Interleukin-6 as an emerging regulator of renal cell cancer

BackgroundOur knowledge on the molecular basis of kidney cancer metastasisis still relatively low. About 25-30% of patients suffering from clear cell renal cell carcinoma (ccRCC)present metastatic disease at the time of primary diagnosis. Only 10% of patients diagnosed with stage IV disease survive 5 years and 20-50% of patients diagnosed with localized tumor develop metastases within 3 years. High mortality of patients with this cancer is associated with a large potential for metastasis and resistance to oncologic treatments such as chemo- and radiotherapy. Literature data based on studies conducted on other types of cancers suggest that in metastatic ccRCC, the complex of interleukin-6 (IL-6) and its soluble receptor (sIL-6R; complex IL-6/sIL-6R) and the signal transduction pathway (gp130/STAT3) might play a key role in this process.PurposeTherefore, in this review we focus on the role of IL-6 and its signaling pathways as a factor for development and spread of RCC. Analyzing the molecular basis of cancer spreading will enable the development of prognostic tests, evaluate individual predisposition for metastasis, and produce drugs that target metastases. As the development of effective systemic treatments evolve from advancements in molecular biology, continued studies directed at understanding the genetic and molecular complexities of this disease are critical to improve RCC treatment options.     

Granulocyte-macrophage colony-stimulating factor and interferon-alpha 2B in patients with advanced renal cell carcinoma.

OBJECTIVE: Biological response modifiers such as interferon-alpha2B (IFN-alpha2B) have well-known clinical activities against renal cell carcinoma (RCC). Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) has antitumorigenic effects both in vitro and in vivo. Therefore, a phase-I/II trial of IFN-alpha2B and GM-CSF was performed in patients with metastatic RCC. METHODS: 21 patients in groups of 3 patients received GM-CSF at 7 different dose levels (15-300 microg) subcutaneously in combination with IFN-alpha2B at a fixed dose of 10 x 10(6) IU s.c. three times weekly for 12 weeks. RESULTS: Two complete remissions have been observed, both with lung metastases only. With increasing dose levels of GM-CSF a slight tendency to more toxicity was detectable. Due to grade-3 toxicities 5 patients (24%) dropped out of the treatment schedule. Increases in WBC, neutrophils, lymphocytes, and monocytes were noted but were not related to the dose levels of GM-CSF. CONCLUSIONS: Results demonstrate that simultaneous administration of GM-CSF and IFN-alpha2B is tolerated up to doses of 120-150 microg GM-CSF three times weekly. But there is no additional antitumorigenic effect of GM-CSF because the overall response rate of the combined administration of GM-CSF/IFN-alpha2B is similar to IFN-alpha2B alone and there is no obvious dose relationship between increasing doses of GM-CSF and the responses.     

Interleukin-2, interferon-alpha and 5-fluorouracil immunotherapy for metastatic renal cell carcinoma: the all Ireland experience

OBJECTIVE: To analyse the long-term efficacy of combined interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) subcutaneously, with 5-fluorouracil (5-FU) intravenously in a general multicentre setting, as treatment for metastatic renal cell carcinoma (RCC). METHODS: Fifty-nine patients with metastatic RCC were scheduled to receive an 8-week cycle of immunotherapy. Karnofsky score ranged from 70 to 100 (median 90). Thirty-one patients at presentation had metastases of which 14 underwent nephrectomy. Metastases occurred in multiple organs (lung 74%, mediastinal lymphadenopathy 22%, bone 21%). Therapeutic response and survival were analysed. RESULTS: Nine patients died from disease progression prior to completion of one full cycle. Six cases (10%) have stable disease at a follow-up of 51 months (range 20-88 months). Currently 11 patients (19%) are alive at a mean follow-up of 45 months (range 18-88 months). Forty-eight patients (81%) died of their disease at a mean follow-up of 10 months (range 0.5-46 months). Survival rate at 1 year was 53%, at 2 years 21%, at 3 years 16% and at 5 years 5%. Overall median survival is 10 months. CONCLUSION: IL-2 and IFN-alpha with 5-FU based immunotherapy achieve durable survival rates at 3 years in a minority of patients. Addition of 5-FU does not increase survival in our group. This study population is very different to other reported series. However it reflects better the entire population with metastatic RCC though results are subsequently poorer. Identifying patients that will respond is paramount.     

