isotretinoin and Carcinoma--Renal-Cell

Metastatic renal cell carcinoma remains one of the most treatment-resistant malignancies in humans. As such, long-term survival is limited to a minority of patients. Interferon-alpha and interleukin-2 induced major responses in some patients with renal cell carcinoma, and in so doing generated a great deal of interest and hope. However, clinical benefit is limited to relatively few patients. Here, we briefly discuss the management of metastatic renal cell carcinoma, and then elaborate on several novel treatment approaches in development, including retinoids, monoclonal antibodies, and antiangiogenesis strategies.

Topics: Adjuvants, Immunologic; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Combined Modality Therapy; Humans; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Neoplasm Metastasis; Prognosis; Retinoids

Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids and have synergistic anti-tumor activity when combined. We performed a Phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor vorinostat and isotretinoin in patients with advanced renal cell carcinoma (RCC). Vorinostat was administered at 300 mg orally twice daily in combination with escalating doses of isotretinoin for 3 consecutive days per week. A standard 3 + 3 dose escalation design was used. Dose limiting toxicities (DLT) were assess during the first cycle to determine the maximum tolerated dose (MTD). Fourteen patients enrolled on the trial of which 12 were evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. One patient in cohort 1 experienced a DLT (grade 3 depression). Common grade 1-2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). MTD was established as vorinostat 300 mg with isoretinoin 0.5 mg/kg twice daily 3 days per week. Best responses in evaluable patients included 1 partial response and 9 stable disease, lasting a median of 3.7 months (range 1.8-10.4 months). The combination of vorinostat and isotretinoin is safe, tolerable and associated with responses in patients with refractory metastatic RCC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Isotretinoin; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Progression-Free Survival; Vorinostat

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-alpha2a (sc-IFN-alpha2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate < or =70 mm h(-1) and neutrophil counts < or =6000 microl(-1) (group I) were randomised to arm A: sc-IL-2, sc-IFN-alpha2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-alpha2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoma, Renal Cell; Deoxycytidine; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Germany; Humans; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins; Survival Analysis

A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-alpha-2a) was superior to IFN-alpha-2a alone in patients with progressive metastatic renal cell carcinoma.. Three hundred twenty patients were randomly assigned to treatment with IFN-alpha-2a plus 13-CRA or to IFN-alpha-2a alone. IFN-alpha-2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU by increments of 3 MU. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN-alpha-2a.. Median time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN-alpha-2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN-alpha-2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN-alpha-2a and 13-CRA, and 13.2 months for patients treated with IFN-alpha-2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN-alpha-2a.. Progression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN-alpha-2a plus 13-CRA were significantly longer compared with patients on IFN-alpha-2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Recombinant Proteins; Survival Analysis; Treatment Outcome

We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma.. Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN-alpha-2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN-alpha-2a and IV vinblastine.. Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P =.0248). Both arm A (median overall survival, 25 months; P =.0440) and arm B (median overall survival, 27 months; P =.0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN-alpha-2a-based therapies were moderately or well tolerated.. Our results established the safety and improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF-alpha-2a-based outpatient immunochemotherapies, compared with sc-INF-alpha-2a/IV vinblastine.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Female; Fluorouracil; Humans; Immunotherapy; Infusions, Intravenous; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Survival Rate; Treatment Outcome; Vinblastine

In patients with metastatic renal cell carcinoma (MRCC), interferon-alpha (IFN) monotherapy leads to response rates of 5-15%, dependent on the selection of patients. In 1995, preclinical and clinical data indicated an improvement of these results if IFN was combined with 13-cis retinoic acid (CRA).. In a randomized Phase II study, patients with measurable MRCC received either subcutaneous IFN (9 MU daily; Arm A) or the same daily subcutaneous dose of IFN plus oral CRA (1 mg/kg; Arm B). A central expert panel reviewed the X-ray documentation of objective responses.. In the 50 eligible patients from Arm A, the objective, expert-reviewed response rate was 6% (95% confidence interval [95% CI], 1.3-16.6%; 2 complete responses [CRs] and 1 partial response [PR]). A 19% response rate (95% CI, 9.4-32.0%) was stated for 53 eligible patients from Arm B (2 CRs and 8 PRs). Only one of the four CRs claimed by the clinical investigator was confirmed by the central review committee. Conversely, the expert committee deemed that 3 of 12 investigator-stated PRs were CRs. Constitutional toxicity (flu-like symptoms) and/or side effects from skin, mucosa, or eyes led to discontinuation of treatment in 22% of nonprogressing patients, more often in Arm B than in Arm A.. The results from this randomized Phase II study support expansion of the trial into a Phase III study to evaluate the effect of IFN-CRA combination therapy on the survival of patients who undergo nephrectomy prior to IFN-based immunotherapy. The considerable interobserver variability of response evaluation (individual investigator vs. expert panel) indicates the necessity of a central review of claimed responses in future Phase II studies involving patients with MRCC.

