Phase I trial of weekly docetaxel and daily temozolomide in patients with metastatic disease.

UNLABELLED: Docetaxel is second generation taxoid that has shown activity against a variety of cancers and has been approved for use in cancers of the breast, lung, head and neck, ovaries and prostate. Temozolomide is an alkylating agent which crosses the blood brain barrier and has demonstrated antitumor activity against a broad range of tumor types, including malignant glioma, melanoma, non small cell lung cancer and carcinoma of the ovary and colon. A Phase I trial was conducted to determine the toxicity of this combination in refractory solid tumor patients. METHODS: Twenty five patients with metastatic cancers were enrolled in a Phase I dose escalation trial. Docetaxel was administered weekly in 5 escalating doses of 25 to 35 mg/ m(2) as a one-hour bolus intravenous infusion for 3 consecutive weeks. Temozolamide was administered orally daily for 3 weeks (escalating doses of 75 to 100 mg/m(2)). Cycles were repeated at 4 week intervals. RESULTS: The maximum tolerated dose (MTD) was not determined in this study. The most commonly reported adverse events were mild to moderate nausea, vomiting and fatigue. Thrombocytopenia was the most commonly observed grade 3 and 4 hematological toxicity. Eight patients had dose interruptions for adverse events and only one patient had a dose reduction while receiving 30 mg/ m(2) of docetaxel and 90 mg/ m(2) of temozolomide due to grade 3 thrombocytopenia. Two patients achieved partial responses and 88% of the patients are deceased. The median survival is 8.4 months. CONCLUSIONS: The combination of docetaxel and temozolomide was well tolerated and these agents can be safely combined. For phase II trials, docetaxel 35 mg/ m(2) IV day 1, 8 and 15, and daily temozolomide at 100 mg/ m(2) day 1-21 are recommended.

Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib.

BACKGROUND: Sorafenib is an orally bioavailable vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity in metastatic renal cell carcinoma (RCC). Sunitinib, also a VEGFR inhibitor, induces biochemical hypothyroidism in 85% of metastatic RCC patients, the majority of whom have signs or symptoms of hypothyroidism. Hence, the incidence of thyroid function test (TFT) abnormalities in patients with metastatic RCC receiving sorafenib was investigated. PATIENTS AND METHODS: Sixty-eight patients with metastatic RCC were treated with sorafenib at the Cleveland Clinic Taussig Cancer Center, and 39 patients had TFTs available. RESULTS: Eight patients (21%) had thyroid dysfunction possibly caused by sorafenib [seven hypothyroidism (18%) and one hyperthyroidism (3%)] and eight additional patients (21%) had findings compatible with nonthyroidal illness. Only two patients had clinical signs and symptoms secondary to thyroid dysfunction and received thyroid hormone replacement. CONCLUSIONS: In summary, clinically significant TFT abnormalities were not common in patients treated with sorafenib, and replacement therapy was rarely indicated. TFTs should be measured before sorafenib therapy in RCC patients and subsequently only if clinically indicated.

Phase I trial of three-weekly docetaxel, carboplatin and oral lenalidomide (Revlimid) in patients with advanced solid tumors.

INTRODUCTION: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different toxicity profile. In preclinical trials it has shown synergy with chemotherapy. PATIENTS AND METHODS: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically proven solid tumors, < or =2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled. Dose limiting toxicities (DLT) were defined as > or = grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors were used during cycle 1. RESULTS: Three of four patients treated at dose level 1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1-14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level -1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1-14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer. CONCLUSIONS: Docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted.

Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma.

