Janice P. Dutcher

A phase II study of taxol in patients with malignant melanoma

Based on results of a phase I study demonstrating antitumor activity of taxol in patients with melanoma, 34 patients with documented metastatic melanoma received taxol, 250 mg/m2, as a 24-hours infusion, repeated every 21 days, in this phase II study. All patients received premedication with dexamethasone, diphenhydramine and cimetidine. Four patients experienced anaphylactic reactions and stopped treatment. Other significant toxicity of this drug included short-lived but severe neutropenia (< 1,0007mm2) and peripheral neurotoxicity. Four of 28 evaluable patients demonstrated objective response (14%) (confidence interval, 4%–33%) including 3 complete responses and 1 partial response. Two complete responders are continuing at 25 + and 38 + months after achieving CR. Minor evidence of anti-tumor activity was noted in five additional patients. Taxol has significant activity in melanoma and should be further studied in combination with other agents in this disease.

Cytoreductive surgery for stage IV renal cell carcinoma.

To facilitate the regression of extra renal disease in response to systemic therapy, cytoreductive surgery has been advocated as step 1 in the treatment of stage IV renal cell carcinoma. To determine the effect of surgery on subsequent clinical course, we reviewed the treatment records of 30 patients with known stage IV carcinoma of the kidney who underwent nephrectomy or additional procedures in preparation for systemic therapy. Of 30 patients only 7 (23%) underwent systemic therapy postoperatively. Progression of the disease, surgical morbidity and mortality were the factors preventing 77% of our patients from continuing with treatment. Since regression of extra renal lesions is the goal of systemic therapy, our data suggest that nephrectomy and most other cytoreductive operations in preparation for systemic therapy are not efficient treatment strategies.

CHARACTERIZATION OF TUMOR-INDUCED PLATELET AGGREGATION: THE ROLE OF IMMUNORELATED GPIb AND GPIIb/IIIa EXPRESSION BY MCF-7 BREAST CANCER CELLS

Tumor cell induced platelet aggregation is thought to be an early step in the metastatic process. Here we show that platelet aggregation induced by MCF-7 cells is mediated, in part, through an ADP-dependent mechanism based on inhibition of aggregation by pretreatment of the tumor cells with apyrase and the identification of ADP in tumor cell-free supernatants by HPLC. By applying immunocytochemical and flow cytometric techniques, we demonstrate that platelet immunorelated glycoproteins, GPIb, GPIIb/IIIa, GPIb/IX, and the integrin alpha v subunit are expressed on the surface of MCF-7 cells. The expression of an immunorelated GPIb was further confirmed by immunoblot and autoradiography of 125I-labelled MCF-7 cells. MCF-7 cell immunoblot preparations demonstrated one major protein reactive to an anti-GPIb alpha MoAb under nonreduced conditions with a molecular weight of 200 kD and two major proteins reactive with the anti-GPIb alpha MoAb under reduced conditions with molecular weights of 92 kD and 38 kD. Platelet aggregation is inhibited by preincubating the MCF-7 cells with antibodies to GPIb and GPIIb/IIIa. These findings document expression of adhesive glycoproteins by MCF-7 cancer cells and suggest that these receptors, together with ADP, play a role in tumor induced platelet aggregation.

Infusional cyclophosphamide, doxorubicin, and etoposide in relapsed and resistant Non-Hodgkin's lymphoma : evidence for a schedule-dependent effect favoring infusional administration of chemotherapy

PURPOSE This study attempted to determine the efficacy of cyclophosphamide (C), doxorubicin (D), and etoposide (E) administered as a continuous intravenous (IV) infusion (infusional CDE) over 4 days in patients with relapsed or resistant non-Hodgkins lymphoma (rNHL) and in patients with previously untreated (uNHL) who had poor prognostic features. PATIENTS AND METHODS Fifty-eight patients with rNHL and 10 patients with uNHL received infusional CDE every 28 or more days; all but one had intermediate- to high-grade histology. The cumulative doses of C, D, and E administered per treatment cycle were 750 mg/m2, 50 mg/m2, and 240 mg/m2, respectively. In the rNHL group, all patients had previously received C, most (81%) had received D, and a minority (16%) had received E. RESULTS Objective response occurred in 30 patients with rNHL (52%; 95% confidence interval, 39% to 65%); 10 patients had a complete response (CR) (17%; 95% confidence interval, 7% to 27%). Eleven patients (19%) remain progression-free (median follow-up, 22 months; range, 10+ to 38+), and six patients (10%) are disease-free (median follow-up, 25 months; range, 10+ to 38+). Among 10 patients with uNHL, eight (80%) had a CR, and none have relapsed (median follow-up, 11 months; range, 9+ to 24+). Toxicity was primarily hematologic. Two treatment-related deaths (3%) occurred, both attributable to infection in the relapsed or resistant group. CONCLUSION Infusional CDE produced a CR in substantial proportion of patients who had previously been exposed to at least two of the agents administered as an IV bolus, suggesting a schedule-dependent effect in favor of the infusional administration of certain cytotoxic agents in patients with lymphoid neoplasms. In addition, infusional CDE was effective and tolerable in patients with poor-prognosis NHL when used as initial therapy, and merits further study in that setting.

