Clinical Factors

Performance status and comorbid conditions are amongst the most important prognostic factors. Moreover, these determinants are also of utmost importance for the selection of therapy, as outlined later. The systematic determination of comorbidities is an essential component to preselect appropriate chemotherapy regimens and to provide the best supportive care.

In addition to noncancer-related comorbidities, patients also suffer from symptoms related to the primary tumor, mediastinal spread, or paraneoplastic syndromes. Moreover, lung cancer commonly produces systemic effects such as anorexia, weight loss, weakness, and profound fatigue. In a study of 12,428 NSCLC patients in the international staging database of the International Association for the Study of Lung Cancer (IASLC), performance status, age, and gender appeared to be independent prognostic factors for survival in addition to clinical stage. In advanced NSCLC, some routine laboratory tests (mainly white blood cells and hypercalcemia) were also found to be significant prognostic variables. Nowadays, the clear majority of lung cancer cases are diagnosed in patients aged >65 years. Age at diagnosis is another important factor that needs to be considered for therapy decision making. Often, increasing age is accompanied by multiple comorbidities, which further limit therapeutic options and outcome of the patient.

Ethnicity

While lung cancer remains a leading cause of mortality for all races, recent research has focused on ethnic variations in this disease. One of the most striking disparities seen is the difference in lung cancer risk and survival for African and Asian ethnicities. For example, the epidermal growth factor receptor ( EGFR ) mutation rate differs considerably between various ethnicities. Epidemiologic research has focused on behavioral, cultural, and socioeconomic factors that may influence risk, although no clear link has been established. Access to care is also variable among various ethnic groups and remains an important barrier to the delivery of optimal therapy.

Tumor Stage

The anatomic extent of the disease, as described by the TNM classification, is the most important prognostic factor in NSCLC. The seventh edition of the TNM classification that came into effect in 2010 derived from the analysis of the largest database ever generated for this purpose, with data from 46 sources in more than 19 countries around the world and with information about patients treated with all modalities of care. An important change involved the recognition that patients with extrathoracic disease have a slightly less favorable outcome compared with patients with metastatic spread confined to the thorax, even within the stage IV category. This has resulted in the division of stage IV to M1a and M1b based on the presence or absence of extrathoracic metastasis. It has also been recognized that malignant pleural or pericardial effusions portend a particularly poor prognosis among those with stage IV disease. In recognition of the importance of this, malignant effusions were moved from stage IIIB to IV disease in the seventh edition.

With additional cases analyzed in this international database, there will be further changes to the TNM classification system forthcoming in the eighth edition. The increased importance of T stage in prognosis has resulted in upstaging of tumors greater than 5 cm to T3 and those greater than 7 cm to T4. There will also be a new staging grouping, IIIC, created for patients with N3 nodal involvement and T3 or T4 primary tumors, to reflect the worse prognosis of these most locally advanced tumors. Finally, within metastatic disease, patients with a solitary metastasis in a single extrathoracic organ will be classified as M1b. Presence of oligometastases merits consideration of local therapies in addition to systemic therapy. These patients have similar survival to patients classified as M1a with lung, pleural or pericardial involvement and will share the stage IVA designation. The majority of metastatic patients who present with multiple metastatic lesions will be considered M1c disease and will be characterized as stage IVB.

Histology

The distinction between squamous and nonsquamous histology was the first step in the personalized treatment of patients with advanced NSCLC. Hence, accurate diagnosis of tumor histology has become essential in treatment decision-making and can impact considerations of both toxicity and potential efficacy of selected agents used in the management of this disease. For example, the use of the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab is associated with a higher risk of pulmonary bleeding when used in patients with predominantly squamous cell histology. Also, the cytotoxic drug pemetrexed was found to be inactive in patients with squamous NSCLC. Therefore, the classification of NSCLC into the major categories of squamous cell carcinoma, adenocarcinoma, and large cell carcinoma is critical for treatment decisions. However, histologic subclassification of NSCLC remains a challenge for many reasons. The tumor is very heterogeneous in every aspect: pathology, presence of molecular alterations, radiographic appearance, clinical presentation, and response to systemic therapy. The initial diagnostic biopsies often have a limited amount of material that is inadequate to conduct necessary tests to identify histology and genotype. The availability of immunostains such as TTF-1, p63, and p40 has greatly improved the accuracy of histologic subclassification.

