Infusional interleukin-2 and 5-fluorouracil with subcutaneous interferon-α for the treatment of patients with advanced renal cell carcinoma: a Southwest Oncology Group phase II study.

Background: A Phase II trial was conducted to determine the response rate of patients with advanced renal cell carcinoma to a three-drug combination of 5-fluorouracil (5-FU), interleukin-2 (IL-2), and interferon-alpha-2b (IFN-alpha).Methods: A 2-stage accrual plan was used that was designed to determine whether response to this regimen was consistent with a true response rate of ⩾30%. The regimen was comprised of 5 treatment days weekly for 4 weeks every 6 weeks. Each weekly treatment was comprised of 5-FU, 1750 mg/m², continuous intravenous (i.v.) infusion over 24 h followed by IL-2, 6 MIU/m²/day, continuous i.v. infusion for 4 days. IFN-alpha, 6 MU/m², was given subcutaneously on Days 1, 2, and 5.Results: Thirty-eight patients were entered on study, 3 of whom were ineligible. Among the 35 eligible patients there were 3 confirmed partial responses (PR) and 1 complete response (CR), for an overall response rate of 11% (95% confidence interval, 3–27%). One patient considered as having a PR had minimal evidence of residual disease and was free from disease progression at >2.5 years of follow-up, as was the patient with CR. Three additional patients not qualified as having a PR were showing signs of response at the time they were removed from protocol, and another patient who was removed from protocol early for management of an infection subsequently responded to the same regimen off protocol. Thirteen patients were considered nonassessable (NASS) for response, many of whom had multiple poor risk features and were unable to complete 1 cycle of treatment.Conclusions: This multicenter study failed to confirm an advantageous overall response rate for this three-drug regimen. However, there were two durable responses and indications of responsiveness not scored as PRs among patients with more favorable risk factor patterns, and many poor risk NASS patients. For these reasons, the response rate reported in the current study may be a conservative reflection of the effectiveness of this regimen.     

A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX?) and interferon-alpha-2a in metastatic renal cell carcinoma patients

Purpose  

To evaluate the efficacy and safety of WX-G250, a chimeric monoclonal antibody that binds to carboxy anhydrase IX, combined with low-dose interferon-alpha (LD-IFNα) in patients with progressive metastatic renal cell carcinoma (mRCC).     

Immunotherapy of advanced renal cell cancer using subcutaneous recombinant interleukin-2 and interferon-α

Summary The combined administration of subcutaneous recombinant human interleukin-2 (rIL-2) and interferon- (rIFN-) was studied in a phase II trial on patients with advanced progressive renal cell cancer. Safety, tolerance and clinical response rate of this outpatient treatment protocol were assessed in 29 evaluable patients who received a total of 47 cycles, each consisting of s.c. rIL-2 at 14.4–18 million IU m^–2day^–1 on days 1 and 2, followed by 6 weeks of combined administration of s.c. rIL-2 at 3.6–4.8 million IU m^–2 day^–1 on 5 days a week, and s.c. rIFN- at 3–6 million units m^–2 three times weekly over a period of 6 consecutive weeks. In patients exhibiting stable or regressive disease upon combined IL-2 and rIFN-, the therapy was continued. The overall response rate was 31% (95% confidence limits = 15%–51%), with 6 out of 29 patients achieving partial remission (PR, 21%) and 3 patients complete remission (CR, 10%). In addition, 12 patients presented with stable disease. The median duration of response was 8.5 months in PR and 19+ months in CR. Long-term treatment using this regimen was associated mainly with moderate (WHO grade I–II) toxicity including fevers, chills, malaise, nausea and/or vomiting, anorexia and transient local inflammation at the injection sites. No toxic deaths occurred. Altered thyroid function was observed in more than half the patients. The combination regimen resulted in a significant increase in peripheral blood eosinophils and natural killer cells (P<0.005). Up-on treatment, 14 patients developed non-neutralizing activity against rIL-2, and 2 of these developed specific neutralizing antibodies after consecutive cycles; no anti-rIFN-2b antibodies were detected. In summary, subcutaneous long-term outpatient treatment with low-dose rIL-2 and rIFN- is feasible, with moderate toxicity, and results in an objective tumor response rate comparable to that obtained previously with high-dose rIL-2 i.v. regimens.     