Disseminated strongyloidiasis with central nervous system involvement diagnosed antemortem in a patient with acquired immunodeficiency syndrome and Burkitts lymphoma.

A 45‐year‐old man presented with central nervous system involvement as the initial manifestation of disseminated infection with Strongyloides stercoralis. Several concurrent clinical factors contributed to this event, all related to the patients immunosuppression, including high‐grade lymphoma, corticosteroid therapy, and acquired immunodeficiency syndrome. This is only the third case of CNS involvement in disseminated strongyloidiasis diagnosed antemortem.

Cardiac monitoring of patients receiving arsenic trioxide therapy

Arsenic trioxide (ATO) is approved for the treatment of acute promyelocytic leukaemia and is under investigation for other malignancies. We report the cardiac findings in 18 patients with haematologic malignancies treated with ATO and assess the role of cardiac factors in fluid retention syndrome observed during ATO therapy. Based on initial observations in 10 patients treated with ATO, cardiac functions in the subsequent eight patients were evaluated prospectively. Evaluation included pre‐ and during‐treatment electrocardiograms, Holter monitoring, echocardiograms, multigated acquisition scan and cardiac stress tests if indicated. All eight patients developed fluid retention during ATO, evidenced by pulmonary congestion, oedema and pleural/pericardial effusions. No cardiac factors were identified that contributed to fluid retention. Six patients had prolonged corrected QT (QTc) compared with baseline, three developed ventricular tachycardia. Sinus tachycardia, ventricular premature contractions, and non‐sustained ventricular/supraventricular tachycardia were seen during ATO treatment. Fluid retention and cardiac events did not correlate with the dose or total amount of ATO or prior anthracycline therapy. In summary, fluid overload during ATO therapy does not appear to be cardiac in origin but appears to be drug‐related, and may reflect cytokine‐induced capillary leak. QTc prolongation, transient arrhythmias and clinically significant arrhythmias were seen with therapeutic doses of ATO.

Phase Ib trial of the effect of peritumoral and intranodal injections of interleukin-2 in patients with advanced squamous cell carcinoma of the head and neck : an eastern cooperative oncology group trial

Thirty-six patients with unresectable squamous cell carcinoma of the head and neck were entered into a phase Ib trial evaluating the toxicity, maximally tolerated dose (MTD), and immunomodulating effects of locally administered interleukin-2 (IL-2). Patients received daily IL-2 injected perilesionally in divided doses in each of four quadrants and bilaterally into the superior jugular lymph nodes. The dose of IL-2 began at 200 U/day and was escalated to 4 x 10(6) U/day in groups of six patients. Overall, regionally administered IL-2 was well tolerated. The most frequently encountered toxicities were fever, hepatotoxicity, and hypotension. Dose-limiting toxicity was encountered at 4 x 10(6) U. Of the 36 patients treated, 2 partial responses were noted at 2,000 and 4 x 10(6) U. We conclude that regionally administered IL-2 is well tolerated in patients with head and neck cancer and that the MTD is 2 x 10(6) U/day, similar to what has been reported with systemically administered IL-2. Although the overall response rate was low, it may be improved with prolonged administration of IL-2 or by combining it with other biologic or cytotoxic agents.

Adenocarcinoma arising in vulvar breast tissue

A patient with adenocarcinoma arising in vulvar ectopic breast tissue is described. Hormonal receptors of the tumor are analyzed. This is the first case in which an intensive treatment with combined surgery, radiation, hormonal therapy, and cytotoxic chemotherapy was given. Five cases reported previously in the literature are reviewed.

A pilot study of alpha-interferon and plicamycin for accelerated phase of chronic myeloid leukemia

Thirteen patients with accelerated phase of chronic myeloid leukemia (CML-AC) were treated with intravenous plicamycin and subcutaneous alpha-interferon. Two patients stabilized, three patients had partial hematologic responses and one patient had a hematologic complete response with a major cytogenetic response. Two patients, progressing on hydroxyurea, did not respond, but demonstrated re-sensitization to hydroxyurea after completion of induction therapy and had prolonged return to chronic phase for 30 months and 25 months. Four non-responders subsequently received additional chemotherapy and responded. Median survival of all study patients from the development of accelerated phase of CML was 24 months: substantially longer than other reported series (median 6 months). Plicamycin appears to add efficacy to interferon in the stabilization of accelerated phase of CML.

Orbital T-cell Lymphoma Human T-cell Leukemia Virus-I Infection

This is the first report of orbital involvement in systemic adult T-cell leukemia/lymphoma (ATLL). The etiologic agent of ATLL is the human T-cell leukemia virus-I (HTLV-I), the first retrovirus demonstrated to induce cancer in humans. The diagnosis of ATLL is based on characteristic clinicopathologic features in combination with serologic or virologic evidence of HTLV-I infection. Serum antibodies to HTLV-I were identified by immunofluorescent microscopy. Viral particles characteristic of HTLV-I were found in a culture of the patients peripheral blood lymphocytes. The patient was a native of the Caribbean, one of the known endemic foci of HTLV-I infection. Adult T-cell leukemia/lymphoma should be considered in the differential diagnosis of orbital T-cell lymphomas.