Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success?

The success of targeted therapies, including inhibitors of the vascular endothelial growth factor pathway or the mammalian target of rapamycin, in the treatment of metastatic renal cell carcinoma led to interest in testing their efficacy in the adjuvant setting. Results from the first trials are now available, with other studies due to report imminently. This review provides an overview of adjuvant targeted therapy in renal cell carcinoma, including interpretation of currently available conflicting data and future direction of research. We discuss the key differences between the completed targeted therapy adjuvant trials, and highlight the importance of accurately identifying patients who are likely to benefit from adjuvant treatment. We also consider reasons why blinded independent radiology review and treatment dose may prove critical for adjuvant treatment success. The implications of using disease-free survival as a surrogate end point for overall survival from the patient perspective and measurement of health benefit have recently been brought into focus and are discussed. Finally, we discuss how the ongoing adjuvant trials with targeted therapies and checkpoint inhibitors may improve our understanding and ability to prevent tumor recurrence after nephrectomy in the future.

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma.

BACKGROUND: In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters. METHODS: Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment). RESULTS: Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category. CONCLUSIONS: A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.

Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma.

BACKGROUND: We retrospectively analyzed sunitinib outcome as a function of age in metastatic renal cell carcinoma (mRCC) patients. METHODS: Data were pooled from 1059 patients in six trials. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were compared by log-rank test between patients aged <70 (n=857; 81%) and ≥70 (n=202; 19%) years. RESULTS: In first-line patients, median PFS was comparable in younger and older patients, 9.9 vs 11.0 months, respectively (HR, 0.89; 95% CI: 0.73-1.09; P=0.2629), as was median OS, 23.6 vs 25.6 months (HR, 0.93; 95% CI: 0.74-1.18; P=0.5442). Similarly, in cytokine-refractory patients, median PFS was 8.1 vs 8.4 months (HR, 0.79; 95% CI: 0.49-1.28; P=0.3350), while median OS was 20.2 vs 15.8 months (HR, 1.14; 95% CI: 0.73-1.79; P=0.5657). Some treatment-emergent adverse events were significantly less common in younger vs older patients, including fatigue (60% vs 69%), cough (20% vs 29%), peripheral edema (17% vs 27%), anemia (18% vs 25%), decreased appetite (13% vs 29%), and thrombocytopenia (16% vs 25%; all P<0.05). Hand-foot syndrome was more common in younger patients (32% vs 24%). CONCLUSIONS: Advanced age should not be a deterrent to sunitinib therapy and elderly patients may achieve additional clinical benefit.

Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-α.

BACKGROUND: In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis. METHODS: In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes. RESULTS: Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α. CONCLUSION: Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.

Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis.

BACKGROUND: A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity. METHODS: Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan-Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model. RESULTS: In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations. CONCLUSION: Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.

Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: Analysis of prognostic factors for progression-free survival (PFS) and overall survival (OS) was performed using final data from a randomized phase III trial of sunitinib versus interferon-α (IFN-α) as first-line metastatic renal cell carcinoma (RCC) therapy. DESIGN: A multivariate Cox regression model analyzed baseline variables for prognostic significance. Each variable was investigated univariately and then multivariately using a stepwise algorithm. RESULTS: Each treatment arm comprised 375 patients. For sunitinib, multivariate analysis of PFS identified five independent predictors, including serum lactate dehydrogenase (LDH) level, presence of ≥2 metastatic sites, no prior nephrectomy, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline platelet count, while multivariate analysis of OS identified serum LDH level, corrected serum calcium level, time from diagnosis to treatment, hemoglobin level, ECOG performance status, and presence of bone metastasis as predictors. For IFN-α, LDH level and presence of ≥2 metastatic sites were common predictors of PFS to those for sunitinib, as were all predictors of OS except ECOG status. CONCLUSIONS: This analysis identified prognostic factors for PFS and OS with sunitinib as first-line metastatic RCC therapy and confirmed that the Memorial Sloan-Kettering Cancer Center model is applicable in the era of targeted therapy.

