C-reactive protein: a biomarker of survival in patients with metastatic renal cell carcinoma treated with subcutaneous interleukin-2 based immunotherapy

PURPOSE: In patients with metastatic renal cell carcinoma treated with low dose subcutaneous interleukin-2 based immunotherapy we evaluated a panel of biohumoral and clinical parameters before treatment to verify their correlation with clinical outcome. MATERIALS AND METHODS: We analyzed the records of 110 patients treated at our institution. Before treatment total lymphocytes, lactate dehydrogenase, the erythrocyte sedimentation rate, albumin, C-reactive protein (CRP) and fibrinogen were analyzed and correlated with clinical parameters, namely performance status, patient age, sex, prior nephrectomy, number and sites of disease, and disease-free interval (DFI) from nephrectomy to metastatic disease. RESULTS: Median survival was 12 months (partial and complete response 33, stable disease 14 and progression 7). The overall response was 24% for a partial and complete response, 37% for stable disease and 39% for progression. On univariate analysis good performance status (p = 0.0000), prior nephrectomy (p = 0.0001), DFI longer than 12 months (p = 0.0003), bone disease site (p = 0.0013), a low number of metastatic sites (p = 0.0449), normal albumin (p = 0.0001), low/normal fibrinogen (p = 0.0140), low/normal lactate dehydrogenase (p = 0.0430) and low/normal CRP (p = 0.0000) were related to better survival. On final multivariate analysis only CRP (p = 0.002) and DFI (p = 0.0497) were found to have an independent role in survival. When we correlated clinical and biohumoral factors, only CRP correlated with DFI (p = 0.021) and prior nephrectomy (p = 0.041). CONCLUSIONS: Our data confirm that some clinical and biohumoral factors may be strongly related to survival in metastatic renal cell carcinoma. The interesting new aspect emerging from this study is the prognostic value of CRP and fibrinogen, which are able to discriminate a good from a poor prognosis.     

肾透明细胞癌孤立转移瘤的手术治疗

目的探讨肾透明细胞癌转移瘤的手术治疗及预后。方法回顾性分析5例肾透明细胞癌转移瘤行手术治疗患者的临床资料。本组5例,男3例,女2例,发病年龄42～73岁。转移部位:肺转移3例(其中1例肺转移2次),骨转移1例,脑转移1例(该患者发生2次脑转移),局部复发1例,鼻腔转移1例(该患者发生4次鼻腔转移)。均手术切除患肾及转移瘤。结果随访7月～16年,3例存活大于15年,1例已存活超过1年,1例肾切除术后7月死亡。结论对肾透明细胞癌孤立的转移瘤和局部复发灶应积极手术切除,可以延长患者生存期和提高生活质量。     

肾细胞癌免疫治疗的研究进展

肾细胞癌通常有对经典放疗或化疗方法仅有轻微的反应和预后差的特点。免疫治疗是在已建立的传统的治疗模式基础上发展的替代治疗形式。事实上,以细胞因子为基础的治疗方法已被使用了许多年,在小部分患者中产生了良好的临床效应。在过去的几年中,免疫治疗以肾细胞癌的肿瘤相关抗原为试验靶点已被报道过,现综述以下几方面取得的研究进展,包括以细胞因子为基础的治疗,分子靶点、抗血管生成试剂治疗,RCC肿瘤相关性抗原和疫苗方案相关方面。     

Sunitinib efficacy against advanced renal cell carcinoma

PURPOSE: We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). RESULTS: Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months. CONCLUSIONS: The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation.     

Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis

PURPOSE: Metastatic renal cancer is associated with a poor prognosis. Recent advances in immunotherapy for this problem have rekindled interest in cytoreductive nephrectomy. We report a combined analysis of 2 prospective randomized trials that used an identical study protocol. MATERIALS AND METHODS: A total of 331 patients were randomized to 2 identical protocols comparing cytoreductive nephrectomy plus interferon alpha-2b vs interferon alpha-2b alone in patients with metastatic renal cancer, in whom the primary tumor was present and believed to be resectable. The primary end point for each trial was overall survival with a secondary end point of the response rate. Patients were stratified at pre-randomization by performance status (0 or 1), site of metastases (lung only vs other) and disease measurability. All results were analyzed by intent to treat criteria. Assuming a median survival of 1 year for interferon only, the Southwest Oncology Group trial was designed to detect a 50% improvement in median survival duration and a 15% improvement in response rate with a power of 0.85. The European Organization for the Research and Treatment of Cancer accrued an additional 80 patients in that study. RESULTS: The combined analysis of these 2 trials yielded a median survival of 13.6 months for nephrectomy plus interferon vs 7.8 months for interferon alone. This difference represents a 31% decrease in the risk of death (p = 0.002). There was no evidence of a difference in the size of the treatment effect according to pre-randomization stratification factors. CONCLUSIONS: Cytoreductive nephrectomy appears to improve significantly overall survival in patients with metastatic renal cancer treated with interferon immunotherapy independent of patient performance status, the site of metastases and the presence of measurable disease. Although it is highly statistically significant, the overall survival advantage is only 5.8 months for the entire group. These data emphasize the need to determine if this survival advantage can be further improved using more aggressive immunotherapy or other novel agents in the setting of cytoreductive nephrectomy.     

