Stage IB Nonsmall Cell Lung Cancers: Are They All the Same?

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1 ORIGINAL ARTICLES: GENERAL THORACIC GENERAL THORACIC SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Stage IB Nonsmall Cell Lung Cancers: Are They All the Same? David R. Jones, MD, Thomas M. Daniel, MD, Chadrick E. Denlinger, MD, Brian K. Rundall, DO, Mark E. Smolkin, MS, and Mark R. Wick, MD Departments of Surgery, Health Evaluation Sciences, and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia Background. There is renewed interest in adjuvant chemotherapy after complete resection of nonsmall cell lung cancer, including stage IB (T2N0) cancers. Given the heterogeneity of the T2 classification, we hypothesize that there are survival differences in patients with stage IB NSCLC based on specific histopathologic tumor characteristics. Methods. A retrospective evaluation of 119 consecutive patients from 1999 to 2004 with a pathologic diagnosis of T2N0 nonsmall cell lung cancer was performed. Patient follow-up was 97%. Overall survival and disease-free survival rates were calculated by the Kaplan-Meier method. Univariate analysis was performed using the log rank test and multivariate analysis by Cox s proportional hazard model. Data were significant if p < Results. The 4-year overall survival and disease-free survival rates were 62% and 60%, respectively. The local and distant recurrence rates were 5% and 18%, respectively. Tumor size (p 0.001), histologic grade (p 0.002), the Eastern Cooperative Oncology Group performance status (p 0.002), angioinvasion (p 0.03), and visceral pleural involvement (p 0.02) were predictors of overall survival by univariate analysis. Multivariate analysis demonstrated increasing tumor size (1.26 [95% confidence intervals 1.12, 1.64]) and histologic grade (4.05 [95% confidence intervals 1.38, 11.90]) to be significant independent predictors of a worse overall survival. The 4-year survival of patients without any of these variables was 89% compared with 56% if one or more of these factors were present (p 0.03). Conclusions. There is significant heterogeneity in the T2N0 class of nonsmall cell lung cancer. Risk stratification using specific histopathologic variables may help determine which patients will benefit most from adjuvant therapy. (Ann Thorac Surg 2006;81: ) 2006 by The Society of Thoracic Surgeons Despite an enhanced appreciation of complete nodal dissection and the need for an R 0 resection, the overall survival for pathologically staged T2N0M0 or stage IB nonsmall cell lung cancer (NSCLC) remains approximately 60% [1]. This modest result for node-negative NSCLC has been a source of frustration for thoracic surgeons and their patients. One explanation for the lower than expected survival of these patients is the heterogeneity in the T2 classification. The current T2 classification includes tumors that are greater than 3.0 cm, tumors that invade the visceral pleura regardless of size, tumors that involve the mainstem bronchus but are greater than or equal to 2 cm distal from the carina, and tumors that result in atelectasis or lobar collapse radiographically [1]. This T2 classification schema has remained unchanged for the past 30 years. Consideration of these criteria suggests that the T2 Accepted for publication Dec 7, Presented at the Fifty-first Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 2 4, Address correspondence to Dr Jones, Thoracic and Cardiovascular Surgery, PO Box , University of Virginia, Lee Street, 4th Floor, Suite 4823 Charlottesville, VA ; djones@virginia.edu. classification is based chiefly on tumor size and location, which is a simplistic approach at best, and an inaccurate one at worst. Advances in tumor biology have resulted in the evaluation of numerous proteins that may provide a more accurate, or at least a complimentary, prognostication tool compared with the current TNM staging system [2]. Although clinical application of molecular signatures in NSCLC remains a laudable goal, which subset of biologic markers to use and universal agreement on the type and method of technique for measurement of such markers continue to limit widespread use of biomarkers to help stage or recommend treatment to patients. Recent findings of the International Adjuvant Lung Cancer Trial suggest that adjuvant chemotherapy offers improved survival for R 0 resected pathologic stages IB to IIIA [3]. Similarly, analysis of the phase III multiinstitutional Cancer and Leukemia Group B 9633 trial suggests that adjuvant chemotherapy improves overall and disease-free survival in patients with resected T2N0M0 NSCLC [4]. What is unclear from these studies, and others [5], is whether all patients with pt2n0m by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg JONES ET AL 2006;81: STAGE IB NSCLC disease should receive chemotherapy, and, if not, whether there are criteria that may identify those patients who are likely to receive the most benefit from such an approach. Given the heterogeneity of the current T2 classification, the limitations with clinical applicability of biomarker(s), as