Molecular Markers

NSCLC tumors often harbor mutations in a number of critical genes such as p53, K-RAS, and LKB-1. The prognostic relevance of these mutations continues to be defined for patients with advanced NSCLC. Certain markers have gained attention because they also harbor predictive value. For example, the presence of an activating EGFR mutation translates into both predictive and prognostic information. Patients with EGFR mutation have overall better outcomes compared with those with wild-type EGFR , and also derive robust benefits from specific therapeutic inhibitors of the EGFR pathway. Similarly, limited early evidence indicates that patients with abnormal anaplastic lymphoma kinase ( ALK ) gene rearrangement have higher risk of recurrence following surgery for early-stage disease and a higher clinical benefit with pemetrexed therapy. The prognostic role of K-Ras mutations in lung adenocarcinoma has been debated extensively. Earlier evidence suggested poor sensitivity to chemotherapy and overall prognosis with K-Ras mutation, but emerging recent data have failed to confirm this. K-Ras mutated patients appear to have a very low likelihood of objective response with EGFR inhibitors. The knowledge of the prognostic and predictive potential of various molecular markers is bound to increase significantly in the coming years as molecular testing is adopted to routine practice settings.

Systemic Chemotherapy

Systemic chemotherapy prolongs survival and leads to symptom palliation compared with best supportive care alone for patients with advanced NSCLC. Similar to therapeutic developments for other solid tumors, the efficacy of a variety of cytotoxic agents has been tested in both preclinical and clinical studies in NSCLC in the last decades. Initial results on single-agent therapy, including cisplatin (CDDP), ifosfamide, vinblastine, vindesine, etoposide, and mitomycin-C, indicated limited activity leading to objective response rates of ≤15% and median response durations of 2 months to 3 months. However, complete responses after these treatments were rare, and their benefit on median survival, with the exception of cisplatin, was inconsistent. The relatively modest efficacy and the considerable toxicity of these cytotoxic agents led to considerable nihilism regarding the use of chemotherapy for NSCLC for many years. Starting in the mid-1980s, several novel cytotoxic drugs were evaluated in NSCLC, such as vinorelbine, paclitaxel, docetaxel, irinotecan, gemcitabine, and oxaliplatin, which showed response rates of 20% to 25% ( Table 44.1 ).

Combinations of various agents have also been evaluated in patients with NSCLC. Two meta-analyses showed a clear significant survival advantage for a two-drug regimen versus monotherapy, but on the other hand also demonstrated a significant increase in hematologic and nonhematologic side effects. Among several combinations, platinum-based chemotherapy was shown to lead to higher response rates and prolonged survival in comparison with monotherapy, albeit with the cost of increased toxicity. Given the limited availability of supportive care for chemotherapy-related toxicities in the early 1990s, the use of chemotherapy in patients with metastatic NSCLC was still under debate despite the consistent evidence for its modest activity.

Platinum Compounds

Platinum compounds form DNA adducts, which ultimately result in activation of p53-dependent and p53-independent apoptosis. As monotherapy, cisplatin has anticancer activity comparable with that of other single agents, leading to response rates of approximately 15% and a median survival of 6 to 8 months. In order to increase the efficacy of systemic treatment, several combination regimens have been extensively studied ( Table 44.2 ). Several randomized trials as well as meta-analyses provided scientific evidence that platinum-based combination therapy prolonged the survival of patients with advanced NSCLC. In 1995, a meta-analysis using updated data on 1190 patients with advanced NSCLC from 11 randomized clinical trials was published. The results, updated in 2008, demonstrated a 27% reduction in the risk of death for patients treated with cisplatin-containing regimens compared with supportive care alone, which translated to an absolute improvement in survival of 10% (5% to 15%) at one year.

