Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer. METHODS: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways. RESULTS: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08). CONCLUSIONS: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.

Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors.

BACKGROUND: STEALTH(®) liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients. METHODS: As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured. RESULTS: For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43 ± 31 and 58 ± 26%, respectively (P = 0.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41 ± 31 and 45 ± 36%, respectively (P = 0.50). For NL-CKD602 (n = 42), the percent decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R(2) = 0.82), compared with patients ≥60 (R(2) = 0.30). CONCLUSIONS: Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60.

Phase I and pharmacokinetic study of pegylated liposomal CKD-602 in patients with advanced malignancies.

PURPOSE: S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors. EXPERIMENTAL DESIGN: S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone+hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated+released) CKD602 measured by liquid chromatography-tandem mass spectrometry. RESULTS: Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602. CONCLUSIONS: S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.

Extraosseous osteosarcoma of the esophagus: a case report.

Extraosseous osteosarcoma (EOO) is a malignant mesenchymal neoplasm that is located in the soft tissues without direct attachment to the skeletal system and that produces osteoid, bone, or chondroid material. EOO is an extremely rare disease, accounting for only 1% of soft tissue sarcomas, and typically presents in either an extremity or the retroperitoneum. This paper presents the case of a 45-year-old Caucasian male with extraosseous osteosarcoma of the esophagus.

A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies.

BACKGROUND: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel. METHODS: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1. RESULTS: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 +/- 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 +/- 0.51. CONCLUSIONS: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.

Renal cell carcinoma from a transplanted allograft: two case reports and a review of the literature.

We report 2 cases of renal cell carcinoma (RCC) in which the tumor arose from a transplanted allograft. The first case is a 52-year-old man with a failed cadaveric renal transplantation found to have metastatic RCC. The tumor was proven to be from the allograft, as fluorescence in situ hybridization analysis of biopsy material showed a female karyotype, consistent with his female donor. The second patient is a 45-year-old man who had undergone cadaveric renal transplantation in 1985 for chronic glomerulonephritis and, after 22 years, presented with renal failure. Biopsy and subsequent allograft nephrectomy revealed innumerable microscopic foci of RCC. There are only a few reported cases of RCC arising in kidney allografts and even fewer with reports of metastatic disease from the allograft. Treatments in patients with disease confined to the kidney have included partial nephrectomy and total nephrectomy. A literature search did not find any reports of treatment of metastatic RCC that arose from a renal allograft.

Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases.

OBJECT: Endothelial proliferation has been recognized as a marker of high-grade or aggressive glioma. Bevacizumab is a humanized immunoglobulin G1 monoclonal antibody to vascular endothelial growth factor that has been shown to have activity in malignant gliomas when combined with irinotecan. The authors report on a case series of 13 patients with recurrent heavily pretreated malignant glioma that was treated with the combination of bevacizumab and irinotecan. METHODS: Standard therapy with primary resection followed by adjuvant chemotherapy and radiation had failed in all patients. The median number of therapies applied, including initial surgery, was 5 (range 3-7 therapies). Nine patients were started on bevacizumab at a dose of 5 mg/m2 every 2 weeks. Four patients received bevacizumab at a dose of 10 mg/m2; irinotecan was given at a dose of 125 mg/m2 every week for 3 weeks. RESULTS: Of the 13 treated patients, 10 (77%) had a radiologically demonstrated partial response and 3 (23%) had stable disease. Six patients (46%) had a clinical response. The median time to disease progression while on treatment was 24 weeks. The median overall survival was 27 weeks. The disease progressed in 8 patients, despite an initial response. Five patients are still responding to therapy. Six of the 8 patients whose disease progressed have died. Bevacizumab was discontinued in 2 patients because of nonfatal intracranial bleeding. CONCLUSIONS: The combination of bevacizumab and irinotecan is safe and has excellent activity even in this relapsed, heavily pretreated population of patients with high-grade malignant glioma, most of whom would not be candidates for clinical trials.

Results of a Single Institution Experience with Dose-Escalated Chemoradiation for Locally Advanced Unresectable Non-Small Cell Lung Cancer.