Topics: Adult; Aged; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Europe; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Probability; Prognosis; Recombinant Proteins; Reference Values; Risk Assessment; Survival Analysis; Treatment Outcome

We conducted a prospective quality-of-life analysis during outpatient immunotherapy in 22 patients with progressive metastatic renal cell carcinoma (RCC) treated with subcutaneous interferon-alpha2a and subcutaneous interleukin-2. Patients' quality of life was assessed by the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before (week 0) and once during immunotherapy (week 3). Advanced renal cancer patients completed a total of 30 questionnaires before therapy (week 0) and after 3 weeks of therapy. Their mean quality of life (global-quality-of-health status) deteriorated significantly, from 64 to 41 (P

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Health Status; Humans; Injections, Subcutaneous; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Outpatients; Prognosis; Quality of Life; Treatment Outcome

The goal of the current report was to demonstrate the long-term efficacy of outpatient subcutaneous (sc) interferon alpha (IFN-alpha) and sc interleukin 2 (IL-2)-based combination regimens in patients with metastatic renal cell carcinoma.. In three consecutive clinical trials, 443 patients received combined sc IFN-alpha and sc IL-2 (n = 97 patients); combined sc IFN-alpha, sc IL-2, and intravenous (iv) 5-fluorouracil (5-FU) (n = 260 patients); or combined sc IFN-alpha, sc IL-2, and iv 5-FU with oral 13cis-retinoic acid (n = 86 patients).. The median overall survival was 21+ months. The 2-year, 5-year, and 13-year survival rates were calculated at 45.26%, 15.96%, and 8.96%, respectively. The median time to disease progression was 6 months. The 2-year, 5-year, and 13-year progression free survival rates were 17.84%, 9.54%, and 9.20%, respectively.. The current data suggest that combined outpatient sc IFN-alpha and sc IL-2, according to the Atzpodien regimen, achieves long-term survival benefits in a subset of patients with metastatic renal cell carcinoma, both with and without 13-cis-retinoic acid and/or 5-fluorouracil.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Outpatients; Recombinant Proteins; Survival Analysis

The aim of this study is firstly to determine the response rates and toxicity of two regimens containing vinblastine (VBL) in combination with interferon-gamma (IFN-gamma) in the treatment of patients with advanced renal cell carcinoma (RCC), and secondly to evaluate the additional efficacy of 13-cis retinoic acid (13-CRA) in RCC.. Twenty-nine patients were included in the first trial (Trial 1) and 40 in the second one (Trial 2). The therapy given in Trial 1 consisted of VBL 0.15 mg/kg i.v. every 2 weeks and IFN-gamma 100 microg s.c. 3 times weekly. In Trial 2, the therapy consisted of the same two drugs, in the same doses, plus oral 13-CRA 40 mg/day.. In Trial 1 there were 3 (10.3%) patients with complete response, 3 (10.3%) patients with partial response, 8 (27.6%) patients with stable disease and 15 (51.7%) patients with progressive disease. In Trial 2, there was no complete response, however, 3 (7.5%) patients had partial response. Additionally, 15 (37.5%) patients maintained stable disease and 14 (35%) patients had progressive disease. In Trial 1, the median survival was 12.56 months (95% CI, 6.8-18.3, range 0.59-42.49) and the median time to progression was 3.21 months (95% CI, 1.7-4.7, range 0.03-42.49). In Trial 2, the median survival was 9.54 months (95% CI, 5.9-13.1, range 0.43-24.1) and the median time to progression was 3.9 months (95% CI, 0.8-7, range 0.26-24.1). In Trial 1, granulocytopenia grade 3 and 4 appeared in 5 (17.2%) patients and anaemia grade 3 in 1 (3.4%) patient. In Trial 2, there were grade 3 toxicities, as granulocytopenia in 5 (12.5%) patients, anemia in 4 (10.0%) patients, stomatitis in 3 (7.5%) patients, fatigue/malaise in 3 (7.5%) patients and 1 (2.5%) had diarrhea. No toxic deaths occurred in both studies.. The use of IFN-gamma does not enhance the low response of VBL-based chemotherapy. The additional administration of 13-CRA with the combination of VBL and IFN-gamma does not add to the efficacy of this combination in patients with advanced renal cell carcinoma. New active agents are needed to treat patients with this disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Humans; Interferon-gamma; Isotretinoin; Kidney Neoplasms; Middle Aged; Neoplasm Staging; Survival Analysis; Time Factors; Vinblastine

