Long-term complete response to very-low-dose interleukin-2 therapy in patients with metastatic renal cell carcinoma: report of two cases

Before the advent of molecular-targeted agents, immunotherapy using cytokines, such as interferon-α (IFN-α) and interleukin-2 (IL-2), had been the mainstay of treatment for patients with metastatic renal cell carcinoma (mRCC), and this therapy may still be occasionally recommended for such patients. In this report, we present two cases of mRCC who were treated with very-low-dose IL-2 therapy and subsequently achieved complete response (CR). Both cases received adjuvant IFN-α therapy following radical nephrectomy; however, multiple lung metastases developed 4 and 12 months after surgery, and low-dose IL-2 (0.7 million U/day) was then administered twice per week for 14 and 35 months, respectively. In both cases, metastatic lesions completely regressed 3 and 20 months after the start of IL-2 therapy, and these responses have persisted for 81 and 67 months, respectively, to date. These findings suggest that immunotherapy with IL-2, even at a very-low-dose setting, may achieve the induction of CR in mRCC; accordingly, IL-2-based immunotherapy should be considered as the initial treatment for appropriately selected patients with mRCC.     

Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-2a), for patients with metastatic melanoma.Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6–18 × 10⁶ IU/m²/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-2a was administered subcutaneously at 3 × 10⁶ IU three times each week until progression.Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 × 10⁹ (range, 1–43 × 10⁹), and the median period of culture was 52 days (range, 45–60). rIL-2 was administered at doses ranging between 6 and 18 × 10⁶ IU/m²/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2–35%).Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.     

Presence of the human leukocyte antigen class II gene DRB1*1101 predicts interferon gamma levels and disease recurrence in melanoma patients

Background Increased interferon γ (IFN-γ) levels are an independent predictor of melanoma recurrence. Human leukocyte antigen (HLA) class II genes can regulate cytokine production; we investigated whether these genes would predict IFN-γ levels and recurrence in melanoma patients. Methods Of 591 patients who presented with localized melanoma, 579 underwent identification of HLA class II alleles; 233 melanoma patients and 90 controls underwent determination of plasma IFN-γ levels. HLA class II genes were examined for association with IFN-γ levels and disease recurrence. Results After a median follow-up of 60 months, melanoma patients with IFN-γ levels above the mean control value were more likely to have developed disease recurrence compared with patients with levels below the mean. The HLA class II geneHLA-DRB1*1101 was the strongest predictor of recurrence, andHLA-DRB1*1101-positive melanoma patients had increased levels of IFN-γ compared with patients lacking the gene. Conclusions Among patients with localized melanoma, bothHLA-DRB1*1101 and increased IFN-γ levels were associated with an increased risk for recurrence;HLA-DRB1*1101-positive patients had relatively increased levels of IFN-γ. HLA class II genes may mediate cytokine production in melanoma patients, and this mechanism may help determine the risk of disease recurrence. Presented at the 53rd annual meeting of the Society of Surgical Oncology, Washington, DC, March 16, 2001.     

Metastatic type-2 papillary renal cell carcinoma responded to interleukin-2 therapy: case report

This report documents a case of metastatic papillary renal cell carcinoma (PRCC) which successfully responded to interleukin-2 (IL-2) therapy. A 59-year-old male presented with a left renal mass measuring 3.0 cm in diameter and a right adrenal mass measuring 5.0 cm in diameter. He underwent a left partial nephrectomy and a right adrenalectomy. The histological findings revealed pT1bN1M1 type-2 PRCC and metastatic renal cell carcinoma in the right adrenal gland. The patient was given interferon-α (IFN-α) after the operation for 3 months. A CT scan revealed a metastatic nodule measuring 6.0 cm in diameter near the surface of the liver at 4 months after the opereation. The patient was given interleukin-2 (IL-2), 7 × 10⁵ units/day intravenously, for 3 days per week. A CT scan revealed this hepatic nodule to have decreased in size from 6.0 to 4.0 cm after 4 months of IL-2 therapy. However, a new metastatic nodule measuring 6.0 cm in diameter was found which came in contact with the spleen. Next, the patient was given an increased dose of IL-2 from 7 × 10⁵ to 1.4 × 10⁶ units/day intravenously, for 3 days per week. At 9 months of follow-up after the dose escalation, a CT scan revealed a dramatic decrease in the size of these two metastatic nodules to 1.5 and 0.5 cm, respectively. This is a very rare case in that it represents a type-2 PRCC which dramatically responded to low-dose IL-2 therapy.     

