Lung Cancer: Symptoms, Treatment and Literature

Lung Cancer: Symptoms, Treatment and Literature Introduction According to Cancer research UK lung cancer is a rapid and uncontrol proliferation of cells that may start in trachea, bronchioles or pulmonary tissue (Cancerresearchuk.org, 2017). It is broadly classified into Non-Small Cellular lung cancer (NSCLC) type and small cellular lung cancer (SCLC). Additionally, NSCLC is further subdivided into the squamous cell, adenocarcinoma, large cell carcinoma and undifferentiated NSCLC (Travis et al., 2015). Clinically both types are presented with similar symptoms (prolong cough, thoracically lymph node enlargement), and typical X-ray image (shadows with define outline). However, a specialized distinction can be done with the help of biopsy and genotypic analysis (Hoffman, Mauer and Vokes, 2000). Current literature analysis will focus on epidemiological features, clinical features, and available treatment options, as well as highlight gaps in the lung cancer understanding. According to Cancer Research UKs statistical data, lung cancer accounts for 13% of all causes in the UK. In addition, 22% of all cancer death is attributed to lung cancer, with 23% of all male cancers and 21% female. Additional examination shows that SCLC accounts for 12% of all lung cancers and NSCLC for 87%, with adenocarcinoma as a most common type (Cancer Research UK, 2017). Major cause of lung cancer is the tobacco consumption. The US statistics supports this notion, indicating that 90% of all lung cancer death in men and 80% of cases in women are caused by tobacco consumption (Szklo, 2001). Apart from environmental factors, there are individual genetic and epigenetic traits, which will alter lung cancer susceptibility. For example, according to meta-analysis data, having causes of lung cancer in family attributes to 1.7 fold increase in cancer development, with an additional increase if two or more relatives were affected (Lissowska et al., 2010). Studies identified DNA methylation markers, in cell cycle regulatory and repair genes. Specifically, significant changes in methylation patterns occurred in   BNC1, MSX1, CCNA1,p16, LOX genes in comparison to non-malignant cells (Licchesi et al., 2008). There are multiple classifications which allow identifying a lung cancer stage. However, the current essay will focus on two mainstream classifications by American Joint Community of Cancer (AJCC) (Goldstraw and Crowley, 2006) and Veterans Administration Lung Study Group (VALSG) (Zelen, 1973) which are based on clinical and pathological examination. SCLC According to International Association of Lung cancer, the TNM classification is recommended for classification of patients with SCLC. Current 7h edition of the AJCC manual identifies three major criterias: T (TX-T4) local cancer spread; N (NX-N3) metastatic involvement of lymph nodes; M (M0-M1)- presence or absence of metastasis (classification check online). With grouping, SCLC causes into four stages (Table 1)( (Egner, 2010). However, TNM classification is not widely used in clinical practice, in comparison to VALSG classification (Zelen, 1973. Which divides SCLC into limited stage (encapsulated) and extensive stage ( local spread of tumor).   Adaptation of the TNF was supported by a study involved 8000 patients worldwide, which pointed out limitations of VALSG. (Shepherd et al., 2007). Allowing to conclude that stratification of patients based on tumor encapsulation only does not accurately represent the patients prognostic outcomes. Overall, SCLC has a poor prognosis with su rvival rates up to 4 months without treatment (Foster et al., 2009). A major prognostic factor per TNM is the local disease spread, with metastasis as a critical factor for stage rectification. Thus, median survival for treated patients with Stage I-III disease progression is around 15-20 month with around 20% chance for 2 years survival. On the other hand, Stage IV of the disease is attributed to 8-13-month survival and only 5% survival up to 2 years (Lally et al., 2007). NSCLC Staging of NSCLC is fully regulated by the AJCC classification and divided into four stages. It has similar principles of TNM division mentioned above, with some prognostic adaptations (Egner, 2010). Specifically, variations within tumor size (T), are associated with decreased survival rates, for instance, primary tumor with diameter 2cm (53%), 3 cm (47%), 5cm (43%), more than 7cm (26%) (Rami-Porta et al., 2007). Lymphatic nodule involvement is a debatable topic due to a large degree of variability in classifications, but TNM staging attributes to worsening of the disease outcome (Rusch et al., 2009). Lastly, metastatic involvement is considered as the Stage 4 of the disease with average 8-month survival rate (Postmus et al., 