Compared with older regimens such as cisplatin with vindesine or vinblastine, cisplatin and mitomycin-C with vinblastine or vindesine, or cisplatin with etoposide, combinations of cisplatin with newer drugs (referred to as third-generation drugs: gemcitabine, taxanes, vinorelbine, topoisomerase I inhibitors) seem to exert somewhat higher efficacy and improved tolerability. For example, compared with platinum–gemcitabine combinations, several studies indicated inferior response rates, time to progression, and median overall survival (OS) for cisplatin, ifosfamide and mitomycin, cisplatin and vindesine, or cisplatin and etoposide regimens. Hematologic toxicity, especially thrombocytopenia, was pronounced in the gemcitabine-platinum groups whereas nonhematologic side effects appeared more frequently in the “classic” arms. Moreover, Le Chevalier et al. showed a significantly better response rate and survival for cisplatin–vinorelbine compared with cisplatin–vindesine.

The choice of the newer agent (gemcitabine, paclitaxel, or vinorelbine) that is combined with cisplatin does not seem to significantly affect the treatment efficacy (see Table 44.2 ). For instance, phase III studies (e.g., Southwest Oncology Group [SWOG] 9509) failed to demonstrate superiority of carboplatin–paclitaxel over cisplatin–vinorelbine in 408 patients. Similarly, the Italian Lung Cancer Study Group failed to detect any significant difference in outcome for cisplatin–gemcitabine, carboplatin–paclitaxel, and cisplatin–vinorelbine in 612 patients with previously untreated advanced NSCLC. However, both studies demonstrated differences between these regimens regarding their toxicity profiles. In the largest study that included 1207 patients (Eastern Cooperative Oncology Group [ECOG] 1594), Schiller et al. found no significant efficacy differences among the regimens cisplatin–paclitaxel, cisplatin–gemcitabine, cisplatin-docetaxel, and carboplatin–paclitaxel regarding response rates (17% to 22%) and median survival (7.4–8.1 months). Differences were only noted in toxicity profiles, with cisplatin–gemcitabine causing more thrombocytopenia, cisplatin–docetaxel causing more neutropenia, and the carboplatin–paclitaxel arm experiencing the lowest rate of potentially life-threatening toxicities. Another phase III study (TAX 326) randomized 1218 patients to receive cisplatin–docetaxel, carboplatin–docetaxel, or the control arm of cisplatin–vinorelbine. Patients treated with cisplatin–docetaxel had a higher response rate (31.6% vs. 24.5%, p = 0.029) and median survival (11.3 vs. 10.1 months, p = 0.044). Based on these observations, platinum-based chemotherapy remains the standard therapy in advanced or metastatic NSCLC. With the current combination partners, a plateau of efficacy has been reached.

Cisplatin Versus Carboplatin

Carboplatin is another platinum derivate with a tenfold longer half-life than cisplatin. Due to structural differences from cisplatin, it exhibits lower reactivity and slower DNA binding kinetics in vitro. In clinical studies, the nonhematologic tolerability of carboplatin is superior to that of cisplatin, making it a more convenient platinum analog for palliative chemotherapy.

Several studies have compared the efficacy of cisplatin with carboplatin in the management of advanced NSCLC. Rosell et al. reported a significantly improved survival for cisplatin–paclitaxel compared with carboplatin–paclitaxel with a higher rate of nonhematologic side effects in the cisplatin arm and a higher rate of neutropenia and thrombocytopenia in the carboplatin arm. In the TAX 326 trial, there was a nonsignificant trend toward improved survival for the combination of cisplatin–docetaxel over carboplatin–docetaxel. In contrast, the ECOG 1594 trial noted similar survival duration between the cisplatin and carboplatin-based treatment arms. However, there was a lower incidence of nonhematologic events such as nausea, vomiting, nephrotoxicity, and neurotoxicity with carboplatin-based therapy. This observation has also been made in other smaller trials with carboplatin-based regimens.

