Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery

BACKGROUND

Brain metastases are a frequent complication in patients with metastatic clear cell renal cancer. Survival after whole‐brain radiotherapy (WBRT) is disappointing. A retrospective analysis of multimodality treatment was performed in patients who had received linear accelerator (LINAC)‐based stereotactic radiosurgery (SRS).

METHODS

Thirty‐two patients underwent SRS‐based treatment for 71 metastatic foci between 2000 and 2006. All patients had a Karnofsky performance status ≥70 and all 32 patients had extracranial metastatic disease (Radiation Therapy Oncology Group recursive partitioning analysis [RPA] Class 2). Survival was calculated from the time of diagnosis of brain metastases. The minimum potential follow‐up was 1 year after SRS. Univariate and multivariate analysis of potential prognostic factors affecting survival was performed.

RESULTS

Twenty‐six patients required only 1 SRS treatment (84%) to achieve central nervous system (CNS) control, whereas 5 patients received 2 to 3 treatments (16%). The median survival of renal cancer patients from the diagnosis of brain metastases was 10.1 months (95% confidence interval, 6.4‐14.8 months). One‐year and 3‐year survival rates were 43% and 16%, respectively. The addition of surgery or WBRT did not appear to prolong survival. Immunotherapy after control of brain metastases with SRS appeared to result in significantly improved survival. Survival was also found to be strongly influenced by prognostic stratification of metastatic disease using Motzer or modified risk criteria.

CONCLUSIONS

The results of the current study demonstrated that SRS‐based treatment of patients with up to 5 brain metastases from clear cell renal cancer is feasible and results in excellent CNS control. Survival beyond 3 years from the time of diagnosis of brain metastases was achievable in 16% of patients and was associated with the use of systemic immunotherapy with interleukin‐2 and interferon but not antiangiogenic agents. Cancer 2008. © 2008 American Cancer Society.     

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.     

Adjuvant therapy for advanced renal cell carcinoma

Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear.

Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors.

Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.     

抗血管生成联合免疫检查点抑制剂治疗晚期肾癌的理论基础及研究进展

近年来,抗血管生成联合免疫检查点抑制剂治疗恶性肿瘤已经成为研究热点。这些研究的理论基础是免疫系统与血管生成系统相互作用可以增加抗肿瘤活性。例如:美国食品和药物管理局(Food and Drug Administration,FAD)批准阿维单抗联合阿昔替尼用于晚期肾癌一线治疗。尽管抗血管生成联合免疫检查点抑制剂在晚期肾癌治疗方面取得了不错成果,但同时也加重了与治疗相关的不良反应。虽然大多数患者在免疫检查点抑制剂治疗间歇期出现了与免疫治疗相关的不良反应,但研究发现联合治疗并未加重与免疫治疗相关的不良反应,而是与抗血管生成药的毒性反应有关。因此,本文旨在总结抗血管生成联合免疫检查点抑制剂治疗晚期肾癌的理论基础与研究进展进行如下综述。     

Sunitinib in metastatic renal cell carcinoma patients with brain metastases

BACKGROUND:

In a broad patient population with metastatic renal cell carcinoma (RCC), enrolled in an open‐label, expanded access program (EAP), the safety profile of sunitinib was manageable, and efficacy results were encouraging. Here, the authors report results for patients with baseline brain metastases participating in this global EAP.

METHODS:

Previously treated and treatment‐naive metastatic RCC patients ≥18 years received sunitinib 50 mg orally, once daily, on Schedule 4/2. Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention‐to‐treat (ITT) population, consisting of all patients who received ≥1 dose of sunitinib.

RESULTS:

As of December 2007, 4564 patients had enrolled in 52 countries. Of these enrollees, 4371 were included in the modified ITT population, of whom 321 (7%) had baseline brain metastases and had received a median of 3 treatment cycles (range 1‐25). Reasons for their discontinuation included lack of efficacy (32%) and adverse events (8%). The most common grade 3‐4 treatment‐related adverse events were fatigue and asthenia (both 7%), thrombocytopenia (6%), and neutropenia (5%), the incidence of which were comparable to that for the overall EAP population. Of 213 evaluable patients, 26 (12%) had an objective response. Median progression‐free survival and overall survival were 5.6 months (95% CI, 5.2‐6.1) and 9.2 months (95% CI, 7.8‐10.9), respectively.

CONCLUSIONS:

In patients with brain metastases from RCC, the safety profile of sunitinib was comparable to that in the general metastatic RCC population, and sunitinib showed evidence of antitumor activity. Cancer 2011. © 2010 American Cancer Society.     