Retinoids and interferon alpha have shown synergistic activity against metastatic renal cell carcinoma in previous preclinical and clinical studies. Based on these results, we conducted a phase II trial of 13-cis-retinoic acid (cRA) at 1 mg/kg/dose interferon alpha2a (IFN) at initial dose of 9 MU three times a week. Thirty-one patients were entered, all evaluable for toxicity and 30 evaluable for response. One patient achieved a partial response and 10 patients achieved stable disease. Toxicity was mild and primarily related to interferon. No toxic deaths were reported. Median survival time was 10 months. At the dose and schedule used, cRA and interferon-alpha2a showed low activity against metastatic renal cell carcinoma. Further studies with this combination are not recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Recombinant Proteins; Survival Analysis

It is suggested that immunotherapy may have a better role than cytotoxic chemotherapy in the treatment of metastatic renal cell carcinoma.. A phase II study of alpha-interferon 2a (IFN2a) and 13-cis-retinoic acid (CRA) in the treatment of metastatic renal cell carcinoma.. Twenty-two patients with no previous systemic therapy were treated with IFN2a daily at 3 million units (MU) and escalated to 6 and 9 MU if tolerated, together with CRA given orally at 1 mg/kg per day in two divided doses. Changes in quality of life were also assessed.. Twenty patients were available for assessment. Three patients (14%) achieved a partial response and five patients (23%) had stable disease. No patient achieved a complete response. A durable response was observed in partial responders with median length of response of 44 weeks (range 32-59 weeks). Therapy was stopped in seven (35%) patients due to treatment-related toxicities, and quality of life was worsened in the majority of patients.. IFN2a and CRA has a low response rate and significant toxicity, and the combination as standard treatment of metastatic renal cell carcinoma is not recommended, despite the suggestion that CRA may lengthen the response to IFN2a.

Topics: Adult; Aged; Biopsy, Needle; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Recombinant Proteins; Survival Rate; Treatment Outcome

Interferon and 13-cis-retinoic acid (13-CRA) therapy showed clinical response rates of 30% in advanced renal cell carcinoma (RCC). This combination also enhanced sensitivity to paclitaxel in a bcl-2 and mutant p53 expressing renal carcinoma cell line. Based on this, the authors conducted a Phase II clinical trial of the combination of interferon, 13-CRA, and weekly paclitaxel, in advanced RCC.. The eligibility criteria consisted of unresectable or metastatic RCC, measurable disease, a Southwest Oncology Group performance status of 0-2, and adequate bone marrow, hepatic, and renal function. Prior cytotoxic or immunologic treatment including interferon was permitted. Paclitaxel was administered at a dose of 80 mg/m(2) as a 1-hour intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. Interferon was administered at a dose of 3 million units subcutaneously daily and 13-CRA at 1 mg/kg/day orally in 2 divided doses for the first 21 days of each cycle.. Twenty-one patients were enrolled with a median age of 52 years, 16 males and 5 females, 10 patients with no prior therapy, 5 each with prior interleukin-2 or interferon therapy, and 1 patient with both. Four patients had also received prior investigational chemotherapy. A total of 61 cycles were administered with a median of 2 per patient. Grade 3 and 4 toxicities were neutropenia in three patients, anemia in four patients, and asthenia, skin rash, and hypersensitivity reaction in one case each. Of the 20 evaluable patients, one objective partial response was observed for a duration of 7+ months. Seven patients had disease stabilization. The median survival of the entire population was 9.5 months (range, 4-18+ months).. The combination of 13-CRA, interferon, and weekly paclitaxel was well tolerated and had minimal efficacy in advanced RCC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Treatment Outcome

