Lung cancer
Contraindications to a chemotherapy
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Contraindications to a chemotherapy:
Now Cyclophosphanum is one of recognized all over the world the antitumoral preparation having expressed activity at a LC. It is included in numerous schemes of a polychemotherapy. Several new agents, including paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, and gemcitabine have been shown to be active in the treatment of advanced LC (See table 1). Table 1. Standard agents in case of LC
At a chemotherapy the strict control of a peripherial blood condition, a medullar hemopoiesis, function of a liver, kidneys and cardiovascular activity is necessary. Clinical analyses of a blood are carried out not less often 2 once a week. The hematological control continues also within 7-12 days after end of a course of chemotherapy. The most often complication is oppression of hemopoiesis function: downstroke of amount of leucocytes and thrombocytes, an anemia. Chemotherapy of Nonsmall Cell Lung Cancer A place for chemotherapy before surgery has been controversial for the last 10 years. There are two issues: first, what is the role for neoadjuvant chemotherapy in conventionally resectable patients, that is, those with Stage I or II disease (T1, T2, or T3, N0; T1, T2, or T3, N1) and also limited Stage IIIA disease, that is, unforeseen N2 disease with normal nodes at CT but microscopic N2 disease at mediastinoscopy? The second issue is whether chemotherapy can "debulk" more advanced disease, for example, N2 nodes found on CT, T4 primary tumors, or N3 disease. These patients would not normally be considered for surgery and are treated by radical radiotherapy or chemotherapy–radiotherapy. However, if chemotherapy were a really effective treatment, could surgery follow chemotherapy and be more effective than radical radiotherapy? The answer to the first question is "possibly," and the answer to the second is not at all clear. The place of chemotherapy after surgery is likely to emerge clearly within the next 2 to 3 years. The meta-analysis did not derive a significant advantage for the addition of chemotherapy after surgery (p < 0.08) and, therefore, several studies are now in progress, or have recently completed, that will be expected to answer this question, either as a single study or, more probably, as a new meta-analysis. With the lack of any clear advantage for adjuvant chemotherapy or postoperational radiotherapy in resected N2 lung cancer, the possible benefits of combining chemotherapy with radiotherapy after resection have been studied. The logic is that radiotherapy decreases local rates of recurrence and chemotherapy may both add to this and treat distant occult disease. There have been four randomized controlled trials of surgery plus adjuvant chemotherapy–irradiation versus surgery and radiation alone. All these studies failed to show an advantage in overall survival, with the most recent failing to demonstrate any improvement in disease-free survival or overall survival with the addition of chemotherapy to radiotherapy. Another question concerns the timing of radiation in relation to chemotherapy. The studies described above all gave chemotherapy before irradiation (i.e., sequential chemoirradiation). A European Organisation for Research and Treatment of Cancer (EORTC) three-arm study compared split-course radiotherapy concurrent with daily or weekly cisplatin versus radiotherapy alone. There was no advantage for the weekly chemotherapy plus radiotherapy arm.
The latter is still difficult to quantify and remains "soft" data. Most studies have taken patient subsets for quality of life analysis, used different measures with no agreed criteria for reporting, and, because of the attrition of the disease itself, the numbers returning questionnaires fall by 30–50% by 6 to 12 weeks, making the data more difficult to interpret. Most studies show that, if quality of life is to improve, it does so in most patients after two courses of chemotherapy and worsens after prolongation of treatment. Of course, not all patients with advanced disease will benefit from chemotherapy. Disease stage and performance status are the most important prognostic factors at presentation. Those patients most likely to respond to chemotherapy and tolerate side effects well are those with a good performance status, female sex, a single metastatic site, normal calcium and serum lactate dehydrogenase, hemoglobin at more than 11 g/dl, and the use of cisplatin chemotherapy. Of these, performance status is the most important factor, and of other variables analyzed, a poor prognosis is conferred if there are subcutaneous metastases, bone marrow infiltration, thrombocytosis, and non-large cell histology.
