A phase II study of cisplatin plus methotrexate with folinic acid rescue in metastatic or locally recurrent transitional cell carcinoma of the urothelium.

34 patients with metastatic or recurrent transitional cell carcinoma (TCC) of the urothelium were treated with cisplatin 100 mg/m2 plus methotrexate 250 mg/m2 with folinic acid rescue every 3 weeks. A response rate of 55% was achieved with two complete and 15 partial responses in 31 evaluable patients. The overall median survival was 7 months, 9 months for responding and 4 months for non-responding patients. Toxicity was generally moderate. However, 1 patient with previous infectious problems died of neutropenic sepsis. Overall, 83% of the scheduled doses of cisplatin and 96% of the scheduled doses of methotrexate were given. In conclusion, this schedule of the combination of cisplatin and methotrexate did not improve response rate or survival compared with previous studies of this two-drug combination.

Tumor imaging with technetium-99m-labeled hydrazinonicotinamide-Fab' conjugates.

UNLABELLED: This study compares the in vivo properties of direct versus indirect 99mTc-labeling for two Fab' fragments from antibodies that recognize tumor-associated antigens. METHODS: Fab' fragments of two IgG2a monoclonal antibodies were either radiolabeled directly or via the linker bromoacetyl hydrazinonicotinamide hydrobromide (BAHNH) conjugated site specifically at protein thiols. A thiol assay was used to determine the number of thiols in the Fab' and to monitor their consumption during conjugation with BAHNH. Both preparations were labeled to > 95% incorporation of 99mTc, with the isotope tracking the single 50 kD absorbance peak seen on size-exclusion HPLC. The labeled preparations were tested in tumor-bearing and control mice, with dissections at 4 and 24 hr and gamma scintigraphy of the tumor-bearing mice. RESULTS: The major difference between the two labeled preparations for either antibody fragment was the greater accumulation of isotope in the tumor for the indirectly labeled preparations. This increase ranged from 1.5- and 2.7-fold at 4 hr to 2.6- and 3.2-fold at 24 hr for the two antibodies, respectively. Since blood clearance was similar for the two labeling methods, the higher tumor accumulation with the indirectly labeled fragments resulted in higher tumor to blood ratios. Tumors could be imaged with both antibodies with either type of labeling with greater clarity and sensitivity at the 24 hr time point. CONCLUSION: While both labeling methods resulted in tumor detection through imaging, the images obtained with the indirectly labeled antibody fragments were more easily visualized due to the combination of higher radioisotope accumulation in the tumor and similar blood clearances compared to the direct labeled fragment.

Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer. A phase III study.

PURPOSE: To compare the efficacy and toxicity of epirubicin to that of the combination of epirubicin and cisplatin in patients with advanced breast cancer. PATIENTS AND METHODS: A total of 155 patients were randomized to receive either epirubicin (70 mg/m2) days 1 and 8 every 4 weeks or epirubicin (60 mg/m2) days 1 and 8 plus cisplatin (100 mg/m2) day 1 every 4 weeks. Epirubicin was continued until disease progression or to a cumulative dose of 1000 mg/m2. Cisplatin was discontinued after six cycles. In 45 premenopausal women an oophorectomy was performed. None of the evaluable patients had received chemotherapy for metastatic disease. RESULTS: Among evaluable patients (74 in the epirubicin group and 65 in the epirubicin plus cisplatin group) there were 19% vs 29% complete responses, and 42% vs 37% partial responses, with no significant difference. In the epirubicin plus cisplatin group the response rate was significantly higher in previously untreated patients as compared with patients who had received adjuvant chemotherapy (74% vs 55%, P = 0.002). Median times to disease progression were 8.4 months in the epirubicin group and 15.3 months in the epirubicin plus cisplatin group (P = 0.045). Median survival times were 15.1 and 21.5 months, respectively (P = 0.41). In the epirubicin plus cisplatin group leukopenia and thrombocytopenia were significantly more frequent, 29% of the patients developed mild to moderate peripheral neurotoxicity, 34% reported tinnitus and hearing changes, 6 patients developed nephrotoxicity (one died due to nephrotic syndrome), and 3 patients developed leukaemia (two died of this cause). Congestive heart failure occurred in six patients in the epirubicin group and three patients in the epirubicin plus cisplatin group. CONCLUSION: Cisplatin plus epirubicin is an active, although highly toxic regimen when used as first-line therapy in advanced breast cancer. The time to disease progression was significantly longer in the cisplatin plus epirubicin group (increased by 82%). Due to toxicity, the combination regimen cannot be recommended. However, the study indicated a very high activity of cisplatin in advanced breast cancer. Studies of first-line therapy in advanced breast cancer including cisplatin or other platin derivatives in combination with, for example, the taxanes are suggested.

