Treatment Therapies

Chemotherapy

First-line Therapy

During the 1980s, a global consensus was established regarding the use of cisplatin-based chemotherapy (with or without radiotherapy) for the first-line treatment of unresectable advanced-stage IIIB/IV NSCLC (Table 3).¹ The combination of cisplatin with etoposide, vinblastine or vindesine was considered to be state-of-the- art treatment.²

The data from a large meta-analysis demonstrated that cisplatin-based regimens could reduce the risk of death by 27%, and this was equivalent to an absolute increase in survival of 10% after 1 year.³ However, it was not clear from this analysis which of the various cisplatin-based combinations was superior. Later, carboplatin was developed in an attempt to overcome the administration and toxicity issues associated with cisplatin-based therapies. Whether or not carboplatin provides better survival is uncertain, but it is thought to be associated with less leucopenia, nausea and vomiting, and diarrhoea, compared with cisplatin.⁴ Typically, cisplatin as a single agent can provide a response rate (RR) of 11% with a 1-year survival rate of approximately 30% whereas, when combined with etoposide, RRs can be in excess of 20%, but with little change in 1-year survival over that seen with cisplatin alone.⁴ Recent years have seen the introduction of several new agents into first-line cisplatin-based treatment combinations such as the antimicrotubule agents (paclitaxel and docetaxel), an antimetabolite (gemcitabine), a vinca alkaloid (vinorelbine), and topoisomerase I inhibitors (topotecan and irinotecan). The activity of these new ‘third generation’ combinations was confirmed in randomised trials that reported median survival periods of 9–10 months and 1-year survival rates approaching 40%.⁵ The more common combinations have been examined in several large randomised studies (Table 3).

Table 3. Common drugs for the treatment of NSCLC.

Generation	Drug class	Names	Mechanism
First (Pre-1980s)	Alkylating agents	Chlorambucil Cyclophosphamide Busulphan Ifosfamide	Cross links DNA (and other molecules in the cell)causing damage and leading to cell death. Alkylating agents are not cell-cycle specific
	Anthracycline (cytotoxic antibiotics)	Doxorubicin Epirubicin Daunorubicin	DNA intercalating agent. Stabilises DNA structure and blocks replication and cell division
Second ~ 1980s	Platinum compounds	Cisplatin Carboplatin	Cross links DNA causing damage and leading to prevention of cell division
	First generation vinca alkaloids	Vinblastine Vindesine Vincristine	Binds to the protein tubulin to disturb formation of the mitotic spindle, so arresting cell division at metaphase
	Podophyllotoxin	Etoposide	Binds to tubulin and also inhibits topoisomerase II, an enzyme required during DNA replication and cell division
Third ~ 1990s	Taxanes	Paclitaxel Docetaxel	Stabilises microtubules during mitosis and causes cell cycle arrest at G2/M
	Anti-metabolite	Gemcitabine	Nucleoside analogue that inhibits DNA synthesis
	Camptothecins	Irinotecan Topotecan	Inhibits topoisomerase I, an enzyme required during DNA replication and cell division
	Second generation vinca alkaloid	Vinorelbine	Binds to the protein tubulin to disturb formation of the mitotic spindle so arresting cell division at metaphase. Second generation exhibits higher specificity for cancer cells
Contemporary	Antifolate	Pemetrexed	Inhibits enzymes of the folate pathways
	Hypoxic cytotoxic	Tirapazamine	Cytotoxic with selective action in hypoxic cells
	Anti-HER1/EGFR-TKIs	Tarceva^™ Gefitinib	Inhibits intracellular signalling by the HER1/EGFR receptor that is overexpressed in many different tumours and promotes cell growth and spreading
	Anti-HER1/EGFR monoclonal antibodies	Cetuximab Trastuzumab	Monoclonal antibodies that bind to and inactivate specific members of the HER1/EGFR family of cell surface receptors
	Anti-VEGF antibody	Bevacizumab	Monoclonal antibody that binds to VEGF and inhibits the development of new blood vessels (angiogenesis) that would supply the tumour with oxygen and nutrients.
	Proteasome inhibitors	Bortezomib	Specifically blocks proteasomes, which are enzyme complexes in the cell responsible for breaking down a variety of proteins, including many that regulate cell division
VEGF = vascular endothelial growth factor

Regimen	n	Response rate (%)	1-year survival (%)	Median survival(months)
ECOG TRIAL 1594³⁷
Paclitaxel/cisplatin	288	21	31	7.8
Gemcitabine/cisplatin	288	22	36	8.1
Docetaxel/cisplatin	289	17	31	7.4
Paclitaxel/carboplatin	290	17	34	8.1
SWOG TRIAL 9509³⁸
Cisplatin/vinorelbine	202	28	36	8.0
Paclitaxel/carboplatin	208	25	38	8.0
Southern Italy Cooperative Oncology Group³⁹
Cisplatin/gemcitabine/vinorelbine	69	47	NA	11.5
Cisplatin/vinorelbine	67	25	NA	7.8
Cisplatin/gemcitabine	63	30	NA	10.8
Italian Lung Cancer Study Group⁴⁰
Cisplatin/gemcitabine	205	30	37	9.8
Paclitaxel/carboplatin	201	32	43	9.9
Vinorelbine/cisplatin	201	30	37	9.5
Spanish Lung Cancer Group 98-02⁴¹
Cisplatin/gemcitabine	166	43	35	8.7
Cisplatin/gemcitabine/vinorelbine	176	39	31	7.9
Gemcitabine/vinorelbine
followed by vinorelbine/ifosfamide	175	26	35	8.1
SWOG = South-Western Oncology Group; NA = not available

Although response rates can be elevated to approximately 35% or higher, median survival remains stubbornly around 10 months and none of these studies showed a significant difference between arms in either 1-year survival rates or median survival. The time to progression for these combinations typically ranges from 3.3 to 4.5 months.

References:
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2. Novello S, Le Chevalier T. Chemotherapy for non-small-cell lung cancer. Part 2: Advanced disease. Oncology 2003;17: 457–71.
3. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small-cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899–909.
4. Haura EB. Treatment of advanced non-small-cell lung cancer: a review of current randomized clinical trials and an examination of emerging therapies. Cancer Control 2001;8:326–36.
5. Novello S, Le Chevalier T. Chemotherapy for non-small-cell lung cancer. Part 2: Advanced disease. Oncology 2003;17: 457–71.
6. US Environmental Protection Agency (EPA). Respiratory health effects of passive smoking: lung cancer and other disorders. EPA Publication No. 600/006F, Washington, DC: US Government Printing Office, 1992.