Small cell lung cancer (SCLC) is sensitive to several chemotherapeutic agents, and most if given as single agents will elicit at least a partial response (50% or greater reduction in tumor size) in more than 30% of previously untreated patients. Several new agents have shown similar activity. A plethora of studies in the 1970s showed combinations of agents to be superior to single agents both in terms of the response rates and the duration of the response and prolongation of survival. Several combination regimens have shown acceptable and fairly similar activity, producing an objective response rate of 80 to 90%, with complete response (no tumor detectable on restaging tests) in up to 50% of patients, depending on the stage of presentation. Patients presenting with limited stage disease (disease confined to the hemithorax and including the ipsilateral supraclavicular fossa) do better than those with extensive stage disease. Median survival averages up to 20 months for limited disease and up to 7 to 10 months for extensive disease after treatment compared with 3 months and 6 weeks for untreated limited disease and extensive disease. The optimal duration of combination chemotherapy is probably six to eight cycles. Long-term results after chemotherapy remain disappointing. Criteria have been identified for patients who have a realistic chance of living 2 years and those who are likely to die quickly. Apart from disease extent, performance status, serum alkaline phosphatase, plasma albumin, and sodium concentrations carry independent prognostic information. Serum lactate dehydrogenase can be substituted for alkaline phosphatase. Taken together, these simple serum analyses and performance status give more prognostic information than disease extent defined by more detailed and expensive imaging tests. The value of prognostic factors is that they identify patients with a chance of cure, but also patients with limited disease at risk of early death and patients with extensive disease with a chance of living 18 months with chemotherapy; and they help to facilitate comparisons between trials. Although the toxicity from chemotherapy is well understood and to a considerable extent predictable, the side effects can be a major problem and a dose-limiting factor, particularly in an increasingly elderly population of patients.
In tumor models one of the simplest ways to overcome drug resistance is dose intensification. In the 1970s Cohen and coworkers conducted a series of trials with increasing doses of cyclophosphamide and lomustine with standard doses of methotrexate. They observed a higher response rate and prolonged survival in the high-dose arm. Also, longer term survival was seen only in the high-dose group. By today's standards the doses used would appear modest, but they introduced the concept of high-dose chemotherapy for this disease. Weekly chemotherapy The concept of increasing intensity by more frequent administration of chemotherapy has resulted in trials comparing conventional 3-weekly with weekly regimens. However, one of the difficulties with weekly chemotherapy was in achieving administration of the intended dose, which in our group's study was only 71% of intended in the weekly group. Late intensification chemotherapy There are theoretical advantages for late intensification, as initially patients are ill and symptomatic as a consequence of the extent of their disease. Patients achieving a complete response with induction chemotherapy might be good candidates for high-dose consolidation treatment. However, the results of this approach contain few comparative data as the cases treated tend to be selected from the responders and the attrition rate from toxicity is high, with only a small number of patients achieving the intended treatment. No useful survival advantage has been reported from late intensification studies.
