Predictors of Long-Term Survival in Patients with Lung Cancer Included in the Randomized Spanish Lung Cancer Group 0008 Phase II Trial Using Concomitant Chemoradiation with Docetaxel and Carboplatin plus Induction or Consolidation Chemotherapy

Docetaxel and Carboplatin Plus Induction or Consolidation Chemotherapy

Pilar Garrido; Rafael Rosell; Bartomeu Massutí; Felipe Cardenal; Vicente Alberola; Manuel Dómine; Inmaculada Maeztu; Alfredo Ramos; Antonio Arellano


Clin Lung Cancer. 2009;10(3):180-186. 

In This Article


The overall survival (OS) rates of patients with locally advanced NSCLC remain unsatisfactory, with a 5-year survival of 16%.[9] Individual differences between patients probably exert a greater influence on survival duration than type of therapy. In addition to disease stage, several other factors have been reported to influence survival in NSCLC. Few studies, though, have focused on prognostic factors in stage III NSCLC despite the difficulty in choosing the appropriate multimodality treatment schedule and the need for a careful balance between efficacy and tolerability in these patients.

Sculier et al recently analyzed the impact of prognostic factors on survival in patients included in the large international database of the International Association for the Study of Lung Cancer (IASLC),[10] used for the IASLC revision of the tumor-node-metastasis (TNM) staging system for lung cancer.[11] Data on 12,428 patients with NSCLC showed that advanced age, more advanced stage, male sex, poorer PS, and nonsquamous histology (only in stage IIIA disease) were significantly associated with decreased survival. Disease stage was the strongest prognostic factor, followed by PS, sex, and age. Similar prognostic factors have been reported in other series, usually retrospective analyses of databases of clinical trials in advanced disease performed by cooperative groups.[12,13,14] In all these modern series, PS remains one of the most powerful prognostic factors.[15,16,17] Recent clinical trials have included more patients with favorable prognostic factors, including female sex, less weight loss, and lower PS, highlighting the importance of examining additional prognostic factors in these patients.

The influence of sex on outcome in stage III NSCLC is still unclear. Although the HR for sex (0.48) in the current study suggests improved outcome in women, the relatively low number of women makes it difficult to draw any definite conclusions. The impact of age also remains uncertain.[18,19,20] Although NSCLC is largely a disease of the elderly, the benefits of chemoradiation therapy are unclear in patients aged > 70 years. In fact, only selected elderly patients are usually entered in chemoradiation studies. In a secondary analysis of the RTOG 9410 trial,[19] a greater survival benefit for concurrent CT/TRT was observed in "fit, elderly" patients than in younger patients. In contrast, an analysis of the RTOG database, including 1999 patients with locally advanced NSCLC, revealed that advanced age had a negative impact on survival,[21] whereas in the current study, there was no association between age and survival.

In addition to younger age, the RTOG analysis found 12 other characteristics significantly associated with improved survival: use of CT; CT delivered without major deviation; abnormal pulmonary function tests; normal Hb, protein, lactate dehydrogenase, and blood urea nitrogen; presence of dyspnea, hemoptysis, cough, or hoarseness; uninvolved lymph nodes; T1 or T2 stage; no malignant pleural effusion; weight loss of < 8%; KI ≥ 90; adenocarcinoma; and female sex. In the recursive partitioning analysis, 5 prognostic groups were identified based on PS, use of CT, pleural effusion, age, and histology. In contrast, T stage and N stage were not significant prognostic factors in the recursive partitioning analysis.[21] A later study of 207 patients with inoperable NSCLC treated with 3-dimensional conformal RT[22] also concluded that T stage and N stage were not independent prognostic factors.

