Rapidly alternating chemotherapy and radiotherapy instead of cystectomy for the treatment of muscle-invasive carcinoma of the urinary bladder: long term results of a pilot study.

BACKGROUND: The authors studied rapidly alternating chemotherapy and radiotherapy as the initial treatment for patients with muscle-invasive transitional cell carcinomas of the urinary bladder whose advanced age and lack of strength precluded cystectomy. METHODS: Twenty-one patients with T2 (28%) or T3 (72%) NXM0 carcinomas were treated by transurethral resection followed by chemoradiotherapy. Their median age was 73 years. The chemotherapy (consisting of methotrexate, vinblastine, doxorubicin, and cisplatin) was given during Weeks 1, 4 and 7. Radiotherapy (1.8-2 Gray [Gy] twice a day, to a total dose of 18-20 Gy per week) was given during Weeks 2, 5 and 8, for a final dose of 40 Gy to the pelvis plus 14-20 Gy boost to the affected bladder. RESULTS: There was 1 treatment-related death (5% of patients), but otherwise the acute toxicity was relatively mild. Cystoscopy 1 month after chemoradiotherapy did not reveal invasive cancer in any patient. Subsequent cystoscopies detected recurrent invasive cancer in 3 patients after 30, 44, and 82 months, respectively. The observed survival rate after 5 years was 37%, the cause specific survival rate was 63%, the metastasis free rate was 71%, and the local control rate was 80%. Eighty-four percent of patients had normal bladder function. CONCLUSIONS: Transurethral resection plus chemoradiotherapy was successful in preserving bladder function in the majority of the patients. The survival and progression free rates compared favorably with what has been reported recently after radical cystectomy and chemotherapy, and they add to the growing body of evidence that chemoradiotherapy might be a safe, effective alternative to cystectomy for many patients with muscle-invasive carcinoma of the urinary bladder.

Adoptive transfer of ex vivo activated memory T-cells with or without cyclophosphamide for advanced metastatic melanoma: results in 36 patients.

Autolymphocyte therapy (ALT) is the infusion of autologous peripheral blood mononuclear cells (PBMC) activated ex vivo by a cytokine-rich supernatant (T3CS) generated from a previous autologous lymphocyte culture using low doses of the anti-CD3 mitogenic monoclonal antibody. The mechanism of action is enhancement of a recall response by CD45RO+ (memory) T-cells (ALT cells) to host tumour without dependence on exogenous interleukin (IL)-2. The existence of anti-tumour-specific T-cells in melanoma patients has been well described, and efforts to utilise them therapeutically have achieved modest tumour response rates. However, few long-term survival data have been reported. From 1986 to 1992, we treated 36 patients with disseminated melanoma using ALT alone (26 patients) or adoptive chemoimmunotherapy using ALT and cyclophosphamide (CY) (10 patients). Over this time period, the cell activation method evolved from using cytokine supernatants derived from a one-way allogeneic mixed lymphocyte culture (MLCS), to the current practice of utilising anti-CD3 and autologous cytokines (T3CS). There were 21 men and 15 women, average age 57 years, range 30-82. 27 had failed prior therapies and 9 had no prior therapy. A total of 161 infusion of ALT cells were given: 65 with cells activated in MLCS and 96 with T3CS. There were no grade 3 adverse events, and an approximate 20% incidence of grades 1 and 2 reactions to ALT-cell infusions. Transient cytopenias were seen in patients receiving CY. Sixty-one per cent (22/36) of patients received the planned six ALT-cell infusions, while 39% did not due to progressive disease. In 33 evaluable patients, there were four complete responses, four partial responses and 6 patients with stable disease (SD). Responding patients and those with SD had prolonged survival compared to historical controls when matched for number of organ systems involved. Ex vivo depletion of CD45RO+ T-cells revealed preferential lysis of autologous and HLA-A-matched melanoma targets that was dependent on these memory T-cells. These data suggest that adoptive cellular therapy using ex vivo activated memory T-cells with and without CY is active, has low toxicity, is tumour-specific and can result in clinical benefit in patients with disseminated melanoma.

Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: tumor lysis syndrome of a metastatic soft tissue sarcoma.

Adoptively transferred immune cells in combination with chemotherapeutic agents form the basis for adoptive chemoimmunotherapy (ACIT) of neoplastic disease. Autolymphocytes (ALT-cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor-specific CD45RO+ (memory) T-cells. These ALT-cells combined with cimetidine (CIM) as autolymphocyte therapy (ALT), have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). We have previously described an effective ACIT protocol using ALT and cyclophosphamide (CY) for patients with relapsed and refractory non-RCC solid tumors. We now report a case of a patient with a metastatic gastric leiomyosarcoma to the liver, who developed a clinical picture consistent with a tumor-lysis syndrome (TLS), following salvage therapy for his tumor with ACIT using ALT and CY. TLS is a well-known complication resulting from the treatment of rapidly proliferating hematopoietic tumors such as Burkitt's lymphoma and acute lymphocytic leukemia. TLS has also been rarely described in chronic lymphocytic leukemia, as well as certain solid tumors such as breast cancer, small cell lung cancer, and medulloblastoma. However, there have been no previous reports of TLS occurring either secondary to immunotherapy or in sarcomas. The nature of these unusual findings is discussed.