Phase 2 study of granulocyte-macrophage colony-stimulating factor plus thalidomide in patients with hormone-naïve adenocarcinoma of the prostate

ObjectiveTo assess the efficacy of granulocyte macrophage colony-stimulating factor (GM-CSF) in combination with thalidomide on prostate-specific antigen (PSA) reduction in hormone-naïve prostate carcinoma (HNPC) patients with rising PSA levels after definitive local treatment.Materials and methodsHNPC patients (n = 21) with evidence of progression demonstrated by 3 consecutive rises in PSA and no evidence of radiographic involvement were treated on a chronic dosing schedule with GM-CSF. Patients received 250 μg/m² (maximum 500 μg) 3 times a wk by subcutaneous injection, with injections at least 24 h apart. Thalidomide administration began concurrently with an initial dose of 100 mg daily for 7 consecutive days. During wk 2 to 4, the dose was escalated every 7 d by 100 mg per individual tolerance to a maximum of 400 mg. The maximum tolerated dose of thalidomide was continued without interruption. PSA, testosterone, and routine laboratory parameters were measured every 6 wk.ResultsOne patient was not evaluable because of noncompliance. For the 20 evaluable patients, baseline PSA levels ranged from 1.3 to 61.0 ng/ml. Nineteen patients left the study at 3.0 to 33.3 mo, secondary to individual tolerance, progressive disease, or development of a second primary tumor. One patient continues to receive therapy at 33.8 mo. Two patients did not respond to the therapy. For the 18 patients who did respond, the median reduction in PSA level was 59% (range 26%–89%), and the median duration of response was 11 mo (range 4.5–36). Grades 1–2 toxicity included peripheral neuropathy, fatigue, skin rash, and constipation. One patient had deep-vein thrombosis/pulmonary embolism.ConclusionsGM-CSF plus thalidomide can be administered successfully with encouraging antitumor activity and reversible toxicity. This may represent an alternative to hormonal therapy.     

A case of favorable response after combination treatment with interferon-α and cyclooxygenase-2 inhibitor against metastatic renal cell carcinoma

We present a patient showing favourable response after combination treatment with interferon-α (IFN- α) and cyclooxygenase-2 (Cox-2) inhibitor (celecoxib) against metastatic renal cell carcinoma (RCC). The patient underwent left radical nephrectomy for RCC on 18th April, 2005. On follow-up computed tomographic scan, mediastinal metastasis was detected 3 years after nephrectomy, and metastasectomy was performed. The histological features were clear cell carcinoma as was the primary RCC, and immunohistochemical analysis revealed negative for Cox-2 staining both the primary and metastatic lesions. Aiming at the treatment of residual mediastinal RCC, the patient started to receive IFN-α, and this cytokine therapy lasted for 1 year and 2 months. Nevertheless, the outcome was progression of disease (PD), namely, new lung field lesions were observed. A different type of IFN-α treatment also resulted in PD. Based upon these results, a combination of IFN-α and Cox-2 inhibitor was newly adopted for treatment. After the combination therapy for 3 months, 68.75% of metastases disappeared. We concluded that Cox-2 inhibitor is a potent medicine in combination with IFN-α for metastatic lung tumour from RCC.     

Sequential treatment of patients with advanced renal cell carcinoma with autologous tumor vaccine and subcutaneous administration of recombinant interleukin-2 and interferon α2b

Summary Thirty patients with advanced renal cell carcinoma (RCC), 23 of whom had distant metastases in at least one organ, were entered after nephrectomy into a protocol involving vaccination with Newcastle disease virus (NDV)-modified autologous tumour material, with a subsequent induction week and repetitive bi-weekly cycles of interleukin-2 (rIL-2) and interferon _2b/rIFN-_2b at a lower s. c. dose (1.5 million Cetus units m^–2 day^–1 every 12 h on 2 days and 3 million IU/m² once a day on days 1, 3 and 5). The inpatient treatment was followed by a maintenance phase during which 0.3 million Cetus units/m² rIL-2 was given s. c. every 12 h on days 1–5 and 3 million IU m^–2 day^–1 rIFN-_2b was administered on days 1, 3, and 5 on an outpatient basis. All but 3 patients completed the induction week and 6 weeks of outpatient therapy. No grade 3 or 4 toxicities occurred during the therapy. Therapy was discontinued for 3 patients because of rapid tumour progression. Of the 23 evaluable RCC patients, 3 exhibited a complete response and 4 displayed partial remission, 7 showed stable disease during 1–18 months (median = 5 months) of therapy, and progression was seen in 9. We conclude that vaccination with autologous tumour material combined with s. c. rIL-2 and rIFN-_2b administration can induce regressions in patients with advanced RCC and that even in non-responding patients a more favourable course of the disease can be achieved.     