Management of brain metastases from ovarian and endometrial carcinoma with stereotactic radiosurgery

BACKGROUND

Metastases to the brain from ovarian and endometrial carcinoma are uncommon and to the authors' knowledge consensus regarding optimal management is lacking. Stereotactic radiosurgery (SRS) has proven useful for the treatment of many benign and malignant brain tumors. In the current study, the authors evaluated outcomes after SRS in patients with ovarian and endometrial carcinoma.

METHODS

Twenty‐seven patients with brain metastases underwent gamma–knife SRS. Six patients had endometrial carcinoma, whereas 21 patients had ovarian carcinoma. Eighteen patients also received whole–brain radiotherapy. A total of 68 tumors were treated with gamma–knife SRS.

RESULTS

At the time of last follow–up, 1 patient was still alive and 26 had died. The median survival was 7 months after the initial diagnosis of brain metastasis and 5 months after SRS. The 1‐year survival rate after radiosurgery was 15% and that from the diagnosis of brain metastases was 22%. On final imaging, all tumors were controlled without further growth. Two patients (7.4%) developed new or progressive neurologic deficits after SRS.

CONCLUSIONS

SRS is an acceptable choice for the treatment of brain metastases resulting from ovarian and endometrial carcinoma, and provides local tumor control with limited morbidity. Careful patient selection is warranted in the setting of patients with uncontrolled systemic disease in whom a limited survival benefit is expected. Cancer 2008. © 2008 American Cancer Society.     

Impact of tyrosine kinase inhibitors on the incidence of brain metastasis in metastatic renal cell carcinoma

BACKGROUND:

This study was designed to evaluate the impact of tyrosine kinase inhibitors (TKIs) on incidence of brain metastasis (brain metastasis) and overall survival (OS) in patients with metastatic renal cell cancer (mRCC).

METHODS:

All patients who presented with mRCC but no brain metastasis in the intervals 2002 to 2003 and 2006 to 2007 were identified using the institutional tumor registry. The following data were collected: age, sex, Fuhrman grade, disease sites, nephrectomy, systemic therapy including TKIs (sorafenib or sunitinib), Memorial Sloan‐Kettering Cancer Center risk category, brain metastasis treatment, and vital status. Statistical analysis was performed using the Cox proportional hazards model and the Kaplan‐Meier method.

RESULTS:

Of the 338 patients who were identified; 154 (46%) were treated with a TKI before brain metastasis, and 184 (54%) were not. There were no significant differences in age, histology, nephrectomy, involved sites of disease other than lung, or Memorial Sloan‐Kettering Cancer Center risk category between the groups. Median OS was longer in the TKI‐treated group (25 months vs 12.1 months, P < .0001). In multivariate analysis, TKI treatment (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.38‐0.74; P < .001) was associated with improved OS. Forty‐four (13%) patients developed a brain metastasis, including 29 (15.8%) of the non‐TKI group and 15 (9.7%) of the TKI group. The 5‐year actuarial rate of brain metastasis was 40% versus 17%, respectively (P < .001). TKI treatment was associated with lower incidence of brain metastasis in Cox multivariate analysis (HR, 0.39; 95% CI, 0.21‐0.73; P = .003). Lung metastasis increased the risk of brain metastasis (HR, 9.61; 95% CI, 2.97‐31.1; P < .001).

CONCLUSIONS:

Treatment with TKI agents reduces the incidence of brain metastasis in mRCC. Lung metastasis is a risk factor for brain metastasis development. Cancer 2011;. © 2011 American Cancer Society.     

Stereotactic irradiation using a linear accelerator for brain metastasis from renal cell carcinoma

Background The role of stereotactic irradiation using a linear accelerator for brain metastasis from renal cell carcinoma was investigated. Methods Fifteen brain metastases in 11 patients with a history of renal cell carcinoma were treated using convergent narrow x-ray beams from a linear accelerator and rigid fixation of the head with a stereotactic frame. Twelve metastatic tumors in8 patients were irradiated with 25 Gy at the center in a single fraction, and single tumors in 3 patients received the following doses: 25 Gy in 5 fractions, 28 Gy in 3 fractions, or 35 Gy in 4 fractions Results The actuarial local control rate at 12 months was 90.6%. Twelve (92%) of 13 lesions that produced neurologic symptoms before stereotactic irradiation showed an improvement of symptoms. No complication related to the irradiation was observed. The median survival time was 6 months. Conclusion Stereotactic irradiation is more effective in achieving local control than is conventional radiotherapy, and achieves improvement in symptoms and survival rates similar to those of surgical resection of the brain metastasis from renal cell carcinoma. Urologists and oncologists should be aware of the usefulness of stereotactic radiation in the management of patients with renal cell carcinoma.     

