically during surgery to minimize urinary leak. There were no intraoperative or early postoperative deaths and at mean follow up of 16 months there was no evidence of recurrent tumour in 23 patients. Seventeen per cent of lesions removed were benign. Conclusions : Partial nephrectomy for small peripheral lesions is a safe procedure with low morbidity. No definite recurrences are evident at an early stage of follow up, although longer review (probably more than 10 years) will be required to assess cancer‐specific survival following this procedure.     

Cytoreductive surgery with liver-involved renal cell carcinoma

The purpose of this study was to demonstrate the benefits of cytoreductive surgery for renal cell carcinomas that also involve the liver. Between 1994 and 1997, four patients with renal cell carcinoma with liver involvement were surgically treated with nephrectomy and hepatectomy. Two of them underwent a simultaneous hepatectomy and nephrectomy (group 1), and the remaining two patients underwent a hepatectomy after a nephrectomy and had a diagnosis of postoperative recurrence (group 2). Two patients, one from each group, died of multiple bone metastasis and lung metastasis 30 months and 12 months after the hepatectomy; the second patient from group 1 died 40 months after the first operation due to gastrointestinal hemorrhaging. The second patient from group 2 displayed no evidence of recurrence 18 months after the second surgical procedure. The survival rates for these patients were 66% and 33% at 1 and 3 years, respectively. Autopsy studies revealed that one patient from group 2 had a local recurrence in the liver while the other two patients from group 1 did not. Our results suggested that a progressive approach may therefore be useful for patients demonstrating renal cell carcinoma where there is liver involvement.     

小肾癌57例诊治报告

目的提高小肾癌的诊治水平。方法回顾分析57例小肾癌患者的临床资料,探讨小肾癌的诊治方法。蛄杲本组小肾癌病例多无明显症状,通过体检发现。19例行根治性肾切除术（RN）,38例行保留肾单位肾部分切除术（NSS）,所有病例术后均辅以免疫治疗。随访14～63个月,除1例死亡外,均无瘤存活。结论定期体检有助于早期发现小肾癌。采取RN或者NSS治疗小肾癌均能获得良好预后。有条件者应建议行术后免疫治疗。     

Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience

PURPOSE: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dubé syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm, then performing parenchymal sparing surgery. We present a 5-year update on our experience. MATERIALS AND METHODS: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including von Hippel-Lindau disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dubé syndrome in 1, and 1 with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205). RESULTS: A total of 50 patients underwent 71 operations resulting in unilateral nephrectomy in 6, bilateral nephrectomy in 1 and partial nephrectomy in 65, with 1 to 51 tumors removed from each kidney (mean 14.7). Mean patient age was 39.5 years (range 18 to 70). Of the 65 (40%) partial nephrectomies 26 were performed with cold renal ischemia. Mean blood loss was 2.9 +/- 0.5 l (range 0.15 to 23). Postoperative complications included renal atrophy in 3 patients. Mean preoperative serum creatinine was 1.05 +/- 0.03 mg/dl (range 0.6 to 1.8), and postoperative creatinine was 1.06 +/- 0.04 mg/dl (range 0.6 to 2.0). No patient who underwent renal parenchymal sparing surgery required renal replacement therapy. Metastatic disease developed in 1 patient with a 4.5 cm renal tumor. CONCLUSIONS: Parenchymal sparing surgery with a 3 cm threshold in patients with hereditary renal cancer appears to be an effective therapeutic option to maximize renal function while minimizing the risk of metastatic disease.     

Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma

Study Type – Therapy (economic) Level of Evidence 2b What’s known on the subject? and What does the study add? Cost‐effectiveness of new targeted molecular therapies in patients with mRCC have been examined compared to interferon‐α. This study compares cost‐effectiveness of three new targeted therapies in mRCC head‐to‐head based on indirect comparison of clinical efficacy. The study shows that sunitinib is a cost‐effective therapy in first line treatment for patients with mRCC in the USA and Sweden compared to sorafenib and bevacizumab+interferon‐α.

OBJECTIVE

? To assess the economic value of targeted therapies as first‐line metastatic renal cell carcinoma (mRCC) treatment in the US and Sweden by indirect comparison of survival data.

METHODS

? A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon‐α (IFN‐α) in both countries. ? Results, in life‐years (LYs), progression‐free LYs (PFLYs), quality‐adjusted LYs (QALYs) gained and treatment costs (2008 USD) were obtained through deterministic and probabilistic analyses over the patient’s lifetime.

RESULTS

? Sunitinib was more effective and less costly than sorafenib (gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs and savings/patient of $13 576 in the US) and bevacizumab plus IFN‐α (gains of 0.19 PFLYs, 0.23 LYs and 0.16 QALYs in both countries and savings/patient of $67 798 and $47 264 in the US and Sweden, respectively). ? Results were most influenced by hazard ratios for progression‐free and overall survival and treatment costs, making results generalizable across other countries if relative costs were to fall within the ranges of those in the US and Sweden.

CONCLUSION

? The present analyses suggest that first‐line mRCC treatment with sunitinib is a cost‐effective alternative to sorafenib and bevacizumab plus IFN‐α.     

Pulmonary metastasectomy of renal cell carcinoma: Local experience

Objective: Up until now, the prognosis of a patient with disseminated renal cell carcinoma is poor with 5‐year survival less than 2%. In a small subset of patients with isolated pulmonary metastasis, long‐term survival after pulmonary metastasectomy has been reported to be acceptable. The purpose of the present study was to evaluate the result of pulmonary metastasectomy in a local cardiothoracic surgical centre. Methods: Patients who had renal cell carcinoma and pulmonary metastasectomy for isolated pulmonary metastasectomy were recruited for the study. Their survival was analysed. Results: Between 1992 and 2004, 13 patients underwent 15 operative procedures for pulmonary metastases from renal cell carcinoma. The median follow up was 39.8 months (from 4.6 to 127.5 months). The five‐year survival after pulmonary metastasectomy was 48.3% and median survival was 25.4 months. There was no postoperative mortality. Pulmonary recurrence was the commonest recurrent site after pulmonary metastasectomy. Conclusion: Pulmonary metastasectomy for renal cell carcinoma is a safe and effective procedure. And, as the lung is the commonest site of first recurrence after pulmonary metastasectomy, the present study on the control of these occult metastases is necessary.