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Published on 1 September 2007

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Advances in the treatment of nonsmall-cell lung cancer

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Antoinette J Wozniak
MD

Professor of Medicine and Oncology

Karmanos Cancer Institute
Wayne State University
Detroit, MI
USA

E: wozniakt@karmanos.org

Nonsmall-cell lung cancer (NSCLC) is the most common cause of cancer deaths in both men and women in the USA and is a major health problem worldwide. Unfortunately, the majority of patients present with advanced disease and only 15% of all patients diagnosed with NSCLC survive five years. The most common cause of lung cancer is still cigarette ­smoking, with only 10–15% of patients being never-­smokers. Currently there is no accepted routine screening for early detection of lung cancer. The International Early Lung Cancer Action Program is an example of a screening trial using spiral computerised tomography to detect earlier-stage lung cancer.(1) There are still several issues ­regarding screening programmes for lung cancer, including identification of the population at risk and whether ­screening actually is cost-­effective and reduces mortality from lung cancer. There have been steady advances in the ­treatment of NSCLC, ­particularly with better surgical and radiotherapy techniques and the development of novel chemotherapeutic and molecularly targeted agents.

Early-stage lung cancer
Surgery remains the standard of care for the initial treatment of early-stage NSCLC. Patient outcome is closely linked to the stage of the cancer. Radiological imaging advances such as positron emission tomography (PET) help establish more accurate preoperative staging. A number of minimally invasive techniques such as endobronchial ultrasound (EBUS) and transoesophageal ultrasound are being used to evaluate lymph nodes prior to surgery. Accurate staging identifies appropriate surgical ­candidates and thus improves outcome. Despite all these advances, surgery is an imperfect treatment and long-term survival has been disappointing due to distant and local recurrences of the lung cancer. Ninety percent of disease recurrence after surgery is in the form of distant metastases, which cause the majority of patient deaths.

Adjuvant chemotherapy – treatment after ­surgery to reduce disease recurrence – would seem the ­logical choice to improve survival. Early clinical ­trials were plagued by inadequate p­atient ­numbers, ­inconsistent surgical staging and inferior ­chemotherapy. We now have another generation of ­adjuvant trials with more accurate surgical staging and platinum-based chemotherapy.

The International Adjuvant Lung Cancer Trial (IALT) randomised more than 1,800 patients with resected NSCLC to receive cisplatin-based chemotherapy ­versus observation.(2) The five-year ­survival was ­significantly better for the patients who received chemotherapy after surgery and the chemotherapy-related mortality was less than 1%. This was the first prospective randomised trial to demonstrate a ­survival advantage for adjuvant chemotherapy in resected NSCLC and justified its use in common practice. The intergroup trial JBR.10, led by the National ­Cancer Institute of Canada, and a study by the Adjuvant Navelbine International Trialist Association were additional randomised ­trials that ­demonstrated a survival advantage for ­chemotherapy following ­surgery.(3,4)

The next-generation adjuvant lung cancer trials are incorporating novel agents such as the ­angiogenesis inhibitor bevacizumab and the epidermal growth ­factor receptor (EGFR) inhibitor erlotinib with ­platinum-based chemotherapy to improve outcomes. However, the fact remains that not all patients derive benefit from chemotherapy. A study as part of the IALT trial assessed the expression of a gene (ERCC1) that is involved in repairing ­damage associated with cisplatin chemotherapy in the tumours of patients on the trial. Chemotherapy improved survival in patients whose tumours were ERCC1-negative.(5) Other tumour markers are being assessed for prediction of chemosensitivity.

Another approach that has been taken is an attempt to identify patients at highest risk for relapse of their cancer. The gene profiles of tumours and the evaluation of proteins in cancer cells are being used to identify patients at high risk of relapse of their malignancy.(6,7) These new techniques may ­provide better assessment of tumour biology and help refine the process of selecting patients for adjuvant ­chemotherapy.