Concomitant renal cell carcinoma and chronic myelogenous leukemia: use of a targeted approach.

Numerous therapeutic options have been introduced for metastatic renal cell carcinoma (MRCC) in recent years, including monoclonal antibodies such as bevacizumab and small-molecule tyrosine kinase inhibitors such as sunitinib and sorafenib. Similarly, several other small-molecule inhibitors-including imatinib, dasatinib, and nilotinib-have been approved for the treatment of chronic myelogenous leukemia (CML). The combination of these targeted agents is an area of intense clinical investigation. Here, we describe a patient diagnosed with MRCC)while on imatinib therapy for cml. Treatment of this patient with the combination of bevacizumab and imatinib led to a 6-month period of stable disease, with no treatment-related adverse events. More extensive clinical exploration of this combination of agents may therefore be warranted.

Granulocyte macrophage colony-stimulating factor and interleukin 4 enhance the number and antigen-presenting activity of circulating CD14+ and CD83+ cells in cancer patients.

Antigen-presenting cells (APCs) are essential for stimulating antigen-specific immunity, including immunity against tumor cells. We hypothesized that systemic administration of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, which promote monocytes to differentiate into dendritic cells in vitro, might enhance the number and antigen-presenting activity of CD14+ cells in vivo. Patients with metastatic solid malignancies were treated with daily s.c. injections of either GM-CSF alone (2.5 microg/kg/day) or GM-CSF in combination with IL-4 (0.5-6.0 microg/kg/day) in a multicohort study. When given alone, GM-CSF increased the number of CD14+ cells but did not enhance the cells' expression of APC markers or antigen-presenting activity. In contrast, combination therapy with GM-CSF and IL-4 stimulated CD14+ cells to acquire several APC characteristics including increased expression of HLA-DR and CD11c, decreased CD14, increased endocytotic activity, and the ability to stimulate T cells in a mixed leukocyte reaction. Combination therapy also induced a dose-dependent increase in the number of CD14-/CD83+ cells with APC activity. Clinically significant and sustained tumor regression was observed in one patient. Systemic therapy with GM-CSF and IL-4 may provide a mechanism for increasing the number and function of APCs in patients with cancer.

Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. The Lung Cancer Study Group.

Mutations that prevent the normal expression of the retinoblastoma susceptibility gene (RB) have been linked to the pathogenesis of several human malignancies. Mutational inactivation of this tumor-suppressor gene appears to initiate the development of retinoblastoma, and may also contribute to the pathogenesis of osteosarcomas, soft-tissue sarcomas, small-cell lung cancer and other malignancies. In cooperation with the Lung Cancer Study Group, we studied the structure and expression of the RB gene in a cohort of 219 primary non-small-cell lung cancers (NSCLCs). RB gene structure was studied at the DNA level by Southern blot and chromosome 13 restriction fragment length polymorphism analyses. Expression of the RB gene was evaluated by Northern analysis of the transcript and immunohistochemical analysis of the protein (p105RB). Immunohistochemistry of the RB protein proved to be the most sensitive method for the detection of Rb gene inactivation. Absent or abnormal RB protein staining was detected in 53/163 (32%) evaluable cases studied, while Northern analysis showed 22/219 cases to have an altered or absent RB transcript. Southern analysis revealed only two cases of structural alteration of the gene, but loss of heterozygosity from chromosome 13 was common in tumors that failed to express the protein. Analysis of the clinical outcomes of the patients whose tumors were studied did not show any correlation of RB inactivation with time to relapse or death. The data from this study indicate that the RB gene is inactivated in a significant number of NSCLCs. The role that these mutations may play in the development of NSCLC remains to be defined.

Expression patterns of immediate early transcription factors in human non-small cell lung cancer. The Lung Cancer Study Group.