Toxicity and effects of adjuvant therapy in colon cancer: results of the german prospective, controlled randomized multicenter trial fogt-1

In this adjuvant three-arm multicenter trial, we studied whether modulating the standard 5-fluorouracil (S-FU) treatment with either folinic acid (FA) or interferon-alpha-2_a (IFN-α) was superior to the recommended standard of adjuvant treatment in RO resected colon cancer, 5-FU plus levamisole (LEV) for 12 months, in terms of toxicity and outcome. From July 1992 to October 1999, a total of 813 patients with resected colon cancer in stage II (T4N0M0; n = 63) or stage III (TxNl-3M0; n = 750) were randomized into three treatment groups and stratified according to N stage and participating centers (64 hospitals). The patients received a postoperative loading dose of S-FU (450 mg/m² on days 1 to 5 [arms A and C]) or S-FU (450 mg/m²) plus FA (Rescuvolin, Medac, Hamburg, Germany, 200 mg/m² on days 1 to 5 [arm BJ). After completion of the first chemotherapy cycle, LEV was administered orally at a dosage of 1.50 mg per day on days 1 to 3, once every 2 weeks. After a 4-week chemotherapy-free interval, the treatment was continued weekly for 52 weeks. Treatment in one arm A ("standard") (n = 279) consisted of 5-FU intravenously (450 mg/m² on day 1, once a week) plus LEV 5-FU plus LEV was modulated in arm B (n = 283) with FA (200 mg/m² on day 1, once a week) and in arm C (n = 251) with IFN-α at 6 million units three times a week repeated weekly. Treatment dosages were adjusted if toxic events above WHO grade 2 occurred. Patients were closely followed to determine recurrence and survival; the latter was calculated according to Kaplan-Meier analysis. Toxic events above WHO grade 2, mainly leukopenia, diarrhea, and nausea, occurred in 113 (14%) of 649 patients who had completed treatment in arms A (8.4%), B (13.5%), and C (31.7%). Discontinuance rates were as follows: 28% for all patients, 29% in arm A, 21% in arm B, and 34% in arm C. Overall relapse rates were 27% for all patients, 30% in arm A, 24% in arm B, and 28% in arm C. Relapses were local (8%) distant (78%), or combined (12%). Fouryear overall survival rates in arms A, B, and C were 66.1%, 77.5%, and 66.2%, respectively. The 4-year survival rate in arm B was significantly higher compared to arm A (P <0.02, log-rank test) with arm A being equal to arm C. Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV for 12 months). IFN-α modulation of 5-FU (plus LEV) adds to the toxicity with no therapeutic benefit.     

Induction of angiogenesis and osteogenesis in surgically revascularized frozen bone allografts by sustained delivery of FGF‐2 and VEGF

Large conventional bone allografts are susceptible to fracture and nonunion due to incomplete revascularization and insufficient bone remodeling. We aim to improve bone blood flow and bone remodeling using surgical angiogenesis combined with delivery of fibroblast growth factor (FGF‐2) and vascular endothelial growth factor (VEGF). Frozen femoral allografts were heterotopically transplanted in a rat model. The saphenous arteriovenous bundle was implanted within the graft medullary canal. Simultaneously, biodegradable microspheres containing phosphate buffered saline (control), FGF‐2, VEGF, or FGF‐2 + VEGF were placed within the graft. Rats were sacrificed at 4 and 18 weeks. Angiogenesis was determined by quantifying bone capillary density and measuring cortical bone blood flow. Bone remodeling was assessed by histology, histomorphometry, and alkaline phosphatase activity. VEGF significantly increased angiogenesis and bone remodeling at 4 and 18 weeks. FGF‐2 did not elicit a strong angiogenic or osteogenic response. No synergistic effect of FGF‐2 + VEGF was observed. VEGF delivered in microspheres had superior long‐term effect on angiogenesis and osteogenesis in surgically revascularized frozen bone structural allografts as compared to FGF‐2 or FGF‐2 + VEGF. Continuous and localized delivery of VEGF by microencapsulation has promising clinical potential by inducing a durable angiogenic and osteogenic response in frozen allografts. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1556–1562, 2012     

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.     

