During the last few decades, progresses in biology, diagnostics and therapy have resulted in a slow but steady improvement in the treatment of advanced NSCLC. Overall median survival of patients with metastatic disease improved from 5–6 months in 1980s to 12 months at present with the incorporation of targeted drugs such as bevacizumab into conventional chemotherapy. However, survival among patients varies significantly, based upon tumor biology and clinical factors, such as poor performance status and significant weight loss. Other factors including gender, metastasis, or laboratory abnormality such as leukocytosis and increased LDH were suggested in some but not all studies. shows the findings of five large retrospective analyses based on selected randomized studies from cooperative groups conducted within the last three decades.1,5–7
Survival Prognostic Factors and Prediction Models for Non-Small Cell Lung Cancer from Five Retrospective Analyses
In our prior analysis which is based on ECOG 5592 and ECOG 1594, we found six poor prognostic factors predicting survival of NSCLC patients treated with platinum-based doublets involving paclitaxel, docetaxel, or gemcitabine, including: skin metastasis, lower performance status 1 or 2, loss of appetite, liver metastasis, ≥ four metastatic sites, and no prior surgery.1
There are several differences between our prior and current analysis. This analysis is based on the trial ECOG 4599 which accrued bevacizumab eligible population only (non-squamous histology, no significant hemoptysis). Furthermore, we included both clinical and laboratory variables. More importantly, the treatment regimen involved paclitaxel and carboplatin with or without bevacizumab.
In this analysis, 11 poor survival factors were identified. Similar to our previous report, we found that skin metastasis carries the worst survival prognosis with a highest HR (4.49) and prognostic score (130) in the 1Y-OS model. Skin metastasis also predicted the worst 6M-PFS. Although skin metastasis from primary lung cancer is an uncommon event, reported in only 4–12% of patients in prior ECOG studies involving all NSCLC histology subtypes, and in 1.4% in ECOG 4599, its presence likely suggests an aggressive biological behavior of the disease causing widespread metastasis. Other investigators also found the negative impact of skin or subcutaneous spread on survival in NSCLC.5,7
Significant weight loss of more than 5–10% total body weight within 6-month period and loss of appetite have been considered among the most important negative prognostic factors in NSCLC. However, not all patients are able to quantify their weight loss. Therefore, in this study, we decided to evaluate BMI at baseline, prior to the start of chemotherapy, which can be calculated easily based on patient’s weight and height, as a potential prognostic factor. The results demonstrated that underweight patients with BMI <18.5 had a poorer survival compared to those with normal or overweight (BMI ≥18.5), corresponding to the second highest HR (2.09). Interestingly, the relation between excess body weight and cancer mortality has been documented in many cancer types, although the underlying mechanism is not clear yet. In a report involving more than 900,000 American adults accrued in the prospective Cancer Prevention Study II, high BMI was in general associated with increased cancer related death rates in both obese men and women cohorts with BMI ≥35.0.8
That observation was seen across several solid and hematologic cancers, with the only exception being lung cancer. Indeed, contrary to other cancers, BMI was inversely correlated to lung cancer mortality. The relative risk of lung death in cohorts with BMI ≥35.0 in that study was approximately 0.67. Low serum albumin level is also a poor prognostic overall survival in our model, with a HR of 1.45. It is possible that low BMI, low serum albumin, and weight loss/loss of appetite all are biologic indicators of an aggressive cancer leading to a quick decline in nutritional and overall general health status.
Accumulating data have suggested that there is a gender difference between women and men with lung cancer.9
Some studies have suggested that women are more susceptible to carcinogenic effects of cigarette smoking.10,11
On the other hand, female patients with NSCLC are more likely to be never-smokers,12
harbor mutations in the EGF receptor,13
and live longer than their male counterparts with chemotherapy9
. In this analysis, although there was no difference in PFS, men had a lower chance of surviving at one year, with a HR of 1.39. The difference in outcome suggests gender is an important factor in designing clinical trials, and that gender should be a stratification factor in randomized trials.
In our analysis, patients with large cell carcinoma or NOS histology had a poorer survival compared to those with adenocarcinoma or adenocarcinoma with lepidic pattern suptype, with a HR of 1.29. It was unclear if the histology of NOS cases was undefined due to poor histological differentiation or lacking of tissue samples from fine needle aspiration. Patients with poorly differentiated, high-grade cancer may have more aggressive course and poorer prognosis.
Our study demonstrated that increase in LDH was significantly associated with shorter one-year survival with a HR of 1.74. LDH is an enzyme which catalyzes the forward and backward conversion of pyruvate to lactate, an important step in the process of cellular glycolysis and energy production. Cancer cells primarily metabolize glucose into lactate through the anaerobic glycolysis (Warburg effect), while most normal cells rely on the more efficient oxidative phosphorylation in mitochondria to produce ATP. The isozyme M-LDH (LDH-5) is increased in several human tumors compared to normal tissues,14
and elevated serum LDH is associated with chemotherapy and radiation resistance,15
as well as poor prognosis in a variety of cancers including NSCLC.6,15,16
The overexpression of LDH-5 in NSCLC tumor samples was linked to the expression of several angiogenic markers (VEGF, bFGF, bFGFR), the hypoxia-inducible factor HIF 1
, and survival in patients with resected disease.15,17
Findings from our study as well as others suggest that serum LDH and albumin are two simple blood tests which can be used to evaluate prognosis in NSCLC patients. However, it should be noted that LDH is not specific, as it can also be elevated in patients with underlying medical diseases such as cardiac, lung and liver disorders. Prospective studies are needed to validate the prognostic value of tumor LDH-5 expression for clinical use.
Finally, the addition of bevacizumab to chemotherapy is a positive prognostic factor for improved PFS and one-year survival rate. In regard to PFS, bevacizumab is the second most important factor, second only to skin metastasis. Compared to triplet therapy PCB, treatment with paclitaxel and carboplatin alone correlated with a HR of 1.52 for PFS. However, the benefit of bevacizumab on one-year survival appeared relatively modest in comparison to other factors. Indeed, among the 11 poor factors predicting one–year survival, bevacizumab impacts the least with a HR of 1.18 in patients receiving chemotherapy alone. Although survival advantages of bevacizumab in NSCLC have been proven, the drug is associated with certain morbid and fatal adverse effects such as bleeding, GI perforation or fistula. Because of the modest gain by adding bevacizumab to chemotherapy in patients without poor prognostic factors (such as patient 2 in the above example), patients with good factors and borderline risks to bevacizumab (for example, hemoptysis <1/2 teaspoon, labile hypertension) may elect a non-bevacizumab containing regimen, either with standard chemotherapy or enrolling into clinical trials.
Multiple potential biomarkers for bevacizumab and other antiangiogenic agents such as VEGF, basic fibroblast growth factor (b-FGF), intercellular adhesion molecule (ICAM), E-selectin, thrombospondin-2, microvessel density have been investigated in clinical trials in lung cancer as well as other cancers.18–21
However, to date, no biomarkers for anti-angiogenic therapy have yet been validated for clinical use. Thus, these nomograms may be helpful in identifying NSCLC patients most likely to benefit from the addition of bevacizumab to chemotherapy. By doing so, one may maximize the therapeutic gain, while minimizing potential morbidity and mortality and reduce the cost to the health care system.
In conclusion, our analysis identified several clinical factors predicting survival in non-squamous NSCLC patients treated with first-line paclitaxel and carboplatin with or without bevacizumab. Our nomograms offer a tool to estimate the possibility of survival. Those prognostic factors and models may help investigators in designing clinical trials and assist clinicians in selecting the most appropriate therapy for their patients.