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ABSTRACT: This paper reports on the development and validation of two biologic response modifier (BRM) subscales for use with the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life (QOL) questionnaire.
Using the FACT-G as a base, 17 additional questions related to symptoms common to interferon and retinoid therapy were developed. Data collected at baseline (n = 191) and week 2 (n = 168) in a randomized trial of interferon +/- 13-cis-retinoic acid in advanced renal cell carcinoma patients were used to validate this measure.
Using a combined empirical and conceptual approach, the 17 questions were reduced to 13 questions consisting of two subscales: 'BRM-physical' (7 items; baseline coefficient alpha(alpha) = 0.70; week-2 alpha = 0.75) and 'BRM-mental' (6 items; baseline alpha = 0.79; week-2 alpha = 0.78). Internal consistency of the trial outcome index (TOI) combining physical well-being, functional well-being and the BRM subscales, was 0.91 for baseline assessments and 0.92 for week 2. Discriminant validity was demonstrated for the TOI by its ability to differentiate among prognostic risk groups, and for the total FACT-G, TOI and total FACT-BRM scores by their ability to distinguish between groups differing in performance, response and toxicity status.
The 'BRM-physical' and 'BRM-mental' subscales can be combined with the FACT-G to form the 'FACT BRM' scale, useful for measuring QOL in cancer patients who are receiving treatment with biologic response modifiers.
Quality of Life Research 03/2004; 13(1):137-54. · 2.30 Impact Factor
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ABSTRACT: Purpose: This paper reports on the development and validation of two biologic response modifier (BRM) subscales for use with the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life (QOL) questionnaire. Methods: Using the FACT-G as a base, 17 additional questions related to symptoms common to interferon and retinoid therapy were developed. Data collected at baseline (n = 191) and week 2 (n = 168) in a randomized trial of interferon 13-cis-retinoic acid in advanced renal cell carcinoma patients were used to validate this measure. Results: Using a combined empirical and conceptual approach, the 17 questions were reduced to 13 questions consisting of two subscales: BRM-physical (7 items; baseline coefficient alpha() = 0.70; week-2 = 0.75) and BRM-mental (6 items; baseline = 0.79; week-2 = 0.78). Internal consistency of the trial outcome index (TOI) combining physical well-being, functional well-being and the BRM subscales, was 0.91 for baseline assessments and 0.92 for week 2. Discriminant validity was demonstrated for the TOI by its ability to differentiate among prognostic risk groups, and for the total FACT-G, TOI and total FACT–BRM scores by their ability to distinguish between groups differing in performance, response and toxicity status. Conclusions: The BRM-physical and BRM-mental subscales can be combined with the FACT-G to form the FACT–BRM scale, useful for measuring QOL in cancer patients who are receiving treatment with biologic response modifiers.
Quality of Life Research 01/2004; 13(1):137-154. · 2.30 Impact Factor
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ABSTRACT: Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority.
Journal of Interferon & Cytokine Research 05/2001; 21(4):257-63. · 3.06 Impact Factor
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R J Motzer, B A Murphy,
J Bacik,
L H Schwartz,
D M Nanus,
T Mariani,
P Loehrer,
G Wilding,
D L Fairclough,
D Cella,
M Mazumdar
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ABSTRACT: 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.
Journal of Clinical Oncology 08/2000; 18(16):2972-80. · 18.37 Impact Factor
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ABSTRACT: 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.
Journal of Clinical Oncology 09/1995; 13(8):1950-7. · 18.37 Impact Factor
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ABSTRACT: Germ cell tumors (GCTs) are characterized by a capacity to differentiate in vivo and in vitro. The authors' previous work highlighted the finding that retinoid-mediated GCT differentiation in vitro correlates with expression of the retinoic acid receptor-gamma.
