Long-term outcome of postoperative interferon-α adjuvant therapy for non-metastatic renal cell carcinoma

AIM: To investigate the long-term efficacy of postoperative interferon-alpha (IFN-alpha) adjuvant therapy in preventing recurrence in non-metastatic renal cell carcinoma treated with radical nephrectomy and to identify related prognostic markers. METHODS: Long-term follow-up was conducted to study rates of survival and non-recurrence in 88 subjects following radical nephrectomy for non-metastatic disease. RESULTS: The overall survival rate was 90% at 5 years and 88% at 10, with corresponding non-recurrence rates of 81% and 74%. Survival rates reviewed by preadministration pT stage showed a falling tendency from T1 through to T3 in line with pathological progression; when cases at stage pT1b or below were compared with those at stage pT2 or above, the latter showed a tendency to lower survival rates (P = 0.0966, Breslow-Gehan-Wilcoxon). Similarly, non-recurrence rates tended to fall in line with pathological progression, with a significant difference found in the comparison of cases at stage pT1b or below with those at stage pT2 or above (P = 0.0265, log-rank, Mantel-Cox). Duration of IFN-alpha administration showed a tendency to positive correlation with long-term survival (P = 0.3765, Breslow-Gehan-Wilcoxon). Non-recurrence rate was not found to differ according to duration of administration. Comparison of groups with normal and abnormal preadministration immunosuppressive acidic protein values showed that the normal group tended to have higher rates of survival and non-recurrence (P = 0.3371, Breslow-Gehan-Wilcoxon). CONCLUSIONS: Immunosuppressive acidic protein values appear to be a useful predictive marker for recurrence. A randomized trial, examining long-term outcome according to tumor stage and variables such as duration of administration, dose, administration time, and dosing schedule is required.     

Dendritic cell therapy in combination with interferon-α for the treatment of metastatic renal cell carcinoma

Objectives:   To evaluate the safety and efficacy of dendritic cell (DC) therapy in combination with interferon-α (IFN-α) in patients with advanced renal cell carcinoma.
Methods:   Seven patients, with progressive disease following IFN-α and interleukin (IL)-2 treatment, were treated with monocyte-derived DC (Mo-DC) and IFN-α between February 2004 and September 2006. They received Mo-DC once a week for 5 weeks and then every 2 weeks either intradermally or intratumorally. IFN-α (5–6 million U) was subcutaneously administered three times a week. Tumor size was evaluated by computed tomography scans before and after the 5th and 10th DC vaccination. A delayed-type hypersensitivity test was performed after the 4th and 5th DC administration for immunological monitoring.
Results:   Five patients had stable disease while the remaining two patients had progressive disease following 4 months of vaccination. In six patients the time to progression was prolonged in comparison with the previous cytokine treatment. Six patients showed delayed-type hypersensitivity after the 4th or 5th immunization. Three patients developed high fever following DC immunization. Treatment was associated with transient flu-like symptoms.
Conclusions:   Our data indicate that DC therapy combined with IFN-α is safe and has the potential for prolonging the time to progression in patients with advanced renal cell carcinoma.     

A case of renal cell carcinoma with multiple lung metastases refractory to interferon-α showing complete remission by interleukin-2 monotherapy

We report a case in which a regimen of interleukin-2 (IL-2) achieved pathologically complete remission against renal cell carcinoma with multiple lung metastases. A 63-year-old man was admitted to the Osaka University Hospital with a right renal tumor and multiple lung metastases. Right radical nephrectomy was performed and the histological diagnosis was clear cell carcinoma, G3 > G2, INFbeta, pT3a, pN0. Postoperatively, despite treatment with interferon-alpha, the lung metastases progressed. Consequently, intravenous administration of IL-2 was started at a dose of 70 x 10(4) JRU/day five times per week. After 16 weeks of IL-2 therapy, most of the multiple lung metastases completely vanished and the largest metastatic lung mass was reduced in size. Resection of this residual lung mass was performed and pathological examination revealed no viable cancer cells.     

