Neoadjuvant intra-arterial chemotherapy in the treatment of advanced transitional cell carcinoma of the bladder: results and followup

The long-term results of regional chemotherapy plus intra-arterial cisplatin with or without doxorubicin as an adjuvant before cystectomy and urinary diversion in patients with invasive transitional cell carcinoma of the bladder were evaluated. A total of 27 patients with T3aNxMo (8), T3bNxMo (14) and T4NxMo (5) disease participated in a phase II trial completed in 1985. Of the patients 19 received cisplatin and doxorubicin intra-arterially, and cyclophosphamide intravenously, and the remaining 8 received 70 to 100 mg. per m.2 cisplatin intra-arterially. A total of 19 patients underwent cystectomy after chemotherapy. Patients in this group had a pathological complete response (no evidence of disease after surgical restaging) or the presence of residual disease at operation that could (surgical complete response) or could not (pathological partial response) be completely resected. Of the 19 patients undergoing cystectomy surgical complete response was observed in 47.4%, pathological complete response in 26.3% and pathological partial response in 26.3%. At a median followup of 27 months for the group 66% of the patients with a surgical complete response, 100% with a pathological complete response and 40% with a pathological partial response were alive with no evidence of disease. The over-all survival for patients with a pathological or surgical complete response is 76.9%. In the patients not operated upon because of persistent or advanced disease after chemotherapy survival was brief (less than 4 months). Prolonged survival in patients achieving a pathological or surgical complete response with neoadjuvant chemotherapy occurs, and this modality may have a role in patients with invasive tumors.     

Clinical modulation of doxorubicin resistance by the calmodulin-inhibitor, trifluoperazine: a phase I/II trial

Drug resistance to chemotherapy agents such as doxorubicin appears to be an important cause of therapeutic failure in cancer treatment. Based on preclinical information demonstrating that the phenothiazine calmodulin-inhibitor trifluoperazine can enhance retention and cytotoxicity of doxorubicin in resistant cells, a phase I/II trial of the combination was performed to determine the maximally tolerated dose (MTD) of trifluoperazine that could be administered with doxorubicin. Patients with intrinsic (no previous response) and acquired (previous response with relapse) doxorubicin resistance were eligible. Doxorubicin was administered as a 96-hour continuous infusion (60 mg/m2) on days 2 through 5. Trifluoperazine was administered in divided doses orally on days 1 through 6, with dose escalation from 20 to 100 mg/d. Thirty-six patients were evaluable. The MTD of trifluoperazine was 60 mg/d, with dose-limiting toxicity being extrapyramidal side effects. No alteration of doxorubicin toxicity was observed. Seven of the 36 patients responded (one complete response [CR], six partial responses [PR]), with seven of 21 patients having acquired resistance, and zero of 15 with intrinsic resistance demonstrating responses. Doxorubicin plasma levels were not affected by trifluoperazine, and the maximal trifluoperazine plasma levels achieved were 129.83 ng/mL. This trial demonstrates the combination of trifluoperazine and doxorubicin is well tolerated, and the schedule recommended for phase II trials is doxorubicin, 60 mg/m2 (continuous infusion) days 2 through 5, and trifluoperazine, 15 mg four times per day orally days 1 through 6. Continued investigation of this combination is indicated for patients with acquired doxorubicin resistance.     

Synthesis and some reactions of 2-cyanomethylimidazo [4,5-b]pyridine. Tuberculostatic investigations of obtained compounds

2-Cyanomethylimidazo [4,5-b]pyridine 1 was obtained and its properties during acid and basic hydrolysis, esterification, and reaction with hydrogen sulfide were investigated. Condensation of 1 with aromatic aldehydes was also studied. Some of the obtained compounds were tested on tuberculostatic activity.     

Ion-conducting grafted polypropylene film, 2. Volume grafting of polypropylene and gradient composition of poly(propylene-g-acrylic acid)

Grafting of acrylic acid onto a pre-activated polypropylene film was investigated, varying the concentrations of monomer and Fe²⁺ -ions, the polymerization time and temperature. Experiments were planned according to a scheme of a latin square, and statistical analyses were performed for the optimization of the grafting variables. The concentration of ferrous ions was found to be the most significant variable for the graft level. At low concentration, ferrous ions act as activator of grafting but no grafting takes place at relatively high concentrations. The distribution of grafted poly(acrylic acid) within a PP film was examined by microphotometry of the coloured slides of the film. The grafted layer of PP reaches the center only at about 30% of grafted poly(acrylic acid) and up to 70% the distribution of grafted poly(acrylic acid) is still non-uniform with a decreasing amount of the polyacid from the surface to the center. The film samples containing 30% of grafted poly(acrylic acid) already show conductivity in alkaline media and are interesting ion conducting materials.     