Functional characterization of Foxp3-specific spontaneous immune responses.

Tumor-infiltrating CD4+CD25+ regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. The transcription factor forkhead box P3 (Foxp3) is generally expressed in Tregs. Here, we identify and characterize spontaneous cytotoxic immune responses to Foxp3-expressing cells in peripheral blood of healthy volunteers and cancer patients. These immune responses were directed against a HLA-A2-restricted peptide epitope derived from Foxp3. Foxp3-reactive T cells were characterized as cytotoxic CD8+ T cells. These cells recognized dendritic cells incubated with recombinant Foxp3 protein indicating that this protein was indeed internalized, processed and cross-presented in the context of HLA-A2. More importantly, however, Foxp3-specific T cells were able to specifically recognize Tregs. Similarly, Foxp3+ malignant T cells established from a Cutaneous T-cell lymphomas (CTCL) patient were readily killed by the Foxp3-specific cytotoxic T lymphocytes. The spontaneous presence of Foxp3-specific cytotoxic T-cell responses suggest a general role of such T cells in the complex network of immune regulation as such responses may eliminate Tregs, that is, suppression of the suppressors. Consequently, induction of Foxp3-specific cytotoxic T-cell responses appears as an attractive tool to boost spontaneous or therapeutically provoked immune responses, for example, for the therapy of cancer.

Phase II study of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck.

BACKGROUND: Results with docetaxel as single drug in squamous-cell head and neck cancer have been encouraging. The purpose of the present phase II study is to evaluate the antitumour efficacy and toxicity of the combination of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck (SCCHN) for whom no curative therapy is available. PATIENTS AND METHODS: Eligibility criteria included: written informed consent; WHO performance status < or = 2; age 18-70 years; adequate bone marrow, liver, and renal function; measurable or evaluable disease; no previous systemic chemotherapy (prior radiotherapy and/or surgery were allowed), no other previous or concurrent malignancy; no peripheral neuropathy. Treatment consisted of docetaxel 75 mg/m2 in a one-hour infusion after pre-treatment with prednisolone, followed by cisplatin 75 mg/m2 in a half-hour infusion preceded and followed by hydration. Treatment was repeated every three weeks for a maximum of eight cycles. RESULTS: Twenty-five patients (median age 52 years, range 33-66) entered the trial, all were evaluable for survival, twenty-four for response and toxicity. Twenty-four patients had undergone prior radiotherapy and seventeen had also had surgery. Nineteen had local-regional recurrence only, three had local-regional disease and distant metastases, and three had distant metastases only. Patients received a median of 5 treatment cycles (range 2-8). Overall response rate was 33% (8 of 24) of patients; complete response rate was 8% (2 of 24) of patients, lasting 2.2 and 17.1 months, respectively; partial response rate was 25% (6 of 24) of patients, lasting for a median of 4.9 months (range 1.7-11.6 months). Median survival was 11 months. Toxicity was relatively well tolerated. However, one patient died of probable toxicity (neutropenia and infection) and three patients discontinued treatment because of toxicity (massive oedema, myocardial infarction, persistent thrombocytopenia). The most frequent moderate-to-severe toxicity (75% of patients) was grade 3-4 neutropenia, transient in all but one patient. Grade 3 neuropathy occurred in one patient, none had grade 4. Grade 3 oral mucositis occurred in three patients, none had grade 4. Grade 2-3 hypomagnesaemia occurred in 10 patients requiring magnesium infusion. CONCLUSIONS: Docetaxel and cisplatin is an active combination in patients with recurrent or disseminated SCCHN. Remissions are however fairly short. Toxicity is significant, but generally manageable.

