Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25–30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.     

Combined cytoreductive laser therapy and immunotherapy for palliation of metastatic renal cell carcinoma to the head and neck

Interleukin-2 (IL-2) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC), but minimally invasive surgical techniques have provided new options for the combined treatment of RCC. Two patients with metastatic RCC to the head and neck treated by combined laser-induced thermal therapy and IL-2 were described in this case report. Both patients had an extended survival compared to the historical survival of 10 months for metastatic RCC but eventually succumbed to progressive disease. The authors’ initial experience with metastatic RCC suggests that laser thermoablation and immunotherapy in selected patients with metastatic RCC is warranted as a palliative treatment, but a larger study with long-term follow-up is necessary to determine the effectiveness of this approach.     

Emerging immunotherapy in advanced renal cell carcinoma

Immunotherapy has recently catapulted to the forefront of treatments for patients with solid tumors. Given its inherent immunogenic properties, renal cell carcinoma (RCC) has historically responded to immunotherapy and remains primed for further development. Although immunotherapy with high-dose interleukin 2 was a primary treatment for advanced RCC (aRCC), recent discoveries of key molecular and immunological alterations have led to the FDA-approval of nivolumab, an antiprogrammed cell death inhibitor, which has demonstrated an overall survival in patients with previously treated aRCC. However, despite recent therapeutic advances, aRCC remains an incurable disease for most patients. In this review, we assess the current landscape and future developments of immunotherapy in aRCC.     

Immunotherapy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma has a poor prognosis. Conventional therapies such as chemotherapy, radiation or hormonal treatment have hardly any effect on the progression of this disease. As renal cell carcinoma seems to be an immunogenic tumor, several immunotherapeutic approaches with different response rates have been developed since the early 1990s. We present an overview of various immunotherapeutic approaches such as cytokine-based regimes, with and without different cytotoxic chemotherapy, of metastatic renal cell carcinoma. In addition, local therapies (e.g. inhalation of interleukin-2) are reviewed.K. Rohrmann and M. Staehler contributed equally to the project and are to be considered as co-first authors     

The role of initial immunotherapy as selection for nephrectomy in patients with metastatic renal cell carcinoma and the primary tumor in situ

OBJECTIVE: A prospective pilot study in patients with metastatic renal cell cancer and the primary in situ to assess the feasibility of immunotherapy prior to nephrectomy and to evaluate the rationale for a future randomized trial to define the role of response to upfront immunotherapy as selection for cytoreductive surgery. PATIENTS AND METHODS: Sixteen patients with synchronous multiple metastases were treated with the primary tumor in place and were evaluated with regard to age, sex, sites of extrarenal disease, morbidity, response, nephrectomy rate, time to progression and overall survival. Immunotherapy consisted of 2 courses low-dose IL-2 4MIU/m(2), subcutaneous GM-CSF 2.5 microg/kg and interferon-alpha (IFN-alpha) 5MU flat on day 1-13 and 22-34. Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by a third and fourth course. RESULTS: No response was seen in the primary tumors. With regard to extrarenal sites SD was noted in nine cases, PR in two and progressive disease (PD) in five. Eleven patients underwent nephrectomy. No surgical complete response (CR) could be achieved. All patients with PD died after a median overall survival of 3 months versus 11.5 months (range 4-22) in those who underwent nephrectomy. Four patients are still alive at 10, 12, 18 and 19 months. Median duration of response was 6 months (range 2-10). One patient with SD following nephrectomy developed CR after two additional cycles, which is currently maintained for >10 months. CONCLUSIONS: Absence of progression at metastatic sites following immunotherapy may be used as a selection for nephrectomy in this selected group. Non-responding patients can be spared from surgery. A randomized study is needed to assess the timing of nephrectomy in combination with immunotherapy with regard to morbidity, overall survival and quality of life.     