A number of growth factors and their cognate receptors are expressed by lung cancers or their adjacent stromal cells, thus producing autocrine and paracrine growth stimulation loops. Several are encoded for by proto-oncogenes which become activated in the course of lung cancer development. The ERBB family is a group of transmembrane receptor tyrosine kinases which, together with their ligands, constitutes a potential growth stimulatory loop, particularly for NSCLCs. The two members important for lung cancer are the epidermal growth factor receptor (EGFR, ERBB1) and HER2/neu (ERBB2), which are expressed independently of one another in NSCLC. On ligand binding, ERBB receptors homodimerise or heterodimerise, thereby inducing intrinsic kinase activities that initiate intracellular signal transduction cascades including the MAP kinases. EGFR regulates epithelial proliferation and differentiation and can be overexpressed in lung cancers. Moreover, lung cancer cells also express ligands for EGFR such as epidermal growth factor (EGF) and transforming growth factor Monoclonal antibodies against the EGFR (C225, ImClone) are entering clinical trials in combination with chemotherapy. In addition, tyrosine kinase inhibitors that have some selectivity such as ERBB1 blockers (CP358774, ZD1839-Iressa, OSI774) are also being tested, most with the advantage of being orally active. Another ERBB family member, HER2/neu, is highly expressed in about 30% of NSCLCs, especially adenocarcinomas. High HER2/neu levels are associated with the multiple drug resistance phenotype and increased metastatic potential in NSCLC, which may help to explain the poor clinical outcome linked to HER2/neu overexpression reported by some but not all investigators. Clinical trials investigating chemotherapy combined with trastuzumab (Herceptin), a monoclonal antibody against the HER2/neu receptor, are in progress in lung cancer. The autocrine loop comprising stem cell factor and its tyrosine kinase receptor CD117 is activated in some lung cancers—more often in SCLC than NSCLC—with resultant growth promotion or chemoattraction. The recent development of specific tyrosine kinase inhibitors to target this pathway may translate into novel approaches for this highly lethal subtype. Similarly, the gastrin releasing peptide (GRP) growth stimulatory loop is involved in 20–60% of SCLCs. The therapeutic potential of inhibiting this pathway with a neutralising monoclonal antibody directed against GRP, as well as by antagonists of GRP (also referred to as bombesin), is being tested in early clinical trials of SCLC. The GRP receptors belong to a G-protein coupled receptor superfamily including GRP-, neuromedin B- and bombesin subtype-3 receptors; all of these can be expressed in lung cancers of all histological types and some bronchial epithelial biopsies from smokers, implying an early pathogenic role for this family. The GRP receptor is expressed more frequently in women (where there are two expressed copies of the X linked gene) than in men in the absence of smoking. Its expression is activated earlier in women in response to tobacco exposure, which may be a factor in the increased susceptibility of women to tobacco induced lung cancer. Other putative growth factor systems include insulin-like growth factors (IGF) I and II, the type I IGF receptor, platelet derived growth factor/receptor, and the hepatocyte growth factor/receptor. Each of these should be further studied for any potential clinical usefulness. Insulin-like growth factor binding protein-6 (IGFBP-6) activated programmed cell death in NSCLC cells while IGFBP-3 inhibited cell growth in human lung cancers, suggesting that these binding proteins might potentially be new treatments. In addition, high levels of blood IGF-I and enhanced mutagen sensitivity of peripheral blood lymphocytes were individually associated with an increased risk of lung cancer, which suggests that genetic polymorphisms in IGFs may predispose to the development of lung cancer. The RAS proto-oncogene family (KRAS, HRAS, and NRAS) which encodes 21 kD plasma membrane proteins comprises an important signal transduction pathway. Its members, especially KRAS, can be activated in some lung cancers by point mutations, leading to inappropriate signalling for cell proliferation. Mutations are found in 15–20% of all NSCLCs apart from SCLCs, especially adenocarcinomas (20–30%). KRAS mutations correlate with smoking, often being the G–T transversions associated with polycyclic hydrocarbons and nitrosamines. In mice, somatic activation of KRAS by spontaneous recombination predisposes the animals to tumours, predominantly early lung cancer onset. While the prognostic importance of KRAS mutations is debated, it does not appear to predict the response to chemotherapy. Two recent large studies in resected NSCLC showed that KRAS mutations were independent but weak predictors of survival. The MYC proto-oncogene family encodes nuclear products which are the ultimate target of RAS signal transduction; the most frequently involved family member is c-MYC in both SCLC and NSCLC, unlike MYCN and MYCL which are generally activated only in SCLC. Activation occurs as a result of protein overexpression caused by gene amplification or by transcriptional dysregulation. There also appears to be a change in lung cancers leading to increased stability of MYC mRNA. Approximately 18–31% of SCLCs had amplification of one MYC family member compared with 8–20% of NSCLCs. MYC amplification appears to occur more frequently in chemotherapy treated patients, and the "variant" SCLC subtype may correlate with adverse survival. Recent studies have suggested that low levels of MYC amplification occur in NSCLC and are associated with impaired survival; the combination of MYC expression with loss of caspase-3 (an apoptosis inducer) expression results in worse survival. MYC expression may represent an avenue for therapeutic manipulation.