Results of immunochemotherapy with interleukin-2, interferon-alpha2 and 5-fluorouracil in the treatment of metastatic renal cell cancer

OBJECTIVE: In patients with advanced metastatic renal cell carcinoma (RCC) seen at a single institution, the toxicity and long-term clinical effects of a combination therapy with recombinant interleukin-2 (rIL-2), recombinant interferon-alpha2 (rIFN-alpha2) and 5-fluorouracil (5-FU) were evaluated. METHOD: From August 1992 through August 1997, 47 consecutive patients (38 men) with metastatic RCC were treated using rIL-2 and rIFN-alpha2 subcutaneously in combination with intravenous 5-FU. An average of 2. 4 cycles/patient (range 1-9) was administered. RESULTS: Toxicity grades II and III (World Health Organization) were observed in 24 and 17 patients, respectively. We achieved 9 major responses (7 complete responses (CR) and 2 partial responses (PR)) for an objective response rate of 19.1% (95% confidence interval 9.1-33.3%). A further 13 patients (27.7%) had a stabilization of disease. After a mean follow-up of 17.9 (2-53) months, 4 patients are alive with no evidence of disease. The 1- and 3-year survival probability was 70 and 37%, respectively. In an univariate analysis, two prognostic factors were correlated with disease outcome: Karnofsky performance index (p = 0.01) and the presence of bone metastases (p = 0.023). CONCLUSION: This triple-drug combination therapy was effective in the treatment of progressive RCC in almost every fifth patient.     

Preliminary results of the alternating administration of natural interferon-alpha and recombinant interferon-gamma for metastatic renal cell carcinoma.

OBJECTIVE: To evaluate the efficacy and toxicity of the alternating administration of natural (n) interferon (IFN)-alpha and recombinant (r) IFN-gamma for metastatic RCC. PATIENTS AND METHODS: The study comprised 24 patients (median age 60 years, range 42-77), 20 of whom were evaluable for response and all 24 evaluable for toxicity. Initially, nIFN-alpha was administered subcutaneously on days 1 and 3, and rIFN-gamma on day 2, for 1-2 weeks in the evening or at night, both at doses of 3 MU. If this regimen was tolerated, nIFN-alpha and rIFN-gamma were administered at the same doses on days 1, 3 and 5, and on days 2 and 4, respectively. RESULTS: There were three complete remissions and two partial remissions, giving a total response rate of 25%. All responders (complete plus partial remission) had undergone nephrectomy. Multiple lung metastases completely disappeared from four responders. The median and maximum time to remission in the responders were 2 and 7 months, respectively. The survival time of the responders was significantly longer than that of those not responding (stable and progressive disease, P=0.0202). Toxicities were mostly limited to WHO grades 1 and 2, with grade 3 leucopenia and grade 4 hepatic dysfunction in only one patient each. These toxicities were transient and there were no treatment-related deaths. CONCLUSION: The alternating administration of nIFN-alpha and rIFN-gamma is an effective treatment for metastatic RCC. This treatment is particularly suitable for patients who have undergone nephrectomy and have lung metastases.     

Interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline

Objective

We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of interleukin-2 (IL-2) for the treatment of patients with unresectable or metastatic renal cell carcinoma (RCC).

Methods

We searched the literature to identify RCTs or meta-analyses of RCTs comparing treatment regimens with IL-2 to those without. Outcomes of interest included overall or progression-free survival, response rate, toxicity and quality of life.

Results

We identified 36 RCTs, and 6 met the eligibility criteria (1098 patients). We studied IL-2 alone and in combination with other agents, including interferon-alpha (IFN-a), 5-fluorouracil (5-FU), and 13-cis-retinoic acid or tamoxifen. No trials comparing high-dose IL-2 to non-IL-2 regimens were identified. A meta-analysis of 1-year mortality data from the 6 trials did not show a difference between IL-2-based regimens and non-IL-2 controls. Two of the 6 trials detected statistically significant longer survival with IL-2 combined with IFN-a and 5-FU. Of the 4 trials that assessed progression-free survival, 3 reported significantly longer progression-free intervals with IL-2-based regimens. Five trials reported response rates; pooling the rates from these trials gave an overall weighted response rate of 13.3% (range 9%–39%) and 5.3% (range 0%–20%) for IL-2-containing regimens and non-IL-2 regimens, respectively. IL-2-based regimens were more toxic than were non-IL-2 controls; the most frequently reported grade 3–4 toxicities were hypotension (range 6%–68%), fever (2%–56%), nausea or vomiting or both (6%–34%), diarrhea (1%–28%) and cardiac toxicity (11%–25%). None of the trials reported health-related quality-of-life data.