In 1995, there will be 172,000 new cases of lung cancer diagnosed and 153,000 deaths from this disease in the United States. While the pathogenesis of the disease process is poorly understood, a growing body of evidence suggests that abnormalities in cellular regulatory genes may play an important role in the induction, maintenance and/or progression of some tumor types. These genes include both growth promoting oncogenes as well as growth inhibitory or suppressor genes. Included among these genetic sequences are several cellular transcription factors. A group of these factors including c-jun, c-fos and EGR1 are members of a class of genes known as immediate early genes whose expression are inducible by a variety of stimuli including mitogenic and differentiation inducing growth factors, indicating a potential important role for these genes in normal growth processes. Since these genes are involved in early regulation of cellular growth properties and at least two (c-jun and c-fos) can act as oncogenes, we wished to determine whether their expression levels were altered in human non-small cell lung cancers (NSCLC) compared to normal lung tissue. To address this, Northern blot analyses were performed using c-fos, c-jun and EGR1 probes on RNA extracted from 101 NSCLC tumor specimens and adjacent uninvolved lung tissue. Analysis of this cohort revealed that 72% of the normal tissues demonstrate significantly greater expression of these transcription factors as compared to adjacent malignant tissue. Moreover, this expression pattern appeared to be coordinate for all three genes in the majority of cases. This differential expression pattern was confirmed at the protein level using an immunohistochemical approach with antibodies directed against the c-jun, c-fos and EGR1 gene products. Southern blot analyses demonstrated no gross alterations of these sequences at the DNA level, indicating that the observed differential expression pattern was not due to gross structural changes in the genes. These data suggest that down-regulation of these genes may be involved in the pathogenesis of lung cancer.

Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: an outpatient multicenter trial.

PURPOSE: A prospective multicenter phase II trial was undertaken to define the activity of a low-dose subcutaneous regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN) in patients with metastatic renal cancer. PATIENTS AND METHODS: Between December 1990 and October 1991, 42 patients with metastatic renal cancer who had received no prior immunotherapy were treated with IL-2 (4 x 10(6) U) days 1 through 4 and IFN (9 x 10(6) U) day 1 and 4 each week of a 4-week treatment course followed by a 2-week rest period. Maximum duration of therapy was 1 year. Concomitant therapy with acetaminophen, diphenhydramine, and indomethacin was recommended. Treatment was administered on an outpatient basis. RESULTS: With a median follow-up duration of 18 months, responses occurred in five of 42 patients (12%; 95% confidence interval [Cl], 2% to 22%). One pathologic complete remission, one surgical complete remission, and three partial remissions occurred. Toxicity was modest, with a symptom complex of rash, fever, anorexia, fatigue, mild weight loss, lymphocytosis, and eosinophilia occurring in 85% to 90% of patients. Renal dysfunction (creatinine > 2 mg/dL) occurred in 19% of patients, while three patients (7%) refused further IL-2 and IFN. No toxic deaths occurred. The median survival duration was 14.5 months. CONCLUSION: This outpatient low-dose subcutaneous regimen induced mild toxicity, a modest response rate, and an excellent median survival duration in previously untreated patients. Phase III trials are now needed to compare IL-2 plus IFN with IL-2 alone or to various IL-2/IFN regimens. However, the major task is to identify unique new agents with activity in renal cancer.

Concomitant administration of recombinant human interleukin-2 and recombinant interferon alfa-2A: an active outpatient regimen in metastatic renal cell carcinoma.