Cancer of the nasal cavity and paranasal sinuses. Prognosis and outcome of treatment.

A retrospective study of 121 patients, 77 men and 44 women, with sino-nasal cancer, admitted to the National University Hospital, Rigshospitalet, during the period 1983 1993, is presented. The median follow-up time was 21 months, (range 3 124). Forty-six percent of the tumors originated from the nasal cavity, 29% from the maxillary sinuses and 5% from the ethmoid sinuses. In 18% of the cases, the site of origin was not clear due to advanced local growth. Sixty-five patients received primary radiation therapy with curative intention of whom 5 underwent secondary surgery. Forty-nine patients underwent primary surgery, 38 of them received postoperative radiation therapy. The overall 5-year survival rate in this material was 35% and the disease-specific 5-year survival was 45%. Patients with well-differentiated squamous cell carcinomas had a significantly higher 5-year survival rate than patients with poorly differentiated carcinomas and patients with regional metastases had a significantly poorer 5-year survival than patients without. The 5-year local control was 48% (41/121). Six of 9 patients with regional metastases at admission were controlled locally, whereas 16 patients developed regional metastases after primary treatment.

[99mTc]tricine: a useful precursor complex for the radiolabeling of hydrazinonicotinate protein conjugates.

The stannous reduction of [99mTc]pertechnetate in the presence of tricine results in the formation of the new labeling precursor complex [[99m-Tc]tricine. This complex has improved efficacy for the 99mTc labeling of hydrazinonicotinate-modified IgG compared to [99mTc]glucoheptonate. FAB mass spectral analysis of the product formed by the reaction of [TcOCl4](-1) with tricine indicates the formation of [TcO(tricine x 2H)2](-1).

Sino-nasal cancer in Denmark 1982-1991--a nationwide survey.

Cancer of the nasal cavity and paranasal sinuses is a rare disease. The many different histologies and sites make the management of this disease a challenge. The current report from the Danish Society for Head and Neck Oncology comprises a joint analysis of five retrospective series covering the entire country, with 315 patients seen in the 10-year period from 1 January 1982 to 31 December 1991. Tumour sites were nasal cavity (n = 156), maxillary sinus (n = 139), ethmoid sinus (n = 14), sphenoid sinus (n = 5) and frontal sinus (one case). The most common histologies included squamous cell carcinoma (126 cases), adenocarcinoma (41 cases), malignant melanoma (38 cases) and malignant lymphoma (34 cases). A total of 284 patients (90%) received treatment with curative intent; most of these patients were treated with radiotherapy, either alone (120 patients) or in combination with surgery (111 patients). There was no significant difference between the five centres in disease specific survival and overall survival. The results showed that histology, localization and nodal involvement were significant prognostic factors for locoregional control and survival. Patients with squamous cell carcinoma had a significantly poorer prognosis compared with patients with adenocarcinoma. However, a Cox multivariate analysis revealed that this was likely the result of tumour localization, as most adenocarcinomas were in the nasal cavity. The experience from this data collection has inspired the Danish Society for Head and Neck Oncology to arrange common data registration of several other clinical head and neck series. In the future, the Society plans to expand this activity further.

Preparation of hydrazino-modified proteins and their use for the synthesis of 99mTc-protein conjugates.

The syntheses and protein linking properties of succinimidyl 4-hydrazinobenzoate hydrochloride (SHBH) and succinimidyl 6-hydrazinonicotinate hydrochloride (SHNH), two new heterobifunctional linkers which lead to hydrazino-modified proteins, are described. SHBH-modified proteins are unstable due to the presence of the phenylhydrazine moiety. This problem was overcome by synthesizing the hydrazinopyridine analogue SHNH, and the conjugates derived from this linker are stable. Tc(V) oxo precursors readily add to hydrazinopyridine-modified proteins to yield the desired 99mTc-radiolabeled protein. 99mTc-hydrazinopyridine-polyclonal IgG conjugates are useful agents for the imaging of focal sites of infection.