Stefan Madajewicz

Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients

Recent research advances show that tumor cell intravasation (entry into the circulation) and metastasis occur very early in breast cancer progression. Clinical studies also illustrate the potential importance of detection of circulating tumor cells (CTCs) in outcomes of patients with metastatic breast cancer. Whether these cells exhibit the invasiveness and express tumor stem or progenitor markers, hallmark of the metastatic phenotype, is less well characterized. To detect CTCs with the invasive phenotype and to explore their molecular features, we applied a functional cell separation method, called collagen adhesion matrix (CAM) assay, as enrichment and identification steps. The CAM‐coated device successfully recovered tumor cells spiked in 1 ml of blood with a 54% ± 9% (n = 18) recovery rate and 0.5–35% purity, and detected invasive tumor cells in 10/10 blood samples (100% yield) from patients with metastatic breast cancer with a range of 18–256 CTCs/ml and average of 126 ± 25 (mean ± SD) CTCs/ml. CTCs were detected in blood samples of 28/54 (52%) Stage I–III breast cancer patients with a mean count of 61 CTCs/ml. Furthermore, the relative frequency of these cells correlated to the staging, lymph node‐status and survival of patients with early stage breast cancer. CAM‐captured cells were capable of propagation in culture. Gene expression and multiplex flow cytometric analyses on CAM‐captured cells demonstrated the existence of distinct populations of CTCs including these of epithelial lineage and stem or progenitor cells. Thus, CAM‐initiated CTC detection provides advantages for examining invasiveness and tumor progenitor phenotypes.

Phase II study—intra-arterial bcnu therapy for metastatic brain tumors

Thirty‐one patients with metastatic brain tumors (MBT) from lung cancer and ten patients with MBT from melanoma received BCNU, 100 mg/m2, every four weeks by intracarotid and/or vertebral artery infusion into each involved site. Twenty‐five patients with lung cancer and all melanoma patients are currently evaluable. Twelve patients with lung cancer had complete and partial responses lasting from 1 to 14 months. Four of them with the histologic diagnosis of small cell carcinoma, one with large cell carcinoma and one with squamous cell carcinoma showed complete responses. None of the patients with melanoma MBT experienced any response. All of the patients had periorbital erythralgia and/or occipital pain during the infusion. Four patients manifested mild focal seizures during the infusion or 6 to 24 hours after the treatment. Transient confusion with disorientation was observed in two patients 4 and 24 hours, respectively, after a BCNU infusion. Two patients developed reversible thrombocytopenia after the fifth course of the IA chemotherapy. Median survival of patients with MBT from lung carcinoma was 4 months, with two of them still alive at 10 and 14 months, respectively. Only one patient of the 25 with lung carcinoma died from MBT. Failure to control the primary disease resulted in the deaths of a vast majority of the patients.

Therapy for patients with high grade astrocytoma using intraarterial chemotherapy and radiation therapy.

High grade astrocytomas account for approximately 40% of all primary brain tumors. The median survival is approximately 8–10 months for patients with glioblastoma multiforme and 36 months for patients with anaplastic astrocytoma. The results of systemic chemotherapy in the treatment of brain tumors have been reported to be less than satisfactory, mainly because of the blood‐brain barrier impermeability for chemotherapeutic drugs. Intraarterial chemotherapy has been an attractive alternative with which to overcome this problem.

Intracarotid chemotherapy with etoposide and cisplatin for malignant brain tumors

Chemotherapy for tumors of the central nervous system has a limited efficacy presumably because of restricted blood‐brain barrier permeability. The advantage of regional intra‐arterial administration of anticancer drugs is an increased uptake during the first passage of the drugs through tumor capillaries. Twenty patients with high‐grade astrocytomas (HGA) and 28 patients with metastatic brain tumors (MBT) received intracarotid/intravertebral infusion of etoposide and cisplatin. Eight patients with HGA who underwent incomplete resection responded to chemotherapy alone. Four additional patients had complete resection of the tumor. Median survival time of the group (responders and nonresponders) has been 14 months. Twelve patients with MBT responded to chemotherapy alone (six had complete response [CR], and six had partial response [PR]) with a median survival time of 7 months. Intra‐arterial chemotherapy (IAC) appears to be effective with acceptable toxicities. Accrual of additional patients is required before a final conclusion can be reached.

Management of metastases-induced acute pancreatitis in small cell carcinoma of the lung

Metastases‐induced acute pancreatitis is an uncommon condition that has a poor prognosis. Risk factors of acute pancreatitis in known cases have been studied and there is a low survival rate with more than three risk factors on presentation regardless of treatment rendered. These patients should be treated conservatively. Chemotherapy may be attempted in patients with three or fewer poor prognostic signs.

