Incorporating blood-based liquid biopsy information into cancer staging: time for a TNMB system?

Tissue biopsy is the standard diagnostic procedure for cancer. Biopsy may also provide material for genotyping, which can assist in the diagnosis and selection of targeted therapies but may fall short in cases of inadequate sampling, particularly from highly heterogeneous tumors. Traditional tissue biopsy suffers greater limitations in its prognostic capability over the course of disease, most obviously as an invasive procedure with potential complications, but also with respect to probable tumor clonal evolution and metastasis over time from initial biopsy evaluation. Recent work highlights circulating tumor DNA (ctDNA) present in the blood as a supplemental, or perhaps an alternative, source of DNA to identify the clinically relevant cancer mutational landscape. Indeed, this noninvasive approach may facilitate repeated monitoring of disease progression and treatment response, serving as a means to guide targeted therapies based on detected actionable mutations in patients with advanced or metastatic solid tumors. Notably, ctDNA is heralding a revolution in the range of genomic profiling and molecular mechanisms to be utilized in the battle against cancer. This review will discuss the biology of ctDNA, current methods of detection and potential applications of this information in tumor diagnosis, treatment, and disease prognosis. Conventional classification of tumors to describe cancer stage follow the TNM notation system, heavily weighting local tumor extent (T), lymph node invasion (N), and detectable metastasis (M). With recent advancements in genomics and bioinformatics, it is conceivable that routine analysis of ctDNA from liquid biopsy (B) may make cancer diagnosis, treatment, and prognosis more accurate for individual patients. We put forward the futuristic concept of TNMB tumor classification, opening a new horizon for precision medicine with the hope of creating better outcomes for cancer patients.

Can high-field MREIT be used to directly detect neural activity? Theoretical considerations.

We sought to determine the feasibility of directly studying neural tissue activity by analysis of differential phase shifts in MRI signals that occurred when trickle currents were applied to a bath containing active or resting neural tissue. We developed a finite element bidomain model of an aplysia abdominal ganglion in order to estimate the sensitivity of this contrast mechanism to changes in cell membrane conductance occurring during a gill-withdrawal reflex. We used our model to determine both current density and magnetic potential distributions within a sample chamber containing an isolated ganglion when it was illuminated with current injected synchronously with the MR imaging sequence and predicted the resulting changes in MRI phase images. This study provides the groundwork for attempts to image neural function using Magnetic Resonance Electrical Impedance Tomography (MREIT). We found that phase noise in a candidate 17.6 T MRI system should be sufficiently low to detect phase signal differences between active and resting membrane states at resolutions around 1 mm(3). We further delineate the broad dependencies of signal-to-noise ratio on activity frequency, current application time and active tissue fractions and outline strategies that can be used to lower phase noise below that presently observed in conventional MREIT techniques. We also propose the idea of using MREIT as an alternative means of studying neuromodulation.

Magnetic resonance microscopy and immunohistochemistry of the CNS of the mutant SOD murine model of ALS reveals widespread neural deficits.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons and descending motor tracts of the CNS. We have evaluated the CNS of a murine model of familial ALS based on the over-expression of mutant human superoxide dismutase (mSOD; G93A) using magnetic resonance microscopy (MRM) and immunohistochemistry (IHC). Three-dimensional volumetric analysis was performed from 3D T2*-weighted images acquired at 17.6 T at isotropic resolutions of 40 mum. Compared to controls, mSOD mice had significant reductions in the volumes of total brain, substantia nigra, striatum, hippocampus, and internal capsule, with decreased cortical thickness in primary motor and somatosensory cortices. In the spinal cord, mSOD mice had significantly decreased volume of both the total grey and white matter; in the latter case, the volume change was confined to the dorsal white matter. Increased apoptosis, GFAP positive astrocytes, and/or activated microglia were observed in all those CNS regions that showed volume loss except for the hippocampus. The MRM findings in mSOD over-expressing mice are similar to data previously obtained from a model of ALS-parkinsonism dementia complex (ALS-PDC), in which neural damage occurred following a diet of washed cycad flour containing various neurotoxins. The primary difference between the two models involves a significantly greater decrease in spinal cord white matter volume in mSOD mice, perhaps reflecting variations in degeneration of the descending motor tracts. The extent to which several CNS structures are impacted in both murine models of ALS argues for a reevaluation of the nature of the pathogenesis of ALS since CNS structures involved in Parkinson's and Alzheimer's diseases appear to be affected as well.

Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre.

BACKGROUND: An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma. METHODS: Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method. RESULTS: Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking. IMPLICATIONS: Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: the case for studies in previously treated patients.

PURPOSE: This review was undertaken (1) to determine the antitumor activity of agents studied in phase II trials in small-cell lung cancer (SCLC) patients, (2) to evaluate the adequacy of published trials, (3) to determine if previously treated patients are suitable for phase II trials in SCLC, and (4) to develop an improved design for phase II trials. DESIGN: English-language, single-agent efficacy trials in SCLC, published from 1970 to 1990, were reviewed. Study design and reporting of results were assessed for clinical and statistical methodology. Response rates observed in previously treated patients were compared with those observed in previously untreated patients. RESULTS: One hundred forty-one articles evaluating 57 agents in 3,042 patients were reviewed. Eleven drugs were active (defined as a response rate greater than or equal to 20% in a trial with greater than or equal to 14 assessable patients), and 12 were inactive. Due to methodologic problems with the clinical trials, the usefulness of the remaining 34 drugs (60%) remains uncertain. Deficiencies identified in trials include inappropriate sample sizes, poorly defined response criteria, and failure to report important prognostic factors. When studied in adequate trials, all agents known to be active in SCLC had an observed response rate greater than or equal to 10% in previously treated patients. CONCLUSIONS: Over the past 2 decades, phase II trials in SCLC have failed in their primary task of effectively identifying agents that warrant further clinical study and rejecting inactive agents. If only previously treated patients had been entered into these trials, no useful agent would have been missed provided that a lower observed response rate had been used as evidence of antitumor activity. We propose a two-stage sequential study design, entering previously treated patients, for future phase II trials in SCLC.

A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy.

A comprehensive three-dimensional digital atlas database of the C57BL/6J mouse brain was developed based on magnetic resonance microscopy images acquired on a 17.6-T superconducting magnet. By using both manual tracing and an atlas-based semi-automatic segmentation approach, T2-weighted magnetic resonance microscopy images of 10 adult male formalin-fixed, excised C57BL/6J mouse brains were segmented into 20 anatomical structures. These structures included the neocortex, hippocampus, amygdala, olfactory bulbs, basal forebrain and septum, caudate-putamen, globus pallidus, thalamus, hypothalamus, central gray, superior colliculi, inferior colliculi, the rest of midbrain, cerebellum, brainstem, corpus callosum/external capsule, internal capsule, anterior commissure, fimbria, and ventricles. The segmentation data were formatted and stored into a database containing three different atlas types: 10 single-specimen brain atlases, an average brain atlas and a probabilistic atlas. Additionally, quantitative group information, such as variations in structural volume, surface area, magnetic resonance microscopy image intensity and local geometry, were computed and stored as an integral part of the database. The database augments ongoing efforts with other high priority strains as defined by the Mouse Phenome Database focused on providing a quantitative framework for accurate mapping of functional, genetic and protein expression patterns acquired by a myriad of technologies and imaging modalities.

Ultra-wide bore 900 MHz high-resolution NMR at the National High Magnetic Field Laboratory.

