Cancer and Leukemia Group B, Chicago, IL, USA
*Correspondence to: Dr M. A. Socinski, Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, CB 7305, Chapel Hill, NC 27599, USA. Tel: +1-919-966-4431; Fax: +1-919-966-6735; Email: socinski{at}med.unc.edu
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Abstract |
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Patients and methods: Six hundred and ninety-four patients included in five trials conducted by the Cancer and Leukemia Group B evaluating CMT in stage III NSCLC were included in this analysis. The primary objective was to identify factors that were predictors of survival and selected radiation-related toxicities using Cox regression models and logistic regression analysis.
Results: The Cox model shows that performance status (PS) 1 [hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.061.45; P=0.009] and thoracic radiation therapy (TRT) only (HR 1.58; 95% CI 1.222.05; P=0.001) predicted for poorer survival, while baseline hemoglobin 12 g/dl predicted for improved survival (HR 0.67; 95% CI 0.550.81; P
0.0001). Multivariate logistic regression showed an increase of grade 3 + esophagitis among patients with PS 0 [odds ratio (OR) 1.7; 95% CI 1.12.7; P=0.029), >5% weight loss (OR 2.9; 95% CI 1.36.6; P=0.008) and patients receiving concurrent chemoradiation (OR 7.3; 95% CI 3.415.6; P=0.0001).
Conclusions: Baseline hemoglobin and PS, as well as the use of CMT, have the greatest effect on survival in unresectable stage III NSCLC. The use of concurrent chemoradiation increases the risk of esophagitis, which remains the primary radiation-related toxicity.
Key words: chemoradiation, combined modality therapy, non-small-cell lung cancer, prognostic factors
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Introduction |
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The Cancer and Leukemia Group B (CALGB) initiated a trial in 1984 that was very influential in changing the standard of care in unresectable stage III NSCLC [10, 11
]. The Dillman trial (CALGB 8433) suggested that sequential chemotherapy with cisplatin and vinblastine followed by TRT improved survival over TRT alone. In that trial, the median survival time and 5-year survival rates were 9.7 months and 7%, respectively, for TRT alone, compared with 13.8 months and 19%, respectively, in the sequential chemoradiation arm (P=0.006). Following that pivotal trial, several subsequent trials involving both sequential and concurrent designs confirmed the observation that combined modality therapy improved survival over TRT alone [12
16
]. Since CALGB 8433, several phase II and III trials evaluating the contribution of concurrent chemotherapy as well as new cytotoxic agents in the paradigm of sequential and concurrent chemoradiation have been completed by the CALGB and are reported elsewhere [17
20
].
The analysis of prognostic factors in NSCLC has been useful in defining subsets of patients with differing survival outcomes. Most of the prognostic information previously published in stage III NSCLC has predominantly analyzed patients treated with TRT alone [2024
], although recent reports include increasing numbers of patients treated with CMT [25
29
]. Some of these analyses have yielded conflicting information [26
, 27
]. For example, a recursive partitioning analysis performed by the Radiation Therapy Oncology Group (RTOG) [26
] suggested that advanced age (
70 years) had a negative impact on survival, while a secondary analysis of RTOG 94-10 [27
] suggested a greater survival benefit for concurrent chemoradiation in the elderly compared with their younger counterparts. Given these variations, continuing analysis of baseline prognostic factors predicting both survival and selected toxicities is warranted. Since the CALGB has completed several trials involving CMT for patients with stage III NSCLC, we analyzed the CALGB database with the primary intent of evaluating various baseline factors and their impact on overall survival and on the risks of developing certain toxicities characteristic of CMT.
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Patients and methods |
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Statistical analysis
The primary objective of this retrospective analysis was to identify factors that were predictive of survival and selected radiation-related toxicities among patients with stage III NSCLC. Predictors considered in this analysis included age (<70 versus 70 years), gender, PS (0 versus 1), weight loss (<5% versus
5%), stage (IIIA versus IIIB), baseline hemoglobin (<12 versus
12 g/dl and as a continuum) baseline WBC count (<12 000 versus
12 000/mm3) and treatment strategy (TRT alone versus sequential chemoradiation versus sequential and concurrent chemoradiation).
Cox regression models were used to examine the relationship between predictors and survival, where survival time was defined as the time between registration and death or last known follow-up. Backwards elimination was used to reduce the number of variables included in the model containing all predictors. KaplanMeier curves were used to graphically describe the distribution of survival within patient subgroups. Logistic regression analysis was used to identify factors related to the radiation-induced toxicities of esophagitis, pneumonitis and fatigue/malaise. Toxicities were dichotomized as grade <3 or 3. The backwards elimination approach was also used for modeling toxicity data. The analysis was performed using SAS software. Statistically significant differences are reported for P<0.05.