Tumour cells often escape the normal physiological response (termed programmed cell death or apoptosis) when challenged by cellular and DNA damage. Key players include the p53 gene and the BCL2 proto-oncogene. BCL2 protects against apoptosis and its expression is higher in SCLC (75–95%) than in NSCLC. These findings are seemingly unexpected as SCLCs are more sensitive to chemotherapy, which often induces an apoptotic response. In any case, the prognostic value of BCL2 expression is controversial. BCL2 expression in tumours actually predicts increased survival of patients with NSCLC. BAX is a BCL2 related protein which promotes apoptosis and is a downstream transcription target of p53. BAX and BCL2 expression is inversely related in neuroendocrine cancers; high BCL2 and low BAX expression occurs in most SCLCs which are usually p53 deficient. Expression of the inhibitor of apoptosis protein (IAP)-1 acts as an important anti-apoptotic protein mediating sensitivity to deoxynucleotide analogues in NSCLC cells. Among the anti-apoptosis strategies in preclinical trials are studies of antisense BCL2 in SCLC (to downregulate BCL2 protein expression), BCL-xL antisense in NSCLC, and a bispecific BCL2-BCLxL antisense to target both SCLC and NSCLC. Insensitivity to anti-growth signals: tumour suppressor genes (TSGs) TSGs play a critical role in controlling normal cell growth. They generally inhibit the tumorigenic process but can also be involved in the response and repair of DNA damage. TSGs are rendered inactive by chromosomal loss of one allele (loss of heterozygosity (LOH)) and damage to the other by genetic mutation or the epigenetic hypermethylation of its promoter. Studies of LOH as a marker of TSG inactivation have shown that a number of chromosomal regions are damaged in overt lung cancer cells. For instance, a genome wide search for LOH in 36 lung cancer cell lines using There is an intense hunt for the candidate genes in chromosomal regions with high frequencies of LOH where the precise TSG is not known. For example, several candidate genes are located on 3p where LOH can be found in up to 96% of lung cancers and 78% of preneoplastic/preinvasive lesions, as well as by homozygous deletions. The frequency and size of 3p LOH increased with the severity of histopathological preneoplastic/preinvasive changes. There are also TSG candidates at the 3p21.3 region which appear to suppress the tumorigenic phenotype when introduced back into lung cancers with numerous other genetic lesions. Expression of wild type but not tumour acquired mutant FUS1 dramatically suppresses the growth in vitro of lung cancer cells, while systemic delivery of FUS1 in an adenovirus vector resulted in regression of metastatic disease in a lung cancer mouse xenograft model. Wild type SEMA3B reintroduced into lung cancer cells induces apoptosis, unlike SEMA3B missense mutants. In addition, transfection of SEMA3B into cells results in conditioned media that induce the death of lung cancer cells, which raises the possibility of using this soluble secreted protein as a systemic anticancer treatment. Other chromosomal regions affected by LOH in lung cancers house known TSGs such as p53, retinoblastoma (RB), and p16, and these are often found to be abnormal by immunohistochemical examination in lung cancer. p53 is a key TSG; its protein helps maintain genomic integrity in the face of DNA damage from  or UV irradiation and carcinogens. DNA damage or hypoxia upregulates p53 which acts as a transcription factor regulating a number of downstream genes including p21, MDM2, GADD45, and BAX, thereby helping to regulate the G1/S cell cycle transition, G2/M DNA damage check point, and apoptosis. p53 inactivation occurs in  75% of SCLCs and about 50% of NSCLCs, with mutations correlating with cigarette smoking and comprising the G–T transversions expected of tobacco smoke carcinogens. Missense p53 mutations can prolong the protein half life leading to