Phase II trial of interleukin 2, interferon α, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1–4 of the 8-week regimen. During weeks 1 and 4, dosage for rIL-2 was 10 MIU/m² twice daily on days 3–5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m² on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m² on days 1, 3, 5. During weeks 5–8, 5-fluorouracil (750 mg/m²) was administered once weekly by i.v. infusion, and IFN-alpha2B (9MIU/m²) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10–25). The median response duration was 8 months (range, 3–51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1–53+ months. Toxicity was primarily constitutional, and treatment modifications were designed to maintain toxicity at grade 2/3. The most toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts were directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment vs. treatment with outpatient s.c. injection of IL-2 plus IFN.     

Overall survival in patients with metastatic renal cell carcinoma initially treated with bevacizumab plus interferon-α2a and subsequent therapy with tyrosine kinase inhibitors: a retrospective analysis of the phase III AVOREN trial

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? Multiple active treatment options are available for patients with mRCC. Current data suggest that it is difficult to use these therapies in combination due to toxicity concerns. The ability to use these active therapies sequentially provides the potential for improved patient outcomes. This retrospective post‐hoc analysis from a double‐blind, randomized phase III study provides further evidence for improved outcomes with sequential treatment in patients with mRCC. Additionally, it suggests the potential for improved outcomes and long‐term survival (>3 years) with first‐line bevacizumab plus IFN followed by subsequent TKI therapy in patients with mRCC and good/intermediate MSKCC risk at baseline.

OBJECTIVE

• ? To retrospectively evaluate the effect of subsequent tyrosine kinase inhibitors (TKIs) after first‐line bevacizumab + interferon‐α2a (IFN) or IFN + placebo in the phase III AVOREN (Avastin and Roferon in Renal Cell Carcinoma) trial.

PATIENTS AND METHODS

• ? A total of 649 patients with untreated metastatic renal cell carcinoma (mRCC) were randomized to receive IFN (9 MIU three times a week for up to 1 year) in combination with bevacizumab (10 mg/kg every 2 weeks) or placebo until disease progression.
• ? The protocol allowed the use of any post‐protocol anti‐cancer therapy for patients with progressive disease or those in whom the trial therapy was discontinued. Data regarding the timing and type of subsequent therapy were recorded and overall survival (OS) analysed.

RESULTS

• ? Patients were randomized to bevacizumab + IFN (n= 327) or IFN + placebo (n= 322); 180 (55%) patients in the bevacizumab + IFN, and 202 (63%) in the IFN + placebo arm, received post‐protocol anti‐cancer therapy.
• ? TKIs were the most common post‐protocol therapy, received by 113 (35%) and 120 (37%) patients in the bevacizumab + IFN and IFN + placebo arms, respectively.
• ? The median OS in patients who received any subsequent TKI was 38.6 months in the bevacizumab + IFN arm and 33.6 months in IFN + placebo arm [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.56–1.13; P= 0.203]. In an additional retrospective analysis that censored patients who received subsequent TKIs, median OS was 25.0 and 20.7 months, respectively, in the bevacizumab + IFN and IFN + placebo arms (HR, 0.84; 95% CI, 0.67–1.05; P= 0.123).

CONCLUSIONS

• ? These retrospective exploratory data of sequential bevacizumab + IFN followed by TKIs in patients able to receive multiple lines of therapy suggest that sequential therapy could be a promising approach to improve patient outcomes in mRCC.

     

Is there a role for partial nephrectomy in patients with metastatic renal cell carcinoma?

ObjectivesThe incidence of metastatic disease in patients with renal cell carcinoma (RCC) correlates with tumor size. We sought to determine the incidence of metastatic disease by tumor size, and the utilization and impact of nephron-sparing surgery on survival in those with metastatic disease.Materials and methodsUtilizing the Surveillance, Epidemiology, and End Results (SEER) database, we identified 56,011 patients between 1988 and 2005 diagnosed with RCC. Patients were initially separated into two groups—those with and without metastatic disease—and stratified by tumor size. Cox proportional hazard modeling and Kaplan-Meier analyses were then utilized to evaluate the role of gender, age, grade, histology, tumor size, and type of surgery (radical vs. partial nephrectomy) on overall- and cancer-specific survival in patients with metastatic disease.ResultsEight thousand four hundred ninety-eight patients (15%) had metastatic disease. Four percent of patients with tumors less than 2 cm and 5% of patients with tumors between 2 and 3 cm presented with metastatic disease. Two thousand nine hundred fifty patients (35%) with metastatic disease underwent surgery (radical or partial nephrectomy). Seventy patients (2% of those undergoing surgery) had a partial nephrectomy. Those who underwent partial nephrectomy were 0.49 times less likely to die of RCC than those who underwent radical nephrectomy (95% CI 0.35–0.69, P < 0.001).ConclusionsAlbeit small, the risk of metastases in patients with small kidney tumors is distinct and should be considered in management discussions. Partial nephrectomy, when able to be done, should be utilized in the setting of metastatic disease.     

