New Agents – Manifold Consequences: the Management of Lung and Co- Lorectal Cancer Is Changing

Current Cancer Therapy Reviews, 2009, 5, 1-19 1 New Agents – Manifold Consequences: The Management of Lung and Co- lorectal Cancer is Changing

Christine Armbruster*

2nd Medical Department / Otto Wagner Spital Vienna

Abstract: 1,444,920 new cases of cancer were projected in 2007 in the U.S., half of these patients are suffering from cancers of the prostate, the breast, the lung, and the colon/rectum. Colorectal and lung cancer are the most frequent solid tumors in both women and men. However, the US cancer statistics offer some hope. The incidence rates of colorectal and lung cancer rose till 1985 and 1991, respectively after which they fell. Global statistics is the one side of the coin but successful prevention and treatment of solid tumors requires the acceptance that these are not single diseases. This review focuses on the following topics: 1) Tumor biology: inflammation, growth factors (EGF, VEGF, IGF and its receptors), and epigenetic events. 2) Management strategies in diagnosis: Is early diagnosis feasible? a) Tumor-specific antigens. b) Radiological methods. c) Endoscopy. d) Contributions of pathology to diagnosis and treatment decisions. 3) Appropriate patient selection for treatment purposes. a) Evaluation of tumor tissue. b) Tumor staging. 4) Therapy sequencing: drugs, beams, surgery. 5) Clinical trials a) Phase I trials. b) What are the best inclusion criteria and endpoints? 6) The pipeline. 7) New drugs and manifold consequences. 8.) Prevention strategies. 9.) Future directions.

Key Words: NSCLC, colorectal cancer, tumor biology, targeted therapy, therapy sequencing, patient selection.

1. INTRODUCTION Global statistics is the one side of the coin but successful prevention and treatment of solid tumors as lung and colo- 1.1. Epidemiology and Health Care Considerations rectal cancer requires the acceptance that these are not single 1,444,920 new cases of cancer were projected in 2007 in diseases. Lung cancer exists as a variety of phenotypes re- the U.S., half of these patients are suffering from cancers of flecting different response rates to therapy especially to tar- the prostate, the breast, the lung, and the colon/rectum [1]. geted therapeutics [4, 5]. To some extent different pheno- Colorectal and lung cancer are the most frequent solid tu- types can be recognized but for adenocarcinomas in particu- mors in both women and men which accounted for 213,380 lar objective and reproducible histological criteria for sub- lung cancers and 153,760 cancers of the colon/rectum in classification are urgently needed. On the one hand lung 2007 [2]. In the United States the incidence rates of prostate cancer incidence has stabilized over the past decade in West- cancers (145.3 per 100,000 men per year) is exceeding that ern countries on the other hand a major shift has been re- of female breast cancer (117.7 per 100,000 women per year), corded with significant increases in the relative and absolute but death occurs at an equal range (25.4 deaths of prostate incidence of adenocarcinomas [6]. For example registry data cancer and 24.4.deaths of female breast cancer per 100,000 of the USA indicated that the ratio of squamous cell carci- persons per year) [2]. However, the US cancer statistics offer noma (SCC) to adenocarcinoma was approximately 17:1. By some hope. The incidence rates of the most frequent solid 1995 the incidence of these two histological tumor types was tumors as indicated above were on the rise until 1992 and nearly equal. Changes in cigarette design and in the pattern began to decline thereafter [1]. In case of colorectal and lung of smoke inhalation have been suggested as reasons for this cancers the incidence rates rose till 1985 and 1991, respec- shift. Specific mutations in tumor suppressor genes as p53, tively after which they fell [1]. Even if polled data do not Kirsten Rat Sarcoma (KRAS), and the serine/threonine necessarily reflect the situation of single EU member states, kinase LKB1/STK11 are the molecular basis of tumor devel- the latest European figures on cancer incidence and mortality opment reflecting the underlying mechanisms as mutations showed that Europe as a whole lags behind the USA [3]. in KRAS and p53 due to smoking [4]. Although smoking Recently a report studying 18 cancers in 39 European coun- remains the predominant cause of lung cancer, lung cancer in tries demonstrated an increasing incidence of all cancer types never smokers is increasingly subject of investigations. With from 2.9 million in 2004 to 3.2 million in 2006, more than respect to personalized therapeutic strategies further evalua- 1.7 million Europeans died from cancer. Due to an ageing tion of incidence patterns, etiological and biological consid- European population this figure will continue to rise despite erations are warranted [7]. earlier detection and improved treatment and management [3]. Outcome research in cancer is mainly focused on short- term survival and increasingly on quality of life (QoL). In-

formation on long-term survivorship is sparse. Sugimura et *Address correspondence to this author at the Mantlergasse 23/2/12, A-1130 al. dealt with this subject in a review article addressing epi- Vienna, Austria, Europe; Tel: +43 676 62 64 084; E-mail: [email protected] demiological significance of long-term survivors with differ-

Fig. (1). Role of tumor-associated macrophages. The initial step is attraction of macrophages by growth factors (GM-CSF, VEGF) and chemokines. Tumor-associated macrophages produce growth factors (e.g. EGF) for cancer cells thus resulting in angiogenesis and tissue remodeling (Adapted from [13]). ent kinds of malignant solid tumors [8]. Lung cancer survi- nant cells and in tumor angiogenesis are complex and cancer vors scored lowest in health utility compared to long-term cells use escape mechanisms for their growth advantage and survivors of other cancers. Approximately one-quarter of cell survival thereby overcoming different growth factor lung cancer survivors reported to be restricted in physical signaling pathways. activity and to suffer from depressive symptoms. Different management strategies are therefore needed. A five- 2.1. Inflammation and Oncogenesis dimension working model that captures health and QoL has A large number of epidemiological observations on anti- been proposed by Wilson and Cleary [9]. inflammatory drugs as aspirin and the incidence of carcino- Population growth and ageing will impact the number of mas support the role of inflammation in cancer development. long-term cancer survivors in the future. The total number of The immune system naturally acquires the ability to recog- cancer patients is expected to double as well as the number nize cancer cells but tumor growth cannot be controlled. This of cancers in persons aged more than 65 years. Therefore the paradox can be explained by a generalized immunodefi- burden of cancer could significantly increase despite preven- ciency that is associated with the tumor-bearing state or by tion, improved diagnostic tools and treatment [10]. In colo- properties of cancer cells resulting in modulation of the im- rectal and lung cancer improvement in survival rates is de- mune response within the tumor microenvironment [13]. pendent on early detection of the disease, improved systemic Both, cellular immunity comprising T cells and natural killer therapy applied to surgery and/or radiation especially in cells and strategies using antibodies can basically provide early- stage disease. Nevertheless the majority of advanced strong antitumor effects. Oxidative stress resulting in im- stage patients succumb to disease leaving room for immune hypo- responsiveness counteracts these mechanisms provement [11, 12]. [14, 15]. Inflammation is an integral part of cancer biology either fostering or hampering tumor growth. Eradication of In light of such progress the cut of the budget affects sci- cancer might be possible by shifting the balance from a entific work in the fields of diagnostic procedures as molecu- chronic towards an acute inflammation. lar studies of tissue samples and in the fields of cancer treatment and prevention. 2.1.1. Tumor and Tumor-Associated Macrophages

2. TUMORBIOLOGY More than three decades ago researchers noted that tumor-associated macrophages promoted tumor growth and The nature of cancer suggests that it is a disease of chaos. that in most human cancers a high number of macrophages Over the last decade significant progress has been made predicted poor prognosis. The following inflammatory ele- in the understanding of molecular mechanisms being in- ments are involved in cancer development: leucocytes, tu- volved in human cancer development and progression result- mor-associated macrophages, cytokines as tumor necrosis ing in a more personalized treatment of malignant diseases. factor alpha (TNF alpha) and interleukin 1 (IL1), and Some concerns are left with respect to successful therapy: chemokines as the C-C motif of ligand 2 (CCL2) as well as The molecular pathways involved in proliferation of malig- the processes of tissue remodeling and angiogenesis (Fig. 1) [13]. New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 3