Prediction of response to combined immunotherapy with interferon-α and low-dose interleukin-2 in metastatic renal cell carcinoma: Expression patterns of potential molecular markers in radical nephrectomy specimens

Objectives:   To evaluate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) who received combined immunotherapy with interferon-α (IFN-α) and low-dose interleukin-2 (IL-2) and to identify factors predicting susceptibility to this therapy.
Methods:   This study included 40 patients with metastatic clear cell RCC undergoing combined immunotherapy with IFN-α and low-dose IL-2 following radical nephrectomy. Expression levels of 10 markers, including Aurora-A, Bcl-2, clusterin, heat shock protein 27, heat shock protein 90, Ki-67, matrix metalloproteinase-2, matrix metalloproteinase-9, p53 and vascular endothelial growth factor, in RCC specimens were measured using immunohistochemical staining.
Results:   In this series, one, 10, 15 and 16 patients were diagnosed as showing complete response, partial response, stable disease and progressive disease, respectively. Expression levels of Bcl-2 and Ki-67 had significant impacts on the response to this therapy. Furthermore, cancer-specific survival was significantly associated with the expression levels of Ki-67 and Bcl-2 in addition to performance status, presence of metastases at diagnosis, metastatic organ and C-reactive protein on univariate analysis. Only the presence of metastases at diagnosis and Ki-67 expression level appeared to be independent predictors of cancer-specific survival on multivariate analysis.
Conclusions:   It would be useful to consider the expression levels of potential molecular markers, particularly Ki-67, in addition to clinical parameters, such as the presence of metastases at diagnosis, to select metastatic RCC patients likely to benefit from combined immunotherapy.     

Multi-modal treatment of primarily using continuous subcutaneous interferon-α injection in combination with surgery and/or radiotherapy

PURPOSE: Thirty-nine renal cell carcinoma patients with bony metastasis were intensively treated, primarily with immunotherapy using natural type interferon-alpha (IFN-alpha) continuous subcutaneous injection in combination with surgical resection and radiation therapy. Long-term survival was achieved, including three patients with complete response. The results of this study are presented. METHODS: The mode of administration of IFN-alpha was as follows: natural-type IFN-alpha (25,000,000 IU) was dissolved in 60 mL of distilled water and administered via continuous subcutaneous injection (0.5 mL/h) as 'one course of the treatment'. Two courses of IFN-alpha therapy were given 2 weeks preoperatively, while 13 courses of IFN-alpha therapy were given postoperatively (one course per week). Thus, 15 courses of IFN-alpha therapy were administered during the trial period. Thereafter, IFN-alpha therapy was repeated either every week or every other week depending on the condition of the patient. Additionally, blood levels of IFN-alpha were monitored for four patients following initiation of IFN-alpha continuous subcutaneous injection therapy. RESULTS: Immediately after injection of IFN-alpha, blood levels of IFN-alpha started to rise, reaching 40.5 IU/mL on average at 24 h after initiation of IFN-alpha therapy. Thereafter, blood levels of IFN-alpha remained high and measurable blood levels of IFN-alpha were maintained for up to 24 h after completion of IFN-alpha injection. As a whole, IFN-alpha was detectable for 6-8 days and Cmax (maximum blood concentration of IFN) was 167 IU/mL. Thirty-nine patients with bony metastases were treated as follows: IFN mono-therapy (19 patients), IFN and radiation therapy (15 patients) and IFN and surgical resection of bony metastases (five patients). Fourteen patients survived and the details of these 14 patients are as follows: complete response in three cases, partial response in two, no change in six and progressive disease in three. Twenty-five patients died of renal cell carcinoma. The overall 5-year survival rate was 35.0%. CONCLUSIONS: These findings indicate that IFN-alpha continuous subcutaneous injection therapy is a useful modality for renal cell carcinoma patients with bony metastasis if administered in combination of radical nephrectomy and radiation therapy.     