Conclusion

Non-high-dose IL-2 containing regimens do not provide superior treatment efficacy over non-IL-2-based regimens, with added toxicity, and therefore should not be used as standard treatment for patients with unresectable or metastatic RCC. High-dose IL-2 should only be used by experienced physicians in the context of a clinical trial or investigative setting.Renal cell carcinomas (RCCs) account for 3% of all adult solid malignancies.¹ In 2006, it was estimated that 4600 patients would be diagnosed with the disease in Canada.² According to Bukowski, at the time of first diagnosis, 45% of patients will present with localized disease, 25% will have locally advanced disease with lymph node or local organ involvement and the remaining 30% will present with metastases.³ Patients with meta-static disease have a 5-year life expectancy of less than 10% and a median survival time of less than 12 months. However, survival can be quite variable, depending on several prognostic factors, including performance status, lactate dehydrogenase (LDH), hemoglobin and calcium levels, and the absence of prior nephrectomy.⁴For patients presenting with inoperable or metastatic disease, cure is rarely possible, and treatment efforts often focus on effectively controlling symptoms and offering a chance at improved survival. Clinical trials of chemotherapy in the metastatic setting have shown RCCs to be resistant to currently available chemotherapeutic agents.⁵ Immunotherapy agents, however, have shown activity in RCC. Interleukin-2 (IL-2) has been evaluated extensively in the setting of advanced RCC. Various doses and modes of delivery have been studied, attempting to maximize efficacy and decrease the significant toxicities that can be associated with high-dose IL-2 therapy. High-dose IL-2 has been defined as IL-2 administered as an intravenous bolus of at least 600 000 IU/kg every 8 hours, or a dose exceeding 65 mu/m² daily. IL-2 at 18 mu/m² days 1–4 or 5 intravenously is not considered high-dose IL-2.Since its approval by the United States Food and Drug Administration (FDA), high-dose IL-2 has been used in patients with advanced RCC as a standard therapy at many comprehensive cancer centres in the US. This has likely contributed to the paucity of trials without an IL-2 arm. IL-2 was also approved by Health Canada in 2003, but its use has been very sporadic and limited. Because interferon-alpha (IFN-a) is associated with a real, if modest, survival benefit in the randomized setting⁶ and because it is accessible to and tolerated by most RCC patients, it has become a de facto standard of care in Canada.To clarify the role of IL-2 in the treatment of RCC and to develop appropriate recommendations for treatment, the Genitourinary Cancer Disease Site Group (GU DSG) of Cancer Care Ontario''s Program in Evidence-based Care (PEBC) systematically reviewed evidence from randomized controlled trials (RCTs) of IL-2 in patients with unresectable or meta-static RCC.     

A combined treatment of interferon-alpha, 8 MHz radiofrequency hyperthermia and/or irradiation in a patient with advanced renal cancer

A combined treatment of alpha interferon (INF), 8 MHz radiofrequency (RF) hyperthermia using Thermotron-RF Model 8 and/or irradiation was performed on a patient with advanced renal cancer. The patient was a 52-year-old male, who had received arterial embolization with a gelatin sponge and 60 mg of adriamycin for the right renal tumor in January, 1985. He was referred to our clinic in April, 1985. Computed tomography showed a right renal tumor, 120 x 105 x 80 mm. Histological examination revealed clear cell carcinoma of the right kidney. The tumor was unresectable because of the huge tumor size, invasion into the right lobe of the liver, multiple pulmonary metastases and severe dysproteinemia. From the beginning of May, 1985, administration of 3 x 10(6) units interferon-alpha (INF) daily and radiofrequency (RF)hyperthermia for one hour twice a week were started. By June 11, 1985, 10 sessions of RF-hyperthermia were performed. Thereafter, hyperthermia for the renal tumor was maintained once a week until June, 1986. From the middle of June, 1985, a gradual improvement of dysproteinemia and appetite loss, and a decrease of the right renal tumor size as well as disappearance of febrile attacks were attained. In November, 1985, mediastinal lymph node swelling developed. A combined therapy of RF-hyperthermia twice a week and irradiation with 2.0 Gy daily 5 times a week was started. A total of 14 sessions of RF-hyperthermia and 30 Gy of irradiation were delivered until January, 1986. Intratumoral temperature of the renal tumor reached 44.0 degrees C during the heating.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complete response of a large brain metastasis of renal cell cancer to interferon-alpha: case report