easily detected mutant p53 protein by immunohistochemistry. p53 mutations have been linked to response to cis-platinum based chemotherapy in NSCLC and the response to radiotherapy. While there is debate on the prognostic role of p53 abnormalities in NSCLC, the preponderance of evidence suggests that the presence of such abnormalities leads to a worse prognosis. p53 is a prototypic model for gene replacement therapy in lung cancer. Preclinical studies showed that restoring p53 function resulted in apoptosis of cancer cells, and have progressed to phase II clinical trials where adenoviral mediated p53 gene transfer delivered by direct tumour injection appeared feasible when given in conjunction with radiation therapy. Conversely, intratumoral injection of adenoviral p53 appeared to provide no additional benefit in patients receiving first line chemotherapy for advanced NSCLC. Vaccine trials with mutant p53 peptides are also being performed. p53 is kept at virtually undetectable levels in normal cells by an autoregulatory loop involving the production of HDM2, the human homologue of the murine double minute 2 (MDM2) oncogene which blocks p53 regulation of target genes and enhances its proteasome dependent degradation. Conversely, p53 regulates (increases) the expression of HDM2 by directly binding and activating the HDM2 promoter, thereby downregulating itself. The HDM2 protein is overexpressed in 25% of NSCLCs, thus representing another way of abrogating p53 function. HDM2, in turn, is inactivated by p14ARF, the alternative product of the p16 gene whose downregulation is similarly associated with loss of p53/HDM2/p14ARF pathway function.
p16 is part of the p16-cyclin D1-CDK4-RB pathway that is central to controlling the G1–S transition of the cell cycle. This critical cell cycle regulatory pathway is functionally altered or mutated in many cancers including those of lung origin. Each member of the pathway may be rendered dysfunctional during carcinogenesis. Functional loss of the RB gene can include deletions, nonsense mutations, or splicing abnormalities leading to protein abnormalities in most SCLCs and 15–30% of NSCLCs. Functionally, in vitro re-introduction into tumour cells of a wild type RB suppresses SCLC growth. Whereas in SCLC the pathway is usually disrupted by RB gene inactivation, cyclin D1, CDK4 and especially p16 abnormalities are common in NSCLC. Cyclin D1 inhibits the activity of RB by stimulating its phosphorylation by cyclin dependent kinase 4 (CDK4). Thus, cyclin D1 overexpression is an alternative mechanism for abrogating this pathway and is found in 25–47% of NSCLC, possibly with a role as a predictor of poor prognosis. Furthermore, transfection of a cyclin D1 antisense construct into lung cancer cell lines can be shown to destabilise RB and retard growth. CDK4 expression has also been reported in NSCLCs and an example of potential therapeutic manipulation is flavopiridol. This compound, which inhibits cyclin dependent kinase, is being tested in clinical trials. p16 regulates RB function by inhibiting CDK4 and CDK6 kinase activity. p16 (or CDKN2) is situated on the short arm of chromosome 9 at region 21 and undergoes heterozygous and homozygous loss, mutation, and aberrant promoter hypermethylation in lung cancer, ultimately inactivating its function. Perhaps 30–50% of early stage primary NSCLCs do not express p16. The p16 locus also encodes a second alternative reading frame protein, p14ARF, which functions in the p53/HDM2/p14ARF pathway as discussed above. Interestingly, as an example of their evolutionary deviousness, lung tumours have developed distinct ways of interfering with the two different products from a single genetic locus, each of which functions in a distinct growth regulatory pathway. Moreover, the specific mutational targets differ according to lung cancer subtype, indicating the need for efforts to better understand their relative contribution to tumour differentiation.