Efficacy of Continuous Subcutaneous Infusion Therapy Using Interferon α and the Possible Prognostic Indicator of TNF-α in Renal Cell Carcinoma

Background :
In an attempt to improve efficacy by escalating the dose and maintaining higher serum concentrations over a long period of time, this study examines continuous interferon α (IFNα) subcutaneous infusion therapy in patients with renal cell carcinoma (RCC).
Methods :
Seven of 11 patients with RCC had evaluable metastatic lesions. A highly purified natural human IFNα was injected subcutaneously via an infuser pump for 5 consecutive days, followed by a 2-day rest period (25 million IU/week). The treatment was continued for a period of 15 weeks. Serum concentrations of IFNα, IL-1α, IL-1β, TNF-α, and IFNγ were measured at intervals throughout the study period.
Results :
Two of the 7 patients with evaluable lesions achieved a partial response (overall response rate, 29%), while 1 achieved a partial response only to lung metastasis. These 3 cases were defined as responders. No difference was found in the concentration of serum IFNα between responders and nonresponders, however, a significantly higher concentration of serum TNF-a was observed in responders (P<0.05, Mann-Whitney U test). Five cases (45%) had moderate to severe adverse effects, including depression (n = 1), eyeground hemorrhage (n = 2), and general fatigue (n = 2).
Conclusion :
Appropriate patient selection may be necessary for subcutaneous continuous infusion therapy for the treatment of metastatic RCC. Also, the serum concentration of TNF-α measured during the course of treatment reflected well on the outcome of IFNα therapy.     

Phenotype Frequency of Human Leukocyte Antigens in Japanese Patients with Renal Cell Carcinoma who Responded to Interferon-α Treatment

Background: Because of the high cost, low overall response rate (10% to 20%), and poor quality of life during interferon therapy for advanced renal cell carcinoma, it is important to distinguish patients likely to respond to treatment. The expression of human leukocyte antigens (HLA) may serve as a clinical marker for response to interferon treatment in patients with renal cell carcinoma.
Methods: We compared HLA phenotype frequency in 37 Japanese patients with advanced renal cell Carcinoma who showed a favorable response to interferon-α, in 93 similar patients, before treatment, who did not receive interferon-α, and in 939 healthy Japanese volunteers (historical control data).
Results: Six HLA antigens, B35, Bw48, Bw60, DRw6, DRw8, and DR9, were expressed at a significantly lower rate in the 93 pretreatment patients with renal cell carcinoma, compared with the control subjects. Three HLA antigens, excluding Bw60, DRw6, and DRw8, were expressed at a significantly higher rate in the patients who responded to interferon-α, compared with the pretreatment patients with renal cell carcinoma and control subjects.
Conclusion: Three HLA antigens, B35, Bw48, and DR9, were expressed at a significantly higher rate in patients with renal cell carcinoma who showed a sensitivity to interferon-α, and could be important markers for clinical response to this antitumor therapy.     

The prognostic value of flow cytometric DNA analysis in colorectal cancer patients

An association between DNA aneuploidy of tumor cells and a poorer clinical outcome of patients has been recognized in various human solid tumors. In this article, the prognostic value of flow cytometric DNA analysis in colorectal cancer patients is briefly overviewed. DNA aneuploidy appeared to correlate with more advanced disease and a poorer survival in colorectal cancer patients, but reported results were not always consistent. DNA ploidy as a marker for predicting the survival of colorectal cancer patients should not therefore be viewed in isolation, but should be evaluated in combination with other conventional prognostic variables. The S-phase cell compartment within a tumor appears to be promising as a marker for predicting the survival of colorectal cancer patients, but there remain technical problems in establishing an accurate estimation of the S-phase cell compartment within a tumor by conventional flow cytometry. The application of a bromodeoxyuridine (BrdU)-specific monoclonal antibody might be an useful tool for obtaining the accurate flow cytometric estimation of the S-phase cell population within a tumor.     

Neurologic toxicity associated with interferon α therapy for renal cell carcinoma

A 67-year-old man received interferon alpha (IFN alpha) therapy for lung metastases of renal cell carcinoma (RCC). Multiple pulmonary metastases disappeared completely. However, neurological toxicity was detected by magnetic resonance imaging (MRI) as abnormal brain lesions. After discontinuation of IFN alpha therapy, his neurological symptoms and abnormal lesions on MRI disappeared completely. Complete remission of RCC has continued, and results of neurological study have remained normal for 5 years after discontinuation of IFN alpha therapy.     