BACKGROUND: Interferon-alpha (IFNalpha) is a drug widely used in the treatment of metastatic renal cell cancers, especially lung lesions. Successful treatment using IFNalpha for histologically proven brain metastasis has not been reported. CASE REPORT: A large pineal tumor was found in a 51-year-old man with renal cell cancer in the left kidney. The histological diagnosis of biopsied specimens was a brain metastasis from renal cell cancer. The patient was treated with intramuscular injections of IFNalpha. The brain metastasis gradually decreased in size and disappeared completely 6 months after the initial injection of IFNalpha. The IFNalpha therapy was continued for 9 months. Fifteen months later, no recurrence was evident on brain magnetic resonance imaging. CONCLUSION: This is an extremely rare case in which the long-term use of IFNalpha induced a complete response of a brain metastasis from renal cell cancer.     

Hypothyroidism followed by interferon-alpha as adjuvant therapy of renal cell carcinoma: a case report]

A 58-year-old male patient was admitted to the hospital complaining of weight loss. Abdominal computerized tomographic (CT) scan disclosed a mass shadow in the left kidney. From the results of further examination, including drip infusion pyelography (DIP) and angiography, he was preoperatively diagnosed as having a left renal tumor. Left radical nephrectomy was performed on March 15, 1990. The lesion was histologically diagnosed as renal cell carcinoma (clear cell subtype, grade 2) confined by the renal capsule (stage I). No distant metastases were detected. Interferon-alpha was administered every other day as adjuvant chemotherapy. After the patient experienced muscle pain in his thighs and shoulders after exercise on February 11, 1991, the serum creatine phosphokinase (CPK) level progressively increased up to 2,329 U/l. On the basis of the results of various examinations reflecting thyroid gland function, he was diagnosed as having primary hypothyroidism due to Hashimoto's disease. Thyroid function improved after administration of triiodothyronine and thyroxine. Interferon has been reported to influence thyroid function, and, in this case, interferon-alpha therapy may have induced the primary hypothyroidism associated with Hashimoto's disease.     

Interleukin-6 in renal cell carcinoma.

We studied interleukin-6 production in 4 human renal cell carcinoma cell lines and measured the serum level in 71 patients with renal cell carcinoma, thus, clarifying a relationship between interleukin-6 secretion and an occurrence of the paraneoplastic syndrome in the carcinoma. Interleukin-6 was produced by 3 cell lines and detected in 25% of the patients. The level of interleukin-6 did not directly correlate with tumor volume and the differentiation grade of the carcinoma. However, the positive rate increased with progression of the stage. The serum level affected the 5-year survival of patients without distant metastasis. When serum interleukin-6 was elevated patients had a significantly higher frequency of unexplained fever and an elevation of acute phase proteins. These results suggest that some renal cell carcinomas can produce interleukin-6 and this cytokine is responsible for several paraneoplastic syndromes in the carcinoma.     

Anemia associated with pegylated interferon-alpha2a and alpha2b therapy in hemodialysis patients

AIMS: Anemia is a well-known side effect of interferon therapy since interferons are potent inhibitors of erythropoiesis. The aim of this study was to compare the anemia associated with pegylated interferon (PEG-IFN) (alpha2a versus alpha2b therapy in hemodialysis patients (HD) with chronic hepatitis C. METHODS: In order to study the anemia, doses of erythropoietic growth factors (EGF), hemoglobin (Hb) and erythropoietin resistance index (ERI) were compared at baseline and after PEG-IFN-alpha2a or alpha2b therapy in 16 HD patients with chronic C hepatitis. Pharmacokinetic studies were performed in 4 of those treated with PEG-IFN-alpha2b and 2 patients treated with PEG-IFN-alpha2a. Secondary end-points were viral response and serious adverse events. RESULTS: At 4-6 months after the beginning of therapy, both PEG-IFN-alpha induced a significant increment in the erythropoietin resistance index. This increment was significantly higher in patients treated with PEG-IFN-alpha2a when compared with alpha2b (45 vs 9.9, p = 0.012). The pharmacokinetics of PEG-IFN-alpha2a and alpha2b in HD patients were different, the C(max), C(min) and the area under the serum concentration time curve, were all higher in patients treated with PEG-IFN-alpha2a compared with PEG-INF-alpha2b. Discontinuation of therapy occurred in 2 (28.5%) of the 7 patients in the PEG-IFN-alpha2a group and in 4 (44%) of the 9 patients in the PEG-IFN-alpha2b group. Three (42%) subjects in the alpha2a group and 5 (55%) in the alpha2b group had a response at the end of the 48 weeks of therapy. In 4 (44.4%) of the 9 patients treated with alpha2b the viral response was sustained. CONCLUSIONS: In summary, patients treated with PEG-IFN-alpha2a have a major inhibitory effect on erythropoiesis. This could be explained by the different pharmacokinetic properties of PEG-IFN-alpha2a and alpha2b. Further studies are needed to clarify how these findings influence the efficacy, safety and cost-effectiveness of the PEG-IFN-alpha2.     