The essential elements in carcinogenesis that may have perpetuates the neoplastic process. Key to successful cancer an impact on treatment include TNF alpha, IL 1, CCL2, cy- treatment is both specificity in case of modulating T cell clo-oxygenase 2, NFB, and enzymes involved in tissue re- function and shifting the balance from a chronic inflamma- modeling. In response to cytokines and microbial products tory towards an acute inflammatory response. mononuclear phagocytes which are characterized by hetero- Functional arrays defined tumor populations that are geneity and plasticity express specialized and polarized called cancer stem cells (CSC) in an increasing number of properties. In accordance to the T helper 1 and 2 classifica- cancers. CSCs need capable surroundings as growth factors, tion system it can be referred to polarized macrophages as adhesion molecules, and energy sources (e.g. glucose, oxy- M1 and M2 cells. M2 cells are present in established tumors, gen) in order to drive the tumor growth. These surroundings release growth factors for cancer cells as the epidermal are referred to as the ”permissive” CSC niche [23]. In some growth factor (EGF), promote angiogenesis, and conquer instances these factors are incompatible with CSC growth effective antitumor responses [16]. On the other hand these (“non-permissive” niche) thus resulting in CSC dormancy or macrophages are attracted in tumors by VEGF and granulo- death. Various components of the vascular tumor interface cyte-macrophage colony- stimulating factor (GM-CSF) (Fig. may serve as CSC niche. Therefore cells with increased tu- 1). Hypoxia in tumors results probably in both accumulation mor-initiating capability may be preferentially found adja- of macrophages through expression of the chemokine (C-X- cent to tumor vessels producing angiogenetic factors. On the C motif) receptor 4 (CXCR4) and in angiogenesis [17]. other hand CSCs are suggested to be a source of chemo-and 2.1.2. Tumor and Dendritic Cells radiation therapy resistance within tumors [24]. Conse- quently research on CSCs addresses the following aims: a) In contrast to macrophages dendritic cells, the profes- Identification of the molecular mechanisms that are respon- sional antigen presenting cells, do not modulate innate but sible for CSC therapeutic resistance; b) The role of CSCs in adaptive immune mechanisms. M1 activation of macro- regulating tumor vasculature. phages can be induced by dendritic cells leading to tumor- disruptive inflammation. In general induction of tissue- 2.2. Epidermal Growth Factor (EGF) and Oncogenesis specific immunity depends on the tissue origin of these dendritic cells [18]. Infiltration of tumor tissue with dendritic Tumor-associated macrophages of the M2 type produce cells has been observed in breast cancer [19]. The presence growth factors for cancer cells as EGF that interact with cell of mature dendritic cells outside of lymphoid organs means surface receptors thus regulating proliferation, survival, dif- inflammation and it remains to be elucidated whether their ferentiation and metabolism. One hallmark of carcinogenesis presence is beneficial taking in mind the role of chronic in- is loss of control over these vital processes. The epidermal flammation in cancer development. VEGF and several cyto- growth factor receptor (EGFR) and its ligands EGF and kines can suppress dendritic cells in tumor microenviron- transforming growth factor alpha are members of the growth ment. Prostaglandins and thromboxanes that are synthesized factor/receptor tyrosine kinase (RTK) family (Fig. 2). by cyclo-oxygenase 1 and 2 might contribute to tumor growth not only through enhanced angiogenesis but also through inhibition of dentritic cells. Under certain circum- stances dentritic cells can fight back by expressing cytotoxic molecules like granzymes. The perforin-granzyme pathway results in activation of pro-apoptotic caspases. Ex-vivo- generated dendritic cells that have taken up tumor antigens in culture and expressed them further for presentation to T cells have been used as vaccines in order to enhance immunity in cancer patients [20]. Very recently data indicated that CD56+ gammadelta T lymphocytes which use the perforin- granzyme pathway in their action are potent antitumor effec- tors in case of squamous cell carcinomas [21]. 2.1.3. Immune-Mediated Cancer Rejection The pathogenic process could be cleared by turning an indolent immune response into a potent inflammatory reac- tion. That means by mirroring infectious diseases such as hepatitis B and C that symptomatic infection results in viral clearance whereas asymptomatic infection leads to chronic Fig. (2). Signalling pathways following activation of EGFR. First unresolved outcomes. The “danger model of immunity” pre- step: Binding of a receptor-specific ligand to the EGFR or its recep- dicts that antigen exposure needs co-stimulation in order to tors. Second step: Formation of an EGFR-EGFR dimer with auto- activate and sustain effective immune responses [22]. In this phosphorylation. Third step: Intracellular signals to the cytoplasm model danger signals initiate innate immune responses lead- and the nucleus are triggered (Adapted from [28]). ing to recruitment, activation and survival of immune cells. Cancer cells do not have such signals and do not produce the The EGFR is part of a subfamily of four closely related combination of factors being necessary for complete rejec- receptors- EGFR (ErbB-1), HER-2/neu (ErbB-2), HER-3 tion. This deficiency results in chronic inflammation that (ErbB-3), and HER-4 (ErbB-4) - that influence the develop- shares similarities with chronic hepatitis C infection and that ment and progression of the most common human epithelial 4 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster

Fig. (3). EGFR activated signaling pathways downstream of Ras (Adapted from [32]). cancers. Members of the EGFR family are overactive in frame of the KRAS gene converts the proto-oncogene KRAS solid tumors providing therapeutic options in cancer therapy into a potent oncogene (Fig. 3) [32]. [25]. Phillips et al. demonstrated that hypoxia and EGF regu- late the expression of CXCR4 in non-small cell lung cancer 2.3. Vascular Endothelial Growth Factor (VEGF) and (NSCLC) cells [26]. CXCR4 expression is dramatically up- Oncogenesis regulated in metastases in comparison with cancer cells of According to Folkman`s concept a tumor can grow to a the primary tumor. EGFR is a trans-membrane receptor. Af- size of 1-2 mm without new vessels [33]. Different mecha- ter one of ten different ligands binds to the single-chain nisms of tumor angiogenesis such as sprouting angiogenesis, EGFR a receptor dimer is formed that signals within the cell vessel co-option, and vasculogenic mimicry could be identi- resulting in receptor autophosphorylation – Weinberg prefers fied (Fig. 4). the term “transphosphorylation” - through tyrosine kinase activity [27]. Autophosphorylation triggers various intracel- The term angiogenesis describes the formation of new vessels by sprouting from pre-existing ones. Main steps of lular pathways that may stimulate cancer cell proliferation this process are endothelial proliferation, migration, and tube and neovascularization thereby blocking apoptosis. Two formation. Pro-angiogenetic and anti-angiogenetic factors major intracellular pathways are activated by the EGFR, the play a key role in tumor angiogenesis. Pro-angiogenetic fac- RAS-RAF-MEK-MAPK pathway which controls gene tran- tors such as VEGF and its receptors, VEGF-R1 and VEGF- scription and cell-cycle progression from the G1 to the S R2, fibroblast growth factor-2 (FGF2) and its receptors, ma- phase and the PI3K-Akt pathway which activates anti- trix metalloproteases (MMPs) as well as plasmin activator apoptotic and pro-survival signals [28]. Over-expression of receptors and inhibitors are up-regulated by hypoxia in tu- EGFR correlates in some malignancies as NSCLC and breast mor tissue being the key event in tumor angiogenesis. Hy- cancer with poor prognosis and worse clinical outcome. Mu- poxia also induces up-regulation of hypoxia-inducible factor- tated variants of the human EGFR are most frequently char- 1 (HIF) that enhances on the one hand the transcription of acterized by a deletion in the extracellular domain (the type- VEGF being itself induced by e.g. insulin-like growth factor- III mutated variant; EGFRvIII) that leads to activation of its I (IGF-I). Angiogenetic activation leads to expression of tyrosine kinase (TK) domain. endothelial adhesion molecules (carcinoembryonic antigen- Four EGFR antagonists are available for the treatment of related cell adhesion molecule 1; CEACAM1) and E-selectin four different solid tumors. Even in case of high levels of thus resulting in VEGF dependent angiogenesis [34]. Vessel EGFR expression within the tumor some patients do not re- co-option seems to be a transient mechanism that is con- spond to EGFR antagonist therapy suggesting that EGFR trolled by VEGF, angiopoeitin-1 and angiopoeitin-2 and that expression alone is not a reliable predictor of treatment re- is followed by sprouting angiogenesis. Vascular mimicry sponse [29]. Preclinical studies on cancer cell lines showed refers to the property of tumor cells to form blood vessels. that the level of EGFR expression is less important for the The initial mechanism is again hypoxia. Quantitative meas- treatment response than the degree of activation of EGFR- urements showed that the walls of capillaries in tumors are dependent intracellular pathways [30]. Eberhard et al. re- about 10 times more permeable than capillaries in normal vealed a correlation between improved treatment response tissue. Explanations are the deregulated production of VEGF and EGFR exons 18 through 21 and KRAS exon 2 mutations and the defective assembly of capillary walls within tumors in NSCLC patients [31]. This point mutation in the reading [35]. A dramatic change in the behavior of small tumor New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 5

Fig. (4). Angiogenesis induced by implanted human colorectal adenocarcinoma cells over a period of 20 days (Adapted from [35]).