A meta-analysis using data from eight trials demonstrated that cisplatin-based chemotherapy offered a significantly higher objective response rate compared with carboplatin-based chemotherapy (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.15 to 1.61; p = 0.001) and a nonsignificant improvement in survival (hazard ratio [HR], 1.050; 95% CI, 0.907 to 1.216; p = 0.515). In this meta-analysis, a subgroup analysis of the five trials that incorporated cisplatin or carboplatin with a new agent identified a significantly superior median survival for cisplatin-treated patients (HR, 1.106; 95% CI, 1.005–1.218; p = 0.039). These data were confirmed by another meta-analysis including 2968 patients from nine trials. Cisplatin-treated patients experienced a significantly higher response rate (OR, 1.37; 95% CI, 1.16–1.61; p < 0.001). Moreover, cisplatin-based treatment was associated with an improved median OS relative to treatment with carboplatin (9.1 versus 8.4 months; HR, 1.07; 95% CI, 0.99–1.15; p = 0.1) that was significant in subgroup analyses for patients with nonsquamous tumors (HR, 1.12; 95% CI, 1.01–1.23) and those treated with third-generation chemotherapy (HR, 1.11; 95% CI, 1.01–1.21). However, cisplatin-based chemotherapy was associated with more severe nausea, vomiting, and nephrotoxicity while severe thrombocytopenia was more frequent during carboplatin-based chemotherapy. Hence, the selection of the platinum compound should be made based on the regimen most likely to result in the best therapeutic index. In recent years, the availability of effective antiemetic agents has improved the therapeutic index of cisplatin-based regimens.

Triplets for Advanced NSCLC

To further increase the efficacy of systemic therapy in advanced NSCLC, a series of studies have evaluated the potential role for the use of three-drug regimens. These studies have consistently demonstrated that three-drug regimens are associated with higher toxicity, have at times higher objective response rates, but offer no statistically significant improvement in survival as compared with that offered by standard doublets ( Table 44.3 ). For example, a phase III trial of 557 stage IIIB/IV NSCLC randomized patients to receive cisplatin–gemcitabine for six cycles, cisplatin–gemcitabine–vinorelbine for six cycles, or three cycles of gemcitabine–vinorelbine followed by three cycles of vinorelbine–ifosfamide. Response rates were inferior for the nonplatinum sequential doublet while no differences in median survival or time to progression were observed. Predictably, toxicity was significantly higher for the triplet regimen. Similarly, a recent phase II study found no statistically significant difference between doublet (cisplatin–gemcitabine or gemcitabine–vinorelbine) and triplet (cisplatin–ifosfamide–gemcitabine, or gemcitabine–ifosfamide–vinorelbine) combinations; however, grade 3–4 leukopenia was significantly more common in triplets.

In a systematic overview, third generation triplet therapy had a significantly higher response rate (OR, 1.33; 95% CI, 1.50–2.23; p < 0.001) compared with standard doublet therapy; however, median survival (MR, 1.10; 95% CI, 0.91–1.35; p = 0.059) was not statistically different and the incidence of grades 3–4 hematologic toxicity, neuropathy, and diarrhea was significantly increased with triplet therapy. Based on these results, platinum-based doublet chemotherapy remains the standard first-line treatment for patients with metastatic NSCLC.

Platinum-Free Versus Platinum-Based Chemotherapy

In daily practice, several types of patients with advanced NSCLC are not optimal candidates to receive platinum-based chemotherapy due to the presence of certain comorbid conditions such as renal insufficiency, borderline performance status (PS), or preexisting sensory neuropathy. Hence, studies were conducted to evaluate whether the combination of two newer chemotherapeutic agents may be better suited for first-line therapy. In some earlier studies, a trend toward a higher survival was observed in patients treated with platinum-based combinations compared with those treated with platinum-free regimens. In a recent phase II study, a total of 433 stage IIIB–IV NSCLC patients received cisplatin–gemcitabine, gemcitabine–vinorelbine, cisplatin–ifosfamide–gemcitabine, or gemcitabine–ifosfamide–vinorelbine. Platinum-based regimens had a significantly longer overall survival (11.3 vs. 9.7; p = 0.044) compared with the other treatment arms but also resulted in higher incidence of grade 3–4 toxicity. In a meta-analysis based on abstracted data from randomized phase II and III studies, D’Addario et al. observed a significantly higher 1-year survival rate for platinum-based combinations compared with the nonplatinum regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; p = 0.0003). However, when single-agent trials were excluded and platinum-based therapies were compared with third-generation–based combination regimens only, no statistically significant difference could be found (1-year survival, 36% for platinum regimens vs. 35% for nonplatinum regimens). In a more recent systematic review of randomized controlled trials comprising 4920 patients, the use of cisplatin-based doublet regimens was associated with a higher 1-year-survival rate (Hazard Ratio (HR), 1.16, 95% CI, 1.06–1.27; p = 0.001) compared with nonplatinum regimens, but also with an increased risk of anemia, neutropenia, neurotoxicity, and nausea. Conversely, carboplatin-based doublet regimens were associated with a similar 1-year survival rate (HR = 0.95, 95% CI, 0.85–1.07; p = 0.43) to that of nonplatinum doublets. Taken together, nonplatinum regimens do not have a clearly defined role in NSCLC and are only considered appropriate for patients that are not candidates for platinum agents.