A lower dose of thalidomide is better than a high dose in metastatic renal cell carcinoma

OBJECTIVE: To conduct a dose-finding trial using a single low dose and dose escalation of a higher dose of thalidomide in patients with metastatic renal cell carcinoma (RCC), and to evaluate the antineoplastic effectiveness of thalidomide as an anti-angiogenic agent on RCC. PATIENTS AND METHODS: The 14 patients enrolled in the study had progressive measurable metastatic RCC and consented to participate. Patients were randomized to either a fixed low dose of 200 mg of thalidomide or to a high dose of 800 mg that was increased to a maximum dose of 1200 mg daily. Patients were evaluated for response after 8 weeks of therapy. RESULTS: Stable disease was achieved in six patients and was seen in both the low-dose and high-dose thalidomide groups. The median overall survival was 9 months. The low-dose thalidomide regimen was better tolerated and patients survived longer than those on the high-dose regimen (16 vs 6 months, P = 0.04) CONCLUSION: The use of low-dose thalidomide in patients with metastatic RCC was well tolerated and they survived for longer than those on the high-dose regimen.     

Five-year survival results of subcutaneous low-dose immunotherapy with interleukin-2 alone in metastatic renal cell cancer patients

After the discovery of its essential role in anticancer immunity, IL-2 cancer immunotherapy has shown that comparable results may be obtained with different schedules, including intravenous high-dose IL-2 as a bolus or as a 24-hour intravenous infusion or prolonged subcutaneous injection of low-dose IL-2 with or without IFN-alpha. This study shows the long-term results obtained in 92 metastatic renal cell cancer (RCC) patients with low-dose subcutaneous IL-2, which was given at 3 million IU twice/day for 5 days/week for 6 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21-day rest period, followed by maintenance therapy consisting of 5 days of treatment every month until disease progression. Complete response (CR) was achieved in only 2/92 (2%) patients, and partial response (PR) was observed in 19 patients (21%). Therefore, the response rate (CR + PR) was 21/92 (23%), with a median duration of response of 25 months. Stable disease (SD) occurred in 37 patients (40%), whereas the other 34 (37%) had a progressive disease (PD). The response rate was significantly higher in patients with a disease-free interval of >1 year than in those with a lower interval, in patients with a high performance status (PS) than in those with a low PS, and in patients with sites of disease other than the liver. A 5-year survival was obtained in 9/92 (9%) patients, and the percent of survival was significantly higher in patients with a response or SD than in those with PD. The treatment was well tolerated in all patients. This study confirms that low-dose subcutaneous IL-2 alone in an effective and well tolerated therapy of metastatic RCC, with results comparable to those described with more aggressive and toxic IL-2 schedules.     

Influence of interferon-α2b (IFN-α2b) on the prevention of locally advanced bladder carcinoma in mice

In the model of chemically induced bladder carcinoma in mice following application of betahydroxylbutylnitrosamine (BBN) we could not detect a therapeutic influence of systemic treatment with intraperitoneal injection of interferon-α2b (10 × 3 × 10⁵ IU IFN-α2b) on the rate of locally advanced bladder carcinoma (IFN-α2b 37% versus control 41%) nor on the development of tumor precursors (severe dysplasia 100% in both groups). Received: 25 February 1998 / Accepted: 24 February 1999     

Computed tomography in staging of patients with melanoma metastatic to the regional nodes