DNA ploidy as a prognostic factor in muscle invasive transitional cell carcinoma of the bladder

Radical cystectomy represents the treatment of choice for muscle-infiltrative bladder carcinoma; however, about 50% of patients relapse and die from the disease. In the present study, the prognostic significance of the DNA ploidy in transitional cell carcinoma of the urinary bladder (TCCB) is analyzed. The study was carried out on 66 patients with TCCB who underwent radical cystectomy. DNA ploidy was determined by flow cytometry (FCM) on paraffin-embedded specimens, and the results were analyzed and correlated with the tumor malignancy grade and stage and the clinical course. Forty of the 66 tumors studied (63%) were aneuploid. Aneuploid status was correlated with higher tumor T stage (P<0.001) and grade (P<0.001). Median follow up was 68 months (range: 12–105). Median survival was significantly longer in patients with diploid tumors (>60 vs 45 months, P<0.001). All patients with diploid tumors were alive and free of bladder cancer during follow-up, in contrast to only 30% of patients with aneuploid tumors. DNA ploidy was an independent prognostic factor, as shown by multivariate analysis (P=0.006). All patients with pT3b and diploid tumors were alive at the time of analysis as opposed to none with aneuploid tumors. The results of this study suggest that DNA ploidy can provide prognostic information on patients with muscle invasive carcinoma of the bladder and might represent a means of selection for postoperative management.     

Case of α-fetoprotein-producing transitional cell carcinoma of the renal pelvis

An alpha-fetoprotein-producing transitional cell carcinoma of the renal pelvis is extremely rare. To our knowledge, this has not been reported previously. We present the first case of an alpha-fetoprotein-producing transitional cell carcinoma of the renal pelvis in a 70-year-old female.     

Multifocal metastases of recurrent renal cell carcinoma successfully treated with a combination of low dose interleukin-2, α-interferon and radiotherapy

A 59-year-old man presented with a 2-month history of left flank pain and a possibility of gross hematuria. Left renal cell carcinoma stage II was diagnosed and radical left nephrectomy was performed. Twenty-two months postoperatively, lung metastases were demonstrated and 6 x 10(6) units of alpha-interferon (IFN-alpha) were administered for 9 months, only to keep the sizes of the metastases unchanged. Thirty-four months after the operation, liver metastases and bone metastasis in the left sacroiliac joint were revealed. The combination cytokine therapy was performed with 1.4 x 10(6) U of interleukin-2 (IL-2) and 3 x 10(6) U of IFN-alpha for 16 weeks, and the left sacroiliac joint metastasis was treated with radiation therapy of 4 Gy per day for 7 days. Six months after the 16 weeks of immunotherapy, computed tomography and bone scintigraphy revealed that the metastases of the lung, liver and bone substantially disappeared and this complete response is still kept after 16 months.     

Inhibitory Effects of Interleukin-4 on Human Renal Cell Carcinoma Cells In Vitro: In Combination with Interferon-α, Tumor Necrosis Factor-α or Interleukin-2

Background: Immune cytokines have been shown to play important roles in regulating the growth of neoplastic cells, as well as the function of immune cells. The present study assessed the effects of interleukin (IL)-4 alone, and in combination with recombinant interferon (IFN)-α2b, or with IL-2, or with tumor necrosis factor (TNF)-α on the in vitro proliferation of human renal cell carcinoma (RCC) cell-lines.
Methods: Growth-inhibitory effects of IL-4 alone, and in combination with other cytokines, on three human RCC cell-lines, Caki-1, CURC-II, and A-498, were measured by the [³H]thymidine incorporation assay.
Results: IL-4 inhibited proliferation of all three human RCC cell-lines (P< 0.001). The maximum growth inhibition of RCC cell-lines by IL-4 alone was observed at the concentration of 1 to 3 ng/mL, depending on the cell-line. Antihuman IL-4 antisera was able to reverse the growth-inhibitory effects of IL-4 on Caki-1 in a dose-dependent manner, proving that the growth inhibition was mediated by IL-4 itself. When other cytokines were added in combination with IL-4, only IFN-α2b resulted in significant additional growth inhibition ( P < 0.005). However, when the proliferation was compared to that of RCC cells that were not treated with any cytokine, all combinations produced marked growth inhibition. Conclusion: Our data suggest that IL-4 alone, or in combination with IFN-α2b, can be used to develop new strategies for treatment of human RCC.     