well as the resurgence of interest in adjuvant chemotherapy, we sought to determine if specific histopathologic variables may help better define which patients with pt2n0m0 tumors had a worse prognosis, and thus may potentially serve as factors to consider in future clinical trial development and staging system revisions. Material and Methods We performed a retrospective analysis of our general thoracic surgery database for all patients who underwent an R 0 resection for a pt2n0m0 NSCLC at the University of Virginia from July 1999 to January The project was approved by our institutional review board. A total of 119 consecutive patients undergoing resection for a pathologic stage IB disease were identified. Patients who underwent a nonanatomic wedge resection were excluded. Patients who had a carcinoid tumor and those patients who were receiving either induction or adjuvant therapy were also excluded. Patient demographics, performance status, tumor location, type of resection, and overall and disease-free survivals were documented. The criteria for T2 classification were also noted. Specific histopathologic variables evaluated included tumor histology, tumor size, histologic grade, the presence of lymphatic invasion, angioinvasion, or visceral pleural involvement. Low histologic grade was defined as well-differentiated or mildly-differentiated lesions, whereas high-grade tumors had moderately-differentiated or poorly-differentiated lesions. Finally, the site of first recurrence was documented. Follow-Up Patient follow-up was complete in 97% of the study patients. A combination of medical records, tumor registry, and telephone interviews were used to document survival and the presence of any recurrence of their disease. Median follow-up was 25 months (range, 1 to 55 months). Statistical Evaluation Basic summary statistics including frequencies and percentiles were calculated. Kaplan-Meier survival estimates and 95% confidence intervals were obtained for overall survival (OS) and disease-free survival (DFS), both overall and univariately for each of several possible categorical predictors. Log rank tests were used to assess differences in survival across levels of these predictors. Similarly, univariate Cox proportional hazard modeling was used to examine continuous predictors. Multivariate Cox proportional hazards models yielded estimated hazard ratios and 95% confidence intervals used to examine relationships between survival and several predictors of interest. Furthermore, in the Cox proportional hazards context, a more flexible method of modeling a continuous predictor, the restricted cubic spline, was used as needed Table 1. Patient Characteristics Sex Male 68 Female 51 Age (median) 68 (range, 37 88) ECOG performance status Operative procedure Segmentectomy 11 Lobectomy (open) 80 Lobectomy (sleeve) 8 Lobectomy (VATS) 5 Bilobectomy 7 Pneumonectomy 8 Operative mortality 5/119 (4%) VATS video- ECOG Eastern Cooperative Oncology Group; assisted thoracic surgery. to model more complex relationships between survival and a particular predictor. Results 1959 There were a total of 111 (92%) tumors with a tumor size greater than 3.0 cm, 44 (37%) with visceral pleural involvement, 16 (13%) in which the tumor was greater than or equal to 2.0 cm from the carina, and 12 (10%) with lobar collapse. Tumors were classified as T2 lesions after pathologic analysis based on tumor size alone (n 63) or visceral pleural involvement alone (n 9), whereas the remainder of the patients had some combination of criteria (n 47). No patient was classified as a T2 lesion on the basis of hilar atelectasis or lobar collapse or proximity to the carina in the absence of other criteria. As shown in Table 1, there were slightly more men than women, with the median age being 68 years. The majority of patients had an Eastern Cooperative Oncology Group performance status of 0, whereas 38% of patients had a higher performance status. Seventy-eight percent of patients had their tumor resected with a lobectomy, whereas only 7% of patients required a pneumonectomy. The in-hospital mortality rate was 4%, with the cause of death being cardiac (2), pneumonia (2), and pulmonary embolus (1). Evaluation of the histopathologic variables (Table 2) shows there was a median tumor size of 4.5 cm (range, 0.9 to 14 cm). Nearly 40% of the patients had a tumor size greater than or equal to 5 cm. Approximately one-third of patients had visceral pleural involvement, whereas roughly 20% had angioinvasion, and 20% had lymphatic invasion. Importantly, only 33 of 116 (28%) of the tumors had a low-grade histology and an absence of angioinvasion, visceral pleural involvement, and lymphatic invasion. The 4-year OS was 62% (95% confidence intervals 52%, 70%) and the DFS was 61% (95% confidence intervals 51%, 69%). Sixteen patients (13%) died from their cancer and 15 (13%) died from other causes, most commonly GENERAL THORACIC