Fig. (5). Interaction between the IGFs and the IGF-IR and normal as well as cancer cells (Adapted from [36]). masses with respect to angiogenesis has been termed the colorectal cancer [36]. IGFs exert their actions by interacting “angiogenetic switch”. Usually the body denies its cells the with specific receptors on the cell membrane namely with ability to induce angiogenesis. The “angiogenetic switch” the IGF-I receptor (IGF-IR). This interaction is regulated by represents the successful breaching of this barrier by tumor specific binding proteins. The IGF family consists of two cells thus inducing blood vessel growth at will – an impor- polypeptide ligands, IGF-I and IGF-II, two types of cell tant step in tumor growth [35]. A striking correlation be- membrane receptors (IGF-IR and IGF-IIR) and six binding tween density of capillaries and prognosis could be demon- proteins (IGFBP-1 through IGFBP-6). IGFBP proteases may strated. However, it is a point of discussion whether intense also be regarded as part of the IGF family. The IGF family vascularization facilitates more aggressive tumor growth or interacts with a variety of molecules such as sex steroid if intense angiogenesis is the result of an underlying aggres- hormones, growth factors, and products of tumor suppressor sive malignancy. The VEGF and its receptors as well as genes thus being involved in carcinogenesis. The expression MMPs are targets of new therapeutics such as bevacizumab of IGF-I is influenced by nutrition and physical activity be- and sorafenib. ing therefore important in prevention strategies. Beside this the IGF family is involved in tumor angiogenesis as de- 2.4. Insulin-Like Growth Factor (IGF) and Oncogenesis scribed above (Fig. 5). The IGFs play a pivotal role in regulating cell prolifera- 2.5. Epigenetics in Oncogenesis tion, differentiation, and apoptosis. A number of epidemiol- Epigenetic events as repression of some genes by pro- ogical studies showed that increased levels of IGF-I are as- moter methylation and de-repression of others by demethyla- sociated with an increased risk for breast, lung, prostate, and tion may also contribute to tumor progression (Fig. 6). 6 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster

Fig. (6). DNA methylation after replication. After replication the daughter DNA strands lack methylation but short after replication methyl groups are attached by the DNA maintenance methylase. (Adapted from [147]).

Fig. (7). Epigenetic events in cancer management. DNA methylation and histone modification patterns in tumor specimens as management tool in cancer patients (Adapted from [38]).

Epigenetic mechanisms include DNA methylation and explain the contribution of hypomethylation to cancer devel- post-translational modification of core histone proteins, the opment: generation of chromosomal instability, reactivation so-called histone modification. The best known epigenetic of transposable elements, and loss of imprinting. Loss of marker is DNA methylation that is one of the layers of con- imprinting of IGF-II is a risk factor for colorectal cancer and trol of certain tissue-specific genes as MASPIN, a serine disrupted genomic imprinting contributes to the development protease inhibitor and tumor- suppressor protein and the of Wilms` tumor [39]. Hypermethylation of the CpG islands MAGE genes which are usually silent in tissue except in in the promoter region of tumor suppressor genes such as the malignant tumors [37]. retinoblastoma tumor-suppressor gene (Rb) and the breast- cancer susceptibility gene-1 (BRCA1) has been proven as In humans DNA methylation occurs in cytosines that major event in cancer development. Such patterns of epige- precede guanines which are called dinucleotide CpGs. netic inactivation can be the second lesion in Knudson`s two- The hypermethylation of repetitive genomic sequences hit model of how cancer develops. probably prevents chromosomal instability, translocations, and gene disruption. Cells that lack DNA hypermethylation The establishment of DNA methylation and histone modification profiles of the primary tumor specimen might due to spontaneous defects in DNA methyltransferases or be a tool in evaluating the prognosis and treatment responses due to disrupted DNA methyltransferases show nuclear ab- of patients with malignancies (Fig. 7). normalities [38]. Three mechanisms have been proposed to New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 7

3. MANAGEMENT: STRATEGIES IN DIAGNOSIS AND THERAPY

Colorectal and lung cancer are the most frequent solid tumors in both women and men [1, 2]. Therefore the following manuscript sections focus on these two tumors.