Stereotactic radiosurgery for brain metastases: Comparison of lung carcinoma vs. non-lung tumors

In the medical literature, stereotactic radiosurgery (SRS) for brain metastases results in rates of local control of 65 to 85%. To define patient selection criteria, we measured the survival in a population with a high proportion of non-small cell lung carcinoma (NCS lung) metastases that occurred soon after primary diagnosis. Between 9/89 and 10/93 30 adults (21 M, 9 F) had SRS for metastatic NSC lung carcinoma (14 patients) vs. non-lung carcinomas (16 patients having breast (3), renal (3), melanoma (3), GI (2, thyroid (1) or carcinoma of unknown origin (4)). The metastases were solitary for 22 patients and multiple for 8 patients. Average ages (y) (± SD) were 58.6 ± 10.4 for NSC lung patients and 53.4 ± 12.5 (p=0.32) for non-lung patients. The average interval (months) from diagnosis of the primary to metastasis was 23.8 ± 41.4 for all patients. This interval was shorter for NSC lung patients: 3.1 ± 6.0 vs. 48.0 ± 51.7 (p < 0.001) for non-lung patients. Twenty seven patients had conventional radiotherapy (XRT) before (24 patients) or after (3 patients) SRS. Doses (cGy) were 3303 ± 841 for 13 NSC lung patients and 4256 ± 992 for 14 non-lung patients (p = 0.034). The median time from primary diagnosis to SRS was shorter for the NSC lung patients (11 mo) compared to the non-lung patients (35 mo). SRS was given for recurrence of metastases after XRT for 11/14 NSC lung patients and 13/16 non-lung patients. The doses (cGy) of SRS were 1579 ± 484 vs. 1682 ± 476 (p=0.45) for the NSC lung and non-lung groups, respectively. After SRS a decrease in metastasis diameter was observed in 10 of 14 NSC lung patients vs. 12 of 16 non-lung patients (p=0.85 Chi-square). Twenty-seven of the 30 patients have died. For all patients, the median survival after diagnosis of the primary and after radiosurgery was 31.3 and 8.4 months, respectively. The median survival (95% CI) from primary diagnosis was 24.3 months (13.2–27.3) for NSC lung patients and 46.5 months (39.2–65.5) for non-lung patients (p=0.005 logrank test). The median survival (95% CI) after SRS was 7.9 months (3.0–14.3) for the NSC lung patients and 8.4 (2.9–11.9) months for the non-lung patients (p=0.98 logrank test). Within the two groups, no difference in survival was observed for patients who had SRS sooner (< 1 yr for NSC lung; < 3 yr for non-lung) after primary diagnosis: 9.3 vs. 6.5 mo for NSC lung (p = 0.21) and 10.5 vs. 7.2 mo for non-lung (p=0.87). In this series, the shortened intervals from primary diagnosis to SRS for NSC lung metastases was associated with post-SRS survivorship that was equivalent to the more favorable non-lung group.     

Pathologic complete response in renal cell carcinoma brain metastases treated with stereotactic radiosurgery

Renal cell carcinoma (RCC) is often regarded as a radiation-resistant tumor. However, radiation therapy (RT) in the form of stereotactic radiosurgery (SRS) or whole-brain irradiation has been used to treat brain metastases from RCC. To date, there have been no clinical pathologic correlative findings before and after RT. Herein, we present a case of a patient with brain metastases from RCC treated with SRS. The diagnosis of clear-cell RCC was made in 2001 after right radical nephrectomy. He was also found to have lung metastases at diagnosis. He presented with neurologic symptoms in 2004, and magnetic resonance imaging showed 3 brain lesions with a significant amount of edema consistent with brain metastases. The largest lesion caused a midline shift and was surgically resected. Pathology revealed metastatic RCC. The other 2 smaller brain lesions were treated at 20 Gy respectively with shaped-beam SRS using the BrainLab Novalis® system. No whole-brain irradiation was delivered. However, the patient had difficulty weaning off his steroids, and a magnetic resonance imaging performed 6 months after SRS was read as “progression of the lesions.” He then underwent resection of both the irradiated brain lesions. Pathologic examination revealed necrotic tissues without any viable tumor identified. The patient has since been doing very well, now 18 months after SRS and 5 years from the Initials diagnosis. This is the first reported case that demonstrates that precise high-dose radiation in the form of SRS can cause significant tumor cell death (pathologic complete response) in radiation-resistant brain metastases from RCC. This finding also provides a rationale to deliver stereotactic body RT for primary and metastatic RCC extracranially. A prospective clinical trial using stereotactic body RT for primary and metastatic RCC is under way.     