Access to an ultra-wide bore (105 mm) 21.1 T magnet makes possible numerous advances in NMR spectroscopy and MR imaging, as well as novel applications. This magnet was developed, designed, manufactured and tested at the National High Magnetic Field Laboratory and on July 21, 2004 it was energized to 21.1 T. Commercial and unique homebuilt probes, along with a standard commercial NMR console have been installed and tested with many science applications to develop this spectrometer as a user facility. Solution NMR of membrane proteins with enhanced resolution, new pulse sequences for solid state NMR taking advantage of narrowed proton linewidths, and enhanced spatial resolution and contrast leading to improved animal imaging have been documented. In addition, it is demonstrated that spectroscopy of single site (17)O labeled macromolecules in a hydrated lipid bilayer environment can be recorded in a remarkably short period of time. (17)O spectra of aligned samples show the potential for using this data for orientational restraints and for characterizing unique details of cation binding properties to ion channels. The success of this NHMFL magnet illustrates the potential for using a similar magnet design as an outsert for high temperature superconducting insert coils to achieve an NMR magnet with a field >25 T.

Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guérin.

Despite active therapies for small cell lung cancer (SCLC), most patients relapse and die of the disease. The present study evaluates immunization using the anti-idiotypic antibody BEC2, which mimics the ganglioside GD3 expressed on the surface of most SCLC tumors, combined with Bacillus Calmette-Guérin (BCG) as an immune adjuvant. We hypothesized that active immunization could alter the natural history of the disease. Fifteen patients who had completed standard therapy for SCLC received a series of five intradermal immunizations consisting of 2.5 mg of BEC2 plus BCG over a 10-week period. Blood was collected for serological analysis, and outcome was monitored. All patients developed anti-BEC2 antibodies, despite having received chemotherapy with or without thoracic radiation. We detected anti-GD3 antibodies in five patients, including those with the longest relapse-free survival. The median relapse-free survival for patients with extensive stage disease is 11 months and has not been reached for patients with limited stage disease (>47 months), with only one of seven patients having relapsed after a median follow-up of 47 months. Immunization of patients with SCLC after standard therapy using BEC2 plus BCG can induce anti-GD3 antibodies and is safe. The survival and relapse-free survival in this group of patients are substantially better than those observed in a prior group of similar patients. A Phase III trial is being conducted to evaluate BEC2 plus BCG as adjuvant therapy after chemotherapy and irradiation.

Phase I and pharmacokinetic study of 10-propargyl-10-deazaaminopterin, a new antifolate.

The 10-deazaaminopterins are a new class of rationally designed antifolates demonstrating greater antitumor effects than methotrexate in murine tumor models and human tumor xenografts. Their design was aimed at improving membrane transport and polyglutamylation in tumor cells, resulting in increased intracellular accumulation and enhanced cytotoxicity. Compared with other 4-aminofolate analogues, 10-propargyl-10-deazaaminopterin (PDX) is the most efficient permeant for the RFC-1-mediated internalization and substrate for folylpolyglutamate synthetase. PDX demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate or edatrexate. We undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Initially, PDX was administered weekly for 3 weeks in a 4-week cycle. Mucositis requiring dose reduction and/or delay in the first cycle occurred in four of six patients treated at the initial dose level (30 mg/m2), making this the maximal tolerated dose for PDX given on this schedule. The treatment schedule was then modified to every 2 weeks. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles (median, 2 cycles/patient). Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. The recommended Phase II dose is 150 mg/m2 biweekly. At that dose level, the mean area under the curve was 20.6 micromol x h, and the mean terminal half-life was 8 h. Two patients with stage IV NSCLC had major objective responses, and five patients had stable disease for 7 (two patients), 9 (one patient), 10 (one patient), and 13 months (one patient). PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC. A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.

Immunogenicity of a fucosyl-GM1-keyhole limpet hemocyanin conjugate vaccine in patients with small cell lung cancer.

