Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice.

BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and ß-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS: Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS: Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION: Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Weekly docetaxel, cisplatin, and irinotecan (TPC): results of a multicenter phase II trial in patients with metastatic esophagogastric cancer.

BACKGROUND: Recent studies have examined the addition of docetaxel to fluorouracil and cisplatin in advanced esophagogastric cancer. PATIENTS AND METHODS: We carried out a phase I dose-escalation study of weekly docetaxel, cisplatin, and irinotecan (TPC), given on days 1 and 8 every 3 weeks, in patients with chemonaive solid tumors. Subsequently, we completed a multiinstitutional phase II study of TPC in patients with previously untreated, metastatic esophagogastric cancer. RESULTS: Thirty-nine patients were enrolled in the phase I trial; a weekly schedule of TPC was well tolerated. On that basis, docetaxel 30 mg/m(2), cisplatin 25 mg/m(2), and irinotecan 65 mg/m(2) were selected for the phase II trial, where in the first 18 patients irinotecan 65 mg/m(2) caused too much diarrhea and was reduced to 50 mg/m(2). Among 56 eligible patients with previously untreated, metastatic esophagogastric cancer enrolled in the phase II trial, three complete and 27 partial responses were observed (overall response rate=54%), and 15 patients (30%) had stable disease. Median progression-free survival was 7.1 months, and median survival was 11.9 months. At the final irinotecan dose of 50 mg/m(2), grade 3 or higher toxicity included diarrhea (26%), neutropenia (21%), nausea (18%), fatigue (16%), anorexia (13%), and thrombosis/embolism (13%). CONCLUSIONS: Weekly TPC is an active and well-tolerated regimen for patients with esophagogastric cancer.

A phase II study of weekly paclitaxel in elderly patients with advanced non-small cell lung cancer.

PURPOSE: Our aim was to evaluate the efficacy, toxicity, and pharmacokinetic behavior of single-agent paclitaxel given weekly to elderly patients with lung cancer. EXPERIMENTAL DESIGN: Previously untreated patients with stage IIIB/IV non-small cell lung cancer were eligible for the study if they were at least 70 years of age and had preserved organ function. Paclitaxel was administered over 1 h at a dose of 90 mg/m(2) for 6 consecutive weeks on an 8-week cycle. The pharmacokinetics of paclitaxel were assessed during the first and sixth week of therapy in a subgroup of eight patients. RESULTS: A total of 35 patients (median age, 76 years; range, 70-85) were enrolled. The overall response rate was 23%. Median time to failure was 5.2 months, whereas the median survival time was 10.3 months. Survival rates after 1 and 2 years were 45 and 22%, respectively. Grade 3/4 toxicities included neutropenia (5.8%), hyperglycemia (17.6%), neuropathy (5.8%), and infection (8.8%). Two patients died from treatment-related toxicity. There was no significant difference (P = 0.18) between the total body clearance of paclitaxel on the first (17.4 +/- 2.9 liters/h/m(2), mean +/- SD) and sixth (15.8 +/- 4.1 liters/h/m(2)) week of therapy. CONCLUSION: Paclitaxel administered as a weekly 1-h infusion at a dose of 90 mg/m(2) is a safe and effective therapy for elderly patients with advanced non-small cell lung cancer. Its pharmacokinetics in elderly patients do not appear to differ from historical data for younger patients, and there was no suggestion of a change in drug clearance after repeated weekly dosing.

Long-term results of combined modality therapy in primary bone lymphomas.

PURPOSE: To report the Massachusetts General Hospital experience in the management of patients with primary bone lymphoma (PBL) treated with combined modality therapy (CMT). METHODS AND MATERIALS: Records from 37 eligible patients were reviewed. Two patients were treated with complete resection of the tumor, while 35 patients underwent radiation therapy with a median total dose of 54 Gy (range 38.35-66.5). All patients received combination chemotherapy, which contained doxorubicin in 33 cases. We compared the current data with our previous experience in patients treated with local measures only. RESULTS: Actuarial disease-free survival (DFS) at 5 and 10 years is 78% and 73%, respectively, while overall survival (OS) is 91% and 87%, respectively. No local failures were seen. Pathologic fracture at presentation influenced DFS (p = 0.005) and OS (p = 0.017) adversely. OS was compromised in patients older than 60 years (p = 0.059) and DFS in patients with pelvic primaries (p = 0.015). CMT was associated with improved DFS (p = 0.0008) and OS p = 0.0001) compared to our historical controls. Ten patients (27%) developed complications requiring orthopedic procedures following completion of therapy at a median of 25.5 months (range 4-228). CONCLUSION: Patients with PBL have a favorable outcome with CMT, which appears superior to radiation therapy alone. Late complications can be seen, especially in weight-bearing bones.

Anti-B4-blocked ricin: a phase II trial of 7 day continuous infusion in patients with multiple myeloma.

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.

Intracaval extension of germ cell carcinoma: diagnosis via endovascular biopsy and a review of the literature.

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.

Primary tracheal non-Hodgkin's lymphoma. A case report and review of the literature.

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.

Purine Analogs for the Treatment of Low-Grade Lymphoproliferative Disorders.

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.

Malignancy-related pericardial effusion. 127 cases from the Roswell Park Cancer Institute.

BACKGROUND: Malignancy-related pericardial effusions may represent a terminal event in patients with therapeutically unresponsive disease. However, select patients with malignancies sensitive to available therapies may achieve significant improvement in palliation and long term survival with prompt recognition and appropriate intervention. METHODS: From 1968 to 1994, 150 invasive procedures were performed for the treatment or diagnosis of pericardial effusion in 127 patients with underlying malignancies. These cases were reviewed retrospectively to best identify the clinical features, appropriate diagnostic workup, and optimal therapy for this complication of malignancy. RESULTS: Dyspnea (81%) and an abnormal pulsus paradoxus (32%) were the most common symptoms. Echocardiography had a 96% diagnostic accuracy. Cytology and pericardial biopsy had sensitivities of 90% and 56%, respectively. Fifty-five percent of all effusions were malignant comprising 71% of adenocarcinomas of the lung, breast, esophagus, and unknown primary site. In 57 patients, a malignant effusion could not be determined, and no definitive etiology could be established for 74% of these effusions. Radiation-induced, infectious, and hemorrhagic pericarditis each were identified in fewer than 5% of cases. CONCLUSIONS: Subxyphoid pericardiotomy proved to be a safe and effective intervention that successfully relieved pericardial effusions in 99% of cases with recurrence and reoperation rates of 9% and 7%, respectively. Survival most closely was related to the extent of disease and its inherent chemo-/radiosensitivity, with 72% of the patients who survived longer than 1 year having breast cancer, leukemia, or lymphoma.

Prospects for immunotoxin therapy of non-Hodgkin's lymphoma.

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.

Non-Hodgkin's lymphoma presenting with biliary tract obstruction. A discussion of seven patients and a review of the literature.

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.