Faculty Bibliography

Immunotoxins, composed of a monoclonal antibody conjugated to a protein toxin, mediate cell death through novel cytotoxic mechanisms. Anti-B4-blocked ricin (anti-B4-bR) recognizes CD19-positive cells, which includes most B-cell non-Hodgkin's lymphomas (NHLs). Previous Phase I clinical studies of anti-B4-bR, using both bolus and continuous dosing regimens, demonstrated no safety or efficacy advantage to the continuous infusion regimen. This Phase II trial in 16 patients with relapsed CD19-positive NHL was conducted to evaluate the efficacy of anti-B4-bR when administered at the previously established maximum tolerated dose using a daily bolus for a 5 consecutive days schedule. Serum pharmacokinetics were measured in selected patients. Tissue samples of involved lymph nodes and bone marrow were also obtained from a portion of patients for determination of anti-B4-bR penetration into tissues. Toxicity was similar to what has been described previously for anti-B4-bR and consisted mainly of reversible elevations of hepatic transaminases and mild to moderate thrombocytopenia. No sustained clinical responses were documented. Pharmacokinetic measurements demonstrated that serum levels compatible with 3 logs of cell kill in vitro could be sustained for several hours in most patients. Immunohistochemical analysis of tissue samples provided some insight into the low efficacy. The immunotoxin could be detected in three of the four bone marrow aspirate samples but in only two of the seven lymph node specimens. Thus, anti-B4-bR, using a single daily bolus for a 5 consecutive day schedule, is not an active agent in relapsed NHL. Poor penetration into certain sites of disease may be one explanation for its lack of efficacy.

PURPOSE: To review recent advances in the development and clinical roles of monoclonal antibody (MoAb)-based therapies in the treatment of hematologic malignancies. DESIGN: A search of MEDLINE and CANCERLIT was conducted to identify relevant publications. The bibliographies of these references also were used to identify articles and abstracts. These references were then reviewed. RESULTS: In the two decades since the first patient was treated with MoAb therapy, there have been significant advances in the biology, pharmacology, and clinical application of MoAb-based therapies. Three distinct fields of research have emerged: unconjugated MoAbs, immunotoxin-conjugated MoAbs (ITs), and radionuclide-conjugated MoAbs (RICs). The unconjugated MoAbs are less toxic but depend on host mechanisms to mediate cytotoxicity. The ITs carry a potent toxin, although at the cost of a narrow therapeutic index that may limit clinical use. The RICs offer significant potency, even in refractory disease, but their complexity may limit their use to large cancer centers. The current challenges in the development of MoAb-based therapies are to identify the proper target antigens, contend with bulk disease in which penetration may be limited, and choose the optimal clinical settings for their use, such as the minimal residual disease state or in combination with conventional chemotherapy. CONCLUSION: Although significant research is still needed, MoAb-based therapies promise to offer new options for the treatment of patients with hematologic malignancies.

This phase II trial was undertaken to determine the toxicities, response rate, pharmacokinetics and frequency of human anti-mouse antibody (HAMA) and anti-ricin antibody (HARA) when the B-cell restricted immunotoxin anti-B4-bR was administered to patients with previously treated multiple myeloma (MM). Five patients with MM were scheduled to receive a 7 d continuous infusion of anti-B4-bR. The initial four patients received therapy at 40 microg/kg lean body weight (LBW)/d. Two patients received a 7 d infusion, one patient received 6 d, and another patient 5 d of therapy. The fifth patient was treated for 7 d at a lower dose of 30 microg/kg LBW/d because of the side-effects observed in the initial patients. Pharmacokinetic studies demonstrated a peak serum level >2.6 nM in three of the patients. Side-effects of therapy included hepatic transaminase elevations, myalgias, thrombocytopenia, nausea, vomiting, decrease in performance status, and capillary leak syndrome. One patient developed HAMA and two patients HARA. One patient developed neurologic toxicity with akinetic mutism, and died following therapy. No patient demonstrated a significant decline in M-component during therapy. We concluded that anti-B4-bR can be administered by continuous infusion to patients with multiple myeloma, although immunotoxin levels >3 nM were associated with increased incidence of toxicity and required dose adjustment. Future trials using anti-B4-bR in MM will be needed to determine the optimal dose and administration schedule in this patient population, and to determine whether there is evidence of biologic activity.