Telomerase is the enzyme that adds hexameric TTAGGG nucleotide repeats onto the ends (telomers) of chromosomal DNAs to compensate for losses that occur with each round of DNA replication. Normal somatic cells do not have telomerase activity and stop dividing when the telomeric ends of at least some chromosomes have been shortened to a critical length. Immortalised cells, including nearly all lung cancers, probably continue to proliferate indefinitely because they express telomerase. While activation of telomerase is not the earliest step in the pathogenesis of lung cancer, it does occur early enough to be a potential molecular marker that can be detected in preneoplastic cells of the bronchial epithelium and in bronchial lavage specimens. Because all lung cancers express telomerase, studies of the level of expression in individual tumours will need to be correlated with prognosis and appear to correlate with the presence of lymph node metastases. Besides its use as a diagnostic tool, drugs targeting telomerase have therapeutic potential. Several of these involving anti-sense approaches are nearing entry into clinical trials. Sustained angiogenesis Lung cancers engender angiogenesis, and the expression of a large number of tumour blood vessels as manifest by tumour microvascularity counts is generally associated with a poor prognosis, although there are some dissenting opinions. There are several isoforms of vascular endothelial growth factor (VEGF). The expression ratio of the VEGF189 mRNA isoform had a greater correlation with tumour angiogenesis, postoperative relapse time, and survival than those for the VEGF121, VEGF165, and VEGF206 mRNA isoforms, which suggests that it could be used as a prognostic indicator for patients with NSCLC. This increase in tumour neovasculature arises largely because of production of VEGF by lung cancer cells. Part of this dysregulation may arise through loss of p53 function. Clinically, plasma VEGF levels can predict the degree of angiogenesis in NSCLC. Some impressive results have recently been presented in abstract form from clinical trials targeting VEGF with a humanised monoclonal anti-VEGF antibody. These initial trials were fraught with toxicity related to unexpected bleeding from large necrotic lung tumour masses, but this should be approachable by patient selection. Tissue invasion and metastases Many of the changes discussed above lead to the ability of lung cancer cells to invade into tissues and to spread and survive in metastatic deposits. One of the interesting new candidates to participate in invasion and metastasis is CRMP-1, a protein involved in mediating the effect of collapsins. Lung cancer specimens showed that reduced expression of CRMP-1 is associated with advanced disease, lymph node metastasis, early postoperative relapse, and shorter survival, indicating that CRMP-1 is involved in cancer invasion and metastasis. Collapsins are part of the semaphorin family, so CRMP-1 may provide another indication of the role of semaphorins and the pathways they mediate in the pathogenesis of lung cancer. Laminins and integrins are being intensively studied as key markers of tissue invasion through the basement membrane and subsequent development of metastases. The expression of laminin  chains (3 and 5) is often reduced in lung cancer cells; this might contribute to basement membrane fragmentation and subsequent proliferation of stromal elements, as well as having a role in the process of cancer cell invasion. The LAMB3 gene (encoding the laminin ß3 chain, a unique component of laminin-5) was expressed in NSCLC cells and not in SCLC cells. Laminin-5 is a heterotrimeric protein consisting of the 3, ß3, and 2 chains, and another unique component of laminin-5, the 2 chain encoded by the LAMC2 gene. Since 6ß4-integrin, the specific laminin-5 binding receptor, is known to be expressed only in NSCLCs and not in SCLCs, it appears that laminin-5 is a critical microenvironmental factor for the growth of NSCLC but not of SCLC cells. Survival analysis revealed that overexpression of laminin-5 was associated with shorter patient survival and was an independent prognostic factor in NSCLC.