The aim of this study was to determine the response rates and toxicity of two regimens containing granulocyte-macrophage-colony stimulating factor (GM-CSF) in combination with interleukin-2 (IL-2) in the treatment of patients with metastatic renal cell carcinoma.. Therapy given in the first trial (Trial 1) consisted of irradiation to the primary tumor or metastatic site, followed by GM-CSF 100 microg/day administered subcutaneously (sc) for 2 weeks and IL-2 11x10(6) IU sc 4 days per week for 4 weeks. In the second trial (Trial 2), the therapy consisted of GM-CSF 125 microg/day sc for 2 weeks, followed by IL-2 11x10(6) IU sc 4 days per week and interferon-alpha 10x10(6) IU sc 2 days per week for 4 weeks, plus oral 13-cis-retinoic acid 1 mg/kg daily for 4 weeks.. There were no responses among 20 patients in Trial 1, but 3 patients had stable disease. There was 1 partial responder (5%) of 20 evaluable patients in Trial 2 who achieved a complete response with surgical resection. An additional 3 patients maintained stable disease, 2 of whom were rendered disease free by resection of the renal primary and a single metastatic site. The 1-year survival rate was 75% (95% confidence interval [CI], 50-89) in Trial 1 and 48% (95% CI, 20-71) in Trial 2. In Trial 1, Grade 3 toxicities included fever, fatigue, anorexia, nausea/vomiting, hyperbilirubinemia, and mental status change. Toxicity was more frequent in Trial 2 and included Grade 3 fever, fatigue, anorexia, mucositis, and dermatitis. One on-study death may have been therapy-related.. GM-CSF does not enhance the low response rate of IL-2-based immunotherapy for patients with metastatic renal cell carcinoma. New active agents are needed to treat patients with this disease.

Topics: Administration, Oral; Adult; Aged; Anorexia; Antineoplastic Agents; Carcinoma, Renal Cell; Confidence Intervals; Fatigue; Female; Fever; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Injections, Subcutaneous; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Radiotherapy, Adjuvant; Remission Induction; Survival Rate

Treatment of patients with metastatic renal cell cancer (RCC) with interferon-alpha-2a (IFN) and 13-cis-retinoic acid (CRA) was first reported to be tolerable on an outpatient basis and to yield a 30% objective response rate. We sought to confirm these preliminary results by conducting a phase II trial of therapy with IFN/CRA in patients with bidimensionally measurable RCC. Twenty-five patients were enrolled. The median age was 58 (range, 47-75 years) and the median Karnofsky performance status was 90 (range 60-100). Seventeen patients (60%) had undergone prior nephrectomy and none had received prior systemic therapy. Treatment consisted of oral CRA at 1 mg/kg/day and IFN self-administered by subcutaneous injection at 3 MU/day with weekly escalation to 6 and 9 MU/day. Treatment was well tolerated, with cheilitis, influenza-like symptoms, and fatigue the most common toxicities. Severe toxicity was reversible and consisted of grade 4 cheilitis in one patient and grade 3 malaise/fatigue in two patients. One complete and four partial responses were observed, for an objective response rate of 20% (95% confidence interval, 4-36%). We conclude that treatment with CRA/IFN for RCC is tolerable on an outpatient basis and induces objective responses in some patients. The contribution, if any, of CRA to the responses observed will be determined in ongoing randomized phase III trials.

Topics: Administration, Oral; Aged; Carcinoma, Renal Cell; Combined Modality Therapy; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

A randomized phase III trial was conducted to determine whether combination therapy with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFNalpha2a) is superior to IFNalpha2a alone in patients with advanced renal cell carcinoma (RCC).. Two hundred eighty-four patients were randomized to treatment with IFNalpha2a plus 13-CRA or treatment with IFNalpha2a alone. IFNalpha2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU (by increments of 3 MU), unless >/= grade 2 toxicity occurred, in which case dose escalation was stopped. Patients randomized to combination therapy were given oral 13-CRA 1 mg/kg/d plus IFNalpha2a. Quality of life (QOL) was assessed.. Complete or partial responses were achieved by 12% of patients treated with IFNalpha2a plus 13-CRA and 6% of patients treated with IFNalpha2a (P =.14). Median duration of response (complete and partial combined) in the group treated with the combination was 33 months (range, 9 to 50 months), versus 22 months (range, 5 to 38 months) for the second group (P =.03). Nineteen percent of patients treated with IFNalpha2a plus 13-CRA were progression-free at 24 months, compared with 10% of patients treated with IFNalpha2a alone (P =.05). Median survival time for all patients was 15 months, with no difference in survival between the two treatment arms (P =.26). QOL decreased during the first 8 weeks of treatment, and a partial recovery followed. Lower scores were associated with the combination therapy.. Response proportion and survival did not improve significantly with the addition of 13-CRA to IFNalpha2a therapy in patients with advanced RCC. 13-CRA may lengthen response to IFNalpha2a therapy in patients with IFNalpha2a-sensitive tumors. Treatment, particularly the combination therapy, was associated with a decrease in QOL.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Models, Statistical; Multivariate Analysis; Quality of Life; Recombinant Proteins; Statistics, Nonparametric; Surveys and Questionnaires; Survival Analysis; Treatment Outcome