Background: This study addresses the yield and clinical impact of computed tomography (CT) imaging in otherwise asymptomatic patients with stage III melanoma metastatic to the regional nodes. Methods: The database from the University of Michigan Mutlidisciplinary Melanoma Clinic was reviewed and identified 127 asymptomatic patients with stage III melanoma (regional nodal disease) who received CT scans of the head, chest, abdomen, and/or pelvis. Scans were confirmed as true positive, false positive, and normal. Results: Four hundred twenty-six head and body CT scans were performed at the time of presentation of stage III disease. Twenty patients had a true-positive CT scan revealing unsuspected metastases. Fifteen patients had abnormal CT scans subsequently shown to be a benign process or second malignancy. The incidence of true-positive CT scans was not different between the groups of patients who had clinically apparent versus occult nodal disease. There was a significantly higher incidence of abdominal and pelvic metastatic sites identified by CT scan in patients with inguinal nodal disease compared with axillary or head and neck node-positive patients. Conclusions: The yield of detection of unsuspected metastases by CT scans in asymptomatic patients with stage III melanoma was not insignificant. Because patients with resected stage III disease are recommended to have adjuvant interferon-α for 1 year, CT staging plays an important role in identifying appropriate candidates for treatment. The toxicity of interferon-α therapy is not insignificant. The value of routine CT in asymptomatic patients with nodal metastasis deserves further prospective study.     

Combined interferon alpha with levamisole in patients with metastatic renal cell carcinoma

To evaluate the efficacy and toxicity of interferon alpha-2b (IFN-2b) and levamisole treatment regimen in patients with metastatic renal cell carcinoma (RCC). Seventeen patients with metastatic RCC were treated using recombinant IFN-2b at a dose of 10 MU/m2 body surface subcutaneously three times in a week, for 3 months, with levamisole 50 mg t.d.s orally on days 1–3on alternate weeks. The mean follow-up period was 10.7 (range 2–23) months. We achieved 1 complete response (lasting for 12+months) and 1 partial response (lasting for 15 months), for an objective response rate of 11.7%. A further 7 patients (41%) had a stabilization of disease. The overall toxicity was moderate, with mainly grade I or II side effects. Grade III toxicities reported among 3 patients including vomiting (2 patients) and anorexia (1 patient). There was no treatment related death. Although additions of levamisole to IFN- do not result in any significant increase in treatment toxicity, the response rate appears to be no better than IFN- monotherapy reported in the literature.     

Isolated Limb Perfusion With Melphalan and Tumor Necrosis Factor α for Advanced Melanoma and Soft-Tissue Sarcoma

Background Isolated limb perfusion (ILP) with melphalan is used in the treatment of advanced in-transit melanoma but has no real efficacy for irresectable soft tissue sarcomas arising in the extremities. The addition of tumor necrosis factor (TNF)-α may increase response rates for bulky melanoma and for sarcoma, but the potential for major systemic toxicity has limited its use. Methods Between October 2000 and April 2004, 49 ILPs were performed with melphalan and TNF-α. All procedures were performed with continuous leakage monitoring and regional hyperthermia. Results Forty-nine ILPs were performed for melanoma (n = 30), sarcoma (n = 16), or other tumors (n = 3). The most common indications were widespread in-transit disease for melanoma (n = 29) and irresectable primary disease for sarcoma (n = 9). Complete and partial responses for melanoma were 40% and 37%, and for sarcoma they were 20% and 33%. At a median follow-up of 14 months, 66% of melanoma patients who responded had not experienced local progression, compared with only 37% of sarcoma patients. Progression-free survival was significantly less for patients with sarcoma than melanoma (P = .0476). Four of 16 patients with sarcoma subsequently required amputation for progressive disease. Conclusions ILP with melphalan and TNF-α is a valuable treatment for advanced in-transit melanoma. Significant response rates were also seen in irresectable sarcoma, although the duration of response was limited.     