Interleukin-2 immunotherapy followed by resection of residual renal cell carcinoma

We administered 10 (E5) units per kg. interleukin-2, 3 times daily, with or without lymphokine-activated killer cells, to 10 patients with metastatic renal cell carcinoma. All patients had metastases to the lung, and 3 of 5 patients who had previously undergone nephrectomy had metastases to the renal fossa. Of the 9 patients who completed at least 1 course of therapy 3 had complete regression of disease outside the abdomen, including 2 who were rendered disease-free after subsequent cytoreductive surgery (nephrectomy in 1 and resection of the renal fossa recurrence in 1). Viable tumor comprised less than 1% of each surgical specimen. Our results support the view that initial treatment with interleukin-2 immunotherapy, followed by abdominal cytoreductive surgery if the peripheral metastases have regressed, may be preferable to the practice of performing abdominal cytoreductive surgery before administering interleukin-2 immunotherapy for patients with widely metastatic renal cell carcinoma.     

Toothache as a presenting symptom of metastatic renal cell cancer

A 53-year-old man with a 14-year history of renal cell carcinoma (RCC) presented with a 2-month history of right-sided upper jaw pain and severe bleeding during tooth extraction. Pathology review of a lower maxillary sinus/upper gingival mass revealed metastatic RCC. The presentation, differential diagnosis and literature review of this uncommon presentation of metastatic kidney cancer are discussed in this report.     

Interleukin-6 and soluble intercellular adhesion molecule-1 in renal cancer patients and cultured renal cancer cells

Serum interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assay in 62 renal cancer patients: 30 were tumor-free after radical nephrectomy and 32 presented with metastatic disease. Serum IL-6 was undetectable in all but one of the tumor-free patients, whereas 41% (13 of 32) of the metastatic patients presented serum IL-6 levels. Furthermore, there was a significant correlation between serum IL-6 levels and a shorter overall survival (p = 0.009). Moreover, serum sICAM-1 levels were significantly higher (p = 0.05) in the metastatic patients with detectable serum IL-6 than in those without IL-6, suggesting a possible link between IL-6 and sICAM-1. The probability of a shorter overall survival was greater in the metastatic patients with both serum IL-6 and elevated sICAM-1 levels (>635 ng/ml), than in those with elevated sICAM-1 but without IL-6 (p = 0.01). The production of IL-6 by 16 freshly dissociated renal cancer cells cultured in vitro was also observed. It appeared that IL-6 levels did not correlate with the expression and release of ICAM-1 by cultured cells, although the highest values of ICAM-1 release were found in cultures synthesizing the highest values of IL-6. In conclusion, in vivo presence of serum IL-6 and elevated sICAM-1 levels is related to an unfavorable prognosis; it can be speculated that the cells capable of releasing high levels of sICAM-1 and IL-6 may negatively influence the antitumor response.     

自体LAK细胞和rIL－2治疗晚期肾癌的实验与临床研究

应用自体ＬＡＫ细胞和重组白细胞介素－２（ｒＩＬ－２）治疗２０例晚期肾癌患者。自患者周围血分离到的单个核细胞（ＰＢＭＣ）体外经ｒＩＬ－２短期培养，其ＮＫ、ＬＡＫ活性明显增强并于第５、７天达高峰。当这些ＬＡＫ细胞与ｒＩＬ－２过继回输给同一患者后，病人周围血ＮＫ、ＬＡＫ活性明显增加（Ｐ＜０．０ｌ），ＮＫ比率、ＩＬ－２受体表达明显增加（Ｐ＜０．０５），提示对肾癌患者的免疫调节作用。本组病人获部分缓解（ＰＲ）ｌ例，轻度缓解（ＭＲ）３例，平均缓解期５个月。毒副作用主要表现为发热、寒战，病人能耐受，表明ＬＡＫ／ｒＩＬ－２疗法是安全的方法。