Although small cell lung cancer (SCLC) is highly responsive to chemotherapy, relapses are common, and most patients die within 2 years of diagnosis. After initial therapy, standard treatment is observation alone. We have been investigating immunization against selected gangliosides as adjuvant therapy directed against residual and presumably resistant disease persisting after chemotherapy and irradiation. Previously, we reported that the presence of anti-GM2 ganglioside antibodies is associated with a prolonged disease-free survival in patients with melanoma, and that SCLC patients immunized with BEC2, an anti-idiotypic monoclonal antibody that mimics the ganglioside GD3, had a prolonged survival compared with historical controls. In the present trial, fucosyl-alpha1-2Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3) Galbeta1-4Glcbeta1-1Cer (Fuc-GM1), a ganglioside expressed on the SCLC cell surface, was selected as a target for active immunotherapy. Fuc-GM1 is present on most SCLCs but on few normal tissues. SCLC patients achieving a major response to initial therapy were vaccinated s.c. on weeks 1, 2, 3, 4, 8, and 16 with Fuc-GM1 (30 microg) conjugated to the carrier protein keyhole limpet hemocyanin and mixed with the adjuvant QS-21. Ten patients received at least five vaccinations and are evaluable for response. All patients demonstrated a serological response, with induction of both IgM and IgG antibodies against Fuc-GM1, despite prior treatment with chemotherapy with or without radiation. Posttreatment flow cytometry demonstrated binding of antibodies from patients' sera to tumor cells expressing Fuc-GM1. In the majority of cases, sera were also capable of complement-mediated cytotoxicity. Mild transient erythema and induration at injection sites were the only consistent toxicities. The Fuc-GM1-KLH + QS-21 vaccine is safe and immunogenic in patients with SCLC. Continued study of this and other ganglioside vaccines is ongoing.

High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer.

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.

Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Serum cytokines in human heart transplant recipients. Is there a relationship to rejection?

Cytokines are important in the pathogenesis of allograft rejection. Some studies have suggested a positive relationship between serum levels of cytokines and rejection, so this study was designed to investigate the presence of a range of cytokines in a large cohort of cardiac transplant recipients. We used enzyme linked immunosorbent assays (ELISA) to examine sequential serum samples from 28 consecutive heart transplant recipients; length of follow up varied between 2 and 566 days (median 357 days). Serum levels of IL-2, 4, 6, 10, TNF-alpha, and IFN-gamma were measured. We compared these results with detailed data on patients' clinical courses, including histological rejection, infection, and therapeutic use of antithymocyte globulin (ATG). No significant relationship was found between rejection and serum cytokine levels for samples taken more than 30 days after transplantation. Prior to this cytokine levels were significantly disturbed by the use of cytolytic therapy for induction immunosuppression. Serum cytokine levels sometimes showed peaks that appeared to be related to rejection, or occasionally to infection, but these relationships were not consistent. Serum TNF-alpha and IL-6 were consistently elevated within a few days of administration of ATG. We conclude that there is no systematic relationship between serum cytokine levels and histological rejection or infection in cardiac transplant recipients.

Antithymocyte globulin preparations after heart transplantation. Cytokine responses in vivo and in vitro.

It is accepted that antithymocyte globulin (ATG) preparations vary in their bioactivity and side effects. However, this is poorly documented in the literature. We compared the clinical course and cytokine response of heart transplant patients who had received either Merieux or Stanford ATG preparations. The serum cytokine response (interleukin [IL]-6, tumor necrosis factor [TNF]-alpha, IL-4, and IL-10) of 28 consecutive heart transplant recipients was measured for 14 days after surgery using ELISAs. The effect of various ATG preparations on cytokine stimulation of whole blood in vitro was also evaluated. There was a much greater in vivo IL-6 and TNF-alpha response to Merieux than to Stanford ATG (P < 0.0005). There was little IL-4 or IL-10 response with either preparation. No side effects could be attributed to either treatment. No significant difference was seen in the frequency of rejection at 30, 90, or 365 days. More infection episodes occurred in the group treated with Stanford ATG at 30 days (0.5 compared with 0.2 episodes/patient; P = 0.097), 90 days (1.2 compared with 0.5 episodes/patient; P = 0.17), and 365 days (2.8 compared with 1.8; P = 0.59), although none of these differences were statistically significant. When tested in vitro for cytokine stimulation, the in vivo pattern was confirmed, with Merieux ATG producing greater levels of TNF-alpha and IL-6 than Stanford ATG. The differences in cytokine stimulation may be reflected in different immunosuppressive activities. Further research to elucidate the important components of immunosuppressive activity while excluding potentially detrimental effects is important.