Rationale for immunotherapy of renal cell carcinoma

Summary Metastasis to distant organs is the principal cause of death from renal cell carcinoma (RCC). No commonly accepted therapy is available for disseminated RCC at present. Immunotherapy is a mode of therapy that either interferes with the immune system or makes use of drugs that have been derived from soluble mediators of the immune system. Several lines of evidence suggest that combinations of genetically engineered cytokines (e.g. interleukin-2 and interferon alpha) may be particularly active in the treatment of advanced RCC. There are two major rationales for considering immunotherapy for RCC: (1) there is currently no other therapy available, and (2) there is hardly any innovative approach besides immunotherapy. Still, immunotherapy is far from being a standard therapy for disseminated RCC.     

The use of prognostic factors in metastatic renal cell carcinoma

BackgroundOver the last decade, the treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved tremendously. The outcome of patients with mRCC has been improved since the advent of targeted therapy.ObjectiveIn this review, we address the use of prognostic schema in the era of targeted treatment. This article summarizes the current available prognostic models and the evidence to support their use in clinical settings.ConclusionPrognostic models can help guide clinicians in their decision making, as they have been validated in the first- and second-line targeted therapy settings as well as in non–clear cell mRCC. Prognostic factors are important in patient counseling, clinical trial stratification, and therapy planning. Very selected favorable-risk patients with minimal bulk and slow-growing disease could potentially be observed before needing treatment. Patients with poor-risk disease may be eligible for treatment with temsirolimus. Patients with a very poor prognosis may not be suitable candidates for cytoreductive nephrectomy. New biomarkers are on the horizon, though their roles need to be validated and their additive contribution to improve existing prognostic models examined.     

Integration of surgery and systemic therapy for renal cell carcinoma

Proper integration of surgery and systemic therapy is essential for improving outcomes in renal cell carcinoma (RCC). There is no current role for adjuvant therapy after nephrectomy for clinically localized disease. The potential benefits of neoadjuvant therapy for locally advanced nonmetastatic disease are in need of further study. In metastatic disease, the proper integration of cytoreductive surgery and systemic therapy remains to be elucidated. Presurgical targeted therapy is feasible and may be beneficial. Pending the results of randomized controlled trials, upfront cytoreductive nephrectomy in appropriate patients will likely continue as the paradigm of choice in metastatic RCC.     

Patterns of enlarged lymph nodes in patients with metastatic renal cell carcinoma

Objective

We reviewed the imaging studies of patients with known metastatic renal cell carcinoma (RCC) in order to more accurately assess where retroperitoneal lymphadenopathy occurs.

Methods

The database of patients with metastatic RCC was reviewed and 101 patients were found from 2002 to 2006. Each patient's CT scans were then reviewed. Twenty-seven retroperitoneal sections were defined for each patient, with 3 positions in each of the x-, y-, and z-axis. Lymph nodes greater than 1 cm were then counted for each section.

Results

Of the 101 patients, 31, of whom 28 qualified, were found to have retroperitoneal lymphadenopathy of a least 1 cm or greater. Two-thirds of nodes (87 out of 124) exhibited a suprahilar, intra-aortocaval, and retro-aortocaval trend of lymph node enlargement. Three patients (11%) had isolated infrahilar nodes, while 8 patients (29%) exhibited a skip lesion pattern by imaging criteria. Only 4 patients (14%) were noted to have lymph nodes that were confined to the ipsilateral (paraaortic or paracaval) nodes in the perihilar and infrahilar region, which would be readily accessible during renal surgery.

Conclusions

Lymphatic drainage in RCC is ill-defined, likely due to multiple lymphatic outflow channels. However, after a review of retroperitoneal lymphadenopathy imaging in patients with known metastatic RCC, there does seem to be a cephalad, posterior, and medial drainage pattern.     