2007). However, in addition to AJCC classification, it is important to take into account patient related factors such as gender, comorbidity, and age; environmental factors like nutrition and quality of treatment (Gospodarowicz and OSullivan, 2003). Last stateme nts are not strictly limited to NSCLC as similar variables may cause changes in SCLC patients. Treatment for SCLC Standard of care for the extensive stage of the disease during the SCLC will be chemotherapy treatment. Usually, first line treatment will include six cycles of etoposide with cisplatin or carboplatin. Meta-analysis data on this topic is controversial, with no specific recommendations given by the authors about any of the benefits of the treatment (Galetta et al., 2000; Mascaux et al., 2000). A possible explanation was based on the toxicity of cisplatin or inconsistency in patient number in the control arm of the trials (Amarasena et al., 2015). In addition, second set of meta-analysis data, six drug trials with 1476 patients in total, identified irinotecan and platinum as a viable combination for treatment of Stage IV of the SCLC (Jiang et al., 2010). Indicating the lesser amount of off-target effects ( less anemia, thrombocytopenia), and increase in overall survival rates. Thus, patients who are falling into the first line treatment regimen should result in overall response rate mo re than 20 %, and maintain therapy-related mortality as low as 5%. Knowing the limits of chemotherapy, the second line of drugs for SCLC is in development. Possible target therapies include: inhibitors of cell proliferative signaling pathways ( c-Kit, Src, EGFR, m-TOR etc.); angiogenesis ( VEGFR, VEGF); promoters of apoptosis ( Bcl-2, HDAC); immunotherapy and vaccines (CD56, p53); multidrug resistance (P-glycoprotein, MDR-1). It is important to indicate that most of the second line treatments are at the stage of development and majority of them does not show significant results.   For instance, Imatinib did not show any significant response from patients in phase II trial as single drug moderate dose (600 mg daily) or high dose (400mgx2 day) therapy (Johnson et al., 2003) Similar apoptosis regulators with specific Bcl-2 regulates, like Oblimersen, did not show significant results in a clinical trial against a placebo group, despite promising data in the pre-clinical validation (Rudin et al., 2008). Better outcomes can be seen in angiogenesis studies with bevacizumab, monoclonal antibody for VEGF-A receptor, maintenance therapy, phase II clinical trials, with combination with chemotherapy, showed 80% response rate, with 58 % chance of two years progressive free survival (Patton et al., 2006). Treatment for the NSCLC Despite the mainstream therapy with platinum compounds as first line drugs, and signaling pathway, immunotherapy drugs as a second line therapy. Additional surgical intervention can be applied on initial stages of cancer. The main surgical procedure which is implemented in cancer treatment is the lung resection under the video-assisted thoracoscopic access (VATS lung resection). However, results are controversial with the improvement of 5 years survival outcome in 21 studies on one hand, and 1.6-time increase in post-surgical complications in 13 000 patients in the US (Gopaldas et al., 2010). Nonetheless, chemotherapy is the standard of care for stages III and IV. Multiple landmark trials have shaped the treatment plan for the first choice. Starting with the JMDB trial which included administration of pemetrexed with cisplatin or gemcitabine with cisplatin, with overall response rate(ORR) of 30.6% and 28.2% in order (Scagliotti et al., 2009). In addition, both combinations have similar 10.3-month survival rate. Second, ECOG 4599, for nonsquamous carcinomas with the administration of carboplatin/paclitaxel with bevacizumab and carboplatin/paclitaxel alone (Sandler et al., 2006). Study indicate ORR of 15% and 35 % for double combination vs single, with 12.3 months and 10.3-month survival, in the same order. Lastly, the study of IPASS compared carboplatin/paclitaxel against gefitinib with ORR 32% vs 43% in order (Mok et al., 2009). With progression-free survival index of 5.8 and 5.7 months for combination and single therapy. The addition of drugs altering signalling pathways was a promising approach. However, like SCLC trial, most of the NSCLC were not significant. With the exception of angiogenesis inhibition by bevacizumab, listed for first line therapy above, a monoclonal antibody for vascular endothelial growth factor (VEGF). Evidence of a large randomized trial supports the significant improvement in ORR (Wheatley-Price and Shepherd, 2008) Second line therapy for the NSCLC includes docetaxel, pemetrexed (nonsquamous cancers), and tyrosine kinase pathway inhibitors erlotinib and gefitinib. In