To evaluate the therapeutic effects and systemic toxicities of a capecitabine-based home therapy regimen in patients with metastatic renal cell carcinoma, 30 patients were enrolled in a phase II clinical trial. Treatment consisted of oral capecitabine combined with subcutaneous recombinant human interferon-alpha 2a, recombinant human interleukin-2 and oral 13-cis-retinoic acid. There were two (7%) complete responses (CRs) and eight (27%) partial remissions (PRs), for an overall objective response rate of 34% (95% CI 17-53%). Except one, all responses are ongoing, with a median duration of 9+ and 8+ months for CRs and PRs, respectively. Additionally, 12 patients (40%) reached stable disease. Eight patients (27%) showed continued disease progression despite treatment. Therapy was well tolerated and was given in the outpatient setting. Capecitabine-related World Health Organization (WHO) grade 2 and 3 toxicities were observed in five and two patients respectively, and were limited to fatigue, nausea/vomiting, diarrhoea, stomatitis, dermatitis and hand-and-foot syndrome. The substitution of capecitabine for 5-FU in the pre-existing biochemotherapy regimen did not result in a reduced therapeutic efficacy and showed significant anti-tumour activity in patients with advanced renal cell carcinoma.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Capecitabine; Carcinoma, Renal Cell; Deoxycytidine; Female; Fluorouracil; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Treatment Outcome

To determine the response rate and toxicity of oral 13-cis-retinoic acid (CRA) added to an outpatient regimen of subcutaneous interleukin-2 (IL2) and interferon-alpha (IFNA) in previously untreated patients with metastatic renal-cell carcinoma (RCC).. Eligibility included a performance status of 2 or better, no significant end-organ dysfunction, and written informed consent. Characteristics of 47 of 48 assessable patients included a median performance status of 0, prior nephrectomy in 68% of patients, one metastatic site in 30% of patients, and lung-only metastatic disease in 21% of patients. Therapy consisted of IL2 11 x 10(6) IU 4 days per week for 4 weeks, IFNA 9 x 10(6) IU 2 days per week for 4 weeks, and CRA 1 mg/kg daily on a 6-week cycle.. Eight of 47 patients (17%) responded (one complete response, seven partial responses). Three partial responders were rendered disease free by subsequent surgical resection. Four additional patients experienced a minor response in lung or soft tissue metastases. The median duration of response, which included minor responses, was 42 weeks, and median survival was 74 weeks (17 months). Grades 3 or greater toxicities during the first cycle included flu-like symptoms (21% of patients), fatigue (6% of patients), and nausea and vomiting (15% of patients). Significant cumulative toxicities were hyperlipidemia (four of 18 patients), and cardiomyopathy (one of 18 patients). There was one therapy-related death.. Outpatient CRA plus IL2 and IFNA is feasible and modestly effective in metastatic RCC. The prolonged median survival is encouraging, but randomized trials are required to show that the combination represents an improvement over single-agent immunotherapy.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Survival Rate

Eleven patients, pre-treated with chemotherapy and immunotherapy, with renal cell carcinoma were given 13-cis-retinoic acid (CRA) in association with interferon alfa-2a (IFN 2a). 13-ci retinoic acid was administered at the dose of 1 mg/Kg/die while interferon alfa-2a at the dose of 3X10 U.I./die s.c. All patients had been previously treated with chemotherapy in association with immunotherapy. Therapy was not discontinued until neoplastic progression occurred. Clinical results were as follows: partial responses (PR) were observed in two patients, disease stabilization (SD) in 5 and progression (PD), with 8-month median treatment duration, in 4. Side effects were mild.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Middle Aged; Recombinant Proteins