Locally advanced NSCLC
Patients with locally advanced or stage III NSCLC are a heterogeneous group of patients with ­variable survival depending on tumour volume and substage. Despite having disease confined to the chest, these patients are often inoperable because the cancer involves central lymph nodes or major structures within the chest. Treatment challenges include ­control of locoregional and systemic disease as well as selecting patients for aggressive ­treatment. Radiotherapy had historically been the treatment of choice but survival outcomes were dismal. CALGB 8433 was the first trial to establish a role for chemo‑therapy in this disease stage.(8) The next series of ­studies focused on the delivery of chemotherapy concurrent with radiation to take advantage of the radio‑sensitising effect of chemotherapy.(9,10) Large ­trials indicate that there is an advantage to this approach at the cost of more toxicity, so patients have to be carefully selected, taking into account performance status, comorbid illnesses and ­pulmonary function. The next-generation trials are attempting to incorporate into treatment some of the newer chemo‑therapeutic drugs as well as the novel targeted agents. There are still many issues regarding radiotherapy delivery, including optimal dose and schedule as well as refining the technical aspects of treatment planning to maximise benefit and reduce toxicity. The role of surgery in this ­disease stage remains controversial and should only be considered on a case-by-case basis in consultation with a multi‑disciplinary thoracic team.

Advanced NSCLC
Platinum-based chemotherapy is the mainstay of treatment for metastatic NSCLC. Although this ­treatment is not curative, combinations of a ­platinum complex with a taxane, gemcitabine or vinorelbine have resulted in improvement in ­survival and ­palliation of cancer-related symptoms.(11,12) No single best chemotherapy doublet has emerged as superior, so this is still very fertile ground for ­investigation.

Most of the research in this disease stage involves testing novel agents. There are a number of molecularly-targeted drugs that are directed toward a ­specific target within the cancer cell. One such target is angiogenesis (new blood-­vessel ­formation) which is required for the malignant ­process. ­Bevacizumab is a humanised monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), a potent promoter of angiogenesis. ­Bevacizumab combined with chemotherapy has shown a survival advantage for selected patients with advanced NSCLC.(13,14) There are a large number of anti-angiogenesis agents currently under ­investigation, including small-molecule tyrosine kinase inhibitors such as sorafenib and sunitinib that affect multiple targets within the cancer cell.

The fact that there are many trials assessing ­therapy in relapsed NSCLC indicates that we are making progress in this disease because patients are surviving to receive second-line treatment. Docetaxel and pemetrexed have both been shown to have a benefit in this setting.(15,16) Erlotinib is an oral tyrosine kinase inhibitor of the epidermal growth ­factor receptor (EGFR). Aberrant activation of EGFR is an important promoter of the malignant process. In a large trial of patients with advanced NSCLC, ­erlotinib had a demonstrated survival advantage when administered to patients with relapsed ­disease.(17) A considerable amount of research is focused on defining the patient population that derives the most benefit from EGFR inhibition.

Conclusion
Many advances have been made in treating NSCLC, but there is still work to be done. Unfortunately, it is beyond the scope of this article to discuss all the ongoing research efforts. One very important point is the realisation that lung cancer is a very complex disease and may have to be approached ­differently in each patient. Many of the modern-day trials ­collect tissue and blood specimens from patients for ­correlative scientific studies. These ­investigations are very important because they may help define the utility of novel treatment approaches. It is hoped that in the future, the tumour’s makeup as well as certain clinical characteristics may help design ­customised treatments (“patient cocktails”) for patients with lung cancer.

References
1. N Engl J Med 2006;355:1763-71.
2. N Engl J Med 2004;350:351-60.
3. N Eng J Med 2005;352:2589-97.
4. J Clin Oncol 2005;23:624s (Abstract 7013).
5. N Engl J Med 2006;355:983-91.
6. N Eng J Med 2006;355:570-80.
7. J Clin Oncol 2006;24:18s (Abstract 7028).
8. J Natl Cancer Inst 1996;88;1210-5.
9. J Clin Oncol 1999;17:2692-9.
10. J Clin Oncol 2003;22:621s (Abstract 2499).
11. N Engl J Med 2002;346:92-8.
12. J Clin Oncol 1998;16:2459-65.
13. N Eng J Med 2006;355:2542-50.
14. J Clin Oncol 2007;25 Suppl:967s (Abstract LBA7514).
15. J Clin Oncol 2000;18:2095-103.
16. J Clin Oncol 2004;22:1589-97.
17. N Engl J Med 2005;353:123-32.



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