detail, the trial of JMEL examines pemetrexsed and docetaxel, with 9.1% and 8.8% ORR in order, and median survival of both drugs of 8.1 months (Scagliotti et al., 2009). Next drug trial, INTEREST, compared gefitinib and docetaxel , with ORR of 9.1% and 7.6% respectively, and median survival 8.3 and 7.9 month for each drug, same order (Kim et al., 2008). Lastly, clinical trial of BR.21 compared Erlotinib with the placebo group, with ORR of 9% and 6.7-month survival for the TKI (Shepherd et al., 2005). The addition of TKI was verified with a large cohort of patients in the randomized trial, with the exceptional activity of the gefitinib in EGFR mutations (Douillard et al., 2010). Overall NSCLC treatment options are oriented on chemotherapeutic approach with platinum compounds with the addition of EGFR specific TKIs. Gaps in general lung cancer There several potential areas of improvement in current treatment and patient management strategies. Critical gaps in the lung cancer can be seen in delayed patient referrals, administration of first line treatment, undertreatment of old age patients, under-utilisation of palliative care, lack of psychosocial support for patients. The current essay will address first two topics in greater details. One of the major gaps in the lung cancer field is the delay in the patients referral to the specialized help. (Yurdakul et al., 2015) According to UK guidelines people with possible symptoms of lung cancer should be referred to the specialists not later than 2 weeks after first GP visit (Nice.org.uk, 2017). Unfortunately, that is not always the cause and some patients will not see the specialist at all during the disease progression. For instance, it is estimated that 11% of lung patients in Australia will not be able to reach specialized care due to the socioeconomic background or old age (Vinod et al., 2010). Additional studies identified more factors contributing to patients late referral, like 23% of UK lung cancer patients will be diagnosed only in the emergency department even though they have had multiple visits to GP and presented typical pulmonary symptoms (Barrett and Hamilton, 2008). Next area of improvement is the underutilization of potential curative (surgical,chemotherapy) treatments in lung cancer (Blinman et al., 2010). For instance, Netherland study group identified that more patients receive surgical treatment in the active teaching and high-class hospitals than distant (Wouters et al., 2010). On the other hand, Australian group has identified no difference in curative surgical operations between rural and central areas (Jiwa et al., 2010). Raising the question of countries treatment protocols and the need for standardization on the multi-national scale. In continuation, international guidelines for successful chemotherapy utilization are 73% for NSCLC and 93% for SCLC where each patient received at least one course of treatment (Jacob et al., 2010). However, combined data (NSCLC+SCLC) from the UK has dramatic differences , such as 21% for South East England and 20% for South East Scotland, so as the USA with 45% and Australia 30% (Jacob et al., 2010). Differences in numbers are attributed to variation in clinical judgments by a doctor, patient preferences and hospital preferences (Blinman et al., 2010). Thus, it is possible to assume that some patients do not receive any treatment. Statistical studies support this statement indicating that 19% of USA, 33% of Australian, 37% Scotland and 50% of Ireland patients does not get any treatment for lung cancer, even though some cases had a potential curative outcome. Lastly, from the perspective of novel medicinal treatment for pulmonary, it is vital to indicate difficulties associated with potential laboratory and clinical results. The general trend is observed with an adaptation of drugs from CML, breast cancer and colorectal cancers to the needs of lung cancer. However, most of the clinical trial are terminated due to the high toxicity of the drugs (Rudin et al., 2008) or absence of ORR (Johnson et al., 2003). Thus, based on available treatment options further development of monoclonal antibodies or glycoengineering of human-like antibodies seems a promising direction (Patton et al., 2006). In addition, implementation of EGFR related TKIs, erlotinib and gefitinib, seems a good research avenue, with a focus on mutational aspects in EGFR signaling pathway (Douillard et al., 2010; Shepherd et al., 2005). Case Analysis: Freedom of Speech Law Case Analysis: Freedom of Speech Law Case Analysis Research Project: Discuss in detail the basis of any challenges to Section. B and evaluate the Big Bad Bruces fans chances for success. Introduction Freedom of speech, association, political freedom and freedom of public places is common in most states and as such, many