肾癌患者治疗方法的选择

目的:探讨肾细胞癌的不同手术方式、术前肾动脉栓塞及免疫治疗的临床应用价值。方法:回顾性分析179例肾细胞癌患者的临床资料。对患者的临床资料分组进行对比,并对治疗效果和随访结果作进一步统计学分析。结果:小肾癌行肾癌根治术与保留肾组织手术效果比较,在手术时间、术后住院时间、术后5年生存率上差异均无统计学意义(P>0.05);78例术前行选择性肾动脉栓塞者,手术证实栓塞效果满意。结论:保肾单位手术是治疗局限性小肾癌的有效手段;较大的肾癌术前进行肾动脉栓塞术便于手术切除病灶,提高了肿瘤的切除率;免疫治疗是继手术治疗之后的又一种主要临床治疗方式,尤其肿瘤疫苗的出现,对于晚期肾癌及转移癌效果明显。     

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.     

Interferon alpha 2b as medical selection for nephrectomy in patients with synchronous metastatic renal cell carcinoma: a consecutive study

OBJECTIVE: Up to 25% of the patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nephrectomy and interferon alpha-2b (IFN-alpha) will progress rapidly at metastatic sites and undergo needless surgery for an asymptomatic primary. We reversed the timing of surgery and immunotherapy and evaluated the role of initial IFN-alpha as selection for nephrectomy. PATIENTS AND METHODS: Sixteen patients with mRCC and the primary in-situ received initial IFN-alpha for 8 weeks (2 weeks 5x3x10(6)IU/wk; 2 weeks 5x6x10(6)IU/wk; 2 weeks 5x9x10(6)IU/wk and 2 weeks 3x9x10(6)IU/wk). Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by IFN-alpha maintenance at 3x9x10(6)IU/wk. Patients were evaluated with regard to age, sex, metastatic sites, morbidity, response, nephrectomy rate, time to progression and survival. RESULTS: Thirteen patients received 2 months of preoperative IFN-alpha; 3 stopped during the 2 months period due to progressive disease (PD). Eight patients developed either a PR (n=3) or SD (n=5) at metastatic sites and underwent nephrectomy. Survival at 1 year is 50% (4/8 patients). Median progression-free survival was 6 months (3-17 months).Two of the 3 patients with PR developed a CR after 2 months maintenance following surgery. Eight patients with PD did not undergo surgery and had a median survival of 4 months (range 1-8 months). CONCLUSIONS: Absence of progression at metastatic sites following IFN-alpha with the primary tumor in place may be used as selection for nephrectomy in patients with an intermediate prognosis. Currently, a randomized study is underway to assess the role of initial versus delayed nephrectomy in combination with IFN-alpha with regard to morbidity and survival.     

Circulating immune markers in advanced renal cell carcinoma during immunotherapy with interferon gamma

Circulating immune markers sICAM-1, sELAM-1, sMHC-I, ₂-MG, sCD4 and sCD8 were evaluated prior to and during immunotherapy with biologically active doses of interferon gamma (IFN-) in 16 patients with advanced renal cell carcinoma (RCC) over a period of 12 months. Compared to 20 healthy controls, significantly (P < 0.01) elevated baseline levels of circulating adhesion molecules sICAM-1 (mean 1166 vs 230 ng/ml) and sELAM-1 (70 vs 17 ng/ml) were found in all patients. Compared to responders (n = 2) or patients with stable disease (n = 2), progressive disease during therapy (n = 12) was associa ed with significantly (P < 0.05) higher mean concentrations of sICAM-1 (1574 vs 962 ng/ml) and sELAM-1 (86 vs 46 ng/ml). Pretherapeutic and intratherapeutic levels of sMHC-I among the RCC patients were significantly (P < 0.05) lower than among the controls (0.41 vs 0.8 ng/ml). sCD4 levels clearly showed the same tendency (24 vs 33 U/l). sCD8 baseline levels, by contrast, were significantly (P < 0.05) elevated (564 vs 336 U/l), reflecting either activation of the NK-cell subset or increased synthesis of CD8 + T-suppressor cells. Again, significantly (P < 0.05) higher intratherapeutic sCD8 concentrations were observable with progressive disease than with response to therapy or stable disease (721 vs 355 U/l). Interestingly, although the biologically active dose of IFN- was defined by an increase in ₂-MG release of at least 30% within 48 h after injection, none of the other markers showed any significant alteration following IFN- administration, suggesting that IFN- in vivo does not produce changes in circulating markers of activation that might be expected on the basis of its effects in vitro. The finding of significantly elevated concentrations of sICAM-1, sELAM-1 and sCD8 in the presence of low sCD4 and sMHC-I levels might be of clinical significance for indicating ongoing tumor progression.     

