الفهرس 
Risk Factors, Prevention, EarlyOnly 14 pages are availabe for public view
 |  | from | 137 |  |  |
| | | from | 137 | | |
Abstract
Primary lung cancer is the most common malignancy excluding melanocytic skin cancer and the leading cause of human cancer deaths worldwide with smoking being the most common risk factor of lung cancer. In Egypt, Lung cancer has become the 6th common malignancy. Non small cell lung cancer accounts for 80–85% of lung cancers. About 40% of patients have either stage IIIB disease with malignant effusion or stage IV disease at presentation.
As smoking is the overwhelming cause of lung cancer, the most significant lifestyle and behavior modification available is to stop smoking or to never start smoking in the first place. The American College of Chest Physicians recommends against routine screening for lung cancer (even in high risk patients) because there is insufficient evidence that screening is effective at reducing morbidity or mortality.
Diagnosis of lung cancer must be proved histologically. PET-CT has led to an improvement of preoperative lymph node staging specially mediastinal lymph nodes. An evaluation of resectability or the suitability of radiotherapy with curative intent should be made in the context of a solitary brain or adrenal lesion or oligometastatic disease confined to the lungs.
The discovery and development of molecular inhibitors have had a major impact in the treatment of NSCLC. In the last decade, four molecular targeted agents were approved for treatment of lung cancer: gefitinib (2002), erlotinib (2003), bevacizumab (2006), and crizotinib (2011). EGFR, EML4-ALK, K-RAS and VEGF are targets for molecularly targeted agents with new targets under development like mTOR and Her2-neu.
The treatment strategy should take into account the histology, molecular pathology, age, performance status (PS), comorbidities, and patient’s preferences. Four to six cycles of platinum based chemotherapy is the corner stone of the first line treatment of lung cancer. Pemetrexed is preferred to gemcitabine in patients with non squamous tumours. Non platinum based combination chemotherapy with third generation agents should be considered only if platinum therapy is contraindicated. The combination of bevacizumab and other platinum based chemotherapies may be considered in eligible patients with the exclusion of squamous histology due to possibility of fatal pulmonary hemorrhage occurrence. First line treatment with a TKI (erlotinib or gefitinib) should be prescribed to patients with tumours bearing an activating (sensitizing) EGFR mutation. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011.
Introduction of maintenance therapy aimed to increase exposure to effective therapies, decrease chemotherapy resistance, maximize antitumor efficacy and anti-angiogenic effects of therapy in addition to alteration of antitumor immunity.
Decisions about maintenance must take into account the histology, response to platinum doublet chemotherapy, remaining toxicity after first line chemotherapy, PS, and patient preference. Compared with patients achieving complete or partial tumour response (CR or PR), those with SD after first line chemotherapy may have substantial residual tumour burden, continuing symptoms, and a worse prognosis. These patients may, therefore, be particularly suitable candidates for maintenance therapy.
Multiple randomised trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles. None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles. Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy but on the expense of QoL and chemotherapy related toxicity.
In a switch maintenance clinical trial of pemetrexed (JMEN), there was significant improvement of both the PFS and OS with better results in the non-squamous subgroup versus observation alone with tolerable side effects. In the continuation maintenance trial (PARAMOUNT), there was also improvement in both the PFS and OS in patients receiving maintenance pemetrexed.
A trial of continuation maintenance of gemcitabine led to significant improvement in TTP versus observation alone but unfortunately the improvement of OS was insignificant. However, there was a trend toward a larger PFS benefit among patients who received second line pemetrexed and those with an objective response to cisplatin gemcitabine.
In the switch maintenance trial of docetaxel by Fidias et al. median PFS was significantly greater in the immediate docetaxel arm compared with the delayed docetaxel arm. The difference in OS between docetaxel arms did not reach statistical significance.
In a North American continuation maintenance trial of paclitaxel, there was insignificant improvement in both PFS and OS in favor of paclitaxel arm versus BSC.
Westeel et al. designed a trial testing vinorelbine switch maintenance but unfortunately there was no difference in the PFS or OS between both groups.
The oral EGFR TKI erlotinib was shown to significantly improve survival, delay progression of symptoms and improve quality of life versus placebo in patients with advanced pretreated NSCLC in a randomised phase III study. Treatment with erlotinib produces significant survival benefits in a broad patient population and delays the time to the deterioration of key disease symptoms (cough, dyspnea, and pain), without having a negative impact on patients’ QoL. In the switch maintenance SATURN study, PFS was significantly improved in the erlotinib arm with a better response in the CR/PR after first line subgroup. SD after first line chemotherapy was a significant negative prognostic factor. No significant difference in OS was observed in the CR/PR group but the OS benefit in the SD group remained significant.
The EORTC evaluated the role of gefitinib administered after standard first line chemotherapy in patients with advanced NSCLC. The results showed a statistically significant difference in PFS favoring gefitinib but no difference in OS could be detected.
In the continuation maintenance trial of bevacizumab (AVAiL) in patients with non squamous NSCLC, PFS was significantly improved but without a significant OS benefit.
Pirker, et al. conducted a continuation maintenance trial of cetuximab enrolling patients with EGFR expressing NSCLC. There was no improvement in PFS between both arms but OS was significantly improved in the cetuximab arm. Notably, the benefit of cetuximab was seen irrespective of the histological sub-type, which would make the drug particularly attractive for patients with squamous cell carcinoma where treatment options remain limited.
Factors predicting benefit from maintenance therapy include response to first line therapy, performance status, histology and molecular characteristics.
To date, no clinical trial has demonstrated significant improvement in global quality of life with maintenance therapy compared with observation alone. Nevertheless, several have shown that global quality of life does not deteriorate, indicating the favorable toxicity profile of prolonged administration of single agent cytotoxic or biologic agents compared with extended treatment with combination chemotherapy regimens.