cases regarding these freedoms is common. According to the first amendment in the US Bill of Rights, the people have the right to assemble and to free speech. The Supreme Court has therefore provided a list of public places and spaces that expressive activities of right to speech and right to assembly can take place(Henry, 2009). Enthusiastic fans of Big Bad Bruce are planning a gathering at the Baltimore airport to welcome the rock star home and to show support for his candidacy. The Department of transportation in Maryland state owns and controls the Baltimore airportdenies this group of fans permission to gather citing Section B ofairports regulations that make it unlawful for any gathering that exceeds 30 people at any given time at the airport unless for travelling purposes.This paper discusses in details the basis of all challenges to Section B citing laws r egarding public gatherings in airports in Baltimore, Maryland and the United States. This paper also explores the success chances of Big Bad Bruces fans regarding their permission to hold their welcome-home gathering for the rock star. This paper begins with a case brief that gives a condensed and concise summary of the airport opinion and the legal rule of law that applies to the case. The paper then provides the case background including discussions of previously decided related cases using the actual court opinions of other legal cases and laws. The next section analyses the current and future implications of the case this section will discuss how the case is likely to affect current and future events and business laws using court opinions of other legal cases and publications. Also included in this case analysis research project is my personal opinion of the case. This will be based on legal rationale, principles, resources and other cases. The final section of this research paper will be the summary/conclusion of this case based on legal principles and facts. This paper examines how the Section B can be challenged based on the Federal laws and if the rock star’s fans have chances for success in the laws uit. Case brief This case analysis research paper is about Big Bad Bruce and his fans. The rock star is returning home to announce his running for a political office and 200 enthusiastic fans of Big Bad Bruce are planning a gathering at the Baltimore airport to welcome the rock star home and to show support for his candidacy. The enthusiastic fans of Big Bad Brucewere denied permission to gather at the Baltimore airport to welcome the rock star home and express their support for his candidacy. The gathering would involve 200 fans as well as a speech on political views by Bid Bad Bruce to the fans that will take 15 minutes. The Baltimore airport denied them permission for the gathering citing Section B of the airport regulations that technicallymake it unlawful for more than 30 people to gather anywhere in the airport unless they are gathering for travel related issues. According to the airport authorities, such a prohibition is intended to make the airport free of congestion and ensure that activiti es go uninterrupted (Maryland State Archives 2013). Following this decision, the fans are challenging Section B and want to gather at the airport in support of the rock star and welcome him home. The issues that arise in this case include whether Section B follows the First Amendment clause on regulations of the freedoms of speech, which includes political freedoms and freedom of association. Another issue that arises is whether Section B violates the First amendment. Case background Section B of Baltimore airport regulations prohibits any form of gathering of more than 30 people at the airport unless the gathering is travel related. In this case, several issues arise if the lawsuit goes to court. According to the first amendment of the US constitution, all fans that are US citizens have the freedom to speech including freedom of association and political freedoms. This means that the US government as well as the state governments should and must adhere to this first amendment. However, the said governments may and can dictate time, place and other restrictions on the protected speech through the 14th amendment of the constitution. The welcome gathering and political speech that the fans of Big Bad Bruce want to hold is of this nature. Saying so, the Department of Transportation in the stateregulates a public forum with reasonable time, space and other restrictions leaving an open end for communication regarding important government interests. Section B is however neutral as it is not specific to speech and so the rock star fans have the chance to challenge it as an overboard rule that allows no room for their speech related activity. Section B prohibits gathering outside the terminals