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Results |
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Table 5 shows the median survival times, as well as the 1-, 3- and 5-year survival estimates for each of the significant predictors of survival. The impact on median survival times for patients with the favorable baseline predictive factors consistently ranges from 4 to 5 months. Likewise, 5-year survival rates are consistently 47% higher for the more favorable compared with the less favorable patients, tightly clustering in the range of 1314%. Figure 1
shows the survival curves for patients based on PS (0 versus 1), baseline hemoglobin (<12 versus
12 g/dl), CMT (versus TRT alone) and stage (IIIA versus IIIB).
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Discussion |
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Although many reports have analyzed prognostic factors in metastatic NSCLC [30], fewer have focused on stage III disease. In 1995, Jeremic and Shibamoto [25
] evaluated prognostic factors among 169 stage III NSCLC patients treated with hyperfractionated TRT (6468 Gy) with or without etoposide and/or carboplatin chemotherapy. In their multivariate analysis, Karnofsky PS
80%, weight loss
5%, lower disease stage (IIIA), younger age (<60 years) and female gender were all associated with an improved survival. Wigren [22
] used a database of 210 patients to develop a prognostic index of five prognostic factors (disease extent, PS, tumor size, clinical symptom score and hemoglobin) to stratify the patient population into six different groups with significantly differing median survival times. The RTOG [21
] analyzed 1592 patients with locally advanced NSCLC treated between 1983 and 1987 with TRT alone using a recursive partitioning analytical method. The single most important factor was Karnofsky PS, with the cut-off point being 70%. Five prognostic groups were identified with median survival times ranging from 3.3 to 12.8 months. This report, as well as the report of Wigren, is limited in its current value, as the current standard of care in patients with a good PS is combined chemoradiation. In a subsequent analysis by the RTOG [26
] expanding the experience to include five additional RTOG trials that included CMT, the use of chemotherapy was identified as a significant survival factor in patients with a good PS, similar to the data presented in this report. This observation has also been confirmed in several randomized phase III trials [10
16
]. In addition to the use of chemotherapy, the following variables were found to be significantly associated with improved survival in a univariate analysis: weight loss <8%, Karnofsky PS 90100%, age <70 years, T stage, absence of pleural effusion, presence of dyspnea, hoarseness, hemoptysis, cough, abnormal pulmonary function tests, female gender, normal laboratory values for protein, hemoglobin, BUN or lactate dehydrogenase, clinical status, adenocarcinoma or adenosquamous histology, >40 elapsed TRT days, and peripheral tumor location. Utilizing the recursive partitioning analysis methodology, five prognostic groups were identified with the split points involving PS, use of chemotherapy, age (<70 years), presence or absence of a pleural effusion and histology (large-cell or non-large-cell histology). Our data are consistent with the observation regarding PS and use of chemotherapy; however, we did not find age to be predictive for survival. In a subsequent analysis of RTOG 94-10 [27
], the elderly patients (>70 years) actually had a greater survival benefit from concurrent chemoradiation compared with their younger counterparts, which seems contrary to the earlier RTOG age-related observations. Our data are consistent with several recent trials evaluating the impact of age in advanced stage IV NSCLC [31
36
] which suggests that at least the fit elderly have response and survival outcomes similar to their younger counterparts. Given the relative under-representation of the elderly in all these analyses, further studies evaluating the impact of CMT in the elderly are warranted.
The observation regarding the impact of baseline hemoglobin is of interest. Anemia has consistently been identified as a significant baseline predictor of survival in advanced, metastatic NSCLC [37]. As previously noted, this had been observed in the previous RTOG report [26
], as well as in the report by Wigren [22
]. Our analysis provides a more detailed look at baseline hemoglobin on a continuum, and clearly suggests improved survival in patients with baseline hemoglobin values of
12 g/dl. Unfortunately, this analysis did not evaluate changes in hemoglobin during therapy and what impact this may have on survival. McCrae et al. [38
] have carried out such an analysis (albeit retrospectively) on 115 patients who received CMT. They divided the patients into three groups defined by how much the hemoglobin decreased during concurrent chemoradiation: <10%, 1030% and >30%. The median and 2-year survival figures were 26.9 months and 50%, respectively, for those patients with a <10% decrease in hemoglobin, 15.3 months and 33% for those patients with a 1030% decrease in hemoglobin and 9.1 months and 0% for those patients with a >30% decrease in hemoglobin levels (P=0.037). It has also been shown that hemoglobin values are prognostic in head and neck cancer patients undergoing chemoradiation [39
]. This study also suggested that reversal of anemia with erythropoietin improved survival outcomes and provided initially anemic patients with a survival outcome similar to initially non-anemic patients. However, a recent prospective trial [40
] in head and neck cancer using radiotherapy alone and randomizing patients to receive epoetin-ß and placebo did not show a survival or loco-regional benefit. Theoretically, reversal of anemia could improve oxygen delivery to otherwise hypoxic tumors, thereby enhancing the loco-regional effect of chemoradiation. Given these observations, a logical hypothesis would be that prospective correction and maintenance of hemoglobin levels during CMT for unresectable stage III NSCLC would improve survival by enhancing loco-regional control. That enhanced loco-regional control can be a mechanism by which survival is improved has been shown in several trials in stage III NSCLC [15
, 16
], as well as in limited stage small-cell lung cancer [41
]. Furthermore, a systemic effect could also be possible. Crawford et al. [42
] demonstrated recently that hemoglobin levels can be maintained during platinum-based chemotherapy in advanced, metastatic NSCLC by the prospective use of erythropoietin. In that trial, a significant difference was seen in maintaining hemoglobin levels >12 g/dl by the prospective use of erythropoietin versus the reactive use of the same erythropoietin when hemoglobin levels fell to <10 g/dl. Although this trial was not designed to show a survival benefit, the median survival of the control arm was 8.1 months versus 12.3 months in the investigational arm (prospective maintenance of hemoglobin
12 g/dl) [43
]. This cannot be considered definitive as it was not statistically significant; however, it lends further support for a definitive trial testing the hypothesis set forth above.
