Recent advances in the treatment of advanced Non-Small-Cell Lung Cancer.
Globally, lung cancer is the most prevalent type of cancer and the most common cause of death from cancer. Non-small-cell lung cancer (NSCLC) accounts for around 80% of all lung cancers, with the majority of newly diagnosed patients with NSCLC having advanced disease. Standard cytotoxic chemotherapy improves survival and quality of life in advanced disease, although with a one-year survival rate of approximately 35%, the prognosis is poor. Platinum-containing chemotherapy doublets remain the standard first-line treatment for advanced NSCLC, although the toxicity profiles of the commonly used agents cisplatin and carboplatin have led to the development of new chemotherapeutic combinations. Comparison of various combinations of chemotherapeutic agents including non-platinum-based regimens, have shown them to have broadly similar efficacy, differing mainly in their toxicity profiles. The addition of targeted agents, in particular drug1, a humanised human-murine monoclonal antibody against vascular endothelial growth factor, to doublet chemotherapeutic regimens has prolonged survival in the first-line treatment of advanced NSCLC.
Drug1 plus carboplatin and paclitaxel statistically significantly improved median survival, from 10.3 months in the chemotherapy-alone group, to 12.3 months with triple agent therapy. Targeted agents appear to have an increasingly important role in the treatment of advanced NSCLC.
Lung cancer is the most common cancer with 1.35 million new cases reported globally in 2002, representing 12.4% of all new cancers. During the same period, with 1.18 million deaths, it was the most common cause of death from cancer, accounting for 17.6% of the world total . For the year 2000, estimates in men and women for lung cancer cases attributable to smoking tobacco were 85% and 47% respectively. .
Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers and is subdivided into three major subtypes – adenocarcinoma, squamous cell (epidermoid) carcinoma, and large-cell carcinoma. These subtypes however, have a prognosis and management in common and are staged by using the same TNM (tumour–node–metastasis) system . Treatment is dependent on the stage of disease with surgery being the treatment of choice if the primary tumour is resectable and metastatic disease is absent.
However, even in early stage I disease, more than 30% of patients relapse and die within five years of complete resection of lung tumours , presumably due to the presence of micrometastatic disease.
Surgical resection is the treatment of choice for stages I and II NSCLC with adjuvant chemotherapy playing an important role in the treatment of stage II but not stage I disease . Patients with stages I or II NSCLC who are either not suitable candidates for, or refuse surgery can be treated with radiotherapy .
Some type of multimodal therapy is appropriate for patients with stage IIIA NSCLC; an intermediate group of patients between stages I/II in which tumours are generally resectable, and stage IIIB where they are not.
Recommended treatment comprises adjuvant chemotherapy after complete resection of stage IIIA lung cancer encountered unexpectedly at surgery or concurrent combination chemoradiotherapy for prospectively recognised stage IIIA NSCLC with all degrees of mediastinal lymph node involvement .
The benefit of adjuvant chemotherapy in improving overall survival (OS) in completely resected patients with stage I-III NSCLC was shown in a recent meta-analysis of five large clinical trials . Postoperative cisplatin-based chemotherapy conferred a five-year absolute benefit of 5.4% when compared to observation alone, giving an overall hazard ratio (HR) of death of 0.89 (95% Confidence Intervals (CI), 0.82-0.96; p<0.01). The benefit of chemotherapy varied with stage (test for trend p<0.05) with calculated HRs for stage IA = 1.40 (95% CI, 0.95-2.06), stage IB = 0.93; (95% CI, 0.78-1.10), stage II = 0.83; (95% CI, 0.73-0.95) and stage III = 0.83 (95% CI, 0.72-0.94) . Five-year survival rates for stage IIIA range from 23%  to 33-36% in more recent studies [5,6] possibly reflecting improvements in treatment over the last 10 years.