Adoptive chemoimmunotherapy for the treatment of relapsed and refractory solid tumors using ex vivo activated memory T cells (autolymphocyte therapy) and cyclophosphamide.

Autolymphocytes (ALT cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor specific CD45RO+ (memory) T cells. These ALT cells combined with cimetidine as autolymphocyte therapy (ALT) have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). To determine activity of ALT in human TBH with therapy-resistant solid tumors other than RCC and whether it was feasible to combine ALT with chemotherapy, we studied 21 patients with relapsed or primary refractory solid tumors following a study protocol of adoptive chemoimmunotherapy (ACIT) using ALT and cyclophosphamide. Twenty patients were evaluable. Five responses were seen, including two complete responses (CRs) and three partial responses (PRs). ACIT activity was noted in relapsed TBH who had responded to their previous chemotherapy and/or radiation therapy. The toxic effects of this ACIT study were minimal with no treatment-related morbidity or mortality. It appears that in some relapsed but not primary refractory solid tumors, ACIT using ALT (CD45RO+ T cells and cimetidine) together with cyclophosphamide has definite antitumor activity associated with little or no toxic effects. Further studies of ACIT in solid tumors other than RCC are justified.

Treatment of cytomegalovirus retinitis with ganciclovir (9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (BW B759U).

Six patients (11 eyes) with virologically confirmed cytomegalovirus (CMV) retinitis involving the posterior pole of the eye were treated with a new drug, ganciclovir. Treatment with intravenous ganciclovir consistently halted progression of retinitis and produced improvement in measures of visual function. However, within three weeks after cessation of therapy renewed CMV activity and worsening of visual function were observed in most cases. Maintenance therapy with ganciclovir extended the period of remission from CMV retinitis.

[Monotherapy of endemic Kaposi sarcoma with long-term vincristine infusion]. / Monotherapie des endemischen Kaposi-Sarkoms mit Vincristin-Dauerinfusion.

Twelve patients with endemic Kaposi's sarcoma (KS) were entered into a clinical trial of vincristine (VCR) infusion. Patients received 5-day courses of VCR, 0.25 mg/m2/day by continuous infusion, after an 0.5 mg intravenous bolus injection. Courses were repeated every four weeks. Stabilization of disease occurred in nine patients and could be maintained for a mean of 3 months (range: 2-7 months). Complete or partial remissions were not achieved with this protocol. Complications of therapy consisted of development of moderate neurotoxicity and paralytic ileus in one patient. Two patients developed opportunistic infections while on therapy. Hematologic toxicity, nausea or emesis did not occur. Single agent VCR by infusion is well tolerated by patients with the acquired immunodeficiency syndrome (AIDS) but appears to have only limited activity in the treatment of AIDS-related KS.

Isolated leukemia cutis--a case report.

A 67-year-old woman with acute myelomonocytic leukemia had a clinical course characterized by the initial appearance of leukemia cutis without bone marrow involvement. When marrow involvement subsequently occurred, induction chemotherapy cleared all manifestations of the illness. Shortly thereafter, while blood and bone marrow remained in remission, the skin lesions reappeared. The introduction of 6-thioguanine, as part of the maintenance treatment protocol, resulted in the rapid and permanent disappearance of the leukemic skin infiltrates.

Complex chromosomal abnormalities in a patient with lymphoid blast crisis of chronic myelogenous leukemia.

A 46-year-old Chinese man underwent lymphoid blast crisis (Ia+, CALLA+, TdT+) after 5 years of chronic phase, Philadelphia-chromosome positive chronic myelogenous leukemia. Chromosome analysis revealed a hyperdiploid karyotype, including two Philadelphia chromosomes--55,XY,t(9;22) (q34;q11), +2, +5, +5, +6, +10, +18, +19, +21, +del(22)(qll----qter)--in the majority of the leukemic blasts. The constellation of a lymphoid blast crisis and complex chromosomal abnormalities usually associated with myeloid blast crisis as well as the clinical data are discussed.

Acute nonlymphocytic leukemia following gastric adenocarcinoma treated by surgery alone. Evidence for etiologic heterogeneity of "secondary" leukemias.

The case of a 36-year-old Hispanic man who developed acute nonlymphocytic leukemia 18 months following gastric adenocarcinoma treated by surgery alone is presented. Cytogenetic analysis of the leukemic cells revealed numerical and structural chromosomal rearrangements including chromosomes 5 and 7 and immunologic characterization of the blasts revealed terminal deoxynucleotidyltransferase positivity with monocytoid features. This report suggests that not all cases of acute nonlymphocytic leukemia following chemotherapy and/or radiotherapy, which characteristically display similar cytogenetic and immunologic features, should be exclusively ascribed to the leukemogenic properties of anticancer treatment.

Philadelphia-chromosome-negative chronic myelogenous leukemia with incomplete trisomy 1q following chemotherapy for ovarian carcinoma.

A 59-year-old woman was treated with surgery followed by monthly injections of the alkylating agent thiotepa for a granulosa cell tumor of the left ovary. Chemotherapy was continued for 22 years. At the age of 84, chronic myelogenous leukemia (CML) developed. Cytogenetic studies revealed incomplete trisomy of the long arm of chromosome No. 1 as the only karyotypic abnormality. No Philadelphia chromosome was detected. The significance of trisomy 1q as an isolated cytogenetic abnormality in CML and the occurrence of CML following treatment of ovarian cancer are discussed.