Polyethylene glycol conjugated interleukin-2: Clinical and immunologic effects in patients with advanced renal cell carcinoma

Summary Recombinant interleukin-2 (rIL-2) modified with monomethoxypolyethylene glycol (PEG IL-2) was utilized in patients with metastatic renal cell carcinoma in two separate multi-institutional trials. PEG IL-2 was administered as an I.V. bolus days 1, 8, 15, and 22 with cycles repeated every six weeks. The two trials employed different dose levels: A) 20x10⁶ I.U./m² day 1 followed by 12x10⁶ I.U./m² days 8, 15, 22; and B) 12x10⁶ I.U./m² days 1, 8, 15, 22. Thirty-five patients were entered and 31 were evaluable for response (A–15/18, B–16/17). Two of 31 patients had partial responses. Median therapy duration was four weeks (range 1–15), and dose reduction for grade III or IV toxicity was required in 14/35 patients (A-6/18, B-8/17). Toxicity ( grade III) seen included: hypotension 51%, dyspnea 17%, seizures 6%, and mental status changes 11%. No differences in response or toxicity between the two schedules were noted. Hematologic changes included lymphocytosis and eosinophilia in the majority of patients. PEG IL-2 given once weekly has significant toxicity, and may produce tumor regression in patients with renal cell carinoma.     

A population‐based study evaluating the impact of sunitinib on overall survival in the treatment of patients with metastatic renal cell cancer

BACKGROUND:

Sunitinib has replaced interferon (IFN) as a first‐line standard of care in the treatment of metastatic renal cell carcinoma (RCC). This study aimed to determine overall survival and to confirm effectiveness in a population that includes poor prognosis patients.

METHODS:

Data were collected on all patients identified by the BC Cancer Registry with metastatic RCC who were treated with IFN or sunitinib. The IFN group consisted of patients who received IFN between January 2000 and October 2005, and the sunitinib group included patients treated with first‐line sunitinib from October 2005 to September 2007.

RESULTS:

There were 131 and 69 patients in the IFN and sunitinib groups, respectively. The median follow‐up of those still alive was 12.6 months. The median age (62 vs 63 years; P = .41), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria (poor in 19% vs 30%; P = .41), and proportion with >1 metastasis (53% vs 62%; P = .21) were similar between the IFN and sunitinib groups, respectively. The median survival of the IFN and sunitinib groups was 8.7 and 17.3 months, respectively (log‐rank P = .004). The median survival of patients with favorable, intermediate, and poor MSKCC prognostic profiles in the IFN group was 22.9, 8.7, and 4.1 months, respectively (P < .001), whereas in the sunitinib group it was not reached, 16.8, and 10.7 months, respectively (P = .006). The hazard ratio of death after adjusting for MSKCC criteria was 0.49 (95% confidence interval, 0.31‐0.76; P = .001).

CONCLUSIONS:

The introduction of first‐line sunitinib was associated with a doubling of overall survival compared with patients treated with IFN alone. This benefit extended to patients with poor MSKCC prognostic profiles. Cancer 2009. © 2009 American Cancer Society.     

The T cell death knell: immune-mediated tumor death in renal cell carcinoma.

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.     

Amifostine: potential for clinically useful cytoprotection

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radio-protectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclophosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on non-hematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

A phase I trial of intrapleural recombinant human interferon α (rHuIFNα2b) in patients with malignant pleural effusions

The use of intrapleural sclerosing agents to control reaccumulation of pleural fluid in patients with malignant effusions has been widely investigated. A phase I trial of intrapleural recombinant human interferon (rHuIFN2b) was initiated to determine the toxicity and maximal tolerated dose in this group of patients. rHuIFN2b was instilled as a single dose following chest tube (15/16) or percutaneous (1/16) drainage of cytologically proven malignant effusions. Doses of rHuIFN2b were escalated from 25×10⁶ to 200×10⁶ U/m² in cohorts of three to four patients. Toxicity was mild to moderate, and included chills, fever and chest pain, and resembled that produced by systemic administration of rHuIFN2b. Dose-limiting toxicity occurred at 200×10⁶ U/m² and consisted of hepatic enzyme elevations and renal failure. Partial control of the effusions was noted in two patients, with two additional patients having stable disease. Phase II trials of rHuIFN2b should utilize up to 150×10⁶ U/m² for intrapleural instillation.Abbreviation IFN interferon - MPE malignant pleural effusions Supported in part by a grant from the Schering Corporation, Kenilworth, N.J.