and this makes the law unduly overboard as it restricts any form of gathering above 30 people anywhere in the airport. Some parts of the airport might be considered public forums but airports are generally held as not to be public forums even though they are property of the public. A similar case would be that of International Society for Krishna Consciousness (ISCON) v. Lee. In this case, the New York and New Jersey port authorities had put in place a regulation prohibiting solicitation of funds and distribution of literature at air port terminals. The ISCON alleged violation of the first amendment by the regulation(Stone, 1987). On this basis, all public gatherings in the airport can be banned by the concerned authority, which is the Department of Transportation in Maryland, of which it can prohibit the use of the ground for any speech related activity. This will happen if the Section B’s purpose is to ease congestion and promote smooth running of airport activities. There is no provision that enables a person to determine what conduct or activity is precisely prohibited. In this situation, the regulation is overboard as it forbids more conduct than what is considered necessary to achieve the main purpose of the regulation. A similar case would be that of Hague vs. CIO whereby a city official was allowed by an ordinance to decide whether an organization seeking to hold a gathering in public places in the city could do so. In this case, if the city official decided that the meeting would be a risk disturbance, then the request would have been rejected. The law in contention was also vague and overboard (Stone, 1987). Analysis of Current Implications of Case This case is challenging Section B in order to obtain access to the airport for the welcome-home gathering. It is also challenging the use of Section B as a means of contradicting the first amendment that guarantees freedom of speech including freedom of association and political freedom. The State of Marylands Department of Transportation denied the groups of fans permission to have a public gathering at the airport. If the court upholds this decision, it is going to affect current issues and business laws in different ways. First of all, the first amendment prohibits the US government and the states government from forbidding assembly and speech by imposing putting restraints. In The Hague v. CIO case, the Supreme Court upheld the freedom to assemble by siding with the CIO with its intended activity of peaceably distributing literature and organizing labor meetings .The Supreme Court therefore ruled in the CIO favor showing that the city ordinance violated the First Amendment. The government may limit speech or assembly only when the speech or assembly has a compelling interest like presenting a potential harm to the general public(Van William, 2003). Section B tends to violate this law as it prohibits public gathering of the rock star fans as well as his intended public speech. A regulation that limits space, time and manner of assembly or speech may be allowed in some instances mostly in security instances. In the case of Big Bad Bruce’s fans, Section B clearly violated the First Amendment act by prohibiting public gathering anywhere in the airport. Even though airports are not considered public spaces, they are still spaces that the public own. Since the purpose of this law is mainly to decongest the airport and enable smooth running of activities and operations, the fans had the right to assemble as long as they did not cause congestion or interfere with smooth operations of the airport(Van William, 2003). Analysis of Future Implications of Case Since its adoption, the First amendment with its fundamental freedoms of speech, religion, press, assembly and petition have been intensely debated. The US courts have interpreted these freedoms in various landmark cases hence setting the standards for these freedoms. The cases involving ISCON v. Lee, Hague v. CIO and now Big Bad Bruce’s Fans v. Baltimore Airport involve state and public office regulations that violate the First Amendment. However, airports are not considered public spaces even though the public owns and uses the airports. This case involving Big Bad Bruce raises a question on what public organizations the First Amendment applies. According to the US constitution, the First Amendment applies to all government levels including public offices and spaces. Even though courts cases have managed to limit the freedoms to assembly and speech in some instances, the First Amendment protects the citizens. Until another amendment or clause is added by the congress, the freedoms of speech and right to peaceably assemble still stand and the state will and shall protect these freedoms. The government may still limit assembly or speech based