The cure rate for pancreatic cancer remains less than 5% despite more than 20 years of clinical trials. Nevertheless, a select group of patients benefit from therapy at all stages of disease and important concepts regarding patient care have emerged. The development of agents such as gemcitabine and docetaxel have spurred a new generation of clinical trials in pancreatic cancer. An appreciation for the results of the many adjuvant and neoadjuvant trials and the application of lessons learned in the care of these patients is necessary to design the new trials.

OBJECTIVE: Induction chemoradiotherapy followed by surgery may improve survival rates among patients with esophageal carcinoma. We designed a novel intense induction regimen with paclitaxel and high-dose hyperfractionated radiotherapy to maximize complete response rates. METHODS: Forty patients with esophageal cancer were treated in a phase I and II trial of induction chemotherapy (cisplatin, 5-fluorouracil, and paclitaxel) at three dosage levels (75, 125, and 100 mg/m2) and concurrent hyperfractionated radiotherapy (45 Gy to the mediastinum, 58.5 Gy to the tumor). The mean age was 62 years, and 32 patients (80%) had adenocarcinoma. Twenty-eight of 40 (70%) patients had locally advanced tumors (T3, or stage IIB or greater). RESULTS: The average hospitalization for induction treatment was 17 days. Toxicity was substantial, with esophagitis necessitating nutritional support the most common complication. The maximum tolerated dose of paclitaxel was 100 mg/m2. Two patients died during induction treatment. Thirty-six patients (90%) underwent resection. The median length of stay was 10 days, and two patients died after the operation. Fourteen of 36 patients (39%) had a pathologic complete response. Patients who received all prescribed chemotherapy had a higher pathologic complete response rate (50%) than did patients who required dose reduction (17%; p = 0.076). The 2-year survival rate was 61% (95% CI 35% to 86%) with a median follow-up of 11.9 months. CONCLUSIONS: Paclitaxel at a dose of 100 mg/m2 appears to have acceptable toxicity. The high pathologic complete response rate in this regimen is encouraging, but it is associated with substantial toxicity. The toxicity of this regimen is not acceptable and will require substantial reduction in the radiation component. Survival data are too short-term to confirm enhanced survival.

The primary objective of this study was to define the maximum tolerated dose and toxicity profile of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given as a 24-hour infusion, in conjunction with ifosfamide/carboplatin/etoposide (ICE) chemotherapy in patients with advanced lung cancer. Paclitaxel was escalated from 75 to 225 mg/m2 in 25-mg/m2 increments. All patients received granulocyte colony-stimulating factor 5 microg/kg/d from day 4 until the neutrophil count was > or = 10,000/microL. The study population consisted of 41 patients with a median age of 60 years and a median follow-up of 20.7 months. Stage distribution included 5% stage IIIA, 46% stage IIIB, and 49% stage IV. Histology consisted of 61% adenocarcinoma, 12% squamous cell carcinoma, 10% large cell carcinoma, 15% small cell carcinoma, and 2% mixed. The predominant toxicity was hematologic; 63% of patients experienced grade 4 neutropenia and 49% developed grade 4 thrombocytopenia. Fever and neutropenia occurred in 34% of patients. Hematologic toxicity was, in all cases, short-term and reversible and was not dose related. With few exceptions, nonhematologic toxicity was not clinically important. Among 39 patients evaluable for response, 36% achieved a remission (8% complete, 28% partial, 41% had stable disease, and 23% experienced disease progression). Among 33 patients with non-small cell lung cancer, the response rate was 27% (one complete response, eight partial responses, 15 had stable disease, and nine had progressive disease). Among six patients with small cell carcinoma, the response rate was 83% (two complete responses, three partial responses, and one had stable disease). The median survival of all 41 patients was 13.6 months. Survival was almost identical between stage IIIA and stage IV subsets. We conclude that it is possible to safely administer full-dose single-agent paclitaxel with granulocyte colony-stimulating factor support in conjunction with full-dose ifosfamide/carboplatin/etoposide chemotherapy. While response rates observed were not particularly notable, median survival is considerably longer than that usually achieved with combination chemotherapy in advanced lung cancer.

We report a case of testicular carcinoma invading the inferior vena cava. Tumor invasion was diagnosed via endovascular biopsy. This is the first known report of a diagnosis of this entity using endovascular biopsy. We also review the literature on diagnosis and management of inferior vena caval involvement by testicular cancer.