A genetic marker of high TNF-alpha production in heart transplant recipients.

The cytokine TNF-alpha has been implicated in the pathogenesis of both acute and chronic transplant rejection. Levels of the cytokine are known to vary in a normal population, leading to speculation that high responders may be at greater risk of rejection. Particular TNF region polymorphic markers have been associated with increased TNF-alpha levels and a biallelic polymorphism has been identified at position -308 of the TNF-alpha promoter that may contribute significantly to the interindividual variation in healthy persons. We describe here a new association between a polymorphic locus in the TNF gene region and increased production of TNF-alpha in heart transplant recipients. We studied two microsatellite markers that flank the TNFA gene, as well as a biallelic polymorphism at position -308 of the TNFA promoter, and found that the microsatellite allele TNFd3 was significantly associated with the capacity of leukocytes to produce TNF-alpha in vitro. No association was demonstrated for the promoter region polymorphism. Patients were receiving cyclosporine (CsA) and prednisolone (pred) at the time of sampling, which are known to interrupt 5' regulation of TNFA transcription in T cells and macrophages and may therefore negate the influence of the -308 polymorphism. Because of this we suggest that TNFd3 may be a marker for a 3' repressor region polymorphism that is of importance in immunosuppressed individuals.

Expression of cytokine messenger RNA after heart transplantation: relationship with rejection and serum cytokines.

Different groups of cytokines may initiate or inhibit the rejection process. We used the polymerase chain reaction to study the expression of cytokine mRNA for interleukin (IL)-2, -4, -6 and -10, tumor necrosis factor-alpha, and interferon-gamma in 187 biopsy specimens from 24 human cardiac transplant recipients 5-555 days after transplantation. Cytokine levels in the serum were also measured. Cytokine mRNA was detected in 38.5% of biopsy specimens. IL-10 mRNA was detected more frequently with mild or absent rejection (11.6% in grades 0 and 1 - vs. 1.4% in grades 2 and 3, P=0.01). Up to 90 days after transplantation, IL-2 mRNA was detected more frequently with moderate rejection (13% in grades 2 and 3 vs. 0% in grades 0 and 1, P=0.076), and IL-4 mRNA was detected more frequently with mild or absent rejection (16% in grades 0 and 1 - vs. 0% in grades 2 and 3, P=0.061). More than 90 days after transplantation, IL-2 mRNA was detected more frequently with mild or absent rejection (10% in grades 0 and 1 vs. 0% in grades 2 and 3, P=0.078). Serum IL-4 levels corresponding to biopsy specimens positive for IL-4 mRNA were higher than those corresponding to specimens negative for IL-4 mRNA (59 pg/ml vs. 32 pg/ml medians, P=0.028). Our results suggest that IL-10 and possibly IL-4 (T helper 2 cytokines) may suppress graft rejection, whereas IL-2 (T helper 1 cytokine) may promote cellular rejection. In addition, cytokine profiles may change with length of time after transplantation. The association of elevated serum levels of IL-4 with increased expression of intragraft IL-4 mRNA may suggest release of this cytokine from the graft into the circulation.

Cytokine gene polymorphism and heart transplant rejection.