Expression of hypoxia inducible factor-1α and 2α in conventional renal cell carcinoma with or without sarcomatoid differentiation

Objectives

Expressions of hypoxia inducible factor (HIF)-1α and HIF-2α in epithelial and sarcomatoid components from the same patients with clear cell renal cell carcinoma (RCC) are lacking. We performed this study to define better the correlations among these molecules in RCC tissues.

Materials and methods

Immunohistochemical staining of paraffin sections for HIF-1α and HIF-2α was performed in 24 cases of RCC with sarcomatoid differentiation using a streptavidin-peroxidase procedure. Control samples were collected from 58 patients with no sarcomatoid differentiation matched to cases by age, gender, and TNM stage.

Results

HIF-1α was more expressed within the epithelial component of clear cell RCC with no sarcomatoid differentiation (82.8%) than within that with sarcomatoid differentiation (66.7%). HIF-2α was expressed in most of the epithelial component, regardless of the sarcomatoid differentiation. However, HIF-1α and HIF-2α were not expressed in the sarcomatoid component in about 50.0% of clear cell RCC regardless of the sarcomatoid differentiation. Multivariate Cox proportional hazards model analysis showed that HIF-1α expression was an independent predictor of cancer-specific survival in clear cell RCC with sarcomatoid differentiation (P = 0.029).

Conclusions

HIF-1α and HIF-2α are not expressed in the sarcomatoid component in about a half of clear cell RCC with sarcomatoid differentiation, while HIF-2α was consistently overexpressed in the epithelial component in a majority of the tumors. Only HIF-1α expression regardless of tumor component is an independent prognostic factor in clear cell RCC with sarcomatoid differentiation.     

Expression of transforming growth factor β in renal cell carcinoma and matched non-involved renal tissue

TGF1 is one of several cytokines produced by proximal tubular and renal cancer cells. Previous studies have been mainly focused on determining plasma or serum TGF levels, its effect on RCC cultures, and the expression of TGF mRNA. Cancerous and autologous normal kidney samples were obtained from 24 patients treated by radical nephrectomy. TGF1 expression was determined using a semi quantitative Western blot analysis and immunohistochemistry. Blot densities and immunohistochemical expression intensities in normal and neoplastic tissue were compared, and subsequently correlated to tumor stage, histological type and nuclear grade. All tissue samples examined expressed TGF1; mean tumor to non-involved kidney spot density ratio correlated with advancing stage and higher nuclear grade. The overexpression of TGF1 in certain RCCs may partially explain their resistance to the growth suppression action of TGF. The correlation with tumor stage and grade indicates a possible role in the development of metastatic potential as well as in hosts immune response modulation.     

Prognostic value of the immunomonitoring of patients with renal cell carcinoma under therapy with IL-2/IFN-α-2 in combination with 5-FU

After tumor nephrectomy, patients suffering from metastatic renal cell carcinoma (RCC) received interleukin-2 (IL-2), interferon (IFN)--2b and 5-fluorouracil (5-FU) in one to three treatment cycles over 8 weeks Using flow cytometry, we investigated the immunophenotype of peripheral blood lymphocytes from 22 patients during therapy. In all patients, we found an increase in the absolute number of T lymphocytes, especially of the CD4 type, and in the number of HLA-DR⁺, CD25⁺ T cells and natural killer (NK) cells. The mean number of B cells did not increase during therapy. The numbers of CD4⁺, CD8⁺ and CD25⁺ T cells correlated significantly with the clinical response. In addition, we found that the pretherapeutic number of T lymphocytes and B cells but not of NK cells was significantly higher in patients with a therapy-induced clinical response. In conclusion, we describe the predictive value of the number of lymphocytes from peripheral blood for the efficiency of IL-2/IFN--2b therapy in combination with 5-FU in patients with metastatic renal cell carcinoma.     

Quadruple immunotherapy of Bacillus Calmette-Guérin,interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor as salvage therapy for non–muscle-invasive bladder cancer

Background

Bacillus Calmette-Guérin (BCG) is the most effective initial intravesical therapy for high-grade non–muscle invasive bladder cancer, but many patients still fail. Combination intravesical BCG and interferon (IFN) will salvage some patients but results remain suboptimal.

Current status in molecular-targeted therapy and IFNα for renal cell carcinoma in Japan

It has been two years since molecular-targeted therapy became available for advanced renal cell carcinoma (RCC) in Japan. It shall be validated whether molecular-targeted therapy really improved the prognosis of patients with advanced RCC in the near future. Here we review the two phase III clinical studies that demonstrated the superiority of sunitinib and temsirolimus over IFNα and discuss optimal therapy including IFNα for advanced RCC in the future biomarker era.