3.1. Is Early Diagnosis of Malignancies Possible? Early diagnosis of lung cancer and colorectal carcinoma is difficult due to lack of symptoms. The available tools in diagnosing malignancies early can be broadly categorized in non-invasive, minimally invasive, and invasive procedures. Non-invasive modalities that may represent appropriate screening tools include radiological methods as CT and positron emissions tomography (PET) scan. Rapid, non-invasive, and riskless, but unspecific methods are the evaluation of tumor markers. 3.1.1. Tumor Markers (Tumor-Specific Antigens) Fig. (8). Paraffin embedded sections of formalin fixed tissue blocks of a resected lung nodule. Tumor cells with positive NSE im- The adaptive immune response that is provoked by can- munoreactivity. (immunohistochemical stain; x 20). cer cells must be traceable to specific antigens expressed on these cells. Two categories of antigens are defined, the tu- [44]. The initial CTs of 1,968 baseline and 2,343 repeat mor-specific antigens (TSAs) and the tumor-associated anti- screening investigations were reviewed. Among 29 patients gens (TAAs). In contrast to the TSAs which are present in with nodules at baseline that were unchanged or grew after malignant tissue only, the expression of TAAs is not limited antibiotic therapy 15 lung cancers were diagnosed. In order to tumor cells. Therefore TAAs fail to elicit complete toler- to circumvent the need for further, possibly unnecessary, ance [40]. investigations short-term follow-up after two months with or In a recent prospective study the value of three serum without antibiotic therapy is suggested [44]. However, one tumor markers, the carcinoembryonic antigen (CEA), the quarter of the lung cancers were CT occult in a series of 561 cytokeratin 19 fragment (Cyfra 21-1), and the neuron- volunteers [45]. Therefore, different methods have to be specific enolase (NSE) has been investigated in 100 patients combined in high risk patients as heavy smokers in order to suffering from different types of lung cancer [Christ R, detect theses cancers early. Armbruster C; unpublished data]. The sensitivity of CEA, 3.1.3. Endoscopy: Autofluorescence Bronchoscopy (AFB) Cyfra 21-1, and NSE was 51%, 34%, and 58%, respectively. and Colonoscopy Thus, these tumor markers are inappropriate for screening purposes. NSE showed the highest sensitivity of 79.3% in AFB utilizes differences in the biochemical, metabolic, small cell lung cancers. Neuroendocrine differentiation is and structural composition of normal, pre-neoplastic, and reported in some non-small cell lung cancers (NSCLC) by neoplastic tissue. Two multicenter studies have shown that sensitive immunohistochemical methods providing an impor- the sensitivity of detecting high-grade dysplasia, carcinoma tant diagnostic tool for future therapeutic modalities [41] in situ, and micro-invasive cancer increases from 9-11% (Fig. 8). using white-light bronchoscopy to 56%-66% in case of AFB [46, 47]. The role of CEA that is the most commonly used diagnostic and prognostic marker in patients with colorectal can- According to the recent American guidelines colono- cer (CRC) has been evaluated recently [42]. In 173 patients scopy is suggested as screening method for CRC in asymp- CEA was assessed in serum and tumor tissue demonstrating tomatic patients. The diagnostic yield and safety was as- that CEA in tumor tissue but not in serum might be a predic- sessed in 68,324 participants by means of meta-analysis [48]. tive marker for poor outcome after surgical resection. A In 0.78% and 5% of the participants CRC and advanced ade- novel approach in identifying prognostic factors for CRC nomas were detected, respectively. Complications were rare, patients is detection of circulating tumor cells using col- being present as perforation and bleeding in 0.01% and orimetric membrane array. In 194 CRC patients the telom- 0.05% of the cases. Thus these results support the incorpora- erase reverse transcription, the cytokeratin-19, and -20, and tion of colonoscopies into screening and prevention strate- the CEA mRNA were measured in peripheral blood after gies. complete tumor resection [43]. Expression of all four mRNA markers was shown to be independently associated with 3.2. Patients and Their Tumors postoperative relapse thus being an auxiliary tool to conven- 3.2.1. Pathology and Targeted Therapy tional clinicopathological examinations such as depth of invasion, and presence of vascular and perineural invasion. The proliferation signaling pathways in lung cancer seems to be more complex compared to those of breast and 3.1.2. Radiology as Screening Method other organ cancers. There is evidence that alternating path- Computed tomography (CT) screening for lung cancer ways circumvent e.g. EGFR blockade. During the last years results in a diagnosis of stage I disease in more than 80% many antibodies directed against proteins of the signaling 8 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster pathways in cancer are available. Tumor tissue can be inves- given in 66% in this group of patients. Examinations evaluat- tigated similarly using microarray techniques and immuno- ing the molecular characteristics of EGFR and KRAS can histochemical staining in order to evaluate the individual predict whether tumors are sensitive or resistant to antago- expression and up-regulation pattern of signaling molecules nists and can therefore readily be incorporated in clinical in tumor tissue. These examinations are a prerequisite in the trials to further improve patient selection. appropriate patient selection procedure. However, failure to response to targeted therapeutics called for additional meth- 3.2.3. Appropriate Patient Selection and Tumor Stage ods aiming at detection of mutations of different genes such The revised version of the TNM Classification of Malig- as the EGFR exon 18 through 21 mutations. Using fluores- nant Tumors will be published in 2009. The International cence in situ hybridization (FISH) amplification of different Association for the Study of Lung Cancer recommended the genes can be defined. The armamentarium was increased by following changes to the T, N, and M descriptors: Tumors > genomic hybridization arrays and by antibody chip technol- 7 cm move from T2 to T3; pleural effusion is reclassified as ogy for analyzing proteomes that should be performed in M1; T2b N0 M0, T2a N1 M0, and T4 N0-1 M0 are sug- selected cases only [49]. gested to move from stage IB, IIB, and IIIB to IIA and IIIA, respectively [55]. Primary treatment of stage I and II NSCLC 3.2.2. Appropriate Patient Selection and Therapeutic Inter- is surgical resection, in case of resectable stage IIIA tumors ventions preoperative chemotherapy is an option. Unresectable IIIA Recently Li et al. presented data of a prospective study in and IIIB tumors have to be treated by a combination of che- 334 patients suffering from adenocarcinoma of the lung motherapy and radiotherapy. In case of pleural effusions evaluating the mutation patterns of EGFR [50]. Seventy- (stage IIIB) or of stage IV tumors chemotherapy is sug- eight (23%) of these tumors had EGFR mutations with 71% gested. Chemotherapy is the primary treatment of SCLC, exon 19 and 29% exon 21 mutations. The majority of the with radiotherapy in case of limited disease [56]. According patients with EGFR mutations never smoked (17 of 29; to the NSCLC treatment guidelines that have been updated in 59%). EGFR amplification was present in 52% of the EGFR- 2003 by the American Society of Clinical Oncology FDG- mutated tumors but only in 6% of the tumors without muta- PET scanning was incorporated into the staging procedures tion. The association of smoking history and amplification in case of locoregional diseases [57]. status was marginal [50]. In another series of 100 adenocarcinomas of the lung 16 and 14 tumors harbored EGFR and 4. MANAGEMENT OF PATIENTS WITH NSCLC KRAS mutations, respectively. A weak correlation with AND CRC: DRUGS, BEAMS, SURGERY heavy smoking and KRAS mutations was present. These 4.1. Non-Small Cell Lung Cancer (NSCLC) results indicate that tobacco smoke is not correlated with either EGFR or KRAS mutation but with larger tumor size, Improvements in 5-year survival rates that are reported to solid type and poor grade adenocarcinomas [5]. These results be 15% in the U.S. and 10% in Europe are dependent on were supported by another group of 195 adenocarcinoma early detection and improved systemic therapy applied to patients having been evaluated for KRAS mutations. No surgery and/or radiotherapy in early-stage diseases. Unfortu- statistically significant difference could be demonstrated nately, most patients with NSCLC have advanced, unre- with respect to smoking status [51]. In contrast KRAS muta- sectable tumors at diagnosis. Platinum-based doublets can tions were more frequently found in adenocarcinoms improve survival in stage II-IV NSCLC and possibly in stage (p<0.001), in ever-smokers (p=0.01), and in patients from IB diseases, too. However, these treatment regimens are the USA and Australia (p=0.0001) compared to patients toxic thus influencing QoL. New targeted drugs as EGFR from Japan and Taiwan in a series of 617 NSCLC patients and VEGF antagonists that are less toxic have improved the [52]. prognosis for specific patient groups [11]. Up to 40% of the patients treated with first-line platinum-based doublets are Somatic EGFR and KRAS mutations in adenocarcinomas subsequently candidates for second-line chemotherapy. Do- of the lung have both potential prognostic value in patients cetaxel and pemetrexed that is characterized by a more fa- with advanced disease and therapeutic significance. In 150 vorable toxicity profile compared with docetaxel have been tumors that were classified as bronchioloalveolar carcinoma approved by the U.S. FDA as second-line therapeutics. (BAC) and as adenocarcinomas with BAC components EGFR overexpression could be demonstrated in never- 4.1.1. Targeted Therapy smokers and was correlated with improved overall survival Recent advances in genomic analysis gave insights into (OS) and disease free interval [53]. Whether EGFR and the genetic and epigenetic changes present in cancer that KRAS mutations have an impact on survival in patients who seem to cluster around certain pathways. However, contrary undergo surgical resection without targeted therapy was in- to successful treatments in a subset of cancers the hope for vestigated by Marks et al. [54]. Tumors of 296 patients with therapies that are tailored on the genomic profiles of the pa- resections of stage I-III adenocarcinomas were assessed for tient seems to be still elusive. Only 10% of the new medici- both EGFR and KRAS mutations by established methods. nal products progressing to clinical testing are further avail- Fourteen and 17% of the patients showed EGFR and KRAS able as therapeutic agents [58]. Chemogenomics thereby mutations, respectively. Patients with EGFR mutations were studies the interaction of functional biological systems with in 48% never-smokers, presented with stage I disease in 88% exogenous small molecules and represents a descendent of and had a 90% 3-year overall survival [54]. In contrast to conventional pharmaceutical approaches using chemolibrar- other studies 92% of the patients with KRAS mutations were ies for evaluation of the effect on biological targets. Che- former or current smoker [5, 54]. 