We conducted a phase I/II clinical trial evaluating the sequential outpatient combination of S.C. recombinant human interleukin-2 (rIL-2; given at 10 MIU/m2 b.i.d. on days 3-5 weeks 1 and 4 and at 5 MIU/m2 on days 1, 3, and 5 of weeks 2 and 3), s.c. recombinant human alpha-interferon (rIFN-alpha; given at 6 MIU/m2 on day 1 of weeks 1 and 4 and on days 1, 3, and 5 of weeks 2 and 3 and at 9 MIU/m2 on days 1, 3, and 5 of weeks 5-8), i.v. bolus 5-fluorouracil (5-FU; given at 1,000 mg/m2 once weekly during weeks 5-8), and i.v. bolus vinblastine (given at 6 mg/m2 once weekly during weeks 5 and 8) in conjunction with p.o. 13-cis-retinoic acid (13-C-RA; given at 35 mg/m2 daily during weeks 1-8). Therapy was always given in the outpatient setting. Grade 3 constitutional symptoms (malaise, chills, fevers, anorexia) were observed in 4%-8% of treatment cycles and required a 50% reduction in the doses of rIL-2 and rIFN-alpha. None of the patients experienced major 5-FU-related toxicities such as severe diarrhea and/or stomatitis; up to 20% of patients developed vinblastine-associated peripheral polyneuropathy, which was reversible after the cessation of therapy. 13-cis-Retinoic acid produced no significant side effect; no toxic death occurred. Among 24 patients with progressive metastatic disease, there were 4 complete remissions (lung, lymph nodes) and 6 partial remissions (lung, pleura, liver, lymph nodes, and peritoneal carcinosis), for an overall objective response rate of 42% (95% confidence interval, 22%-63%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Combined Modality Therapy; Female; Fluorouracil; Humans; Interferon Type I; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Remission Induction; Treatment Outcome; Vinblastine

A phase II trial of interferon alfa-2a (IFN) and 13-cis-retinoic acid (CRA) was conducted in patients with renal cell carcinoma (RCC). In vitro studies were performed to investigate potential mechanisms of interaction.. Forty-four patients were treated. IFN was given daily at 3 MU and escalated to 6 and 9 MU if tolerated. The dose of CRA was 1 mg/kg/d. The effects of combining CRA and IFN on the proliferation of five RCC cell lines were examined, and retinoid sensitivity was correlated to the expression of retinoic acid receptors.. Thirteen (30%) of 43 assessable patients achieved a major response (three complete and 10 partial). Responding sites included bone metastases and renal primary tumors. Seven responding patients remain progression-free at 10+ to 19+ months. The response proportion was higher than in our prior experience with IFN, which was 10% in 149 patients. Eleven of 12 renal cancer cell lines were resistant to CRA alone; one, SK-RC-06, showed 90% inhibition of cell growth. CRA augmented the antiproliferative effect of IFN in several IFN-sensitive cell lines, but not in IFN-resistant lines. Northern blot analysis showed that expression of retinoic acid receptor-beta (RAR-beta) was repressed and not induced by retinoic acid in retinoic acid-insensitive RCC lines. However, RAR-beta expression was induced by retinoic acid in SK-RC-06 cells.. IFN and CRA showed antitumor activity in patients with advanced RCC, and the proportion and nature of response suggested CRA added therapeutic benefit to IFN. A phase III randomized trial of IFN plus CRA versus IFN alone and a phase II trial of single-agent CRA have been initiated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blotting, Northern; Carcinoma, Renal Cell; Combined Modality Therapy; Drug Synergism; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Receptors, Retinoic Acid; Recombinant Proteins; Remission Induction; Tumor Cells, Cultured

Histone deacetylase (HDAC) inhibitors have been shown to reverse epigenetic repression of certain genes, including retinoic acid receptor beta2 (RARbeta2). In this study, we examined whether RARbeta2 expression is repressed in human renal cell carcinoma (RCC) and whether the HDAC inhibitor MS-275 may revert its epigenetic repression.. Six human tumor RCC cell lines were analyzed for RARbeta2 gene expression and for methylation and acetylation status at the promoter level. Modulation of RARbeta2 expression and correlation with antitumor activity by combination of MS-275 with 13-cis-retinoic acid (CRA) was assessed in a RARbeta2-negative RCC cell line.. RARbeta2 expression was either strongly present, weakly expressed, or absent in the RCC cell lines analyzed. Methylation-specific PCR indicated that the RARbeta2 promoter was partially methylated in three of the cell lines. CRA treatment did not inhibit clonogenic growth in the RARbeta2-negative cell line RCC1.18, whereas MS-275 induced a dose-dependent inhibitory effect. A greater inhibitory effect was observed with combination treatment (MS-275 + CRA). Treatment with MS-275 was associated with histone acetylation at the promoter level and synergistic gene reexpression of RARbeta2 in combination with CRA. RARbeta2 reexpression was associated with synergistic induction of the retinoid-responsive gene HOXA5. In vivo, single-agent CRA treatment showed no significant effect, whereas MS-275 and the combination induced a regression of RCC1.18 tumor xenografts. Discontinuation of treatment produced tumor recurrence in MS-275-treated mice, whereas animals treated with the combination remained tumor free.. The HDAC inhibitor MS-275 seems to revert retinoid resistance due to epigenetic silencing of RARbeta2 in a human RCC model and has greater antitumor activity in combination with CRA compared with single agents. Thus, the combination of HDAC inhibitors and retinoids may represent a novel therapeutic approach in patients with RCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Homeodomain Proteins; Humans; Isotretinoin; Kidney Neoplasms; Male; Mice; Mice, Nude; Mice, SCID; Phosphoproteins; Pyridines; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Tretinoin; Xenograft Model Antitumor Assays