BACKGROUND: We determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose-escalated chemoradiotherapy at the University of Pittsburgh Lung Cancer Program. METHODS AND MATERIALS: The records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received four-dimensional CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log-rank and Cox regression analysis. RESULTS: For the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2- and 4-year OS was 56.0 and 30.7%, respectively. The 4-year LRC and FFDM were 43.9 and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in OS (p = 0.586), LRC (p = 0.440), or FFDM (p = 0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p = 0.037), planning target volume (PTV) over 450 cc (p < 0.001), heart V30 over 40% (p = -0.048), and esophageal mean dose over 20% (p = 0.024), V5 (p = -0.015), and V60 (p = -0.011). On multivariable analysis, PTV above 450 cc (52.2 vs. 25.3 months, p < 0.001) and esophageal V60 >20% (43.8 vs. 21.3 months, p = -0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5 and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V5 was ≤65 (7.4 vs. 23.8%, p = 0.03). Grade 2 or higher acute esophagitis was reduced if V60 ≤ 20% (62 vs. 81.3%, p = 0.018). The use of intensity-modulated radiation therapy was more frequent in stage IIIB compared to stage IIIA patients (56.5 vs. 39.5%, p = 0.048) and was associated with a higher lung V5 and V10. CONCLUSION: The outcomes of a program of dose-escalated chemoradiotherapy for unresectable stage IIIA and IIIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V60 and lung V5 were associated with lower morbidity and mortality.

Phase I study of weekly (day 1 and 8) docetaxel in combination with capecitabine in patients with advanced solid malignancies.

PURPOSE: Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in a number of tumor types, but at the expense of significant toxicity. To improve the therapeutic index, we evaluated a weekly regimen of docetaxel in combination with capecitabine, and determined the maximum tolerated dose, toxicities and pharmacokinetics of this combination. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with docetaxel on days 1 and 8, and capecitabine, twice daily on days 1-14, of an every-21-day cycle. Pharmacokinetics of docetaxel were assessed on days 1 and 8 of the first cycle of chemotherapy. RESULTS: Enrolled in the study were 25 patients. The most frequent toxicities were asthenia, hand-foot syndrome and mucositis. Inability to deliver at least 75% of the planned doses of both drugs during the first two cycles of chemotherapy was noted at dose levels 2, 3 and 4. Dose level 1 (docetaxel 30 mg/m2 and capecitabine 825 mg/m2 twice daily) is the recommended dose for phase II studies. Five patients experienced a partial response, and eight patients had stabilization of disease. Coadministration of capecitabine did not alter the pharmacokinetics of docetaxel. CONCLUSION: The regimen consisting of docetaxel 30 mg/m2 (days 1, 8) and capecitabine 825 mg/m2 twice daily (days 1-14) was well tolerated. Capecitabine did not alter pharmacokinetics of docetaxel. Further testing of this regimen in tumor-specific trials, especially gastric, lung and breast cancer, is warranted.

Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors.

PURPOSE: 9-Nitrocamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m(2)/day x 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration. EXPERIMENTAL DESIGN: On schedule A, 9NC was administered orally daily x 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily x 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography. RESULTS: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m(2)/day, respectively, each providing the same dose intensity (i.e., 24 mg/m(2)/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of approximately 4 to 1. CONCLUSIONS: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m(2) basis does not reduce pharmacokinetic variability.

Stereotactic radiosurgery for spinal metastases from renal cell carcinoma.

OBJECT: The role of stereotactic radiosurgery in treating renal cell carcinoma (RCC) metastases to the spine has previously been limited. In this study the authors evaluated the clinical outcome in patients with spinal RCC who underwent single-fraction radiosurgery. METHODS: Forty-eight patients with 60 RCC metastases to the spine (six cervical, 26 thoracic, 18 lumbar, and 10 sacral) were treated with a single-fraction radiosurgery technique and were followed for a period of 14 to 48 months (median 37 months). All patients were successfully treated in an outpatient setting. The tumor volume ranged from 5.5 to 203 cm3 (mean 61.9 cm3). Forty-two of the total 60 lesions had been previously treated with external-beam radiation therapy (EBRT). The maximum tumor dose was maintained at 17.5 to 25 Gy (mean 20 Gy). The volume of the spinal cord exposed to greater than 8 Gy ranged from 0.01 to 3 cm3 (mean 0.64 cm3); the volume of the spinal canal at the cauda equina level exposed to greater than 8 Gy ranged from 0.01 to 2.2 cm3 (mean 0.65 cm3). No radiation-induced toxicity occurred during the follow-up period. Axial and radicular pain improved in 34 (89%) of 38 patients who were treated primarily for pain. Tumor control was demonstrated in seven of eight patients treated primarily for radiographically documented tumor progression. In time six patients required open surgical intervention for tumor progression that had caused neurological dysfunction after radiosurgery. CONCLUSIONS: Spinal radiosurgery can be a successful therapeutic modality for the delivery of large-dose single-fraction radiation to RCC spinal metastases that are often poorly controlled with conventional EBRT modalities.