3-year overall survival was mogenomics is an interdisciplinary approach requiring the New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 9 expertise in biology, chemistry, and computational science tients could be confirmed by the TALENT trial, a phase III [59]. Current drug discovery is moving away from the one study adding erlotinib to gemcitabine and cisplatin [70]. target-one drug paradigm aiming at the identification of Similar results were obtained adding gefitinib to platinum- molecules that modulate multiple targets simultaneously based chemotherapies in unselected patients. The data of two [60]. In the light of capacities that are no longer sufficient to phase III trials, the Iressa NSCLC Trial Assessing Combina- tackle the testing of a huge amount of compounds against tion Chemotherapy (INTACT 1, INTACT 2) trials were pub- hundreds of targets in silico target profiling methods are pos- lished in 2004 [71, 72]. sibly the answer [61]. Recently study results indicated that there might be an The high molecular heterogeneity of NSCLCs is reflected antagonism between EGFR TKIs and conventional chemo- in low response rates to “conventional” chemotherapeutic therapy in case of wild- type EGFR. Basically EGFR TKIs agents. A main advantage of drugs that target specific recep- stop cell division by G1 cell cycle arrest which reduces the tors is their action mainly on malignant cells. Additionally to cell cycle activity of conventional chemotherapeutic agents EGFR and VEGF inhibitors a variety of novel targeted [73]. In contrast to these unfavorable results combination of therapies is being investigated, such as targets of the protein pemetrexed plus erlotinib is synergistic but only in erlotinib- kinase C (PKC)/RAS/mitogen-activated protein kinase naïve patients [74]. pathway and of the RAF kinase isoforms. Erlotinib and gefinitib are small molecule TKIs, cetuxi- PKC and MMP inhibitors have failed in phase III trials mab represents a chimeric anti EGFR IgG1 monoclonal anti- possibly due to poor patient selection. Some EGFR and body. Cetuximab was shown to be effective in a subgroup of VEGF inhibitors achieved U.S. FDA and EMEA approval as NSCLC patients. Since efficacy did not correlate with EGFR therapeutics for colorectal and lung cancer. Basically these expression level appropriate patient selection is more diffi- inhibitors are provided either as low molecular weight com- cult [12]. Cetuximab improved the efficacy of a cis- pounds or as monoclonal antibodies. The low molecular platin/vinorelbine regimen by increasing the response rates weight compounds (small molecules) concentrate two advan- from 28% to 35% [75]. In contrast progression free survival tages compared with monoclonal antibodies: They are able (PFS) increased only little in patients with advanced NSCLC to penetrate in all the interstices of the tumor and their pro- receiving either docetaxel/carboplatin or gemcitabine-based duction is far easier and less expensive [40]. doublets in combination with cetuximab [76, 77]. However, 4.1.1.1. EGFR Tyrosine Kinase Inhibitors there is some hope since results of the First-Line Treatment for Patients with EGFR-EXpressing Advanced NSCLC Two EGFR tyrosine kinase inhibitors (TKI) have been (FLEX) study combining cetuximab with vinorelbin/cisplatin approved by the U.S. FDA as second and third-line treatment met the primary endpoint of longer OS [78]. These favorable in patients with advanced or metastatic NSCLC. Erlotinib and disappointing results of trials evaluating cetuximab with use resulted in an objective response rate of 8%-12% regard- either vinorelbine or taxanes in different patient groups dem- less of tumor type and preceding chemotherapies [62, 63]. onstrate the importance of appropriate patient selection and The importance of appropriate patient selection has been treatment components. shown in case of gefitinib, an EGFR TKI that got U.S. FDA approval but is not available in the European Union based on For current clinical practice the clinical and molecular data showing a survival benefit only in patients with Asian markers of response to EGFR TKIs remain to be defined. On ethnicity who never smoked [64, 65]. There is evidence that the basis of the BR.21 study that evaluated a scoring system both EGFR TKIs would best be used for tumors with EGFR for patient selection erlotinib has the potential to provide a overexpression, or with EGFR mutations [11]. It has been modest survival benefit to unselected chemotherapy refrac- reported that on the one hand overexpression occurs in up to tory NSCLC patients but in a small subset of patients stabili- 80% of NSCLCs and that on the other hand somatic muta- zation of disease could be achieved in a larger fraction of tion of the EGFR gene is associated with significantly higher cases [79]. response rates [66]. However, in last issue of the “Lancet” Based on these results two questions are arising: What Kim et al. presented data on gefitinib in patients with high are the best endpoints evaluating the efficacy of new drugs? EGFR gene copy number. Superiority of gefitinib compared What is the most fitting indication (first-line versus second- to docetaxel was not proven with respect to overall survival line; stand-alone or in combination, adjuvant after radical [67]. FISH is used to select patients by detecting EGFR gene resection) [80]? Tsao et al. presented data on NSCLC speci- amplification whereas EGFR protein expression is measured mens of 731 patients. Three hundred twenty-five specimens by immunohistochemistry (IHC) [68]. were analyzed immunohistochemically, 197 and 221 samples Combinations of chemotherapies, especially those with were evaluated for EGFR mutations and number of EGFR different mechanisms of action hold promise for improve- gene copies, respectively. Erlotinib treatment resulted in ment in response rates and thus in survival. Careful pre- increased responsiveness in case of EGFR mutations but selection of patients is urgently needed as could be demon- survival was not affected by the status of EGFR expression, strated by at least two trials, The Tarceva Response in Con- the number of EGFR copies, or EGFR mutations [81]. junction with Paclitaxel and Carboplatin (TRIBUTE) and the Tarceva Lung Cancer Investigation Trial (TALENT) [69, HER2 is the preferred EGFR partner and preclinical data 70]. Patients enrolled in the TRIBUTE trial received pacli- have shown that tumors overexpressing HER2 are the most taxel and carboplatin in combination with erlotinib without sensitive ones to gefitinib. In 102 gefitinib treated patients survival benefit except in a subgroup of patients who never HER2 protein expression and HER2 exon 20 mutations smoked [69]. This negative survival effect in unselected pa- could be demonstrated in 7% and 0% of the patients, respec- 10 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster tively. Contrary to the data published by Tsao et al. results of and NSCLC. Two phase III trials have been completed another trial demonstrated that increased HER2 gene copy showing no benefit of adding marimastat to conventional number was associated with an objective response to gefit- chemotherapeutic regimens [87]. inib regarding disease control rate, OS, and time to progression (TTP) [82]. In 2003 Fukuoka et al. presented results of a 4.2. Colorectal Cancer phase II trial comparing two different dosages of gefitinib in 4.2.1. Targeted Therapy NSCLC patients [83]. Symptom improvement turned out to be the best endpoint. Thus gefitinib represents a new treat- As in NSCLC EGFR and VEGFR inhibitors are major ment option for pretreated NSCLC patients. Therefore it player in the treatment of CRC. seems to be feasible to use gefitinib as second- or third-line Cunningham et al. published a randomized study on 329 treatment in order to improve QoL. patients with chemotherapy-refractory mCRC evaluating the 4.1.1.2. VEGFR Tyrosine Kinase Inhibitors efficacy of cetuximab, an EGFR monoclonal antibody [88]. The patients received either cetuximab monotherapy (111 The process of angiogenesis falls in the class of highly patients) or cetuximab in combination with irinotecan (218 complex systems depending on multiple cell types and sig- patients). Combination chemotherapy resulted in higher RRs naling molecules. The more complex a system is the more (22.9% versus 10.8%), increased TTP (4.1 versus 1.5 vulnerable is it to various kinds of disruption. Consequently months), and in survival benefits (8.6 versus 6.9 months). the complexity of angiogenesis offers various targets for Cetuximab was well tolerated thus not deteriorating QoL. intervention. Cetuximab has been approved recently for the treatment of In 2002 Hirata et al. investigated whether the antitumor metastatic CRC (mCRC). effect of gefitinib is partly attributable to an antiangiogenetic Bevacizumab has demonstrated clinical activity against activity of this agent [84]. Vascular endothelial cells were mCRC, particularly in combination with other chemothera- co-cultured with EGF-stimulated cancer cells and incubated peutic agents. with gefitinib. Gefitinib inhibited EGF-induced migration and tube-like formation by microvascular endothelial cells Eight hundred twelve treatment-naïve