Abdominal Aortitis after Use of Granulocyte Colony-Stimulating Factor

Granulocyte colony-stimulating factor (G-CSF) is a recombinant human glycoprotein that promotes proliferation and differentiation of granulocytic-committed progenitors. It is commonly used to treat neutropenia and is generally well tolerated. Occurrences of rare but serious adverse events in association with the use of G-CSF have been described. We report the case of a 54-year-old male with squamous cell carcinoma of the lung who developed abdominal aortitis following the use of G-CSF. Other possible aetiological conditions were excluded based on laboratory and radiological evaluations. To our knowledge, this represents the second case report demonstrating an association between aortitis and the use of G-CSF.

Preclinical and clinical evaluation of 5-fluorouracil biochemical modulation with folinic acid and hydroxyurea for patients with colorectal carcinoma

Background. Approximately 140,000 new cases of colorectal carcinoma will be diagnosed in 1995 in the United States, and more than one‐third of these patients will die from progressive disease. Despite the modest improvement in response rate with chemotherapy, little improvement in patient survival has been noted. Consequently, the evaluation of new agents, modalities, and combinations is needed.

Phase-I clinical trial of sodium cyanate in patients with advanced colorectal carcinoma.

Sodium cyanate, a drug that selectively suppresses amino acid incorporation for protein synthesis in tumor tissue, was given to patients with advanced colorectal carcinoma who had failed to conventional therapy, with the purpose of assessing a maximum tolerable oral dose. At 35 mg/kg p.o. daily, the drug had to be stopped in approximately half (4) of the patients because of gastrointestinal toxicity (nausea, vomiting) and neurologic toxicity (hallucinations, disorientation). However, in 5 other patients, at the same dose, the drug was well tolerated for up to 147 days and for a total cumulative dose of 308 g. In this group of patients, sodium cyanate was stopped because of evidence of tumor progression. No hematologic toxicity was observed. We observed no therapeutic effects. We therefore recommend a starting dose of 30 mg/kg p.o. if a phase-II study is considered.

A Phase II Trial of Carboplatin and Gemcitabine with Exisulind (IND #65,056) in Patients with Advanced Non-small Cell Lung Cancer: An Eastern Cooperative Oncology Group Study (E1501)

Background: Carboplatin and gemcitabine are one standard regimen for patients with advanced non-small cell lung cancer (NSCLC). The oral proapoptotic agent exisulind is a cyclic guanosine monophosphate phosphodiesterase that increases apoptosis in vitro. We performed a phase II trial of carboplatin and gemcitabine with exisulind in patients with advanced NSCLC. Methods: Gemcitabine (1000 mg/m2 days 1 and 8) and carboplatin (AUC = 5 day 1) were administered every 21 days, with exisulind orally at 250 mg orally twice daily continuously, starting day 1. The primary objective was to evaluate the 18-month survival. Secondary objectives included response rate, progression-free survival, and toxicities. Eligibility included stage IIIB (pleural effusion) or stage IV NSCLC, no previous chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. Results: Of 57 eligible patients treated, 34 patients were male and 23 female, 42 had stage IV, six stage IIIB, and nine had recurrent disease. The median age was 63 years (range, 37–83). Twenty-six patients had an ECOG PS of 0 and 31 had a PS of 1. The majority of grade 3–4 toxicities were hematologic. Grade 3–4 nonhematologic toxicity seen in >5% of patients included nausea/vomiting in 16% and fatigue in 23% of patients. The overall response rate was 19.3%. Median progression-free survival was 4.7 months. Median overall survival was 9.0 months. Eighteen-month overall survival was 30%. Conclusion: The chemotherapy combination of gemcitabine and carboplatin with the oral proapoptotic agent exisulind is generally well tolerated with principally hematologic toxicity. The statistical endpoint of 17 patients alive at 18 months was met, but given ongoing developments in advanced NSCLC, ECOG will not be pursuing additional trials of exisulind in NSCLC.

Actual 5-year survival of patients with stage IIIB breast carcinoma: phase II trial of methotrexate, vinblastine, adriamycin, cisplatin, and folinic acid.

Patients with stage IIIB breast carcinoma represent only a small proportion of women with breast cancer in western countries but may constitute up to 50% of cases in underdeveloped countries. The prognosis remains poor despite aggressive treatment. Nineteen patients (11 with inflammatory breast carcinoma) received at least three courses of neoadjuvant chemotherapy of methotrexate, vinblastine, adriamycin, cisplatin, and folinic acid (MVAC/FA) followed by mastectomy. Six months of cyclophosphamide, methotrexate, and 5-fluorouracil were given after surgery. Radiation therapy followed chemotherapy. Seventy percent of patients achieved complete and 14% partial response after MVAC/FA chemotherapy alone. Eleven patients (58%) survived 5 years, and 30% survived at least 8 years. The addition of cisplatin in combination chemotherapy used as first-line treatment for stage IIIB breast carcinoma was well tolerated, resulted in higher response rates, and appeared to have an effect on overall survival.