PURPOSE: To identify prognostic factors (PF) for long-term survival in metastatic renal cell carcinoma (RCC) patients. METHODS: We retrospectively reviewed a metastatic RCC database at the Cleveland Clinic Foundation consisting of 358 previously untreated patients who were enrolled in institutional review board-approved clinical trials of immunotherapy and/or chemotherapy at our institution from 1987 to 2002. In order to identify patient characteristics associated with long-term survival, we compared 226 'short-term' survivors [defined as overall survival (OS) <2 years] with 31 'long-term' survivors (OS >or=5 years). RESULTS: Using logistic regression models, four adverse PF were identified as independent predictors of long-term survival: hemoglobin less than the lower limit of normal, greater than two metastatic sites, involved kidney (left), and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Using the number of poor prognostic features present, three distinct risk groups could be identified. Patients with 0 or 1 adverse prognostic feature present had an observed likelihood of long-term survival of 32% (21/66) compared with 9% (8/91) for patients with two adverse features present and only 1% (1/93) for patients with more than two adverse features. CONCLUSIONS: Independent predictors of long-term survival in previously untreated metastatic RCC include baseline hemoglobin level, number of involved sites, involved kidney, and ECOG PS. Incorporation of these factors into a simple prognostic scoring system enables three distinct groups of patients to be identified.

Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer.

BACKGROUND: Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy. METHODS: Phenoxodiol given by intravenous infusion continuously for 7 days on 14-day cycles was dose-escalated on an inter-patient basis at dosages of 0.65,1.3, 3.3, 20.0, and 27.0 mg/kg/day (three to four patients per stratum). Treatment cycles continued until disease progression. Toxicity was based on standard criteria; efficacy was based on changes in tumor burden (WHO); pharmacokinetic analysis was conducted on plasma samples at specified time points during treatment cycles. RESULTS: Nineteen heavily-pre-treated patients with solid tumors received a median of three cycles of treatment (range 1-13); two patients received >or= 12 cycles. No dose-limiting toxicities were encountered, with emesis and fatigue (one patient) and rash (one patient) the only significant toxicities. Stabilized disease was the best efficacy outcome, with one patient showing stable disease at 24 weeks. Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol. CONCLUSION: A 7-day continuous infusion of phenoxodiol given every 2 weeks is well tolerated up to a dose of 27.0 mg/kg/day.

Enteral nutrition during the treatment of head and neck carcinoma: is a percutaneous endoscopic gastrostomy tube preferable to a nasogastric tube?

BACKGROUND: Multimodality treatments for patients with squamous cell head and neck carcinoma often produce significant mucositis and dysphagia, mandating enteral nutritional support. Patient preference has resulted in the increasing use of percutaneous endoscopic gastrostomy (PEG) tubes rather than nasogastric (NG) tubes. Anecdotal observations of prolonged PEG dependence and of a need for pharyngoesophageal dilatation in PEG patients prompted a retrospective review of the use of both types of feeding tubes. METHODS: Patients who were treated on clinical trials of radiotherapy or chemoradiotherapy for squamous cell head and neck carcinoma between 1989 and 1997 were reviewed retrospectively. Data were gathered regarding demographics, primary tumor site, T and N classifications, and the need for feeding tube placement. In patients requiring feeding tubes, the type and duration of the feeding tube, the need for tracheostomy, the need for pharyngoesophageal dilatation, and the degree of mucositis and dysphagia at baseline and at 1 month, 3 months, 6 months, and 12 months after beginning treatment were recorded. Comparisons were then made between the NG and the PEG groups. RESULTS: Ninety-one feeding tubes were placed in 158 patients over the 8-year interval. A hypopharyngeal primary site, female gender, a T4 primary tumor, and treatment with chemoradiotherapy were predictive of a need for feeding tube placement. NG tubes were placed in 29 patients, and PEG tubes were placed in 62 patients. PEG patients had more dysphagia at 3 months (59% vs. 30%, respectively; P = 0.015) and at 6 months (30% vs. 8%, respectively; P = 0.029) than NG patients. The median tube duration was 28 weeks for PEG patients compared with 8 weeks for NG patients, (P < 0.001). Twenty-three percent of PEG patients needed pharyngoesophageal dilatation compared with 4% of NG patients (P = 0.022). These end points could not be correlated with age, stage, primary tumor site, or tracheostomy placement. CONCLUSIONS: Although patients treated for head and neck carcinoma find that the PEG tube is a more acceptable route for enteral nutrition than the NG tube, in the authors' experience, a PEG tube was required for longer periods of time and was associated with more persistent dysphagia and an increased need for pharyngoesophageal dilatation. A randomized prospective trial is needed to test these observations.