Phase I/II study of IV topotecan in combination with whole brain radiation for the treatment of brain metastases

A phase I/II trial was conducted to determine the toxicities and efficacy (overall response, overall survival, and progression-free survival) of the combination of topotecan and whole brain radiation therapy (XRT) in patients with brain metastases. Patients received 30 Gy XRT given in 10 fractions to the whole brain. In phase I, patients were treated in groups of three at each topotecan dose level; dose escalation proceeded until the maximum tolerated dose (MTD) was identified. The dose-limiting toxicity proved to be grade IV neutropenia at 0.6 mg/m²/d, resulting in an MTD of 0.5 mg/m²/d. One of nine patients showed a response to treatment, and that was partial (OR 11%). Three had stable disease (33%), and four experienced progressive disease (44%). Median progression-free survival was 60 d; median overall survival was 102 d. Intravenous topotecan at 0.5 mg/m²/d concomitant to XRT with 30 Gy in 3-Gy fractions is tolerable in patients with brain metastases. This regimen has the additional advantage of providing systemic treatment to patients with metastases in other locations while whole brain radiation is in progress. Although response and survival outcomes in this small study do not appear higher than expected from historical controls, these were not primary end points, and larger studies on this topic would be useful to elucidate the efficacy of this combination treatment regimen.     

Immune checkpoint inhibitors in hepatocellular carcinoma: A review of current clinical trials

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis due to advanced disease presentation or recurrence despite curative-intent resection. Since the approval of sorafenib in 2007, few systemic therapies offered a significant improvement in treatment outcomes. Over the last 3 years, however, rapid advancements in the field of immunotherapy have led to approval of checkpoint inhibitors in 2020 for use in advanced HCC. Since then, a few other clinical trials have shown promising results in the adjuvant and neoadjuvant setting. The objective of this review is to summarize data from existing clinical trials evaluating the use of systemic immune checkpoint inhibitors in HCC and to follow the natural evolution of this development across the metastatic, adjuvant, and neoadjuvant landscapes.     

非小细胞肺癌脑转移的放射治疗--附32例报告

收集 1995年 6月～ 2 0 0 2年 6月非小细胞肺癌 (non smallcelllungcancer ,NSCLC)脑转移住院患者 3 2例 ,采用放疗或放疗加化疗等综合性治疗 (颅内转移病灶采用全颅二侧野对穿照射 ,中线剂量 :3 0～ 40Gy/15～ 2 0次 ,后缩野追加肿瘤量 16～ 2 0Gy/8～ 10次 ,同时给EP、NP等方案化疗的综合方法治疗 )观察其疗效。初步研究结果提示 ,所有患者在顺利完成治疗后 ,平均存活期达 7个月。肺癌脑转移采用放疗、化疗的综合治疗 ,可延长生存时间 ,提高生存质量     

放疗联合免疫检查点抑制剂治疗非小细胞肺癌的研究进展

肺癌是世界范围发病率和死亡率最高的恶性肿瘤,非小细胞肺癌(non-small cell lung cancer,NSCLC)约占85％,其中30％～40％的患者确诊时为局部晚期,40％的患者为转移性肺癌.肺癌的治疗需要采用综合治疗手段,放疗作为传统治疗手段之一,在各期肺癌的治疗中发挥着重要作用.免疫检查点抑制剂(imm...     

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.MethodsA systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.ResultsAfter screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS (HR = 1.84, 95% CI 1.22-2.77) and systemic progression-free survival (PFS; HR = 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR = 1.31, 95% CI 0.42-4.07).ConclusionsAdministration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.     

Optimal treatment of poor-risk renal cell carcinoma patients with mTOR inhibitors and anti-VEGFR agents

Poor-risk metastatic renal cell carcinoma (RCC) includes a subgroup of patients with unfavorable prognosis, according to both the Motzer and Heng criteria. Overall, owing to the poor prognosis of these patients, the approach is still a challenge for the first and subsequent lines of treatment, particularly for rare histologies other than clear cell renal cell carcinoma. In this review, we investigated the present treatment option of poor-risk metastatic RCC. Areas covered are data with first and further line of therapy with mTOR inhibitors and other agents but without cytoreductive nephrectomy or rare histologies. The current data on systemic therapy in poor-risk metastatic RCC maintain temsirolimus as the preferred first-line therapy. New agents targeting immune checkpoints are being developed in clinical trials.     

Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases

Background:

The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).

Methods:

Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.

Results:

Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.

Conclusion:

Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.