The RTOG also analyzed the influence of the gross tumor volume (GTV), defined as the sum of the volumes of the primary tumor and involved lymph nodes, on the outcome of patients enrolled in the RTOG 9311 trial, in which patients received radiation doses of 70.9, 77.4, 83.8, or 90.3 Gy.[23] Increasing the radiation dose had no effect on progression-free or median survival. In the multivariate analysis, only a smaller GTV (both as a discrete and continuous variable) was a significant prognostic factor for longer survival. Similar results were obtained by Basaki et al, who reported that both GTV and primary tumor volume were significant predictors of survival, whereas nodal volume alone had no independent effect.[24] In a study of 270 patients with stage I-IIIB inoperable NSCLC, Dehing-Oberije et al also found that tumor volume combined with the number of positive lymph node stations was a more important prognostic factor than TNM stage.[25,26]

The V20 value has also been associated with survival in CT/ TRT-treated patients with NSCLC. In the Southwest Oncology Group 0023 trial,[27] median survival time improved from 12 months to 24 months (P = .0006) when a lower percentage of the total lung received a radiation dose of ≥ 20 Gy (V20). In the current study, V20 > 35% was one of the exclusion criteria, and the prognostic value of V20 was not examined.

Ademuyiwa et al recently analyzed 10 prognostic factors in 203 patients enrolled in a phase III trial conducted by the Hoosier Oncology Group and US Oncology between 2002 and 2006.[28] Their results showed that FEV1 > 2 L and higher pretreatment Hb levels (≥ 12) were independent prognostic factors for survival, whereas sex, PS, disease stage (IIIA or IIIB), weight loss, smoking status, or race had no influence on survival.

The prognostic value of Hb levels in NSCLC is not clear. According to MacRae et al, declining Hb during CT/TRT had a significant impact on survival in 115 patients entered in 3 trials.[29] Pretreatment anemia was found in 30% of the patients in the range of 110-130 g/L, and 16% of the patients had < 110 g/L. The mean Hb level before the initiation of therapy was 128 g/L, which declined to a mean of 114 g/L at the end of treatment. In the multivariate analysis, the percentage change in Hb level during therapy emerged as the only factor predictive of survival, whereas age, PS, histology, and disease stage (IIIA versus IIIB) were not significant. In our study, pretreatment Hb level was < 12 g/dL in only 7% of the patients enrolled in the consolidation arm and in 19% of patients in the induction arm. However, this factor did not influence survival in our study, perhaps because of the low hematologic toxicity of the CT regimen administered. Further studies of the prognostic value of Hb level in patients receiving cisplatin-based CT are warranted.

The influence of overall treatment time on outcomes has been analyzed in several studies. Cox et al reported the results of the RTOG database of patients treated with radiation therapy alone.[30] Patients with a high PS who did not have treatment delays had a 5-year survival rate of 15% compared with 0% for patients whose treatment was delayed. In a retrospective analysis of 3 RTOG trials (RTOG 9106, 9204, and 9410) in which concurrent chemoradia-tion was the primary therapy, a slight but nonsignificant improvement in median survival was observed in patients completing treatment on time. However, in the multivariate analysis of treatment time as a continuous variable, prolonged treatment time was significantly associated with poorer survival (P = .02), with a 2% increase in the risk of death for each day of prolongation in therapy.[31] In our study, completion of CT/TRT (P < .0001) and completion of induction or consolidation plus concomitant treatment (P < .0001) were independent prognostic factors, whereas delay in radiation therapy treatment did not influence survival, although these findings should be interpreted with caution because of the small number of patients included and the variety of modalities of chemoradiation therapy used.

Striking improvements in survival can only be accomplished by optimizing therapy. For this reason, there is considerable interest in selecting therapy based on molecular profiles.[32] The SLCG published the first prospective randomized clinical trial testing the concept of customized chemotherapy in NSCLC.[33] The results of this trial demonstrated a significantly improved response in patients with advanced NSCLC with low levels of ERCC1 mRNA expression receiving docetaxel plus cisplatin, although differences in survival were not found. Other molecular markers such as BRCA1 have also been analyzed. Low levels of BRCA1 have been correlated with increased survival in patients with stage III NSCLC treated with neoadjuvant cisplatin/gemcitabine followed by surgery.[34] These findings underscore the need for further research in customizing chemotherapy.

Biomarkers that can accurately predict radiation-induced damage at an early stage are also under investigation. Although no validated blood markers are currently available, studies from different institutions have demonstrated the significant value of several cytokines.[35] These results still need to be validated on a larger scale.