Response of papillary renal cell carcinoma in a solitary kidney to high dose interleukin therapy

Kidney cancer affects 36 000 Americans annually and is responsible for nearly 12 000 deaths every year in the US. Treatment with interleukin-2 (IL-2), the only FDA approved therapy for patients with advanced kidney cancer, is associated with a 10% complete response and a 12% partial response. To date, clear cell renal carcinoma has been the only histological type associated with response to IL-2-based therapy. In the current report, we describe a response to IL-2 therapy in a patient with type I papillary renal carcinoma.     

A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials

PURPOSE: We developed a clinically useful scoring algorithm to predict cancer specific survival for patients with clear cell metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: We studied 727 patients treated with radical nephrectomy for clear cell RCC from 1970 to 2000 who had distant metastases at nephrectomy (285) or in whom metastases subsequently developed (442). A scoring algorithm to predict cancer specific survival was developed using the regression coefficients from a Cox proportional hazards model. RESULTS: There were 606 deaths from clear cell RCC at a median of 1.0 years (range 0 to 14) following metastatic RCC. Constitutional symptoms at nephrectomy (+2), metastases to the bone (+2) or liver (+4), metastases in multiple simultaneous sites (+2), metastases at nephrectomy (+1) or within 2 years of nephrectomy (+3), complete resection of all metastatic sites (-5), tumor thrombus level I to IV (+3), and the primary pathological features of nuclear grade 4 (+3) and histological tumor necrosis (+2) were significantly associated with death from RCC. All patients started with a score of 0 and points were added or subtracted as indicated in parentheses. Cancer specific survival rates at 1 year were 85.1%, 72.1%, 58.8%, 39.0%, and 25.1%, respectively, for patients with scores of -5 to -1, scores of 0 to 2, scores of 3 to 6, scores of 7 or 8, and scores of 9 or more. CONCLUSIONS: This scoring algorithm can be used to predict cancer specific survival for patients with metastatic clear cell RCC.     

Dexamethasone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome

Interleukin-2 (IL-2) in combination with dexamethasone was administered to a 48-year-old man with renal cell carcinoma accompanied by paraneoplastic inflammatory syndrome, including progressive multiple lung metastases and inferior vena caval tumor thrombus. Although non-steroidal anti-inflammatory drugs had no apparent antipyretic effect on the systemic inflammatory syndrome, oral administration of dexamethasone achieved complete antipyresis and improved his quality of life. After a 4-week period of IL-2 treatment, regression of metastasized lesions was demonstrated despite concurrent oral administration of dexamethasone. Steroids might reduce the action of immunotherapeutic drugs, but in some cases, combination therapy can achieve both alleviation of the paraneoplastic syndrome and tumor shrinkage.     

Cytoreductive nephrectomy for metastatic renal cell carcinoma with nonclear cell histology

PURPOSE: To our knowledge the benefit of cytoreductive surgery for patients with metastatic renal cell carcinoma with nonclear cell histology is unknown. In this retrospective study we report our experience with cytoreductive nephrectomy for nonclear cell metastatic renal cell carcinoma at M. D. Anderson Cancer Center. We compared the outcomes with those in patients with clear cell metastatic renal cell carcinoma. MATERIALS AND METHODS: From 1991 to 2006, 606 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy and they formed the basis of this report. Of these patients 92 had nonclear cell metastatic renal cell carcinoma. The remaining 514 patients had clear cell metastatic renal cell carcinoma and they formed a comparative group. Multivariate Cox regression analysis was performed to evaluate the relationship between clinical variables and histology (clear cell vs nonclear cell) on disease specific survival. RESULTS: Compared with patients with clear cell histology those with nonclear cell metastatic renal cell carcinoma were younger (p = 0.0001), and more likely to have nodal metastases (p <0.0001) and sarcomatoid features (23% vs 13%, p = 0.026). On multivariate analysis median disease specific survival in patients with nonclear cell histology was significantly worse than that in patients with clear cell metastatic renal cell carcinoma (9.7 vs 20.3 months, p = 0.0003) even after adjusting for T stage, grade, performance status, age and sarcomatoid features. Sarcomatoid features were a predictor of poor outcome in cases of clear and nonclear cell histology, although even in the absence of sarcomatoid features nonclear cell histology was associated with worse disease specific survival (p = 0.017). Interestingly although there was a significantly higher incidence of positive nodes in patients with nonclear histology (p <0.0001), this phenotype was not associated with a worse disease specific survival, as it was in those with clear cell histology (p = 0.0001). In fact, patients with node negative disease with nonclear cell histology had the worst prognosis overall in the entire group. CONCLUSIONS: Patients with nonclear cell metastatic renal cell carcinoma were younger and had a higher incidence of nodal metastases, a higher incidence of sarcomatoid features and a worse prognosis than those with clear cell histology who underwent cytoreductive surgery.     

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.     

Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy

PURPOSE: We compared outcomes between patients treated with nephron sparing surgery (NSS) without imperative indications for renal preservation and radical nephrectomy (RN) for 4 to 7 cm renal cell carcinoma (RCC). MATERIALS AND METHODS: We identified 91 patients treated with NSS and 841 patients treated with RN for 4 to 7 cm RCC between 1970 and 2000. Cancer specific, distant metastases-free and recurrence-free survivals were estimated using the Kaplan-Meier method. RESULTS: Cancer specific survival rates at 5 years for patients treated with NSS and RN for 4 to 7 cm RCC were 98% and 86%, respectively. On univariate analysis patients treated with RN for 4 to 7 cm RCC were more likely to die of RCC compared to patients treated with NSS. However, after adjusting for features associated with death from RCC including stage, grade, histological tumor necrosis and histological subtype, this difference was no longer statistically significant (risk ratio 1.60, 95% CI 0.50-5.12, p = 0.430). Distant metastases-free survival rates at 5 years for patients treated with NSS and RN were 94% and 83%, respectively. On univariate analysis patients treated with RN were more likely to have tumors that metastasized compared to patients treated with NSS, although this difference was no longer significant after adjusting for the features listed previously (risk ratio 1.76, 95% CI 0.64-4.83, p = 0.273). Recurrence-free survival rates at 5 years for patients treated with NSS and RN were 94% and 98%, respectively. On univariate analysis patients treated with RN were less likely to have recurrence compared to patients treated with NSS (risk ratio 0.32, 95% CI 0.12-0.85, p = 0.022). CONCLUSIONS: There were no statistically significant differences in cancer specific survival and distant metastases-free survival between patients treated with NSS and RN for 4 to 7 cm RCC after adjusting for important pathological features. NSS for 4 to 7 cm RCC results in excellent outcome in appropriately selected patients.     

舒尼替尼在晚期肾细胞癌治疗中的运用

目的：探讨苹果酸舒尼替尼对晚期肾细胞癌治疗的安全性和有效性。方法：晚期肾细胞癌患者22例,男18例,女4例,平均年龄56岁,均为转移性或难以手术的肾细胞癌患者。采用舒尼替尼治疗,其中18例为一线治疗,4例为二线治疗。均为单一服药,口服50mg／d,每4周停药2周者16例;口服37．5mg／d,连续服药者6例。持续用药至肿瘤进展或出现不可耐受的并发症。以6周为1个治疗周期,至少每2个治疗周期进行疗效评价。结果：1例患者服药不足2周期内死亡,可评价病例21例。部分缓解6例（28．6％）,疾病稳定13例（61．9％）,疾病进展2例（9．5％）,无完全缓解病例。常见的不良反应包括手足皮肤反应、皮疹、疲劳乏力、骨髓抑制、味觉变化等。结论：舒尼替尼治疗晚期肾癌患者效果确切,不良反应多数可控制,但对于KPS评分较低,一般情况差,肿瘤负荷大的患者,运用时需慎重。     

Primary apoptosis as a prognostic index for the classification of metastatic renal cell carcinoma

PURPOSE: We identified novel biological markers of prognosis in primary histopathological specimens from patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: Apoptotic indexes (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling), proliferation rates (Ki-67 antigen), p21 (WAF1/cip1) expression and CD95 (APO-1/Fas) expression were determined in paraffin embedded nephrectomy specimens from 73 patients with histologically confirmed, progressive metastatic disease. Kaplan-Meier survival analysis, log rank statistics and 2-proportional Cox regression analysis were done to identify new risk factors in addition to conventional classification criteria, and demonstrate statistical independence. RESULTS: Multivariate analysis indicated that primary tumor apoptosis (p = 0.0116) and the interval from diagnosis to metastatic disease (p = 0.002) had a high predictive impact on overall survival after initial diagnosis. Patients were assigned to 2 risk groups, namely a poor prognosis group with a median survival of 20 months, defined by apoptosis less than 6% in the primary tumor nephrectomy specimen and a time from initial diagnosis to metastatic disease of less than 6 months, and a good prognosis group with a median survival of 56 months, defined as the absence of 1 or 2 risk factors. CONCLUSIONS: Our findings showed that primary tumor apoptosis is a novel independent predictor in patients with metastatic renal cell carcinoma at initial diagnosis. It leads to a new prognostic index in the pretreatment classification of metastatic renal cell carcinoma.     

Hypercalcemia in a patient with renal cell carcinoma producing parathyroid hormone-related protein and interleukin-6

A patient with renal cell carcinoma who developed humoral hypercalcemia of malignancy is reported. A 52-year-old male patient was diagnosed with renal cell carcinoma and multiple lung metastases. A cell line isolated from the surgical specimen exhibited continuous production of parathyroid hormone-related protein (PTHrP) in vitro. The production of PTHrP from the cancer cells was confirmed by RT-PCR and immunoradiometric assay. The serum calcium level was not enhanced, whereas the lung lesion was developing and producing interleukin-6, a possible modulator of osteoclastic resorption. Hypercalcemia was induced when the PTHrP concentration increased up to 3.3 pmol/L.