Chemoimmunotherapy (CIT) with interleukin-2, interferon-alpha2a, and 5-fluorouracil is an accepted treatment option of metastatic renal cell carcinoma (mRCC). Because of the enhancement of the antiproliferative effects of interferon-alpha2a, 13-cis-retinoic acid (13-CRA) might be of potential usefulness for immunotherapy. We have investigated the effect of 13-CRA in patients treated with chemoimmunotherapy. Seventy-two patients with mRCC and a Karnofsky performance index > or = 80% were retrospectively analyzed. Thirty-six patients received chemoimmunotherapy and 36 other patients were treated similarly but with addition of daily 60 mg 13-CRA. Response was assessed according to the UICC criteria. Survival was calculated by Kaplan Meier estimation and compared with the log-rank test. In the CIT group objective remissions occurred in 34.3% (95% CI 19.1-52.2) and stabilizations in 42.9% (median follow-up 16 months). In the CIT plus 13-CRA group, objective remissions were seen in 26.4% (95% CI 12.9-44.4) and stabilizations in 50% (median follow-up 17 months). One- and three-year survival rates were 76% and 32% in the CIT group and 82% and 37% in the CIT plus 13-CRA group. The combination of CIT and 13-CRA did not significantly differ in objective remissions and estimated survival compared with CIT. Our retrospective data suggest that 13-CRA does not enhance the therapeutic efficacy of CIT in mRCC patients with a good performance status.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Division; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Immunotherapy; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Recombinant Proteins; Remission Induction; Retrospective Studies; Survival Rate

The clinical outcome of interferon-gamma treatment of metastatic renal cell carcinoma remains unsatisfactory. To overcome this, a reagent that has a different action on cancer cells is desired. One such candidate may be 13-cRA (cis retinoic acid), a vitamin A derivative known to markedly regulate the differentiation and proliferation of normal and neoplastic cells. Moreover, 13-cRA demonstrates a remarkable synergistic effect with IFN-gamma in certain types of cancer. We investigated the efficacy of concomitant administration of 13-cRA and IFN-gamma. The in vivo anti-tumor effects were evaluated in a lung metastasis model using a mouse renal cell carcinoma cell line (RenCa). The in vitro anti-tumor effects were also assessed by MTT assay. The presence of retinoic acid receptors (RAR)-alpha, -beta and -gamma was examined by PCR analysis. The influence of IFN-gamma on these retinoic acid receptors was evaluated by Northern blotting. IFN-gamma showed anti-tumor effects both in vivo and in vitro. This effect was enhanced synergistically with concomitant 13-cRA treatment. RenCa cells expressed RAR-alpha, and -gamma, but not -beta according to PCR analysis. IFN-gamma treatment increased the expression level of RAR-alpha and RAR-gamma according to Northern blot analysis. Combination therapy using IFN-gamma and 13-cRA showed synergistic anti-tumor effects, which exceeded those of each therapy alone. Moreover, IFN-gamma treatment increased RAR-alpha and RAR-gamma expression. Thus, the augmented anti-tumor effects of IFN-gamma and 13-cRA may be attributable to enhanced expression of RAR-alpha and RAR-gamma by IFN-gamma treatment.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; DNA Primers; Drug Synergism; Female; Interferon-gamma; Isotretinoin; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; RNA, Messenger; Tumor Cells, Cultured