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients.

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM(®). The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes.

Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

S-CKD602 is a pegylated long-circulating liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD-602 following administration of S-CKD602 was developed to assess factors that may influence S-CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S-CKD602 was administered as a 1-hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m(2) . Plasma concentrations of encapsulated and released CKD-602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD-602 was described by a 1-compartment model with nonlinear clearance, and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD-602 and that age significantly influenced the release rate of CKD-602 from S-CKD602. Maximum elimination rate in patients with liver tumor is 1.5-fold higher compared with patients without liver tumor. Release rate of CKD-602 from S-CKD602 in patients less than 60 years old was 2.7-fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents.

Radiosurgery for the treatment of spinal lung metastases.

BACKGROUND: Spinal metastases are a common source of pain as well as neurologic deficit in patients with lung cancer. Metastases from lung cancer traditionally have been believed to be relatively responsive to radiation therapy. However, conventional external beam radiotherapy lacks the precision to allow delivery of large single-fraction doses of radiation and simultaneously limit the dose to radiosensitive structures such as the spinal cord. The current study evaluated the efficacy of single-fraction radiosurgery for the treatment of spinal lung cancer metastases. METHODS: In the current prospective cohort evaluation, 87 lung cancer metastases to the spine in 77 patients were treated with a single-fraction radiosurgery technique with a follow-up period of 6 to 40 months (median, 12 months). The indication for radiosurgery treatment was pain in 73 cases, as a primary treatment modality in 7 cases, for radiographic tumor progression in 4 cases, and for progressive neurologic deficit in 3 cases. RESULTS: Tumor volume ranged from 0.2 to 264 cm(3) (mean, 25.7 cm(3)). The maximum tumor dose was maintained at 15 to 25 grays (Gy) (mean, 20 Gy; median, 20 Gy). No radiation-induced toxicity occurred during the follow-up period. Long-term axial and radicular pain improvement occurred in 65 of 73 patients (89%) who were treated primarily for pain. Long-term radiographic tumor control was observed in all patients who underwent radiosurgery as their primary treatment modality or for radiographic tumor progression. CONCLUSIONS: Spinal radiosurgery was found to be feasible, safe, and clinically effective for the treatment of spinal metastases from lung cancer. The results of the current study indicate the potential of radiosurgery in the treatment of patients with spinal lung metastases, especially those with solitary sites of spine involvement, to improve long-term palliation.

Phase II study of carboxyamidotriazole in patients with advanced renal cell carcinoma refractory to immunotherapy: E4896, an Eastern Cooperative Oncology Group Study.

BACKGROUND: The current study evaluated the response rate and 6-month time to disease progression of the antiangiogenesis agent carboxyamidotriazole (CAI) in patients with metastatic renal cell carcinoma (RCC). METHODS: Fifty-seven patients with histologically confirmed metastatic RCC that progressed after biologic therapy (interferon or interleukin-2) were enrolled. Four patients were ineligible. CAI was administered orally as a 28-day cycle. Response and time to disease progression were evaluated. RESULTS: Fifteen of 53 eligible patients received > 5 cycles, but 13 patients eventually discontinued treatment because of progressive disease. The majority of toxicities were Grade 1. However, Grade 3/4 toxicities did occur, the majority of which were gastrointestinal in nature. One of 47 patients evaluable achieved a partial response (1.9%) lasting 172 days. Six of 53 patients were alive and disease progression free at 6 months from the start of treatment (11.3%). The median overall survival was 12.5 months. The survival periods in the low-risk, intermediate-risk, and poor-risk groups were 16.2 months, 20.9 months, and 5.8 months, respectively. CONCLUSIONS: Patients in trials of second-line therapy appear to have a better prognosis than previously considered, in part because they are eligible for another clinical trial. CAI was found to have little to no effect on the natural history of progressive RCC.

