Faculty Bibliography

BACKGROUND: Primary tracheobronchial non-Hodgkin's lymphoma (NHL) is an uncommon occurrence. The authors report a patient who presented with primary tracheal NHL, the sixth such patient described in the literature. METHODS: Using a MEDLINE search, 41 additional patients presenting with symptomatic primary or secondary tracheobronchial NHL were identified. The characteristics, management, and outcome of these patients are described. RESULTS: Patients with NHL of the upper respiratory tract present with dyspnea, wheezing, and cough, and frequently are misdiagnosed as having asthma. The majority of patients have additional sites of intrathoracic disease with tracheobronchial involvement occurring in the setting of advanced or relapsed NHL. Low grade histology is seen most commonly in patients with primary tracheal NHL. Several patients demonstrate the typical histologic features of mucosa-associated lymphoid tissue. Surgery, chemotherapy, and radiation therapy have been used alone or in combination for treatment. The outcome of these patients does not appear different from that observed in patients with lymphomas of similar histology and stage that do not involve the tracheobronchial tree. CONCLUSIONS: Thoracic surgeons, pulmonologists, and oncologists should recognize that NHL can rarely be confined to the trachea or bronchi. NHL should be considered in the differential diagnosis of airway obstruction, because it represents a highly treatable malignancy.

PRIMARY PURPOSE: Low-grade lymphoproliferative disorders follow an indolent clinical course but are incurable with current therapy. Recently, three active agents for the treatment of these diseases have been identified: the purine analogs fludarabine, pentostatin and 2-chlorodeoxyadenosine. The purpose of this review is to summarize the current knowledge on the mechanism of action, clinical activity and toxicities of the purine analogs. METHODS: Articles, abstracts and letters to the editor appearing in English literature and involving the use of the purine analogs in the treatment of hairy cell leukemia, chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, cutaneous T cell lymphomas and Waldenstrom's macroglobulinemia were reviewed. RESULTS AND CONCLUSION: Purine analogs have marked cytoreductive potential in the treatment of chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma and hairy cell leukemia. Major side effects include myelosuppression and infections. Profound lymphocytopenia can be sustained, predisposing patients to opportunistic infections. Although remissions achieved with these agents can be long-lasting, minimal residual disease frequently persists. Postremission strategies aimed at eradicating such microscopic diseases can potentially improve the results of purine analog therapy. Alternatively, the up-front combination of these agents with traditional chemotherapy may lead to higher response rates and more sustained remissions.

Approximately 3,500 cases of stage I and II Hodgkin's disease are diagnosed each year in the United States. Traditionally, those patients who are considered candidates for primary radiation therapy undergo staging laparotomy (pathologic staging) to rule out definitively the presence of occult subdiaphragmatic disease. An appreciation of the risks of laparotomy and a recognition of the effectiveness of salvage chemotherapy in patients who fail primary radiation therapy have permitted the increased use of clinical staging as the basis for treatment of these patients. This article summarizes the literature regarding the need for staging laparotomy in early stage Hodgkin's disease and suggests alternative approaches to the management of these patients based on clinical criteria and prognostic factors.

The use of unconjugated monoclonal antibodies to treat patients with non-Hodgkin's lymphoma by targeting specific antigenic determinants on malignant cells has been an area of intense laboratory and clinical research. Although occasional clinical successes have been seen, many limitations of such therapy have been identified, including the low endogenous cytotoxicity of most of the antibodies. More recently, investigators have attempted to employ monoclonal antibody-toxin conjugates (immunotoxins) to deliver specific cytotoxins to the lymphoma cell surface. This article describes the preclinical development of immunotoxin therapy as well as the initial results from selected Phase I and II clinical trials in patients with NHL. In addition, future directions are suggested for the use of these agents as adjuvant therapy and as treatment for patients with human immunodeficiency virus-related NHL.

A phase I study was conducted to define the maximally tolerated dose and toxicity profile of the ifosfamide/carboplatin/etoposide/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (ICE-T) regimen in advanced lung cancer. This chemotherapy program uses paclitaxel given as a 24-hour continuous infusion in conjunction with full-dose ICE chemotherapy with growth factor support. The dosage of paclitaxel was escalated from 75 to 225 mg/m2. Thirty-four patients have been accrued to date onto this study. Because hematologic dose-limiting toxicity was defined in terms of neutropenia and/or thrombocytopenia exceeding 7 days' duration, no patient demonstrated what was defined by the protocol as dose-limiting toxicity. Nonetheless, substantial hematologic toxicity was observed. Overall, 26% had fever and neutropenia, 56% had grade 4 neutropenia, and 26% had grade 4 thrombocytopenia. In all cases, hematologic toxicity was short term and reversible. While grade 3 and 4 myelosuppression was frequently observed, it was not dose related (in terms of paclitaxel dosage). Nonhematologic toxicity also was not dose related and, with only a few exceptions, was not clinically significant. Among 27 patients evaluable for response, 41% achieved an objective response, including 15% with a complete response. All of five patients with small cell lung cancer responded (including two with a complete response). Among 22 patients with non-small cell lung cancer, 27% achieved an objective response (also including two with a complete response). The results of this study suggest that with growth factor support, it is possible to safely administer full-dose, single-agent paclitaxel in conjunction with full-dose ICE chemotherapy. We will soon be initiating a phase II study of the ICE-T regimen using paclitaxel at 225 mg/m2 as a 24-hour continuous infusion in advanced lung cancer. We will also conduct a phase I study of ICE-T, with paclitaxel administered as a 3-hour continuous infusion.

BACKGROUND: Biliary tract obstruction is a rare manifestation of non-Hodgkin's lymphoma (NHL). Because of the small numbers of patients studied, management of this condition has been inconsistent. Most patients have been treated with biliary diversion, and doxorubicin frequently has been withheld from initial therapy. METHODS: Seven patients with NHL presenting with malignant biliary tract obstruction were identified at the Massachusetts General Hospital. Relevant clinical characteristics, laboratory values, treatment, and outcome are reported for all patients. Thirty-eight additional patients were identified through a MEDLINE search; and the management and results of the patients reported here are discussed with reference to those patients. RESULTS: Biliary tract obstruction was the presenting symptom in 0.8% of the patients with NHL. Bilirubin values at presentation ranged from 5.0-23.2 mg/dl. One patient had localized pancreatic lymphoma. Four of the seven patients had advanced-stage disease. The tumor was intermediate or high grade in five patients. Four patients underwent placement of a biliary stent or drainage catheter. Six patients received combination chemotherapy without doxorubicin in the initial cycle. Hyperbilirubinemia resolved in all patients within 3 months, regardless of use of a stent. Six patients responded to chemotherapy and one patient had progressive disease. Two of the six responders died, one with relapsed lymphoma. CONCLUSIONS: NHL presenting with biliary tract obstruction can be effectively treated with chemotherapy, with or without a procedure for biliary diversion. The use of doxorubicin in the presence of hyperbilirubinemia secondary to biliary tract obstruction remains controversial, and its omission from the initial cycles of chemotherapy for NHL may not influence outcome.

Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti-B4 (CD19) monoclonal antibody with the protein toxin "blocked ricin." In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4-bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.