patients with [84]. mCRC were randomly assigned either to receive irinotecan/fluorouracil/leucovorin alone or in combination with Sorafenib is an oral multikinase inhibitor targeted at the bevacizumab [89]. The addition of bevacizumab resulted in C-RAF and B-RAF pathways of kinase activity, at the increased PFS (10.6 versus 6.2 months), increased response VEGF-R2 and VEGF-R3, and at the platelet-derived growth rates (RR; 44.8% versus 34.8%), and longer median duration factor receptor family (PDGFR-beta). A phase II trial of of response (10.4 versus 7.1 months). sorafenib in the treatment of NSCLC has to be closed since the initial efficacy criteria were not met. On the other hand The FOCUS trial evaluated an important issue namely various trials are underway evaluating the efficacy of soraf- sequencing of therapeutic actions [90]. Two thousand one enib as single agents or in combination in the treatment of hundred thirty-five chemotherapy-naïve patients were ran- NSCLC. domly assigned to one of three treatment strategies, strategy The increased release of angiogenic growth factors by A, B, and C corresponding with control, single-agent tumor cells under EGF stimulation suggests that EGFR sig- fluorouracil, single-agent irinotecan, and combination che- naling has an indirect effect on angiogenesis. Therefore si- motherapy from onset. Two different chemotherapeutic multaneous blockade of these molecular targets may result in regimens were used, fluorouracil plus irinotecan and greater inhibition of tumor cell proliferation and survival. fluorouracil plus oxaliplatin. Single-agent treatment was One of the first studies evaluating bevacizumab and erlotinib stopped in case of failure. Based on the study results it could in combination for non-squamous stage IIIB/IV NSCLC was be concluded that in a non-curative setting the maximum conducted by Herbst et al. [85]. Partial response and stable tolerable treatment regimen has to be used first-line. The disease were reported in 20% and 65% of 40 patients, re- staged approach of initial single-agent treatment followed by spectively. The OS for the 34 patients who have been treated combination therapy (if necessary) was not worse and is at the phase II dose (150 mg/day erlotinib plus 15 mg/kg therefore an alternative treatment option that has to be dis- bevacizumab every three weeks) evaluating efficacy and cussed with the patients. tolerability was 12.6 months, with a PFS of 6.2 months. In comparison, single-agent erlotinib therapy resulted in an OS 4.3. Therapy and Procedure Sequencing and PFS of 4-6 and 2-4 months, respectively [85]. ZD6474, a 4.3.1. Non-Small Cell Lung Cancer (NSCLC) VEGFR TKI, was compared with gefitinib in NSCLC patients. One hundred sixty patients have been randomized to At diagnosis approximately 30% of the patients have either ZD6474 or gefitinib. ZD6474 produced a statistically stage IIIA and IIIB disease. significant improvement in time to progression (TTP) of Postoperative adjuvant chemotherapy after completely 11.9 weeks compared with 8.1 weeks in the gefitinib group resected lung cancer has been evaluated a few years ago [91, [86]. 92]. In 1,867 and 840 NSCLC patients with different disease 4.1.1.3. Matrix Metalloproteinase Inhibitors (MMI) stages a survival benefit in those receiving adjuvant chemotherapy could be demonstrated. However, the most effective Increased expression of matrix metalloproteinases is as- method in evaluating involvement of lymph nodes has to be sociated with poor prognosis in both small-cell lung cancer defined. N2 disease is often detected on staging chest CT, New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 11 but PET and combination of CT and PET as well as EBUS CRC and up to four liver metastases have been published with fine needle biopsy increased the detection rates of N2 [99]. Three-hundred sixty-four patients with histologically disease [55]. On the other hand the European Organization proven resectable CRC and up to four liver metastases have for Research and Treatment of Cancer (EORTC) conducted a been enrolled and randomly assigned to either six FOLFOX4 randomized trial evaluating the role of surgery versus radio- cycles (oxaliplatin/fluorouracil/leucovorin) before and after therapy after induction chemotherapy with a platinum-based surgery or to surgery alone. The tumor response in the liver regimen [93]. The gold standard for preoperative lymph node was assessed according to Response Evaluation Criteria in staging was mediastinoscopy that showed lymph node in- Solid Tumors (RECIST) after three and six cycles of chemo- volvement in more than 80%. After three cycles of chemotherapy using contrast CT scan [100]. A significant increase therapy the RR was 61%. Three-hundred thirty three out of in the PFS rate at three years could be demonstrated in pa- 582 patients underwent surgery resulting in 50% of complete tients receiving chemotherapy and undergoing resection. In resections (R0). Ninety-three percent of the 165 randomized 7% of the patients the liver metastases progressed during patients received radiotherapy. The median and 5-year sur- chemotherapy that should be regarded as a marker for poor vival rates did not differ between the two arms [93]. None- prognosis. Another concern was the development of liver theless surgery showed better local control than radiother- damage due to chemotherapy resulting in higher complica- apy, but increased extrathoracic recurrence rates. The high tion rates in case of surgery compared to surgery alone. As rate of pneumonectomies (47%) calls for appropriate patient indicated in NSCLC high volume of the procedure of liver selection and for high volume hospitals with respect to car- surgery as well as an experienced team is warranted. Re- diopulmonary function of the patients and expertise of the cently Grünberger et al. presented data on 50 patients with surgeon [94]. CRC and resectable liver metastases receiving six cycles of It remains a point of discussion whether modern tech- XELOX (oxaliplatin/capecitabine) or FOLFOX4 as neoadju- niques providing more precise targeting as tomotherapy, vant chemotherapy [101]. R0 resections were performed in cyberknife and protons will lead to better local control of the all patients, after an objective response rate to chemotherapy tumor by allowing higher radiation dosage combined with of 72% had been observed. The median recurrence-free sur- chemotherapy. vival depended on tumor response ranging from 3.0 to 24.7 Brain metastases are considered as late complication of months. Chemotherapy did not result in increased periopera- malignant diseases. More than 150,000 cases in the U.S. and tive morbidity [101]. In April 2008 preliminary data of a about 5,000 patients in Austria are reported per year. Che- phase II study of perioperative bevacizumab plus XELOX in motherapeutic treatment of metastatic brain tumors is not an equal group of patients have been presented at the “An- standardized since chemotherapeutic agents are thought to do nual Meeting of the Austrian Society of Haematology and not cross the blood-brain barrier (BBB) [95]. The expression Oncology” [102]. Fifty-two out of 56 patients were com- of P-glycoprotein (P-gp), a major component of the BBB pletely resected after a mean of six cycles of bevacizumab which eliminates toxins from the brain, is decreased in the plus XELOX. Again a significant difference in PFS could be neovasculature of metastatic tumors. However, it is hypothe- noticed depending on tumor response to adjuvant chemo- sized that metastatic brain tumors from primary neoplasms therapy. with low expression of P-gp (e.g. lung cancers) may be more Different aims were addressed by both the “CAIRO” and permeable to some kind of chemotherapeutic agents [95]. Furthermore, VEGF expression by the tumor cells facilitates the “QUASAR” study. The CAIRO study investigated their migration through the BBB, which might be a reason- whether combination chemotherapy with capecitabine, iri- able approach for therapy [96]. The primary purpose of the notecan, and oxaliplatin is superior to sequential therapy SMART study is to evaluate if NSCLC patients with brain using the same therapeutics [103]. Eight hundred twenty metastases retain their neurological function after having patients with advanced CRC were randomly assigned to re- been treated with Motexafin Gadolinium and whole brain ceive either capecitabine as first-line, irinotecan as second- radiation [97]. line, and the combination of capecitabine plus oxaliplatin as third-line treatment (sequential therapy in 410 participants) Criteria how to incorporate new treatment options as ra- or capecitabine plus irinotecan as first-line and capecitabine diofrequency ablation and targeted therapeutics in therapy plus oxaliplatin as second-line regimen (combination arm in concepts have to be defined. 410 patients). With the exception of grade 3 hand-foot syn- Molecular markers of prognosis and drug sensitivity and drome that was observed more frequently in the sequential resistance testing, an armamentarium that is commonly used treatment arm no differences with respect to toxicity and OS in infectious diseases, will represent valuable tools in manag- could be observed [103]. The QUASAR Colloborative ing lung cancer patients [98]. Group evaluated in a large group of 3,239 patients with ap- parently curative resection of colon and rectum cancers the 4.3.2. Colorectal Cancer (CRC) size and duration of any survival benefit from adjuvant che- In 40%-50% of the patients with CRC liver metastases motherapy consisting of fluorouracil and folinic acid [104]. are diagnosed. In case of surgical resection the 5 year sur- The absolute improvement in survival was only 3.6% in vival rates are approaching 35%, but relapse occurs in 75% these patients with stage II CRC. It has to be noticed that of the patients. Therefore a combination of surgery and che- QUASAR included a sub-study of stored tumor tissue in motherapy seems to be reasonable. In 2007 results of the order to identify reliable prognostic factors of sensitivity to EORTC Intergroup trial 40983 that evaluated the influence chemotherapy resulting in a more individualized therapeutic of pre- and postoperative chemotherapy in patients with approach. 12 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster

As novel treatments need new management the appropri- rion. This trial is expected to last from 2007 to 2011. An- ate method to classify response to therapy in case of bevaci- other phase II trial of erlotinib and bevacizumab in combina- zumab is still matter of discussion since these tumors de- tion is closed for enrollment, but ongoing. Aim of this study velop necrosis and do not shrink. As a biological marker for is to evaluate tolerability in patients unable to receive cyto- tumor cell survival PET is an option. toxic chemotherapy due to Performance Score (PS 2) [97]. Animal models have demonstrated increased tumor cure Additionally two papers published an incidence of 1.3% rates by co-administering bevacizumab and related agents to 1.6% of gastrointestinal ulcers with bleeding in patients with radiotherapy. Therefore a phase I trial has been initiated receiving bevacizumab [105, 106]. in January 2007 in order to establish both safety and toler- Without adjuvant chemotherapy the majority of the pa- ability of this combination as well as surrogate tumor end- tients with liver metastases would possibly not be resectable. points that might correlate with efficacy [97]. An equal goal Recently the Consensus Recommendations for the state-of- is intended to be achieved by a genetic sub-study associated the art treatment of CRC including metastatic disease have with the Avastin Study MO19390. This study represents an been released [107]. According to these guidelines all active approach to individualize treatment to a greater extend. A chemotherapeutic drugs should be used in strategic patient targeted sample size of 100-500 individuals will receive dif- management in order to turn unresectable tumors into re- ferent chemotherapeutic regimens depending on the BRCA1 sectable ones. Another approach aiming at decreasing tumor mRNA expression. The components of the conventional size is radiofrequency ablation (RFA) of secondary tumors. chemotherapy are cisplatin in combination with either vi- In 2003 Livraghi et al. published a study on 2,320 patients norelbine or docetaxel or vinorelbine with docetaxel. with 3,554 liver lesions, 1,610 of these were hepatocellular Bevacizumab that is co-administered will continue to be carcinoma, 501 participants showed metastases from CRC. used after completion of the chemotherapy cycles till tumor Death, major and minor complications occurred in 0.3%, progression. 2.2%, and 5% of the patients, respectively [108]. In contrast Subject of a National Cancer Institute trial is the question to these data Mulier et al. presented an extended survey of “What comes first in NSCLC patients -chemotherapy, radio- the literature concluding that the morbidity and mortality of therapy or surgery?” The rational of this trimodality protocol RFA is higher as presumed being 8.9% [109]. Efficacy of for the treatment of locally advanced but potentially re- this new technology has been evaluated several years later by sectable NSCLC is that chemotherapeutic agents interact Siperstein et al. [110]. 1997 through 2006 235 patients with colorectal metastases underwent 292 RFAs. The patients with the cell cycle in different ways, radiotherapy damages tumor cells using high-energy x-rays, thus the combination averaged 2.8 lesions with a median diameter of 3.9 cm. The of both modalities may result in shrinkage of the tumor that 3- and 5-year survival was 20.2% and 18.4% and was influ- can be removed by the following surgical procedure. Addi- enced by the size and number of the intrahepatic lesions tionally chemoradiotherapy may kill remaining tumor cells. [110]. Although this minimally invasive technique has been However, the primary outcome measure is not efficacy but described as safe, effective and cost-effective procedure little is published with respect to a possible combination of RFA maximum tolerated dose. Projected accrual of the study that started in 2002 is 57 patients within four years [97]. with other treatment options as surgery [111, 112]. 5.1.2. Novel Agents – Various Combinations 5. THE “PIPELINE” Besides the VEGF endothelial cells represent another 5.1. Non-Small Cell Lung Cancer (NSCLC) target in order to influence angiogenesis. Volociximab is a chimeric monoclonal antibody against the alpha5beta1 in- 5.1.1. New Drugs – New Combinations tegrin. This agent is being evaluated in combination with The TORCH study is evaluating the efficacy and toxicity bevacizumab, carboplatin and paclitaxel as first-line treat- of erlotinib as first-line chemotherapy followed at progres- ment in advanced NSCLC. Chemotherapy-naïve patients sion by cisplatin/gemcitabine or as second-line therapy after with stage IIIB/IV disease are enrolled since December treatment failure of cisplatin/gemcitabine. The study started 2007. The primary endpoint is maximum tolerated dose of in December 2006, completion is expected in 2010 with an volociximab in a dose escalating trial. Second outcome estimated enrollment of 900 participants [97]. Erlotinib is measures are pharmacokinetics and efficacy of the study being evaluated additionally in two current studies. The first drug. one is aimed at RR, OS, and at the toxicity profile of er- Before 1990 lung cancer immunotherapy focused on e.g. lotinib or cisplatin/irinotecan as induction chemotherapy Bacille Calmette Guerin (BCG) as nonspecific immune followed by concurrent thoracic radiotherapy. Preclinical and stimulant. The identification of TAAs led to the development clinical data demonstrating cisplatin and irinotecan as radia- of vaccines priming potent antigen-specific immune re- tion sensitizer are the background of the study design. The sponses. Lung cancers have fewer tumor-infiltrating lym- trial started in February 2008 and completion data is esti- phocytes than e.g. melanomas thus being less immunogenic mated to be March 2011. This study is characterized by di- [113]. However, antigens that are targeted by tumor- viding the patient population into groups with or without infiltrating lymphocytes have shown to result in tumor- EGFR mutation [97]. A phase II trial is intended to provide specific cytolytic T cell responses. The immunological proc- preliminary data with respect to the combination of erlotinib ess starts with ingestion of parts of tumor cells by antigen- plus bevacizumab as first-line treatment compared with con- presenting cells as macrophages and dentritic cells and re- ventional chemotherapy in stage IIIB/IV or recurrent sults in increased phagocytic activity of macrophages and NSCLC. Squamous cell carcinomas are an exclusion crite- enhanced antigen-specific immunity via stimulation of CD4+ New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 13