Metastatic mode and DNA ploidy in gastric carcinoma

We studied the amounts of nuclear DNA in gastric cancer metastases histologically and cytochemically by flow cytometry, which was performed retrospectively on paraffin-embedded specimens from 95 patients. At surgery, all cases of aneuploid cancer were positive for lymph node metastases. Liver metastases were frequently seen in aneuploid cancer (63%, P<0.01), while lung metastases were the most common in diploid cancer (50%, P<0.05). The incidence of peritoneal metastasis was high in undifferentiated diploid cancer (72%, P<0.01). Local lymph node recurrence after surgery was more common in aneuploid than in diploid cancer (P<0.01). The incidence of bone and distant lymph node metastasis was found to be strongly dependant on tissue differentiation. The DNA ploidy pattern is thus considered to be closely linked to lymph node, liver, and lung metastases in gastric cancer.     

Bcl‐2 protein and DNA ploidy in renal cell carcinoma: Do they affect patient prognosis?

AIM: The aim of the present study was to correlate bcl-2 protein expression and DNA-ploidy status with established prognostic parameters in renal cell carcinoma (RCC) and to examine their impact on disease progression and patient survival. METHODS: Both parameters were prospectively measured in 50 consecutive radical nephrectomy specimens using flow cytometry. They were correlated with the tumor grade, stage and histological type. Kaplan-Meier survival analysis for all parameters was performed. RESULTS: Bcl-2 protein expression was higher in RCC compared to normal renal tissue (P < 0.0001). Aneuploid tumors had higher bcl-2 expression compared to diploid tumors (P = 0.015). Bcl-2 expression and DNA content were not correlated with tumor histological types (P = 0.277/P = 0.419), grades (P = 0.690/P = 0.449), T categories (P = 0.637/P = 0.585) or stages (P = 0.726/P = 0.800). Median follow-up time was 46 months (range, 5-84) with a mean overall survival of 61.8 months (95% confidence interval, 53.7-69.9). Tumor stage was the only statistically important prognostic factor (P = 0.0045). CONCLUSION: Although Bcl-2 expression was correlated with tumor DNA content, the prognostic value of these two parameters following radical nephrectomy was not established.     

Long-term results of treatment of chronic hepatitis B, C and D with interferon-α in renal allograft recipients

Abstract The aim of this study was to evaluate the efficacy and safety of interferon-a (IFN-α) therapy of chronic hepatitis B, C and D (HBV, HCV and HDV, respectively) in renal transplant recipients. A group of 42 patients (30 males, 12 females, mean age 38 years) with documented viraemia and chronic active hepatitis (CAH) were studied, of whom 1 had HBV infection alone, 11 had HCV infection alone, 3 had HBV and HDV infection concomitantly, 12 had HBV and HCV infection concomitantly, and 2 had HBV, HCV and HDV infection concomitantly. Patients received 3 MU IFN-α three times weekly for 6 months. After IFN-α therapy, 18 patients (43 %) achieved normal alanine aminotransferase (ALT) activity and a partial response was observed in 12 (29%) patients. Two patients relapsed (one with HCV and one with HBV + HCV infection) immediately after the cessation of IFN-α therapy. Repeated liver biopsy was performed in 16 patients after 6–24 months of therapy and revealed progression to cirrhosis in five patients, remission in two and stable disease in nine. None of the patients cleared HCV RNA, four patients cleared HBeAg (two also HDV), and one both HBV and HCV. Five patients died during IFN-α therapy (one as a consequence of liver failure), and four died during the 6 months after therapy (two as a consequence of liver failure). During IFN-α therapy renal allograft function remained stable in 31 patients and acute rejection episodes occurred in 7, of whom 5 lost their graft and all had experienced rejection episodes before. In 16 patients normalization of ALT continued during long-term follow-up (median 22 months, range 0–84 months). IFN-α seemed to be moderately effective in the treatment of chronic HBV or HCV infections, but cannot be recommended for recipients infected with both HBV and HCV.     