Estimates suggest that, at the time of diagnosis 10-15% and 40% of patients with newly diagnosed NSCLC will have stage IIIB and stage IV disease respectively [2,8]. Five-year survival rates for advanced NSCLC range from 3-7% for stage IIIB depending on subtype, to approximately 1% for metastatic NSCLC (stage IV) . Treatment for stage IIIB NSCLC depends on several variables, including the extent and subtype of disease, comorbid risk factors, patient performance status (PS), age and weight loss. Chemotherapy, radiotherapy, concurrent chemoradiotherapy and resection in a limited number of cases are the therapeutic options for stage IIIB disease . This article will focus on recent advances in the systemic treatment of advanced (stage IIIB/IV) NSCLC.
First-line treatment of advanced (stage IIIB/IV) NSCLC using cytotoxic chemotherapeutic agents
A recent meta-analysis of 2,714 patients from 16 randomised controlled trials demonstrated that chemotherapy in the supportive care setting improves overall survival in patients with advanced NSCLC. This was equivalent to a relative increase in survival of 23% or an absolute improvement in survival at 12 months, increasing from 20% to 29% . Platinum-containing regimens remain the standard treatment for advanced NSCLC although the toxicity profiles of the commonly used agents cisplatin and carboplatin have led to the development of new chemotherapeutic combinations. A comparison by meta-analysis of cisplatin-based with carboplatin-based combination therapies reported that cisplatin-based regimens were associated with nephrotoxicity (p<0.05) and more severe nausea and vomiting (p<0.001), whilst severe thrombocytopenia (p<0.001) was more frequent during carboplatin-based chemotherapy . The incidence of neurotoxicity, leukopenia, neutropenia or anaemia was not different between the two treatment groups. The analysis also provides evidence that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy as the objective response rates (RR) were 30% and 24% respectively (p<0.001). Median survival was 9.1 and 8.4 months for cisplatin-treated and carboplatin-treated patients respectively whilst the respective one-year survival probabilities were 37% and 34% .
Platinum-based compounds are frequently combined with third-generation chemotherapeutic agents, such as vinorelbine, gemcitabine, or with the taxanes, docetaxel and paclitaxel. The majority of phase III trials comparing various combinations of doublet chemotherapeutic agents, including non-platinum-based regimens, have shown them to be broadly similar in terms of survival and RR in the treatment of patients with advanced NSCLC [12-18,20,22,24,25]. In one study however, a cisplatin/docetaxol combination significantly improved overall survival (OS) from 10.1 months obtained with the reference regimen cisplatin/vinorelbine to 11.3 months (p<0.05) . The overall RR was also improved by the taxol-based combination from 26% to 32% (p<0.05). However, the survival benefit and improvement in RR of the cisplatin/docetaxol combination was not replicated in other studies [12,15].
Comparison of cisplatin/pemetrexed with cisplatin/gemcitabine showed no difference in OS; – 10.3 months in each group . However, differences in survival were shown in a subgroup analysis based on histologic type. A significant improvement in survival was shown for patients with adenocarcinoma (p<0.05) or large-cell carcinoma histology (p<0.05) treated with cisplatin/pemetrexed; and squamous cell histology (p<0.01) treated with cisplatin/gemcitabine whilst there was no significant change in OS with patients with non-specific NSCLC histology .
The cisplatin/vinorelbine regimen is associated with increased incidence of grade 3 or 4 myelotoxicity, nausea and vomiting when compared to other platinum-based or non-platinum-based regimens [13,14,18,20]. The platinum/taxane regimen of carboplatin/ paclitaxel had a slightly lower rate overall of toxic effects than other platinum/taxane combinations; with less grade 3 or 4 neutropenia and lower rates of febrile neutropenia, although higher rates of grade 3 or 4 peripheral neuropathy were reported [13-15]. Comparison of the adverse effects of cisplatin/docetaxol with gemcitabine/docetaxel favoured the non-platinum combination with grade 3-4 neutropenia, nausea and diarrhoea having a higher incidence with the cisplatin/docetaxol regimen . Neutropenia is one of the more common side effects of the gemcitabine/docetaxel combination [12,18]. Haematologic toxicity was the most frequent side effect in the comparison of three combination therapies although myelosuppression was significantly lower, (p<0.01) with cisplatin/paclitaxel compared to cisplatin/gemcitabine with paclitaxel/gemcitabine having an intermediate level of toxicity . The platinum/taxane combination of carboplatin/gemcitabine similarly had a higher incidence of myelotoxicity when compared to patients treated with gemcitabine/paclitaxel in which alopecia, myalgia and neurotoxicity were more common . Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with a combination of carboplatin with paclitaxel poliglumex (PPX), a macromolecular polymer-drug conjugate of paclitaxel and poly-l-glutamic acid, when compared to carboplatin/paclitaxel . Grade 3 or 4 neutropenia and grade 3 neuropathy were more common with carboplatin/PPX . Patients treated with cisplatin/pemetrexed had significantly higher rates of grade 3-4 haematologic toxicity – neutropenia, anaemia, and thrombocytopenia; febrile neutropenia and alopecia when compared to a cisplatin/gemcitabine group in which grade 3-4 nausea was more common .