T cells. Recently Barve and co-workers presented data of a 5.2. Colorectal Cancer single-vial peptide vaccine consisting of nine HLA-A2 su- It is well documented that the use of combination chemo- pertype-binding epitopes in 63 stage IIIB/IV NSCLC pa- therapy has the power to render a significant proportion of tients demonstrating good tolerability and suggested efficacy primary unresectable tumors as liver metastases in CRCs to [114]. Immune responses to epitope peptides were associated with significantly longer survival (p<0.001). resectable diseases. However, the selection criteria for patients who are potentially appropriate for resection are not In vitro manipulated dendritic cells represent another well documented and patient management by multidiscipli- promising vaccine formulation. Mucosal T-cell immunity nary teams is still evolving. Therefore the European Colorec- could be enhanced by mucosal delivery of vaccine dendritic tal Metastases Treatment Group released pan-European cells whereas these effects could not be observed in case of guidelines for patients suffering from mCRC [119]. i.m. administration [115]. The mechanism of action of a 5.2.1. Old Agents – New Regimens heat-killed preparation of Mycobacterium vaccae is postu- lated to be, at least in part, due to immune regulation by en- Intravenous bolus fluorouracil plus leucovorin is the hancement of Th1 and down regulation of Th2 cell activity. standard adjuvant chemotherapeutic regimen for CRC. Results of a phase III trial in NSCLC patients evaluating the Capecitabine, an oral fluoropyrimidine which has been efficacy of Mycobacterium vaccae in combination with che- evaluated in various trials in the adjuvant setting represents motherapy were disappointing with respect to survival [116, an alternative therapeutic. One thousand-four and 983 pa- 117]. tients received capecitabine or bolus fluorouracil plus leucovorin. Capecitabine improved relapse-free survival (p=0.04) The dream of a tumor vaccine is being followed by addi- and was associated with fewer side effects (p=0.001) as has tional trials. In a phase I trial Denileukin Diftitox is used been proven in previous trials [120, 121]. In 2004 the Multi- sequentially with vaccine therapy. Patients with CEA ex- center International Study of Oxaliplatin/5-Fluorouracil/Leu- pressing solid tumors receive Denileukin Diftitox followed covorin in the Adjuvant Treatment of Colon Cancer (MO- by active immunotherapy with autologous dendritic cells SAIC) has been published. Two thousand forty-six patients infected with a virus (the CEA-6D expressing Fowlpox- were randomly assigned to receive either fluorouracil/leu- Tricom). Secondary outcome measures are the immune re- covorin (FL) or oxaliplatin after surgical resection for stage sponses as evaluated by ELISPOT. Different tumors such as II and III colon cancer. Adding oxaliplatin to FL decreased breast, colorectal and lung cancer represent conditions fitting cancer associated events and increased the disease-free sur- for that study [97]. vival at 3 years significantly [122]. EMD 273066 targets the cell membrane glycoprotein 5.2.2. New Agents – New Regimens EpCAM that is expressed on epithelial tumors. EMD 273066 has shown the ability to deliver immune cytokines as IL-2 on Recently Saltz et al. presented data on oxaliplatin in tumor cells in preclinical trials [97]. Resistance to re- combination with bevacizumab as first-line treatment in challenge with the same tumor cells could be demonstrated mCRC [123]. A total of 1,401 patients were randomly as- four months later. This immunological memory response signed in a 2x2 factorial design to either XELOX or FOL- may target both dormant and metastatic tumor cells. A simi- FOX4 followed by bevacizumab or placebo. The addition of lar mechanism is addressed using tucotuzumab celmoleukin, bevacizumab resulted in a significant increase of PFS from a recombinant fusion protein comprised of a monoclonal 8.0 to 9.4 months. Neither OS nor RR differed significantly antibody directed against the adhesion molecule EpCAM between the two groups showing that new treatment strate- linked to IL-2. A phase I study in patients with different gies possibly warrant new end-points [123]. Multimodality solid tumors as kidney, bladder, and lung neoplasms has treatment with capecitabine, bevacizumab and radiotherapy been completed [97]. is under evaluation in locally advanced rectum carcinoma [97]. Completion of the study is expected in 2010. Addition- MTOR stands for a master regulator of cell physiology ally, bevacizumab is being investigated in potentially curable and therefore an attractive target for anti-cancer therapy. The mCRC in a phase I, phase II study sponsored by the Austrian first mTOR inhibitor, rapamycin, was isolated in the 1960s. Society of Surgical Oncology. Preliminary data have been A phase II study has been completed evaluating the presented by Gruenberger [124]. Completion date was mTOR inhibitor RAD001 (everolimus) as monotherapy in March 2008. patients with advanced NSCLC [97]. Thirty-two patients Cetuximab has been evaluated and is still used in various have been enrolled in another phase II trial evaluating ever- combinations and dosing regimens in patients suffering from olimus in combination with gefitinib in stage IIIB/IV mCRC. Tabernero et al. presented pharmacokinetic data of NSCLC patients [118]. cetuximab administered every two weeks instead of the ap- Targeted therapy means to direct the drug to the site of proved weekly dosing regimen [125]. Results on pharma- “action”. In this context targeted therapy implies carrying cokinetic profile and efficacy of cetuximab were similar in established drugs as paclitaxel to the tumor cells which has the every- and in the every-two week dosing regimen thus been realized by the paclitaxel albumin-stabilized nanoparti- synchronization of cetuximab with conventional chemother- cle formulation. ABI-007 that is currently under investiga- apy as irinotecan and oxaliplatin will be possible [125]. The same working group published results of a trial evaluating tion is such a formulation [97]. Another example for new cetuximab in combination with FOLFOX4 in 43 patients formulations is the liposomal lurtotecan that is used as study with mCRC showing that this combination represents a drug in an ongoing phase I trial [97]. highly active first-line therapy [126]. A phase IV trial inves- 14 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster tigating the efficacy of cetuximab in combination with et al. presented data with respect to improved efficacy of bevacizumab is currently recruiting patients. Possibly based gefitinib therapy in case of increased IGFR-1 expression on data for sunitinib treated patients exclusion criterion is [130]. In line with these studies is another one evaluating heart disease which might represent an important restriction CP-751,871, a fully human IgG2 monoclonal antibody tar- with respect to the ageing population [97, 127]. geted against IGFR-1 [131]. Efficacy and safety of CP- 751,871 have been evaluated in combination with P/C. Tu- In January 2008 a phase III trial has been initiated evalu- mor IGFR-1 expression was most pronounced in squamous ating panitumumab, an IgG2 fully human monoclonal anti- cell carcinomas in concert with a 72% RR to the triple che- body targeted against EGFR, in combination with ox- motherapeutic regimen [131]. aliplatin/fluorouracil in patients with high-risk CRC that can be removed by surgery. Completion of data collection is ex- In order to identify protein/peptide expression patterns pected in 2012 [97]. Meanwhile panitumumab received FDA pretreatment serum has been investigated using a special approval in the treatment of EGFR expressing mCRC. type of proteomic analysis (VeriStrat). VeriStrat results showed a correlation between specific protein/peptide ex- In accordance to NSCLC the efficacy of mTOR inhibi- pression patterns and survival of NSCLC patients treated tors namely of RAD001 is being evaluated in combination with erlotinib and bevacizumab [132]. Zalcman et al. pre- with irinotecan and cetuximab as second-line chemotherapy for CRC. A phase I/II study is underway and is expected to sented data on various molecular markers as Ras effector RASSF1A promoter gene methylation and chromosome 9p be completed in June 2009 [97]. SU5416 (semaxanib), a loss of heterozygosity (LOH) in order to predict beneficial VEGF-R2 inhibitor, has been evaluated as treatment option effects of pre-, and perioperative chemotherapy [133]. in CRC. None of these trials is ongoing due to severe vascu- RASSF1A promoter gene methylation and 9p LOH were lar toxicities [97]. SU6668, a platelet-derived growth factor associated with a worse PFS independently of tumor stage receptor inhibitor, was used in patients with different solid tumors. Again these studies are not recruiting patients. and histology [133]. Subject of discussion is adjuvant chemotherapy in pa- Resveratrol that is produced by several plants is a mem- tients with complete resection of NSCLC. The International ber of a novel drug class. Its main mechanisms of action are Adjuvant Cancer Trial Biologic Program (IALT) evaluated expression and activity of cyclooxygenase enzymes and in- the multidrug resistant proteins (MRP1 and MRP2) in 782 duction of FAS/FAS ligand mediated apoptosis. A phase I trial started in December 2006 and is currently recruiting patients. MRP2 positive patients (n=313) had a significant shorter survival than MRP2 negative patients. In case of patients [97]. MRP1 no statistically significant difference was present. But, 6. MANIFOLD CONSEQUENCES neither MRP1 nor MRP2 expression predicted response to adjuvant cisplatin-based chemotherapy [134]. Despite the increasing diagnostic and therapeutic armamentarium for lung cancer the survival rates are unchanged. 6.2. Imaging Studies A retrospective study enrolling 1,156 patients over a four- Preoperative imaging tests are crucial in defining which teen- year period demonstrated no decline in death rates de- patients are candidates for surgery. Three hundred thirty- spite new therapeutic modalities [128]. seven patients were randomly assigned to conventional imaging (CI) or PET/CT. Fourteen percent versus 7% of the 6.1. Evaluation of Tumor Tissue PET/CT and CI patients were correctly upstaged thus avoid- The availability of many antibodies directed against pro- ing unnecessary surgery. Importantly this study showed that teins of the signaling pathways warrants investigation of PET/CT could replace CI in staging early-stage NSCLC tumor tissue by microarray techniques and immunohisto- [135]. Various trials using PET in order to predict treatment response to novel targeted therapeutics have been presented chemical staining in order to evaluate the individual expres- 18 sion and up-regulation pattern of signaling molecules. Fail- at the ASCO Meeting this year. F-FDG PET was used in ure to response to targeted therapeutics called for additional patients with chemotherapy in advanced NSCLC. Early PET methods aiming at detection of mutations of different genes restaging after one cycle may predict subsequent objective such as the EGFR exon 18 through 21 mutations. Using response to chemotherapy after two cycles of chemotherapy FISH amplification of different genes can be defined. The [136]. Additionally PET might represent a valuable tool for armamentarium was amplified by genomic hybridization pharmacodynamic evaluation of mTOR inhibitors like arrays and by antibody chip technology for analyzing pro- RAD001 [137]. In contrast, FDG-PET could not predict tu- teomes that should be performed in selected cases only [49]. mor response to rapamycin, another mTOR inhibitor, possibly due to inhibition of TORC2 complex and consequently Recently baseline VEGF plasma levels have been evalu- of Akt and glycolysis [138]. A new approach has been pre- ated using ELISA in NSCLC patients receiving vandetanib sented at the ASCO Meeting 2008 with respect to tailored and gefitinib monotherapy or paclitaxel/carboplatin (P/C) in PET. A specific EGFR TKI, 11C-PD153035 has been devel- combination. Patients with low VEGF plasma levels showed oped for PET imaging demonstrating a promising method for lower risk for progression when treated with vandetanib ver- in vivo imaging of EGFR in NSCLC [139]. sus gefitinib or P/C. In contrast patients with high VEGF plasma levels at baseline demonstrated similar treatment 6.3. Phase I Trials – Are Adapted Criteria for Enroll- benefits in both groups [129]. Besides EGFR and VEGF ment Necessary? expression the insulin-like growth factor receptor expression Probably, yes. Two hundred patients participating in a is hypothesized to play a role in EGFR TKI resistance. Fidler phase I trial were screened for 13 parameters demonstrating New Agents – Manifold Consequences Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 15 that a risk score based on LDH and the number of metastatic Use of bevacizumab as single agent maintenance therapy sites is a helpful tool in selecting patients for phase I trials for advanced NSCLC raised an important debate discussing [140]. Again at the ASCO Meeting 2008 common inclusion the role of maintenance therapy. Randomized trials were criteria for phase I trials were reevaluated. The authors estab- initiated in order to evaluate optimal schedules and response lished a score which was based on the 90 days mortality rates rates of paclitaxel, docetaxel, gemcitabine, and pemetrexed in 97 patients who died within 90 days and 215 patients demonstrating that maintenance therapy may benefit patients comprising the control group. The higher the score (range 1 with NSCLC by improving both the therapeutic potential of to 3) the higher the mortality rate. In patients with a risk available agents and the toxicity profile by limiting conven- score of 2/3 the use of additional biological markers as age, tional combination chemotherapies to four cycles [146]. white blood cell count and PS is suggested [141]. Concerted attempts to convert insights about molecular mechanisms in oncogenesis into attractive ways of curing the 7. PREVENTION – A DREAM? disease have just begun. A major lesson learned is that Life style modification as normal body weight, absti- kinases are druggable targets for anti-cancer therapy. About nence from tobacco and alcohol abuse as well as physical 90 encoded tyrosine kinases are major players in various activity will result in decreased risk for common cancers. human cancers, a number that stands for pleasure for cancer However, there is evidence that in case of adenocarcinoms of researchers and that creates a nightmare for chemists. The the lung women and some ethnic groups showed different integration of genomics in drug discovery and development risk patterns with respect to the development of lung cancer will result in higher success rates at all stages thus shortening even in never smoker. Renehan et al. published recently a timelines. However, therapeutic successes with targeted meta-analysis in the “Lancet” concluding that increased body drugs are in the majority of the cases short-lived and relapses mass index is associated with an increased risk for common occur in most patients depending on time. Multi-drug regi- and less common cancers [142]. Besides screening of high mens with synergistic effects that include alternative agents risk persons as heavy smokers and patients suffering from targeting drug-resistant receptors are urgently needed. adenomatous polyposis few studies are aimed at investigat- There is evidence that in the great majority of human ing agents as prophylactic treatment. In lung and colorectal cancers the two signaling pathways that are controlled by the cancer phase II trials are underway with celecoxib. Further- tumor suppressor genes Rb and p53 are deregulated. Investi- more patients with intrapulmonary nodules were candidates gations suggest that some tumor suppressor genes are miss- for a phase II trial evaluating budesonide [97]. ing from the expressed genes within cancer cells leading to a novel treatment concept: Replacement of the missing tumor 8. FUTURE PERSPECTIVES AND CONCLUSION suppressor gene might turn cancer cells partially or totally The nature of cancer suggests that it is a disease of chaos. into normal cell phenotypes. Such “gene therapies” would largely solve the problem of cancer but they are extremely Three decades ago there was virtually no knowledge about the molecular mechanisms leading to the appearance difficult to realize. Viral vectors being the core of these procedures are ineffective in delivering intact copies of the of malignancies. One hallmark of carcinogenesis is loss of genes to the cancer cells within the tumor mass. As a result control over vital processes that are synchronized by growth the transition of our knowledge about tumor suppressor factors as EGF, VEGF, and IGF. At the core of signal trans- genes into therapeutic practice is still beyond our reach. duction are transcription factors as e.g the activator protein 1 (AP-1) that represents one downstream target for cancer The vast amounts of information about tumor develop- therapy [143]. However, little progress has been made to ment could be integrated into complex interacting systems incorporate these insights into prevention and treatment whose behavior might be predicted by bioinformatics. Con- strategies. The lack of effective screening tools and the mo- sequently many steps of drug development were replaced by lecular heterogeneity of the tumors impede research efforts mathematical models thus saving time and costs. aiming at improving outcomes of the patients. Present chemotherapy regimens reached an efficacy plateau thus leading ABBREVIATIONS to the development of targeted therapeutics which entered AFB = autofluorescence bronchoscopy. the therapeutic arena during the last years. Today management of cancer patients is increasingly focused on both indi- AP-1 = activator protein 1. vidualization of therapy and QoL. The choice of which che- BAC = bronchioloalveolar cancer. motherapy to use is often made after having considered factors as schedule, toxicity profile, and costs. On the one hand BBB = blood-brain barrier. individualized therapy has to be tailored according to the BRCA1 = breast-cancer susceptibility gene-1. molecular profile of the tumor as overexpression of the excision repair cross complementing 1 (ERCC1) gene and Src CEA = carcinoembryonic antigen. kinase activity that have been associated with resistance to CCL2 = C-C motif of ligand 2. conventional chemotherapeutic agents and according to expression and mutation patterns of growth factors as EGF and CEACAM1 = carcinoembryonic antigen-related cell VEGF [50, 64, 144, 145]. On the other hand individualiza- adhesion molecule 1. tion of treatment is going to be realized by synchronization CI = conventional imaging. of different treatment regimens and administration in an out- CpGs = cytosines that precede guanines. patient setting [125]. 16 Current Cancer Therapy Reviews, 2009, Vol. 5, No. 1 Christine Armbruster

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Received: July 21, 2008 Revised: November 14, 2008 Accepted: December 03, 2008