Pegylated interferon-α-based treatment for chronic hepatitis C in renal transplant recipients: an open pilot study

Treatment of hepatitis C in renal transplant recipients remains a controversial issue, as interferon therapy has been associated with a high risk of rejection and poor efficacy. We report here the use of pegylated interferon-α, alone or in combination with ribavirin, in renal transplant recipients with chronic hepatitis C. Eight renal transplant recipients with chronic hepatitis C were recruited. The mean delay between renal transplantation and antiviral therapy was 198.8 months. Sustained virological response was observed in four of out eight patients. Three patients with sustained virological response were genotype 2, one was genotype 1; fibrosis stages were F1 for one patient, F2 for 2, F3 for one. At baseline, renal dysfunction was moderate in seven patients and severe in one patient. No patient experienced rejection episodes during or after pegylated interferon-α therapy. One patient developed haemolytic uraemic syndrome, which eventually resulted in graft loss and return to dialysis. In conclusion, for renal transplant recipients treated with pegylated interferon-α-based therapy, we observed a low risk of renal dysfunction, acceptable tolerance and significant virological efficacy. This is therefore the first study to suggest that pegylated interferon-α could be proposed late after transplantation to renal transplant recipients.     

The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer

Background

The role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma (ccRCC) is controversial.

Objective

To determine the outcome of patients with metastatic ccRCC who receive sunitinib prior to planned nephrectomy.

Design, setting, and participants

The study combined the data from two prospective phase 2 studies that assessed upfront sunitinib (12-16 wk) prior to nephrectomy in previously untreated patients with metastatic renal cell carcinoma (RCC). Sunitinib was discontinued during the perioperative period (median: 29 d).

Intervention

Sunitinib 50 mg in six weekly cycles (4 wk on, 2 wk off).

Measurements

Progression-free (PFS) and overall survival (OS) using the Kaplan-Meier method.

Results and limitations

Twenty-one patients (32%) had Memorial Sloan-Kettering Cancer Centre (MSKCC) poor-risk disease; 45 (68%) had intermediate-risk disease. Nephrectomy was not performed in 19 (29%), most commonly due to disease progression (n = 12). The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1-8.5). Seventeen (36%) patients progressed during the treatment break, 13 (76%) of whom stabilised upon reinitiating of sunitinib. The OS for the cohort was 15.2 mo (95% CI, 10.3-NA). The OS for the intermediate MSKCC risk group was significantly longer than that for the poor-risk group (26.0 mo [95% CI, 13.6-NA] and 9.0 mo [95% CI, 5.8-20.5], respectively; p < 0.01). In multivariate analysis, progression of disease prior to planned nephrectomy (hazard ratio [HR]: 5.34; 95% CI, 3.17-13.27), high Fuhrman grade (HR 3.27; 95% CI, 1.38-7.72), and MSKCC poor risk at diagnosis (HR 4.75; 95% CI, 2.05-11.02) were associated with short survival (p < 0.01). However, in the absence of randomised studies it is not possible to determine if this approach is beneficial.

Conclusions

Upfront sunitinib prior to planned nephrectomy in intermediate-risk disease is associated with a median survival of >2 yr despite frequent progression during treatment break. Progression in metastatic sites prior to planned surgery and MSKCC poor-risk disease was associated with a poor outcome.     

Type-I interferon receptor expression: Its circadian rhythm and downregulation after interferon-α administration in peripheral blood cells from renal cancer patients

Objectives:   To investigate the regulation of interferon-α (IFN-α) receptor expression in metastatic renal cell carcinoma (RCC) after IFN-α administration.
Methods:   Blood sampling was carried out in eight patients with metastatic RCC and six healthy volunteers. Flow-cytometric analysis using a monoclonal antibody against the active subunit of the type-I IFN-α receptor (IFNAR2) was carried out to examine the circadian rhythm of IFNAR2 expression in peripheral blood mononuclear cells (PBMC) as well as its downregulation after IFN-α administration.
Results:   According to its circadian rhythm IFNAR2 in PBMC had a peak expression at night. Once IFN-α is administered, IFNAR2 levels in PBMC showed downregulation within 48 h and recovered within another 48 h.
Conclusions:   Our findings might support the establishment of an optimal schedule for IFN-α administration.