BACKGROUND: Allograft rejection is mediated by cytokines. As polymorphism in cytokine genes can result in interindividual differences in cytokine production, we hypothesize that some patients may have an increased risk of rejection. METHODS: We have related polymorphisms that influence cytokine production in the tumor necrosis factor (TNF)-A and interleukin (IL)-10 genes to early graft rejection in 115 heart transplant recipients. RESULTS: Certain combinations of TNF-A and IL-10 gene polymorphisms are associated with rejection. Five of 19 patients who had high levels of rejection typed as high TNF-alpha/low IL-10 producers compared with 4 of 96 patients with lower levels of rejection (P<0.005). CONCLUSIONS: We have identified a particular cytokine genotype that may confer susceptibility to increased levels of early rejection. Patients with a worse prognosis may be able to be identified pretransplant by DNA analysis of TNF-A, IL-10, and other gene polymorphisms.

New chemotherapeutic agents for non-small cell lung cancer.

The identification of new chemotherapeutic agents for the treatment of non-small cell lung cancer should proceed in a structured, logical fashion. Agents should be evaluated on the basis of multiple objective and subjective end points. A 15% or greater major objective response rate, demonstrated in multiple single-agent phase II trials, is considered the lower limit for an agent to be deemed clinically active in this disease. A number of drugs previously have been identified in this category, including cisplatin, ifosfamide, mitomycin, paclitaxel, and the vinca alkaloids vinblastine and vindesine. Most of these conventional agents have been explored alone, in a variety of doses and schedules, and in combination. In the last several years clinical development has produced new agents, including chloroquinoxaline sulfonamide, docetaxel, edatrexate, gemcitabine, irinotecan, topotecan, and vinorelbine, which hold promise for more successful treatment of this lethal disease.

Paclitaxel (Taxol) and docetaxel (Taxotere): active chemotherapeutic agents in lung cancer.

Paclitaxel (Taxol), the prototype of a new class of plant-derived antineoplastic compounds, is a natural product isolated from the Pacific yew. Docetaxel (Taxotere) is a hemisynthetic product derived from the European yew. These agents share a unique mechanism of cytotoxic action by promoting assembly of microtubules and rendering the microtubules resistant to depolymerization. In vitro studies suggest a possible role for radiation sensitization. In Phase I trials, the dose-limiting toxicity was neutropenia for both agents. Other toxicities include infusion-related hypersensitivity reactions, alopecia, neurotoxicity, mucositis, diarrhoea and myalgias. To prevent infusion-related reactions, routine premedication is recommended. Noncumulative cardiac toxicity has been observed with paclitaxel. Fluid retention and rash have been reported with docetaxel. In Phase II studies of paclitaxel in advanced non-small cell lung cancer, response rates of 21% and 24% were observed. In Phase II studies of docetaxel in similar patients, response rates ranging from 28-38% were reported, including patients previously treated with cisplatin. The most common toxicity in these studies was neutropenia. Combination studies with cisplatin and other agents are in progress. Paclitaxel and docetaxel are among the most active chemotherapeutic agents for non-small cell lung cancer patients. Their testing will dominate trials of new therapies in this disease for years to come.

Effectiveness and toxicity of preoperative therapy in stage IIIA non-small cell lung cancer including the Memorial Sloan-Kettering experience with induction MVP in patients with bulky mediastinal lymph node metastases (Clinical N2).

The use of preoperative chemotherapy with mitomycin, vinblastine and cisplatin (MVP) has led to improved complete resection rates and survival in Stage IIIA non-small cell lung cancer with bulky, ipsilateral, mediastinal lymph node metastases (Clinical N2 disease). The addition of preoperative irradiation has also been explored with results not substantially different from preoperative cisplatin-based chemotherapy alone. While preoperative chemotherapy has been shown to be feasible, the toxicity of both the chemotherapy and the subsequent resection is of concern with an overall treatment-related mortality of nearly 8%. The careful selection of patients, swift management of neutropenia, and meticulous perioperative pulmonary care has the potential to reduce the mortality from multimodality therapy. Having shown survival benefit in multiple single-institution and randomized trials, induction chemotherapy followed by surgery or irradiation is now the treatment of choice for patients with Stage IIIA non-small cell lung cancer with mediastinal lymph node metastases.