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.
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According to Cancer Research UK’s 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.
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 criteria’s: 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 patient’s prognostic outcomes. Overall, SCLC has a poor prognosis with survival 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).
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 O’Sullivan, 2003). Last statements 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 more 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.
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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 patient’s 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 TKI’s, 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).
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