Initial Clinical Response Predicts Outcome and Is Associated With Dose Schedule in Metastatic Melanoma and Renal Cell Carcinoma Patients Treated With High-Dose Interleukin 2

Background High-dose interleukin (IL)-2 is an effective agent for the treatment of metastatic malignant melanoma and renal cell carcinoma. This study evaluated the outcomes of patients receiving two commonly used intravenous IL-2 schedules that have never been directly compared.Methods Forty-seven metastatic malignant melanoma and renal cell carcinoma patients were identified from a prospective database who underwent high-dose IL-2 therapy (720,000 or 600,000 IU/kg) during 1999 to 2003. Disease-specific survival (DSS) was calculated by the Kaplan-Meier method with the log-rank test on an intention-to-treat basis. Multivariate Cox regression analysis of prognostic variables associated with outcome was performed. Factors associated with initial response and prevention of disease progression were determined.Results Objective response (5 partial and 5 mixed) or disease stabilization was noted in 9 (20%) and 10 (22%), respectively, of 46 assessable patients after 1 course of therapy. Four patients (22%) achieved disease-free status after the third course of IL-2 (n = 1) or surgical resection of confined metastatic disease (n = 3). At 19.1 months median follow-up, factors associated with improved DSS included an initial clinical response to IL-2 therapy (P < .001) and a higher administered dose (P = .04). Patients who received 720,000 IU/kg were more likely to experience an initial major objective response (P = .03) and disease stabilization (P = 0.03) independent of the tumor treated. Objective response early in the course of therapy was the only independent predictor of tumor-related mortality (P = .004).Conclusions The initial clinical response to IL-2 therapy is an independent predictor of improved outcome associated with DSS and the 720,000 IU/kg dose. These results support further prospective trials with increased IL-2 dose schedules in a larger cohort of patients.Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.     

Revascularization and bone remodeling of frozen allografts stimulated by intramedullary sustained delivery of FGF‐2 and VEGF

Frozen bone allografts are susceptible to nonunion and fracture due to limited revascularization and incomplete bone remodeling. We aim to revascularize bone allografts by combining angiogenesis from implanted arteriovenous (AV) bundles with delivery of fibroblast growth factor (FGF‐2) and/or vascular endothelial growth factor (VEGF) via biodegradable microspheres. Rat femoral diaphyseal allografts were frozen at ?80°C, and heterotopically transplanted over a major histocompatibility mismatch. A saphenous AV bundle was inserted into the intramedullary canal. Growth factor was encapsulated into microspheres and inserted into the graft, providing localized and sustained drug release. Forty rats were included in four groups: (I) phosphate‐buffered saline, (II) FGF‐2, (III) VEGF, and (IV) FGF‐2 + VEGF. At 4 weeks, angiogenesis was measured by the hydrogen washout method and microangiography. Bone remodeling was evaluated by quantitative histomorphometry and histology. Bone blood flow was significantly higher in groups III and IV compared to control (p < 0.05). Similarly, bone remodeling was higher in VEGF groups. FGF‐2 had little effect on allograft revascularization. No synergistic effect was observed with use of both cytokines. Delivered in microspheres, VEGF proved to be a potent angiogenic cytokine, increasing cortical bone blood flow and new bone formation in frozen allografts revascularized with an implanted AV bundle. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1431–1436, 2011     

Nephrotic syndrome associated with interferon-β-1b therapy for multiple sclerosis

A 43-year-old woman with multiple sclerosis (MS) had nephrotic syndrome 21 months after starting treatment with interferon (IFN)-β-1b (subcutaneous administration). She had taken no drug except for the IFN-β-1b. Because nephrotic syndrome may be induced by IFN therapy, the IFN was stopped. Percutaneous renal biopsy revealed that she had minimal change nephrotic syndrome. As nephrotic-range proteinuria, hypoalbuminemia, and general edema were worsening even 2 weeks after cessation of the drug, oral corticosteroid therapy (prednisolone 40 mg/day) was started. The nephrotic syndrome was treated successfully with prednisolone. The dosage of prednisolone was tapered, without a relapse, and then the corticosteroid therapy was stopped. IFN-β-1b therapy was then resumed, and the patient is in remission for both nephrotic syndrome and MS. Though proteinuria and nephrotic syndrome is a rare adverse effect of IFN-β-1b therapy, physicians treating MS patients with this agent should pay careful attention to new clinical symptoms and laboratory findings.     