Retinoic acid (RA) can potentiate the antitumor effect of interferons (IFN) in a variety of tumor types, including renal cell carcinoma (RCC). The mechanisms by which RA and IFN increase the antitumor effects in RCC are unknown. We used growth assays and mobility shift assays to examine the effects of combining 13-cis-retinoic acid (CRA) and IFN-alpha (plus IFN-gamma) on proliferation and on the expression of the IFN-specific transcription factor IFN-stimulated gene factor 3 (ISGF3) in RCC cell lines. Combining CRA and IFN-alpha resulted in a significant increase in growth inhibition in four cell lines compared with IFN-alpha or CRA alone. Binding of nuclear extracts from RCC cells to an IFN-stimulated response element (ISRE) oligonucleotide probe following incubation with IFN-alpha was not increased by CRA but was significantly increased by pretreatment by IFN-gamma in a time-dependent fashion. Proliferation assays showed that sequential addition of IFN-gamma and IFN-alpha significantly increased growth inhibition. IFN-alpha but not IFN-gamma or CRA increased the cellular levels Stat2 and p48 but not Statl. IFN-gamma pretreatment enhanced the upregulation of p48 levels by IFN-alpha. Combining RA and IFN results in additive growth inhibition on RCC cell lines. This increase in growth inhibition is not mediated by increased ISGF3 expression.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Division; Drug Interactions; Drug Synergism; Humans; Interferon-alpha; Interferon-gamma; Isotretinoin; Kidney Neoplasms; Signal Transduction; Tretinoin; Tumor Cells, Cultured

The synergistic anti-tumor effect of 13-cis retinoic acid (13-cRA) and interferon-alpha/beta (IFN-alpha/beta) was investigated using a highly metastatic mouse renal cell carcinoma cell subline (RenCa/F). Although 13-cRA inhibited tumor growth in vivo as well as in vitro, IFN-alpha/beta did not. Combined administration of 13-cRA and IFN-alpha/beta significantly enhanced the anti-tumor effect of 13-cRA. The retinoic acid receptor (RAR)-alpha and RAR-gamma were expressed in RenCa/F cells. Treatment with IFN-alpha/beta did not influence the expression level of these receptors at the mRNA level, which suggests that the synergism of 13-cRA and IFN-alpha/beta is not mediated through the RAR.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Synergism; Female; Interferon-alpha; Interferon-beta; Isotretinoin; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; RNA, Messenger; Tumor Cells, Cultured

Retinoids are known to control many important biological processes, including differentiation, morphogenesis, growth and tissue homeostasis. More recently, clinical and pre-clinical results provide evidence for an antiproliferative effect of 13-cis-retinoic acid (13cRA) in interferon-alpha (IFN-alpha) treated renal cell carcinoma patients. The manner in which 13cRA augments antitumor effects and modulates biologic and clinical responses of renal cell carcinoma to IFN-alpha remains elusive. In the present study, we report induction of apoptosis and objective tumor regression in response to 13cRA in advanced renal cell carcinoma patients refractory to IFN-alpha. Among 21 patients treated there were one complete and four partial remissions (objective response rate, 24%; median response duration 8+ months). Preliminary evidence suggests that 13cRA acid may reverse IFN-alpha resistance in renal cell carcinoma.

Topics: Aged; Apoptosis; Carcinoma, Renal Cell; Female; Humans; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged

The differentiation and growth suppressive effects of retinoic acid are mediated through retinoic acid nuclear receptors (RARs and RXRs), which are ligand-activated transcription factors. Recent data suggest that both altered and regulated expression of RARs are linked to retinoic acid response in a cell context-dependent manner. This study examined the antiproliferative effects of 13-cis-retinoic acid (cRA) on 12 renal cancer cell lines and correlated these findings with the basal and induced expression of RAR-alpha, -beta and -gamma. Eleven of 12 renal cancers that were either resistant to or only minimally inhibited by cRA did not basally express RAR-beta as determined by Northern blot analysis. In these cells, cRA treatment did not induce RAR-beta expression. In contrast, 1 of 12 cell lines (SK-RC-06) was >90% inhibited by cRA and basally expressed RARbeta. Furthermore, RAR-beta mRNA in SK-RC-06 cells was up-regulated by cRA treatment. Amplification of cDNA using PCR and RAR-beta isoform-specific primer pairs revealed that only SK-RC-06 cells expressed the RAR-beta1 isoform. Expression of RAR-alpha transcripts was abundant in all 12 cell lines examined, whereas low levels of RAR-gamma transcripts were detectable in 6 of 10 renal cancers. Expression of RAR-alpha and RAR-gamma was not affected by cRA. These data showing that the majority of renal cancer cell lines are resistant to cRA suggest that: (a) resistance to the antiproliferative action of cRA correlates with repressed RAR-beta mRNA expression; and (b) the antiproliferative effects of cRA in renal cancer cells are mediated through RAR-beta1.

Topics: Antineoplastic Agents; Blotting, Southern; Carcinoma, Renal Cell; Cell Division; Humans; Isotretinoin; Kidney Neoplasms; Receptors, Retinoic Acid; RNA, Messenger; Tumor Cells, Cultured

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Renal Cell; Drug Synergism; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Recombinant Proteins