PREVENTION OF THE LUNG CANCER Prevention of a LC is divided on initial and secondary. Initial or hygienic prevention assumes system of measures and medical actions directed to the termination or decrease of influence on an organism of carcinogenic factors. Improvement of the ecological situation directed to downstroke of carcinogenic substances in air, water and nutrition, refusal of smoking. The last plays the basic role in initial prevention of a LC. Secondary or clinical prevention is specially organized system of revealing and treatment of pretumor lung diseases, and also observation over contingents of groups of the increased oncologic risk. Persons, сoncerning this category are necessary to undergo 2 times per one year a chest X-ray and 5 times examination of sputum. Patients, who underwent radical treatment concerning LC, should be under observation of the doctor - oncologist 5 years. Within first 2 years control surveys are carried out 1 time in 3 months. The next 3 years - 1 time in 6 months. SURVIVAL The highest 5-year survival for any cell type is for stage I squamous cell carcinoma (50%). For stages I and II, the curves are asymptotic at 2 years, and 8-10% of patients with stage IIIA disease survive 5 years. For stage I adenocarcinoma and large-cell carcinoma, there is little difference in survival when compared to squamous cell carcinoma. In stages II and IIIA, patients with squamous cell carcinoma have a better outcome than those with adenocarcinoma or large-cell carcinoma. The outcome is similar for all cell types in stage IIIB and IV (See table 2). Table 2. Non-small Cell Lung Cancer Survival by Stage
The survivorship data for small-cell carcinoma (SCLC) are poor, although 5-year survival of 20% has been reported in patients with stage I disease. In many of these patients, the diagnosis of SCLC was made at the time of resection for an undiagnosed solitary pulmonary nodule. Patients with limited disease (tumor confined to one hemithorax and its regional lymph nodes) have a more favorable prognosis than patients with extensive disease (See table 3). Weight loss prior to diagnosis, a poor performance status, failure of SCLC to respond to initial chemotherapy regimen, and progression of disease after treatment are adverse prognostic factors. Table 3.
Small Cell Lung Cancer Survival by Stage
THE FUTURE The disappointing prognosis for patients with lung cancer has prompted nihilism on the one hand and determination to improve outcomes on the other. This has led to a search for new agents to complement the antitumor effects of chemotherapeutic drugs. Several observations of lung tumor biology have influenced the selection of candidate drugs, many of which have been designed to affect specific cellular pathways implicated in oncogenesis. Angiogenesis is thought to play an important role in tumor growth and metastasis. Successful blood vessel formation lies in a balance between proangiogenic factors, such as the growth factors vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), and epidermal growth factor (EGF) acting through their receptor tyrosine kinases; the degradation and remodeling of the extra cellular matrix by matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs); and the naturally circulating antiangiogenic molecules angiostatin and endostatin. Some observations in lung cancer itself have reinforced the idea that inhibiting angiogenesis might prove fruitful. For example, in a study of 143 patients with fully resected primary NSCLCs, the median survival of patients with angiostatin-negative/VEGF-positive tumors was significantly less than those with angiostatin-positive/VEGF-negative tumors, 52 versus 184 weeks, respectively. Intratumoral microvessel density (IMD) has also been variably related to a poorer prognosis. Levels of cellular expression of VEGF and its receptor (VEGFR), the EGF receptors (EGFR/HER-1/c-Erb-B1 and HER-2/c-Erb-B2, and MMP-9 have all been found to be increased in certain lung cancers, although how this relates to prognosis is still contentious. At present many candidate molecules have been developed to inhibit angiogenic pathways in the hope of making an impact in cancer treatment, and this review considers those molecules that have reached Phase III trials. The growth factors and their receptors are judged to have enormous potential as novel therapeutic targets. A Phase II trial of a recombinant humanized anti-VEGF antibody (rhuMAb-VEGF, Bevacizumab; Genentech, San Francisco, CA) in combination with paclitaxel and carboplatin in NSCLC was sufficiently encouraging that a large Phase III trial involving metastatic NSCLC is underway. Even more hope has been invested in the EGFR-blocking agents. The