Efstathios Tapazoglou

Activity of flavone acetic acid (NSC-347512) against solid tumors of mice

Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgows osteosarcoma). FAA was curative for colon adenocarcinoma # 10 and pancreatic ductal adenocarcinoma # 03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 °C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual ‘threshold’ behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.

Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer.

In a series of three consecutive pilot studies conducted between 1977 and 1982 at Wayne State University, Detroit, Michigan, 191 consecutive patients with previously untreated, locally advanced head and neck cancer were treated with cisplatin (CDDP), vincristine, and bleomycin or CDDP and 5‐fluorouracil (5‐FU) infusion before definite surgery or radiation. A 39% (75/191) rate of complete clinical responses was achieved. Thirty‐two of the chemotherapy‐induced complete responders underwent radical surgery. Thirteen had no histologic evidence of residual disease in the surgically resected specimen. The CDDP and 5‐FU infusion combination achieved the highest histologic complete response rate. All histologically complete responders who had completed local radiation therapy are clinically free of disease at median follow‐up of 36 months. Patients who achieved complete response both clinically and histologically had superior survival as compared to patients who achieved complete response clinically and were subsequently found to have residual tumor in their surgically resected specimen (P = 0.01). An analysis of the clinical and pathological pretreatment characteristics was performed to identify factors predictive of histologic complete response. Advanced nodal disease correlated inversely with the achievement of negative histology in the surgically resected specimen (P = 0.02). No other factors were significant in predicting response. Cancer 59:233–238, 1987.

Metastatic squamous cell carcinoma of an unknown primary localized to the neck. Advantages of an aggressive treatment

Treatment of patients with squamous cell carcinoma (SCC) of an unknown primary localized to the neck is still controversial, particularly regarding advanced disease. We reviewed 41 such patients treated with surgery and/or radiotherapy (RT) (n = 25) or with combined modality treatment including chemotherapy (CH) (n = 16). The male to female ratio was 28 to 13, and the median age was 58 years (range, 32 to 94 years). There were 27 (66%) patients with poorly differentiated SCC and 8 with moderately differentiated or well‐differentiated cancer. Twenty‐three (56%) patients had N3 disease, 16 (39%) had N2, and 2 had N1. The majority of N3 patients have been treated with CH and RT (n = 12) or with RT alone (n = 9). The combined CH‐RT was well tolerated, with no life‐threatening toxicity. The complete response (CR) to CH‐RT was 81% (11 patients have no evidence of disease [NED] currently). The median survival time of this group was 37+ months. Of the 25 patients who had surgery and/or RT as their first planned treatment, 7 (28%) have NED currently. The median survival time of this group was 24 months. Patients with N3 disease who received CH had a higher CR rate and a longer survival time as compared with those treated with surgery and/or RT, despite a higher (N3) stage of disease. These findings warrant further investigation in randomized cooperative studies.

The Incidence and significance of thromboembolic complications in patients with high-grade gliomas

Coagulation system abnormalities in patients with malignancy ranges from asymptomatic laboratory abnormalities to overt clinical manifestations. To determine the incidence and significance of clinically manifest thromboembolic phenomena in patients with high‐grade gliomas, the records were analyzed of 77 patients that presented between January 1985 and June 1988. Fifteen patients (19%) had clinically manifest deep venous thrombosis and/or pulmonary emboli during the course of their disease. All these patients were ambulatory before and at the time of diagnosis of the event. The thromboembolic episodes occurred at the time of initial management of the primary tumor while there was documented clinical improvement in the functional status of the patient or at the time of progression of the disease. One patient died as a result of a pulmonary embolism; in two others, an embolism was a significant contributor to the patients death. Anticoagulation resulted in complications in two of eight patients treated. Thromboembolic events occur with high frequency in patients with high‐grade gliomas and contribute to the high morbidity and mortality seen in these patients. The optimum approach to screening and the treatment of these events has not been determined. Cancer 68:2621–2624, 1991.

The role of infection in the morbidity and mortality of patients with head and neck cancer undergoing multimodality therapy

Cancer of the head and neck is a common cancer worldwide. The majority of patients present with locally advanced disease. Recently a great deal of improvement has been made in multimodality therapy of this disease, warranting more careful consideration of factors affecting quality of life, disease course, and treatment. Infection is clearly a factor. Analysis of 662 hospital admissions of 169 head and neck cancer patients was performed. A definite infection was documented in 86 febrile episodes, pneumonia contributed to 40%, bacteremia to 13%, skin and soft tissue infection to 12%, and tracheobronchitis to 10%. Among the evaluated risk factors, foreign bodies, specifically intravenous (IV) cannulae and gastrostomy tubes, race, performance status, alcohol intake, and nutritional status were statistically significant variables that predicted for or were associated with infection. Infection contributed to 44% of the deaths.

Chemotherapy for paranasal sinus carcinoma: a 10-year experience at Wayne State University