PURPOSE: A phase II trial of interleukin-2 (IL-2) and interferon alfa (IFN-alpha) in metastatic renal cell carcinoma (RCCa) was conducted. A lower dosage of IL-2 was given via continuous intravenous (IV) infusion, a route with documented tumor activity associated with less toxicity, with the purpose of improving the therapeutic index of this treatment in an outpatient setting. PATIENTS AND METHODS: Thirty patients with metastatic RCCa were treated with the combination of IL-2 and IFN-alpha-2A. IL-2 was administered on days 1 through 4 of each treatment week, as a continuous IV infusion at a dose of 2 x 10(6) U/m2/d. IFN-alpha-2A was administered intramuscularly or subcutaneously on days 1 and 4 of each treatment week, at a dose of 6 x 10(6) U/m2/d. One treatment course included 4 weeks of treatment followed by a 2-week rest. Patients received therapy as outpatients except for the first 4 days of treatment, cycle 1 only. All patients were assessable for toxicity and response assessment. A total of 105 courses of therapy were administered, 51% at full dose. RESULTS: Sixteen patients experienced toxicities resulting in dosage modification. The major treatment-limiting toxicities were gastrointestinal, neurologic, and fatigue. Nine patients (30%) had partial remissions (PRs) with a median duration of responses of 12+ months. The median time to response was 11 weeks. Two partial responders whose sites of metastatic disease were renal fossa and mediastinal lymph nodes (LN), respectively, were found to have achieved a pathologic complete remission (pCR) after surgery. A third patient with a pCR of axillary LN was rendered into a surgical complete remission (sCR) with salvage nephrectomy. Median survival of patients obtaining a PR has not been reached with a median follow-up time of 19+ months. CONCLUSION: IL-2 and IFN-alpha-2A is well tolerated in the outpatient treatment setting and demonstrates significant clinical activity against RCCa.

Recombinant interferon alfa-2a in metastatic renal cell carcinoma: assessment of antitumor activity and anti-interferon antibody formation.

Twenty-one patients with advanced, measurable, renal cell carcinoma (RCC) were administered recombinant interferon alfa-2a (rIFN-alpha 2a) (Roferon-A; Roche Laboratories, Nutley, NJ) intramuscularly beginning at 3 x 10(6) units and escalating to 36 x 10(6) units, 5 d/wk for a total induction period of 14 weeks. rIFN-alpha 2a antibody production was measured using an enzyme immunoassay (EIA). Those sera found to be positive for presence of antibody by the EIA were tested for the presence of neutralizing antibodies (NA) by an antiviral neutralization bioassay (ANB). All patients were evaluable for toxicity, and 19 were evaluable for response and for incidence of antibody formation. Five patients (26%; 95% confidence interval, 6% to 46%) had complete responses (CR) or partial responses (PR) with a median duration of 283 days. An additional ten patients (53%) had minor tumor regressions with a median duration of 86 days. Fifty-one percent of evaluable patients are alive at 18.6 months. Antibodies to rIFN-alpha 2a as measured by the EIA, were detected in 12 (63%) patients. NA were measured in the serum of six (50%) of those EIA-positive patients. Overall, six of 19 patients (32%) developed NA. Median time to the development of antibody as measured by EIA or NA was 8 and 14 weeks, respectively. Median NA titer was 1,200 IFN neutralizing U/mL. NA-positive and -negative patients had a median duration of response of 13.7 v 9.9 months, and survival of greater than 21.3 v 18.3 months, respectively. Clinical toxicity was mild and not therapeutically limiting. Autoantibody production (ANA, rheumatoid factor [RF], Coombs' direct/indirect) occurred in both NA-positive and -negative patients. The clinical significance of the antibodies to rIFN-alpha 2a and the associated autoantibody formation remain unclear; however, presence of antibody was not associated with adverse clinical sequelae.

Improved prognostication of renal cell carcinoma using an integrated staging system.

PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categorized was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival. RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman's grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis. CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients' survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.

Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma.

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

Measuring the incremental cost of clinical cancer research.

PURPOSE: To summarize evidence on the costs of treating patients in clinical trials and to describe the Cost of Cancer Treatment Study, an ongoing effort to produce generalizable estimates of the incremental costs of government-sponsored cancer trials. METHODS: A retrospective study of costs will be conducted with 1,500 cancer patients recruited from a randomly selected sample of institutions in the United States. Patients accrued to either phase II or phase III National Cancer Institute-sponsored clinical trials during a 15-month period will be asked to participate in a study of their health care utilization (n = 750). Costs will be measured approximately 1 year after their trial enrollment from a combination of billing records, medical records, and an in-person survey questionnaire. Similar data will be collected for a comparable group of cancer patients not in trials (n = 750) to provide an estimate of the incremental cost. RESULTS: Evidence suggests insurers limit access to trials because of cost concerns. Public and private efforts are underway to change these policies, but their permanent status is unclear. Previous studies found that treatment costs in clinical trials are similar to costs of standard therapy. However, it is difficult to generalize from these studies because of the unique practice settings, insufficient sample sizes, and the exclusion of potentially important costs. CONCLUSION: Denials of coverage for treatment in a clinical trial limit patient access to trials and could impede clinical research. Preliminary estimates suggest changes to these policies would not be expensive, but these results are not generalizable. The Cost of Cancer Treatment Study is an ongoing effort to provide generalizable estimates of the incremental treatment cost of phase II and phase III cancer trials. The results should be of great interest to insurers and the research community as they consider permanent ways to finance cancer trials.