Six human GCT cell lines were studied to determine whether their growth and differentiation were linked to the retinoic acid response pathway. The maturation and growth inhibitory responses to all-trans retinoic acid (RA) were studied as well as the expression of retinoic acid receptor-gamma (RAR-gamma). The clinical antitumor activity of RA was studied in a Phase II trial of RA in patients with chemotherapy-refractory GCTs.
The RA response pathway was correlated with the control of growth and maturation in three of the six GCT cell lines studied. In one GCT cell line, RA induced RAR-gamma expression and terminal differentiation. In a second, there was high basal expression of RAR-gamma and poor basal proliferative potential. A third cell line showed a more mature basal phenotype than other cell lines studied and marked growth inhibition when treated with RA. Sixteen patients were treated with RA for an average of 7 weeks in the clinical trial. No complete or partial responses were noted.
A Phase II clinical trial of RA failed to show significant clinical antitumor activity in patients with chemotherapy-refractory GCTs. However in vitro data suggest that the control of growth and maturation in some GCT cell lines involve the RA signaling pathway. Further studies are warranted to define the role that other retinoids with receptor selectivity or more favorable pharmacologic properties may play in the maturation or antitumor responses of GCTs.
Cancer 09/1995; 76(4):680-6. · 4.77 Impact Factor
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ABSTRACT: Serum tumor marker regression (alpha-fetoprotein [AFP] and human chorionic gonadotrophin [hCG]) was studied in patients treated with ifosfamide-based chemotherapy for cisplatin-resistant germ cell tumors (GCT) to investigate the role of marker regression as a predictor of treatment outcome.
Fifty-four patients treated with cisplatin and ifosfamide-containing therapy were the subject of this retrospective analysis. The serum tumor marker half-life (T1/2) for the first two cycles of therapy was calculated for each patient using all marker values Day 7 through the end of the second treatment cycle. A calculated T1/2 for hCG of less than or equal to 3 days or a calculated T1/2 for AFP of less than or equal to 7 days was defined as appropriate marker regression; any T1/2 greater than these values was considered prolonged. A variable designated "marker decline" was defined to indicate whether the serum tumor marker half-life of AFP and/or hCG was satisfactory or unsatisfactory for each individual patient. Both univariate and multivariate analyses were conducted to investigate "marker decline" as a predictor for response, event-free survival (time to death or relapse), and overall survival.
Satisfactory marker decline predicted an improved event-free survival and overall survival. The median event-free survival for patients with an unsatisfactory marker decline was 5.8 months versus 20.7 months for patients with a satisfactory marker decline. Survival for patients with an unsatisfactory marker decline was 6.3 months versus 20.7 months for those patients with a satisfactory marker decline. Further evaluation demonstrated that hCG decline was a stronger predictor for improved survival than AFP decline. A multivariate analysis performed on selected clinical variables using a Cox regression model demonstrated that marker decline, pretreatment hCG, and primary site were independent predictors for event-free and overall survival.
The rate of serum AFP and/or hCG decline during the first two cycles of therapy was predictive for event-free and overall survival in GCT patients treated with ifosfamide-based salvage therapy. Those patients with an appropriate serum tumor marker decline had a longer event-free and overall survival. When evaluated separately, the rate of hCG decline was more predictive of treatment outcome than decline of AFP. The rate of serum tumor marker regression during the first two cycles of therapy is a clinically useful tool in assessing treatment outcome at an early point in therapy and may thereby identify patients who could benefit from a change to more intensive therapy.
Cancer 06/1994; 73(10):2520-6. · 4.77 Impact Factor
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ABSTRACT: Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated with iproplatin (CHIP). No objective responses were noted in any of the patients treated. By restricting the entry criteria to heavily pre-treated patients, the identification of new active agents in phase II trials may be hindered. Alternative strategies for the investigation of new agents in patients with GCT should be considered, particularly when studying the efficacy and relative toxicity of platinum analogues.
Investigational New Drugs 12/1992; 10(4):327-30. · 3.36 Impact Factor