most extensively studied of these agents are: 1) monoclonal antibodies against the extracellular domain of the receptor, including IMC-C225 (Erbitux; ImClone Systems, Somerville, NJ) directed against the EGFR and trastuzumab (Herceptin; Genentech) directed against HER-2/c-Erb-B2, 2) inhibitors of the tyrosine kinase region of the receptors such as ZD 1839 (Iressa; AstraZeneca, Wilmington, DE) and OSI-774 (Tarceva; OSI Pharmaceuticals, Melville, NY). So far, only ZD 1839 and OSI-774 have progressed to Phase III studies in NSCLC. There are currently two multicenter Phase III trials of chemotherapy (carboplatin plus paclitaxel in one study, and cisplatin plus gemcitabine in the other) alone or in combination with ZD 1839 in newly diagnosed patients with advanced Stage III/IV NSCLC. Two similar Phase III studies are in early stages, and plan to compare chemotherapy (carboplatin plus paclitaxel in one study, and cisplatin plus gemcitabine in the other) alone or with OSI-774, again in chemotherapy-naive patients with advanced stage NSCLC. The primary end point for all four trials is survival. To date, several potent synthetic inhibitors of MMPs (MMPIs) have been produced and tested in patients. Many of these made it to Phase III trials in advanced lung cancer but, disappointingly, most of these trials were halted following a poorer outcome in the treated group. It is not clear why the results were so poor, but it has been suggested that MMP inhibition is needed at the time of angiogenesis and not once the tumor microvasculature has been established. Neovastat (AE-941; Aeterna, Quebec, PQ, Canada), a naturally occurring MMPI extracted from shark cartilage extract, significantly improved survival in patients with inoperable Stage III and IV NSCLC and recruitment has begun for a Phase III trial in inoperable Stage III NSCLC in combination with platinum-based chemotherapy (cisplatin and vinorelbine or carboplatin and paclitaxel) and radiotherapy. Another inhibitor of angiogenesis is carboxyamido-triazole (CAI); how it works is not entirely clear, although it is known to inhibit calcium-mediated signal transduction. A randomized Phase III study of oral CAI in patients with advanced NSCLC, who have received chemotherapy, is recruiting patients and aims to assess the safety of CAI and to collect data on quality of life and time to progression. Thalidomide has been shown in preclinical models to be antiangiogenic, and although the exact mechanism is not understood it is thought to be involve effects on tumor necrosis factor- Another potential area of interest is that of apoptosis or programmed cell death and both apoptosis-protective molecules such as Bcl-2, and apoptosis-stimulating molecules such as Bax, are being pursued as targets for inhibition or activation, respectively. Genasense (formerly known as G-3139; Genta, Berkeley Heights, NJ), is an antisense oligonucleotide specific for Bcl-2; it is administered as an intravenous infusion and is in Phase III trials for malignant melanoma and earlier phase studies in NSCLC. Another target is protein kinase C (PKC), and some encouraging results have been seen with Isis 3521 (Isis Pharmaceuticals, Carlsbad, CA), an antisense PKC inhibitor that binds to PKC- Other strategies have also been developed, such as vaccines directed against tumor-specific gangliosides; one such anti-idiotypic monoclonal antibody against the GD3 ganglioside is BEC-2 (Mitumomab; ImClone Systems). An international randomized Phase III trial is being conducted to evaluate BEC-2 plus BCG as adjuvant therapy after chemotherapy and irradiation in limited SCLC. In North America, a bivalent ganglioside vaccine, MGV (Bristol-Myers Squibb), is under study at the Phase II level. If results are promising, a Phase III trial will be undertaken. Another attempt at immunomodulation involves the use of Mycobacterium vaccae (SRL172) given as a monthly intradermal injection in newly diagnosed patients with inoperable NSCLC and mesothelioma. Results from a Phase II trial showed a tendency toward a better response in patients who received SLR172 compared with those who received chemotherapy alone. A Phase III study is now in progress. STANDARDS OF LUNG CANCER TREATMENT TREATMENT OF NON-SMALL CELL LUNG CANCER Yüklə 390,43 Kb. Dostları ilə paylaş:
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400 high resolution polymorphic markers showed that tumours had a mean of 17–22 "hot spots" of chromosomal loss. There were 22 different regions with more than 60% LOH, 13 with a preference for SCLC, seven for NSCLC, and two affecting both histological types. The sharing of some LOH regions and the specificity of others may provide an insight into the genes common to