Use of single chemotherapeutic agents in first-line treatment of advanced NSCLC is generally limited to patients with poor performance status (PS 2 or higher) who have limited life expectancies and decreased tolerance for drug-induced toxicities, and elderly patients (70 years of age or more). Comparison of single-agent PPX with single-agent vinorelbine or gemcitabine for patients with advanced NSCLC and PS 2 showed no difference in survival between PPX and the control arm . Grade 3-4 neuropathy, a taxane-specific toxicity, was more common in the PPX arm, whilst grade 3-4 neutropenia and anaemia were reduced with the PPX regimen .
Single-agent docetaxel significantly improved RR (p<0.05) and median progression-free survival (PFS; p<0.001) in comparison to the standard treatment of vinorelbine in elderly patients . The most common grade 3-4 toxicities were neutropenia (docetaxel, 82.9%; vinorelbine, 69.2%; p<0.05) and leukopenia (docetaxel, 58.0%; vinorelbine, 51.7%). Although median OS with docetaxel was increased from 9.9 to 14.3 months, this did not reach statistical significance.
In a second study involving single-agent docetaxel, in comparison with a gemcitabine/docetaxel combination, the doublet combination significantly improved RR (p<0.001) and median OS (p<0.05) resulting in premature termination of the study . Thus single-agent docetaxel may only be suitable, in first-line therapy, for elderly patients with advanced NSCLC.
Triplet combinations of therapeutic agents in the first-line treatment of advanced NSCLC
Several studies have compared a triplet regimen of cytotoxic chemotherapeutic agents with doublet combinations [26-30]. The combination of carboplatin/paclitaxel/gemcitabine in a phase II/III trial significantly increased RR from 20% to 44% (p<0.001), median OS from 8.3 to 10.8 months (p<0.05) and median time to disease progression (TTP) from 5.1 to 7.6 months (p<0.05) when compared with the reference doublet carboplatin/paclitaxel . The one-year survival rate increased from 34% to 45% with the triplet regimen. Grade 3-4 haematologic toxicity was significantly increased (p<0.001) with this triplet drug combination. However, this improvement in survival with carboplatin/paclitaxel/gemcitabine was not replicated in a subsequent phase II/III trial when the comparator was the non-platinum doublet gemcitabine/vinorelbine . A significantly higher incidence of grade 3-4 thrombocytopenia, nausea and vomiting, myalgia, arthralgia, and neuropathy was reported for the triplet combination .
In a further 3 phase III trials, no improvement in survival with triplet chemotherapeutics were reported [26,27,30]. No differences in median OS and TTP in the comparison of cisplatin/gemcitabine/vinorelbine with cisplatin/gemcitabine were found although the RR of the sequential doublet regimen of gemcitabine/vinorelbine followed by vinorelbine/ifosfamide was significantly reduced (p<0.01) in this study . Comparison of cisplatin/mitomycin/ifosfamide with carboplatin/gemcitabine produced a significant reduction (p<0.01) in median OS from 10 to 2.4 months with the triplet regimen . Similarly, no improvement in survival was shown in comparison of a platinum-free, triplet regimen of vinorelbine/gemcitabine followed by docetaxel with the standard platinum-containing, doublet regimen carboplatin/paclitaxel . A significant decrease (p<0.05) in partial RR with the triplet regimen was reported in this study.