Tumor type M2 pyruvate kinase expression in metastatic renal cell carcinoma

The M2 isoenzyme of pyruvate kinase (M2-PK) is specifically expressed in tumor cells (TuM2-PK) and has been detected in the peripheral blood of patients with renal cell carcinoma (RCC). TuM2-PK is not useful as a biological marker in localized RCC. We analysed TuM2-PK in 68 patients with metastatic RCC after initial surgery and prior to or during chemoimmunotherapy of metastases. In 50 patients, the levels of TuM2-PK were measured during chemoimmunotherapy with interleukin-2, interferon-2a and 5-fluorouracil for up to 8 months and were correlated to response as assessed by radiological imaging techniques. TuM2-PK was quantified with a commercially available enzyme linked immunosorbent assay kit using a cut off of 15 kU/l. In 48 of 68 patients (71%), TuM2-PK was elevated above the cut-off. TuM2-PK was significantly higher in G3 tumors than in G2 tumors. In 34 of 50 patients (68%) undergoing chemoimmunotherapy, a positive correlation between TuM2-PK values and response to treatment was observed. Based on these data, we would not recommend the routine clinical use of TuM2-PK in metastatic RCC at this point.     

Contemporary trends in high-dose interleukin-2 use for metastatic renal cell carcinoma in the United States

BackgroundTargeted therapies (TTs) have revolutionized metastatic renal cell carcinoma (mRCC) treatment in the past decade, largely replacing immunotherapy including high-dose interleukin-2 (HD IL-2) therapy. We evaluated trends in HD IL-2 use for mRCC in the TT era.MethodsOur cohort comprised a weighted estimate of all patients undergoing HD IL-2 treatment for mRCC from 2004 to 2012 using the Premier Hospital Database. We assessed temporal trends in HD IL-2 use including patient, disease, and hospital characteristics stratified by era (pre-TT uptake: 2004–2006, uptake: 2007–2009, and post-TT uptake: 2010–2012) and fitted multivariable regression models to identify predictors of treatment toxicity and tolerability.ResultsAn estimated 2,351 patients received HD IL-2 therapy for mRCC in the United States from 2004 to 2012. The use decreased from 2004 to 2008. HD IL-2 therapy became increasingly centralized in teaching hospitals (24% of treatments in 2004 and 89.5% in 2012). Most patients who received HD IL-2 therapy were men, white, younger than 60 years, had lung metastases, and were otherwise healthy. Vasopressors, intensive care unit admission, and hemodialysis were necessary in 53.4%, 33.0%, and 7.1%, respectively. Factors associated with toxicities in multivariable analyses included being unmarried, male sex, and multiple metastatic sites. African Americans and patients with single-site metastases were less likely to receive multiple treatment cycles.ConclusionsHD IL-2 therapy is used infrequently for mRCC in the United States, and its application has diminished with the uptake of TT. Patients are being increasingly treated in teaching hospitals, suggesting a centralization of care and possible barriers to access. A recent slight increase in HD IL-2 therapy use likely reflects recognition of the inability of TT to effect a complete response.     

Overall survival in patients with metastatic renal cell carcinoma and clinical N1 disease undergoing cytoreductive nephrectomy and lymph node dissection

Background

Patients with metastatic renal cell carcinoma (mRCC) have limited treatment options. Cytoreductive nephrectomy (CN) in select patients has been associated with improved survival. We aim to assess the survival in patients with mRCC and cN1 disease who underwent CN with and without lymph node dissection (LND).