on the purpose or content of which standard it is difficult to meet. The public should note that the First Amendment does not specifically require the US and states governments to respond to petitions by citizens on the violation of the First Amendment (Emerson, 1963). Personal Opinion of Case It is clear that the First Amendment guarantees all US citizens the freedom of speech, association and political freedom. The first challenge on Section B would therefore be based on that the law is broad and vague. There is no provision that enables a person to determine what conduct or activity is precisely prohibited. In this situation, the regulation is overboard as it forbids more conduct than what is considered necessary to achieve the main purpose of the regulation. The purpose of â€Å"avoiding congestion at the airport† and â€Å"ensuring smooth airport operations† can therefore,be achieved with less restrictive means of enforcing a regulation(Garvey Schauer, 1996). The amendment also imposes restrictions regarding time, space or other manner of restrictions on the freedom of speech and requires that the right to association or assemble is done in a peaceful manner. The restrictions will however depend on whether the restriction restricts assembly or speech in a public or non-public forum. If the airport is a public space because the public owns and uses the place, then the government can have a restriction for the interest of the government and only if it allows alternative open cannel for communication. In this case, Section B is quite ambiguous and vague and so it is not clear if the purpose is to protect the interest of the government, which is a neutral content. In addition, it appears to restrict all forms of gatherings of more than 30 people unless the gathering is travel related. If the court rules that the restriction serves a neutral purpose, it should then specify if it is to promote an interest of the government. As it is stated in t he regulation, Section B seems to be putting up restrictions more than it is necessary to enable smooth operations of the airport; the neutral purpose is unlikely to be found. If the court also finds Section B to be tailored for the interest of the government, the court should also state whether an alternative open line of communication was provided for. Section B states that there should be no form of gathering â€Å"anywhere† in the airport including concourse, gates, parking lots and grassy knolls so it does not seem to promote a significant interest. Section B should therefore not be held as a valid regulation for a public office since it does not show any narrowly tailored interest and leaves no open channel for alternative communication(Henry, 2009). Summary/Conclusion of Case In conclusion, the First Amendment protects the freedoms of association and assembly in the US including Maryland State that houses Baltimore airport. The 200 fans of Big Bad Bruce that are planning to gather for the welcome home gathering and the intended speech of 15 minutes by Big Bad Bruce on political views are protected by this amendment. However, the amendment applies to all levels of government and public spaces. The amendment also provides for a regulation clause limiting the time, space and other restrictions on the speech and association freedoms. However, the regulation should serve a neutral content like government interest and should allow an open channel for communication. Several issues arise in the case that require jurisdiction of the court. As seen in other cases of this nature, the court and the Supreme Court can deliberate on petitions by the public regarding violations of the First amendment. The court will have to make a ruling based on whether the First Amendm ent is violated, if the regulation serves a narrowed interest and/or if Section B regulation leaves an alternative channel for communication. This case analysis research paperdiscusses how the Section B rule can be challenged based on the law and the chances for success if the rock star’s fans file a lawsuit. References Emerson, T. (1963). Toward a General Theory of the First Amendment.  YaleLaw Journal, Vol.  72, no. 5.pp 877-956 Garvey, J. Schauer, F. (1996). The First Amendment: A Reader. St.Paul,  Minn: West Pub.  Co. Henry, C. (2009). Freedom of Speech and Press: Exceptions to the First Amendment.  Legislative  Attorney. Congressional Research Service. Maryland State Archives (2013). Department Of Transportation. Maryland. Stone, G. (1987). The Burger Court and the Political Process: Whose First Amendment?  Harvard  Journal of Law Public Policy, Vol. 10 Van, A. William, W. (2003). Reconciling What the First Amendment Forbids with What The  Copyright Clause Permits: A Summary Explanation and Review. Law and Contemporary Law Problems, Vol 66, No. 225