Over recent years, a number of targeted agents, including biologics, have been added to doublet chemotherapeutic regimens in an attempt to improve survival of patients with advanced NSCLC [31-44].
Phase II trials using drug2, a humanized monoclonal antibody against the HER2/neu (erbB2) receptor  or drug3, an oral inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) dependent signaling  in combination with platinum-based doublets failed to show an increase in efficacy in comparison to the control arms of the studies.
In contrast, a phase II trial of drug1, a humanised human-murine monoclonal antibody against vascular endothelial growth factor, plus carboplatin and paclitaxel significantly prolonged median TTP (p<0.05) from 4.2 months with carboplatin/paclitaxel to 7.4 months with the triplet regimen . The major adverse effect with drug1 was bleeding – minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology. Consequently in a subsequent phase III trial of drug1, patients with predominantly squamous cell carcinoma and/or clinically significant hemoptysis were excluded . Drug1 (at a dose of 15 mg/kg) plus doublet chemotherapy significantly improved median survival, from 10.3 months in the chemotherapy-alone group, to 12.3 months (p<0.01). The HR for death was 0.79 (95% CI, 0.67-0.92). Median progression-free survival (PFS) and RR were also significantly improved by the triplet regimen. Median PFS was 6.2 and 4.5 months (p<0.001) and RR was 35% and 15% (p<0.001), in the carboplatin/paclitaxel/drug1 and control arms respectively . Similar results were obtained for median PFS and RR in a second phase III trial using drug1 with cisplatin and gemcitabine. A median PFS of 6.1 months for the placebo control group was significantly prolonged by drug1 (7.5 mg/kg) plus chemotherapy to 6.7 months (p<0.001) and drug1 (15 mg/kg) plus chemotherapy to 6.5 months (p<0.01). RRs were 20%, 34% (p<0.001) and 30% (p<0.01) respectively .
Rates of clinically significant bleeding increased from 0.7% with carboplatin/paclitaxel to 4.4% with carboplatin/paclitaxel/drug1 (p<0.001). Grade 3-4 hypertension also significantly increased with this triplet regimen from 0.7% to 7% (p<0.001) . Similarly rates of grade 3-4 hypertension increased in drug1 plus cisplatin/gemcitabine treatment groups; from 2% in the placebo-chemotherapy group to 6% and 9% in the drug1-chemotherapy 7.5 mg/kg and 15 mg/kg groups respectively .
The epidermal growth factor receptor (EGFR) has attracted interest as a target for NSCLC as it is overexpressed in the majority of NSCLC tumours, and is associated with advanced disease and poor survival. A survival benefit in advanced NSCLC was recently reported for the biologic agent drug4, a chimeric human-murine monoclonal antibody against EGFR. Overall survival was improved from 10.1 months with patients treated with cisplatin/vinorelbine to 11.3 months with drug4 plus doublet chemotherapy. The main side effect with drug4 was an acne-like skin rash .
Several phase III studies have evaluated the possible benefit in first-line treatment of NSCLC of the selective EGFR inhibitors drug5 and drug6 [32, 35,38]. Drug6, in combination with cisplatin and gemcitabine, did not improve median OS, TTP or RR when compared to chemotherapy alone . Similarly two studies of drug6, with concurrent carboplatin and paclitaxel , or in combination with cisplatin and gemcitabine , did not confer a survival advantage over their respective chemotherapy control groups. A never-smokers subgroup treated with drug6 and carboplatin/paclitaxel seemed to experience an improvement in survival, although the numbers of patients were relatively small . An increase in the incidence of grade 3-4 rash and diarrhoea were found with both drug5 and drug6) [32,35,38].
As matrix metalloproteinases (MMPs) degrade extracellular proteins and thereby facilitate tumour growth, invasion, metastasis, and angiogenesis, selective inhibitors of MMPs were used in phase III studies to assess their efficacy in advanced NSCLC. Neither prinomastat nor BMS-275291 in combination with platinum-based doublet chemotherapy improved survival resulting in premature termination of both studies [34, 36]. The toxicities associated with prinomastat were arthralgia, stiffness, and joint swelling , whilst flu-like symptoms, rash, hypersensitivity reactions and febrile neutropenia were significantly higher with BMS-275291 .