Primary tumor response to targeted agents in patients with metastatic renal cell carcinoma

Background

The recent development of multiple targeted agents for metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the benefit and optimal timing of cytoreductive nephrectomy is being reevaluated.

Objective

To determine primary tumor response to treatment with targeted agents in patients with mRCC.

Design, setting, and participants

We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between November 2004 and December 2009 without prior systemic treatment who received targeted therapy with their primary tumor in situ.

Measurements

Two independent reviewers measured the diameter of primary and metastatic tumors at baseline and subsequent scans, using Response Evaluation Criteria Solid Tumors (RECIST) v.1.1 to assess disease response.

Results and limitations

We identified 168 consecutive patients with a median 15 mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median maximum primary tumor response was −7.1% (interquartile range: −14.0 to −0.1).A total of 61 patients had multiple studies available for evaluation. In 43 patients with <10% decrease in primary tumor within in the first 60 d, median maximum response was −7.2% at 154 d versus −24.5% maximum response at 174.5 d for 18 patients with ≥10% decrease in primary tumor during the initial 60 d.

Conclusions

Decrease in primary tumor diameter >30% while on targeted therapy for mRCC is rare, with most patients demonstrating minimal or no decrease in primary tumor diameter. Early response predicts a better overall primary tumor response.     

Long-term renal functional outcomes of minimally invasive partial nephrectomy for renal cell carcinoma

ObjectivePreservation of renal function is the major benefit of partial over radical nephrectomy. We evaluated patients undergoing minimally invasive partial nephrectomy (MIPN) to better understand factors predicting long-term renal function.MethodsWe identified 358 patients who underwent MIPN for confirmed renal cell carcinoma between 1998 and 2011 with a serum creatinine level at least 1 year postoperatively. Exposure variables included demographic, clinical, and perioperative information. The primary outcome was clinically significant progression of chronic kidney disease (CKD) class, defined as estimated glomerular filtration rate (eGFR) decreasing from >60 to<60, from 30 to 60 to <30, or from 15 to 30 to<15. Bivariate and multivariate analyses were performed.ResultsMedian follow-up was 39 months. Only 7 patients had a solitary kidney. A total of 47 patients (13%) had CKD class progression. The estimates for remaining free of CKD class progression at 5, 7, and 10 years were 86.98%, 75.45%, and 53.54%, respectively. On multivariate analysis, lower preoperative eGFR (odds ratio [OR] = 0.97, 95% CI: 0.96–0.98), larger tumor size (OR = 1.22, 95% CI: 1.01–1.48), and longer ischemia time (OR = 1.03, 95% CI: 1.01–1.05) were associated with CKD class progression.ConclusionsClinically significant progression of CKD occurs in a minority of patients 5 years after MIPN, but in almost one-half, it occurs 10 years after surgery. Lower preoperative eGFR and larger tumor size are associated with greater incidence of CKD progression. Longer ischemia time, even when most patients had 2 kidneys and when controlling for other factors, nonetheless increased the risk of CKD progression, although this may be a marker of other unmeasured variables.     

Regional immunotherapy of metastatic renal cell carcinoma

We summarized the current literature concerning regional immunotherapy of pulmonary metastases in metastatic renal cell carcinoma and other malignancies using inhaled interleukin-2 (IL-2). Inhaled IL-2 therapy is associated with minimal toxicity and is effective in preventing progression in metastatic renal cell carcinoma, melanoma, and possibly other diseases such as breast cancer. Local (physiologic) use and systemic (pharmacologic) use of IL-2 are not mutually exclusive; a combination may be very appropriate in metastatic cancer. Local physiologic therapy intensifies treatment without intensifying toxicity.     

Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma

Background

Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined.

Objective

To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective.

Design, setting, and participants

One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib–everolimus or temsirolimus–sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment.

Measurements

PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS).

Results and limitations

Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3–6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6–10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data.

Conclusions

Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.