Thyroid function abnormalities associated with the chronic outpatient administration of recombinant interleukin-2 and recombinant interferon-alpha.

We prospectively examined thyroid function during and following chronic, outpatient therapy with recombinant interleukin-2 (rIL-2) and Roferon-A (rIFN-alpha 2a). Twenty-two of 30 patients with advanced renal cell carcinoma treated on a phase II open pilot study of concomitant rIL-2 and rIFN-alpha 2a were included. Serum levels of thyroxine, triiodothyronine, free thyroxine index, thyrotropin, antithyroid antibodies, and thyrotropin (TSH) receptor binding antibodies were measured before therapy and after every other cycle. Selected patients underwent studies after every cycle and following completion of therapy. Twenty patients (91%) developed laboratory evidence of thyroid dysfunction, 11 (50%) developed hypothyroidism, five (23%) had a biphasic pattern, and four (18%) had hyperthyroidism. The incidence of thyroid dysfunction increased with increased number of treatment cycles. Transient hyperthyroidism was noted in six of the 11 patients studied after the first cycle and persisted after cycle three in only two patients. Hypothyroidism was not observed after cycle 1, but became increasingly frequent between cycles 2 (56%) and 6 (90%). Thyroid function normalized following therapy in nine of 12 patients tested. Antithyroid antibodies were identified pretherapy in five patients (23%) and de novo in none; TSH receptor binding antibodies were not detected. This study demonstrates a remarkably high frequency of reversible thyroid dysfunction in patients with advanced renal cell carcinoma treated with repeated cycles of rIL-2 plus rIFN-alpha 2a. We conclude that chronic therapy with rIL-2 and rIFN-alpha 2a produces thyroid dysfunction in virtually all patients most likely secondary to a nonspecific, nonautoimmune, toxic manifestation of prolonged treatment. IL-2 therapy may, therefore, produce thyroid dysfunction by more than one mechanism.

Metastatic renal cell cancer: interleukin-2 toxicity induced by contrast agent injection.

We describe a clinical syndrome occurring after contrast medium injection in patients who previously received recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha 2A treatment for metastatic renal cancer. The clinical picture mimics many aspects of rIL-2-related systemic side effects. The patients were managed conservatively but the potential for severe manifestations can occur, requiring more intensive treatment.

Biotherapy in clinical practice.

The interferons are the first of a new class of biologic response modifiers that include, among others, the interleukins, colony-stimulating factors, erythropoietin, additional growth factors, and monoclonal antibodies. Interferons have exhibited important clinical activity in hematologic malignancies, lymphomas, and solid tumors. Specific diseases responding to interferons include hairy-cell leukemia (HCL), chronic myelogenous leukemia (CML), low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, multiple myeloma, superficial bladder carcinoma, malignant carcinoid, acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma, ovarian carcinoma, renal cell carcinoma, and malignant melanoma. The potentially antigenic nature of the recombinant interferons can result in the formation of antibodies. These antibodies have been associated with the abrogation of some of the clinical responsiveness of some patients treated with interferons. It is hoped that the controversy existing over the role of antibody formation in treatment efficacy can be resolved by prospective trials using standardized methodology in such areas as assay type, sampling time, route of drug administration, treatment schedule, cumulative dose, and duration of treatment.