Similarly, a phase III trial of PF- 3512676, an oligodeoxynucleotide toll-like receptor 9 agonist, in combination with platinum-based doublet chemotherapy was terminated prematurely due to lack of efficacy and increased toxicity. Mild/moderate injection site reactions, flu-like symptoms, grade 3-5 neutropenia, thrombocytopenia and septic episodes were more common in patients receiving PF-3512676 .
Bexarotene, a retinoid selective for retinoid X receptors, in combination with cisplatin and vinorelbine  or carboplatin and paclitaxel,  failed to improve OS in two phase III trials. However, a subpopulation of bexarotene patients in each trial who experienced high-grade hypertriglyceridemia had longer median survival compared with control patients. This failed to achieve statistical significance in one study  but in combination with carboplatin and paclitaxel, bexarotene significantly increased median survival from 9.2 to 12.4 months (p<0.05) in this subgroup who comprised 38% of all patients studied . Hyperlipidoemia, neutropoenia, fatigue, leucopoenia, arthralgia, and diarrhoea were more frequent with bexarotene plus carboplatin/paclitaxel than the control arm . Grade 3-4 leukopoenia was higher with cisplatin/vinorelbine whilst hyperlipoemia, hypothyroidism, dyspnoea and headache were more common in bexarotene with cisplatin/vinorelbine .
Second-line treatment of advanced (stage IIIB/IV) NSCLC
Docetaxel was approved for use in the second-line therapy of advanced NSCLC following improved survival compared with best supportive care, vinorelbine or ifosfamide in patients who had previously failed platinum-containing chemotherapy [45, 46]. Median survival times for docetaxel treated patients were 5.7 to 7.5 months [45, 46]. Neutropoenia, asthenic disorders, and alopecia are the most common toxic effects with docetaxel [45,46,52].
Recent phase II or III trials of chemotherapeutic or targeted agents in the second-line treatment of advanced NSCLC are summarised in table 4 [47-53]. Pemetrexed had equivalent efficacy to docetaxel but fewer adverse events including grade 3-4 neutropoenia (p<0.001) and febrile neutropoenia (p<0.001) . Similarly, PPX and docetaxel produced similar survival results. Compared with docetaxel, PPX had less febrile neutropoenia and alopecia . Median OS and RR were similar between topotecan and docetaxel, although median TTP was significantly longer with docetaxel (p<0.05). Grade 3-4 neutropoenia occurred more frequently with docetaxel whilst grade 3-4 anaemia and thrombocytopoenia occurred more frequently with topotecan .
Placebo controlled phase III trials of drug6 and drug5 produced disparate results. RR, median OS and PFS were all significantly increased by drug6 (p<0.001) . In contrast, drug5 did not improve survival when compared to placebo . Subgroup analysis showed a significant improvement in OS with drug5 in two subgroups: a never-smokers group (p<0.05) and those of Asian origin (p<0.05). There was no significant difference in a third subgroup comprising adenocarcinoma histology . The efficacy of drug5 in second-line therapy was, however, demonstrated in a recent second phase III trial which showed the non-inferiority of drug5 compared with docetaxel for OS, with respective median OS being 7.6 and 8.0 months . The most frequent toxic effects of both drug6 and drug5 were rash and diarrhoea [48, 52].
A phase II trial comparing drug3 plus docetaxel with single-agent docetaxel showed no significant differences in survival. Median PFS was reported as being significantly prolonged with 100 mg drug3 plus docetaxel, but statistical significance was achieved only with a one-sided test. Common adverse events included diarrhoea and rash .
Standard cytotoxic chemotherapy improves survival and quality of life in advanced NSCLC. The introduction of targeted agents such as drug1 to doublet chemotherapy in the first-line treatment of disease has led to further improvements in survival. The increasing role of targeted agents in advanced disease is anticipated, including second-line therapy for patients who had previously failed platinum-containing chemotherapy. Targeting of specific patient subpopulations may also lead to improvements in survival.
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