A clinical trial with chimeric monoclonal antibody WX-G250 and low dose interleukin-2 pulsing scheme for advanced renal cell carcinoma

PURPOSE: WX-G250 is a chimeric monoclonal antibody that binds to carbonic anhydrase IX(G250/MN), which is present on greater than 95% of RCCs of the clear cell subtype. The suggested working mechanism of WX-G250 is by ADCC. Because the number of activated ADCC effector cells can be increased by a low dose interleukin-2 pulsing schedule, a multicenter study was initiated to investigate whether WX-G250 combined with LD-IL-2 could lead to an improved clinical outcome in patients with progressive RCC. MATERIALS AND METHODS: A total of 35 patients with progressive clear cell RCC received weekly infusions of WX-G250 for 11 weeks combined with a daily LD-IL-2 regimen. Patients were monitored longitudinally for ADCC capacity. Radiological assessment of metastatic lesions was performed at week 16 and regularly until disease progression. RESULTS: A durable clinical benefit was achieved in 8 of 35 patients (23%), including 3 with a partial response and 5 with stabilization at 24 weeks or greater. Mean survival was 22 months. In general treatment was well tolerated with little toxicity. The number of effector cells increased during treatment but lytic capacity per cell did not increase. ADCC and clinical outcome did not appear to correlate. CONCLUSIONS: WX-G250 combined with LD-IL-2 in patients with metastatic RCC is safe and well tolerated. With a substantial clinical benefit and a median survival of 22 months in patients with metastatic RCC who have progressive disease at study entry combination therapy showed increased overall survival compared to WX-G250 monotherapy. Survival was at least similar to that of currently used cytokine regimens but with a favorable toxicity profile.     

Interferon-alfa in the treatment of patients with inoperable locally advanced or metastatic renal cell carcinoma: a systematic review

A systematic review was undertaken to determine whether interferon-alfa (IFN-α) is an effective treatment for patients with inoperable locally advanced or metastatic renal cell carcinoma (mRCC). MEDLINE, EMBASE, the Cochrane Library, guideline databases and relevant meeting proceedings were searched. Randomized clinical trials (RCTs) or meta-analyses comparing IFN-α-containing regimens to placebo or non-immunotherapy controls, and that reported response rate, survival, toxicity or quality of life data were eligible. Two systematic reviews and eight RCTs met the selection criteria. A Cochrane review updated in 2005 reported higher response rates and reduced one-year mortality based on 4 RCTs in patients who received IFN-α. Of the eight RCTs, three reporting objective response rate showed significant differences favouring IFN-α. Two of five trials reporting survival data showed longer median survival in the IFN-α group. Adverse effects of IFN-α were consistent across the trials with increased intensity and frequency concordant with increased IFN-α dose. Meta-analyses of seven RCTs for objective response and six RCTs for mortality favoured IFN-α: odds ratio 6.87 (95% Confidence Interval [CI], 3.29 to 14.35) and hazard ratio 0.79 (95% CI, 0.69 to 0.91), respectively. The effectiveness of IFN-α in mRCC has been subject to skepticism. As IFN-α has been used as a control arm in RCTs of new targeted therapies, therapies which not all patients may have access to, information about its effectiveness remains relevant. These data confirm genuine, if modest, effectiveness of IFN-α in mRCC.     

Combined chemotherapy of irinotecan and low-dose cisplatin (I/low-P) against metastatic biliary tract cancer

There is no established or effective standard therapy for metastatic biliary tract cancer, resulting in poor prognosis. Recently, we performed combination chemotherapy of irinotecan and low-dose cisplatin (I/low-P) for three consecutive patients with metastatic biliary tract cancer. The regimen of I/low-P therapy consisted of irinotecan (60 mg/m²) and low-dose cisplatin (6 mg/m²), administered by intravenous infusion weekly or biweekly. Of the three patients, two showed a partial response, with durations of more than 20 months, and 2 months, respectively, while the third patient had stable disease for 3 months. One patient, who had jaundice, had grade 3 thrombocytopenia, but the other patients did not have any severe toxicities. Survival times were more than 20 months, 10 months, and 13 months, respectively. These outcomes suggest that I/low-P therapy is safe and may be worth trying as a first-line chemotherapy for patients with metastatic biliary tract cancer.