The observation that the survival of stage IIIB patients was superior to stage IIIA patients was both interesting and indicative of the inaccuracies of the current staging system in NSCLC [44]. There is tremendous heterogeneity in stage III NSCLC that is not accounted for in the current staging system. This heterogeneity is apparent when one considers the inclusion of supraclavicular adenopathy, contralateral mediastinal adenopathy, locally advanced primary tumor of the T4 category and malignant pleural effusions all in stage IIIB. A similar situation is apparent in stage IIIA NSCLC, where the prognosis with surgery alone differs 10-fold when comparing a single microscopically positive nodal station with patients with clinically apparent N2 disease in multiple nodal stations [45
]. Certainly, a refinement of the staging system is needed, taking these issues into account.
In this analysis, there did not appear to be an advantage of sequential followed by concurrent chemoradiation over sequential chemoradiation alone. The concurrent chemoradiation strategies included both low-dose weekly strategies (CALGB 8831, 9130 and 9534) as well as more standard systemic dose strategies (CALGB 9431). No single trial addressed directly the issue of optimal concurrent chemoradiation strategy as it relates to the optimal chemotherapy strategy (either dose, schedule or agent). This remains a controversial area, and deserves further study.
Several recent randomized trials have suggested that concurrent chemoradiation modestly improves survival compared with sequential chemoradiation [69
]. All of these trials have also suggested increased rates of severe esophagitis (grade 3 or 4 in 2030% of patients) with concurrent therapy compared with TRT alone. Our data suggest a seven-fold increase in the risk of severe esophagitis with concurrent chemoradiation. If one accepts the survival benefit from concurrent chemoradiation, strategies to reduce the risks of esophagitis seem warranted. The suggestion that amifostine may protect the esophagus from TRT-induced esophagitis seen in two small randomized trials [46
, 47
] was not confirmed in a large RTOG randomized trial (RTOG 98-10) [48
]. Other cytoprotectants have not been evaluated, but seem logical to test [49
]. The exclusion of the esophagus from the high-dose field utilizing three-dimensional planning techniques is also a reasonable strategy. In previous trials using three-dimensional planning and doses of TRT escalated to 74 Gy and beyond, rates of severe esophagitis have been <10% [50
, 51
]. No subgroup was identified that appeared to have an increased risk of radiation pneumonitis. The radiotherapy planning constraints were identical on all five trials analyzed here. The observation that women experienced more severe fatigue/malaise was unexpected. Interestingly, age was not a factor in terms of predicting these toxicities. This is in contrast to recent reports from the RTOG and Mayo clinic, where the elderly were found to experience more esophagitis and pneumonitis compared with their younger counterparts [52
, 53
].
In conclusion, this analysis suggests that baseline hemoglobin and PS are predictive of survival in patients receiving therapy for stage III NSCLC. In addition, CMT also improved survival in this analysis, which is consistent with prospective randomized phase III trials addressing this issue. It should be stressed that this analysis was performed on stage III NSCLC patients meeting the eligibility criteria of each of the CALGB trials noted, and therefore may not be representative of the general lung cancer population. However, these observations are pertinent to the design and interpretation of clinical trials in this area, as differences in distribution of these factors amongst trials may account for differences in survival outcomes reported. The observation regarding the impact of anemia is both interesting and logical, and is worthy of investigation in subsequent prospective, randomized trials testing whether correction and maintenance of a threshold level of hemoglobin could influence survival.
Received for publication January 9, 2004. Revision received February 18, 2004. Accepted for publication February 27, 2004.
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