Longterm outcome of Wegener's granulomatosis in patients with renal disease requiring dialysis.

OBJECTIVE: It is known that renal failure is a poor prognostic marker for survival in Wegener's granulomatosis (WG). We investigated the longterm outcome of patients with WG who have severe renal disease requiring dialysis. METHODS: We performed a retrospective analysis of 104 patients with WG followed at our institution between 1982 and 1997. Twenty-three patients who required dialysis were studied in detail to determine outcomes and factors that influenced survival and restoration of renal function. RESULTS: Of 23 dialysis dependent patients with WG, 11 died (Group 1). 7 either remained dialysis dependent or received successful renal transplants (Group 2), and 5 substantially recovered renal function (Group 3). Mean serum creatinine at the end of a mean followup period of 38.4 months for Group 3 was 1.8 mg/dl. There was no apparent difference between groups in regard to disease profile, e.g., distribution of organ involvement or serum creatinine when renal impairment was first recognized (mean serum creatinine for groups: 1: 3.0 mg/dl; 2: 5.6 mg/dl; 3: 5.5 mg/dl) and peak serum creatinine prior to dialysis (means for groups: 1: 9.5 mg/dl; 2: 10.5 mg/dl; 3: 9.6 mg/dl). Infection secondary to immunosuppression was the leading cause of death in Group I patients. CONCLUSION: Because the clinical profile and degree of renal failure, as judged by serum creatinine, did not differ among patients who did or did not regain dialysis independent renal function, we recommend aggressive immunosuppressive therapy in all cases of active WG with acute rapidly worsening renal failure, regardless of the severity of renal impairment.

Interleukin-2 in cancer therapy: uses and optimum management of adverse effects.

Recombinant interleukin-2 (rIL-2) produces remissions in several human tumours, including metastatic renal cell cancer (RCC) and malignant melanoma. High-dose intravenous bolus rIL-2 is approved in the US in these 2 indications, based on evidence of rIL-2-induced durable remissions in a significant minority of patients. Due to the toxicity associated with high-dose rIL-2, alternative regimens were investigated in RCC, including low-dose intravenous bolus, subcutaneous outpatient regimens and continuous intravenous infusion, yielding similar response rates. A prospective randomised trial comparing different doses and routes of administration is underway. Because response rates to single agent rIL-2 are inadequate, combination therapies were studied. In RCC patients, a combination of rIL-2 and IFNalpha resulted in better response rates than either cytokine alone, with no apparent survival advantage. Combination with chemotherapy increased toxicity and had no proven benefit. Results of adoptive immunotherapy studies combining rIL-2 with either lymphokine-activated killer cells or tumour infiltrating lymphocytes were comparable to those of rIL-2 alone. In malignant melanoma, combination therapy of rIL-2 with chemotherapy was explored. Results of single-institution phase II combination studies of variable chemotherapy and rIL-2 and IFNalpha regimens were promising and randomised trials are underway. rIL-2 is being is evaluated in haematological malignancies. The rationale is based on pre-clinical evidence that a variety of leukaemic blasts are sensitive to cytolysis or growth inhibition mediated by rIL-2-activated immune effector cells. New immunotherapeutic strategies may ultimately improve the anti-tumour efficacy of rIL-2-based therapy. Early trials using rIL-2 as adjuvant therapy to vaccines or dendritic cell-based therapy have yielded promising results. rIL-2 therapy initiates a cytokine-mediated pro-inflammatory process leading to an adverse effect profile that is quite different from traditional chemotherapeutic agents. Dose-limiting toxicities are primarily cardiovascular and pulmonary and are dose-dependent in frequency and severity. Patients receiving high-dose regimens may require intensive care unit support, limiting its use to those with excellent performance status and adequate organ function. Patients receiving less intensive dose regimens may require less rigorous screening and monitoring. It has been postulated that rIL-2 related toxicity is mediated through the release of secondary cytokines, including TNF, IFNgamma, IL-6 and IL-1. With the increasing understanding of the pathophysiological mechanisms of the effects of rIL-2, it is possible that concurrent administration of selective cytokine antagonists may reduce the toxicity associated with rIL-2 without interfering with its anti-neoplastic activity.