The role of chemotherapy in the management of patients with cancer of the paranasal sinus has not been defined. An analysis of 24 evaluable patients treated with chemotherapy as part of their overall therapy was performed. There were 16 male patients and eight female patients. Sixteen patients were previously untreated and eight had recurrent disease after surgery and/or radiotherapy. Six of the previously untreated patients had metastatic disease on presentation (four central nervous system (CNS) and two lung), and four recurrent patients had CNS involvement. The majority of patients (78%) had squamous cell carcinoma. The chemotherapy regimens included cisplatin (CDDP), vincristine (VCR), and bleomycin (COB), 5‐fluorouracil (5‐FU) infusion and CDDP, or 5‐FU/CDDP and methotrexate (MTX). All patients had computed tomography (CT) measurable disease. Previously untreated patients underwent surgery and/or radiotherapy postchemotherapy. The overall response rate to chemotherapy for previously untreated patients was 82% (complete response [CR] 44%, partial response [PR] 38%) and for recurrent patients 88% (CR 38%, PR 50%). Predominant toxicities were nausea, vomiting, myelosup pression, mucositis, and renal impairment. The median survival of the previously untreated patients, based on response to chemotherapy, was as follows: CR 21+ months (range, 10+ to 81 months), PR 13.5 months (range, 2 to 21 months), and no response (NR) 3 months (range, 1 to 7 months). The median survival of patients with recurrent disease was as follows: CR 16 months, PR 13.5 months, and NR 5 months. We conclude that patients with paranasal cancers are responsive to CDDP‐containing combinations. The role of adjuvant chemotherapy in previously untreated, locally advanced patients needs to be demonstrated by future randomized trials.

The activity of a single‐agent 5‐fluorouracil infusion in advanced and recurrent head and neck cancer

Although chemotherapy regimens using cisplatin (CDDP) and 5‐fluorouracil (5‐FU) infusion have shown significant activity in advanced and recurrent head and neck cancer, their use requires normal renal function. The use of 5‐FU infusion alone has not been evaluated in these tumors. Retrospective analysis revealed 11 patients who received 5‐FU infusion alone because of poor renal function: 7 patients with recurrent disease who were previously treated with surgery and/or radiation therapy and 4 patients who received 5‐FU as preoperative induction therapy for advanced disease were treated. The infusion dose consisted of 1000 mg/M2/24 hours for 96 hours for patients with previous radiation and 120‐hour infusions for patients without previous radiation. The courses were repeated at 3‐week intervals. Eight of 11 (72%) demonstrated a response (1 complete response [CR] and 7 partial responses [PRs]). Responses occurred in 4 of 4 (all PRs) patients with previously untreated epidermoid cancer, 1 patient with recurrent adenocystic cancer, and 3 of 6 patients with recurrent epidermoid cancer not previously treated with chemotherapy. Three patients, with no prior systemic or local therapy, who were clinical partial responders to 5‐FU infusion went on to surgery and radiotherapy. Their responses were maintained for 18, 14, and 46+ months, respectively. The predominant toxicities were stomatitis (6/11, 55%) and leukopenia (2/11 patients). In this retrospective analysis, 5‐FU infusion alone demonstrated good activity in head and neck cancer with tolerable toxicity. Since the number of patients is small and were selected on the basis of renal function, prospective evaluation is essential.

Meningeal carcinomatosis in head and neck cancer: Report of six cases and review of the literature

Head and neck cancer has rarely been reported to be a cause of meningeal Carcinomatosis. These tumors are known more for their local invasiveness rather than distant metastasis. This would appear to preclude meningeal involvement, but close proximity to multiple cranial nerves may provide an access to the meninges. Six cases of head and neck cancer with meningeal invasion are presented. All six cases had malignant cells in their cerebrospinal fluid. Three cases had malignant cells recovered from a ventricular specimen after lumbar punctures were negative. The most common clinical finding on presentation was cranial nerve involvement. The optic nerve was involved most often with nerves VI and V the next most frequent. Headache was present in four patients and seizures occurred in two. No patient had meningismus. Our current treatment plan involves insertion of an Ommaya Reservoir and intraventricular methotrexate. Only patients whose primary head and neck tumor shows a response to systemic therapy undergo Ommaya placement. Meningeal Carcinomatosis in head and neck cancer may be more prevalent than previously thought and the likely mechanism is via direct extension rather than hematogenous spread.

Ondansetron for the prevention of emesis induced by high‐dose cisplatin. A multi‐center dose‐response study

To determine a dose‐response relationship of ondansetron for the prevention of emesis induced by high‐dose cisplatin and to study the efficacy of the extended dosing schedule of ondansetron during 20 hours after cisplatin administration, 36 patients with malignant neoplasms who had not previously received chemotherapy but who were currently receiving cisplatin were treated. These patients received a six‐dose regimen of 0.01 mg/kg (low dose) or 0.18 mg/kg (high dose) of ondansetron. Seven (41%) patients in the high‐dose group had no emesis and four (24%) patients had one or two episodes. One (5%) patient in the low‐dose group had no emesis and four (21%) patients had one or two episodes. The difference in the number of emetic episodes was significant (P < 0.02). Fifty percent of the high‐dose patients reported no nausea or mild nausea, compared with 11% of the low‐dose patients. Clinical adverse events included mild, transient headache and dizziness in the high‐dose group and headache and diarrhea in the low‐dose group, with no significant laboratory abnormalities. There is a parallel relationship between the ondansetron doses and the antiemetic efficacy. The response rate for the six‐dose regimen of 0.18 mg/kg was not superior to that for the previously reported 0.18 mg/kg regimen given in a three‐dose schedule in a similar clinical setting.

Intracranial astrocytoma with diffuse bone marrow metastasis: a case report and review of the literature

A 41 year old male presented with headache, lethargy, and ataxia and found to have a left temporal lobe mass and a leukoerythroblastic peripheral blood smear. The latter prompted an iliac crest bone marrow biopsy on which a diagnosis of metastatic glioma was made and verified by immunohistologic characterization. The patient was treated with cranial irradiation and simultaneous systemic BCNU (bis-dichloroethylnitrosurea) with complete response. This case with diffuse bone marrow involvement demonstrates that a glioblastoma is capable of extracranial metastases without previous intervention. From a review of reported cases of gliomas of extraneural metastasis, it is concluded that untreated gliomas are capable of vascular spread although less frequently than previously manipulated tumors.