Duration of Chemotherapy

The commonly used NSCLC chemotherapy regimens are administered in 3- or 4-week cycles. Imaging studies are recommended every two to three cycles to assess response to therapy. For patients that achieve an objective response or stable disease, the number of cycles of therapy has been a subject of several randomized studies. Socinski et al. randomized advanced NSCLC patients to treatment with the combination of carboplatin and paclitaxel for either four cycles or to continuation of therapy until disease progression. Interestingly, the median number of treatment cycles administered in both arms was four. There was no statistically significant improvement in OS for the extended chemotherapy approach. Predictably, toxicity was more common with administration of chemotherapy beyond four cycles. Another study by Smith et al. that compared three cycles of chemotherapy with six cycles also found no improvement in OS with the latter. In a systematic meta-analysis including 13 randomized control trials, 3027 patients receiving first-line (largely platinum-based) chemotherapy for three to four cycles were compared with patients with continuation of the same chemotherapy for six cycles or until disease progression. While extending chemotherapy substantially improved progression-free survival (PFS; HR, 0.75; 95% CI, 0.69–0.81; p < 0.00001), there was a statistically significant, but clinically only modest reduction in the hazard for death as compared with standard duration of chemotherapy over three to four cycles (HR, 0.92; 95% CI, 0.85–0.99; p = 0.03). Moreover, extension of chemotherapy was associated with higher toxicity and impaired quality of life. These findings were confirmed in a recent systematic review and meta-analysis of randomized trials comparing six versus fewer cycles of only platinum-based chemotherapy that had individual patient data available for analysis. While an improvement in PFS was observed in the four eligible studies with 1139 patients (HR 0.79; 95% CI, 0.68–0.90; p = 0.0007), there was no overall survival benefit to receipt of six cycles of platinum-based chemotherapy (median 9.54 months versus 8.68 months with fewer cycles; HR 0.94; 95% CI, 0.83–1.07; p = 0.33). This was independent of histology, sex, performance status, and age. Hence, most guidelines recommend limiting the duration of platinum-based first-line therapy to four to six cycles and prefer considering the induction of maintenance therapy.

Maintenance Therapy

After four to six cycles of first-line or induction chemotherapy, approximately two-thirds of patients have nonprogressive disease. Continuation of first-line platinum-based combination regimens beyond four to six cycles results in heightened toxicities and diminished quality of life without providing a major survival advantage. Thus, the standard therapeutic approach has entailed stopping treatment at that point, close clinical and radiographic surveillance, and initiation of second-line treatment at the time of progression. This “wait and watch” approach is frequently chosen after achieving maximal response to initial therapy. However, a “drug holiday” is often associated with patient anxiety about disease recurrence or progression coupled with concerns for clinical deterioration and the inability to receive subsequent therapy.

The availability of effective newer cytotoxic and molecularly targeted agents with overall good tolerability and low toxicity profile has led to the concept of maintenance therapy in order to maintain or improve the disease burden after completion of first-line therapy. Maintenance therapy involves either switching to a different compound (switch maintenance) or continuation of one drug partner of the induction regimen (continuation maintenance) in patients with a response or at least stabilization of disease. The role of maintenance therapy is discussed extensively in Chapter 46 .