Long-term survivors after gamma knife radiosurgery for brain metastases.

BACKGROUND: Stereotactic radiosurgery, with or without whole-brain radiation therapy, has become a valued management choice for patients with brain metastases, although their median survival remains limited. In patients who receive successful extracranial cancer care, patients who have controlled intracranial disease are living longer. The authors evaluated all brain metastasis in patients who lived for > or = 4 years after radiosurgery to determine clinical and treatment patterns potentially responsible for their outcome. METHODS: Six hundred seventy-seven patients with brain metastases underwent 781 radiosurgery procedures between 1988 and 2000. Data from the entire series were reviewed; and, if patients had > or = 4 years of survival, then they were evaluated for information on brain and extracranial treatment, symptoms, imaging responses, need for further care, and management morbidity. These long-term survivors were compared with a cohort who lived for < 3 months after radiosurgery (n = 100 patients). RESULTS: Forty-four patients (6.5%) survived for > 4 years after radiosurgery (mean, 69 mos with 16 patients still alive). The mean age at radiosurgery was 53 years (maximum age, 72 yrs), and the median Karnofsky performance score (KPS) was 90. The lung (n = 15 patients), breast (n = 9 patients), kidney (n = 7 patients), and skin (melanoma; n = 6 patients) were the most frequent primary sites. Two or more organ sites outside the brain were involved in 18 patients (41%), the primary tumor plus lymph nodes were involved in 10 patients (23%), only the primary tumor was involved in 9 patients (20%), and only brain disease was involved in 7 patients (16%), indicating that extended survival was possible even in patients with multiorgan disease. Serial imaging of 133 tumors showed that 99 tumors were smaller (74%), 22 tumors were unchanged (17%), and 12 tumors were larger (9%). Four patients had a permanent neurologic deficit after brain tumor management, and six patients underwent a resection after radiosurgery. Compared with the patients who had limited survival (< 3 mos), long-term survivors had a higher initial KPS (P = 0.01), fewer brain metastases (P = 0.04), and less extracranial disease (P < 0.00005). CONCLUSIONS: Although the expected survival of patients with brain metastases may be limited, selected patients with effective intracranial and extracranial care for malignant disease can have prolonged, good-quality survival. The extent of extracranial disease at the time of radiosurgery was predictive of outcome, but this does not necessarily mean that patients cannot live for years if treatment is effective.

A phase II evaluation of weekly paclitaxel plus carboplatin in advanced urothelial cancer.

This Phase II trial was designed to evaluate the overall objective response rate, complete response rate, efficacy, and safety of weekly paclitaxel (Taxol) and carboplatin (Paraplatin) in the treatment of advanced urothelial carcinoma. Thirty-three patients with measurable, unresectable, stage III-IV carcinoma of the urothelium were enrolled. Paclitaxel (135 mg/m2) and carboplatin (AUC=2) were given by intravenous (IV) infusion weekly x 6 followed by two weeks rest. Patients were premedicated with oral dexamethasone, diphenhydramine, and cimetadine (or equivalent). Patient characteristics included an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 (36%), one (36%), two (28%); median age 70 years (37-83); 29 (88%) male, four (12%) female; 16 (48%) patients had prior chemotherapy [eight postoperative (adjuvant), five neoadjuvant, three for metastatic disease] and eight (24%) had prior radiation therapy. Eight patients (24%) achieved objective responses, three complete responses (CR) and five partial responses (PR); one patient was not evaluable (patient died prior to first dose). The median duration of response was 13 months (range, 2-29). Nine patients (27%) had stable disease (SD) and 15 patients (45%) had progressive disease (PD). Median time to progression was 3.6 months (range, < 1-29) and median survival was 10.3 months (range, < 1-33). Grade 3 and 4 toxicities included: asthenia (46%), neutropenia (36%), leukopenia (15%), thromboembolism (12%), diarrhea (9%), nausea and vomiting (9%), hyperglycemia (7%), and neuropathy (6%). Two patients died of sepsis, one death was treatment-related. Weekly paclitaxel plus carboplatin shows promising activity; however in the current study, efficacy may have been limited by the toxicities associated with this dose-intensive regimen in an elderly, pretreated patient population with poor performance status. This regimen warrants further study, perhaps as a three out of four week regimen or at reduced doses.