3 1960 JONES ET AL Ann Thorac Surg STAGE IB NSCLC 2006;81: Table 2. Tumor Histopathologic Variables Histology Squamous 55 Nonsquamous 64 Tumor size (median, cm) 4.5 (range, ) T 3.0 cm 9 T cm 62 T 5.0 cm 47 Histologic grade Low grade 67 High grade 50 Visceral pleural Present 43 Absent 75 involvement Angioinvasion Present 23 Absent 94 Lymphatic invasion Present 21 Absent 97 cardiovascular (8) or pulmonary (4) causes. Univariate analysis demonstrated that the presence of an increasing tumor size, the Eastern Cooperative Oncology Group performance status, visceral pleural involvement, angioinvasion, and higher histologic grade were associated with worse OS, whereas all of these as previously listed, except visceral pleural involvement, were also associated with shorter DFS (Table 3). Interestingly, tumor histology, the Eastern Cooperative Oncology Group performance status, and the presence of lymphatic invasion were not poor prognostic indicators. Subsequent multivariate analysis of variables that were significant on univariate analysis of both OS and DFS demonstrated that tumor size (as a continuous variable) was predictive of worse OS and DFS (Table 4). In addition, higher tumor histologic grade was associated with an increased risk of death, but not worse DFS. In contrast, the presence of angioinvasion had the highest hazard ratio (ie, 3.35) for having recurrent disease develop. Evaluation of tumor recurrence patterns (Table 5) demonstrates that 28 of 119 (23%) patients had a recurrence of their cancer develop. The locoregional and distant recurrence rates were 5% and 18%, respectively. The low number of locoregional recurrences prevented any accurate analysis of associated factors. In contrast, more than 50% of patients with a distant recurrence had a larger tumor size (tumor size 5 cm) or high-grade tumor histology. Finally, as shown in Figure 1, the 4-year OS of patients with smaller tumors ( 5.0 cm) and no evidence of angioinvasion and lower-grade tumor histology (n 25 of 108 [23%]) is superior to patients with one or more of the histopathologic variables (p 0.03). The actual OS for the low-risk versus high-risk groups are as follows: at 1 year, 96% (confidence interval [CI], 88%, 100% vs 95% (CI, 90%, 99%); 2 year, 96% (CI, 88%, 100%) vs 76% (CI, 66%, 88%); 3 years, 88% (CI, 74%, 100%) vs 56% (CI, 41%, 75%); and 4 year, 88% (CI, 74%, 100%) vs 51% (CI, 36%, 75%). Similar results were seen with DFS in which patients without any of the previously listed variables compared with patients with one or more of the variables had survival estimates of 87% (95% CI, 60%, 96%) and 47% (95% CI, 36%, 56%) (p 0.01). Comment Stage IB NSCLC is the most common pathologic stage accounting for 29% of resected pathologic stages IA to IIIA [1]. The incidence of new cases of lung cancer in the United States in 2004 is 174,000, of which approximately 139,000 are NSCLC [6]. Accepting that 25% to 30% of these patients would be offered surgery based on a clinical stage of I, II, and selected IIIA disease [7], this translates into an estimate of 12,000 patients with pathologic stage IB disease annually in the United States. Thus the number of patients with pathologic stage IB NSCLC is significant being only slightly less than all new cases annually of esophageal cancer [6]. Despite advances in the imaging of lung cancer, as well as a better understanding of its tumor biology, there have been no significant changes to the staging system to reflect this progress. Although there remains significant hope for using immunohistochemical protein analysis or other molecular biology or gene-array analyses of tumors to prognosticate and guide therapy, published results for the majority of such biomarkers are frequently conflicting, and their use in clinical practice has been limited to a discouragingly few clinical trials. In contrast, basic histopathologic tumor variables are uniformly utilized and reported [8], although their ability to guide adjuvant therapy has never been rigorously evaluated. We believe that this is the first study that has evaluated all of these variables with respect to pathologic stage IB NSCLC only. As shown in our data, the classification of a T2 lesion is largely based on either size or visceral pleural invasion criteria, with no patient being classified solely on the presence of atelectasis or lobar obstruction or the 2 cm carinal proximity rule. This suggests that the latter stated two T2 criteria could be omitted in future iterations of the staging system. Given the 57% 5-year survival for pathologic staged T2N0M0 NSCLC [1], it is highly likely that there are unrecognized tumor biologic variables in the current staging classification that account for worse prognosis Table 3. Univariate Analysis for Overall and Disease-Free Survivals Overall Survival p Values a Disease-free Survival Sex Performance status Operative procedure Tumor histology Tumor size Visceral pleural involvement Angioinvasion Lymphatic invasion Histologic grade (low vs high) a p 0.05 considered significant. All variables with a positive p value are associated with a worse prognosis.

4 Ann Thorac Surg JONES ET AL 2006;81: STAGE IB NSCLC Table 4. Multivariate Analysis for Overall and Disease-Free Survivals Overall Survival p Value a Disease-free Survival p Value a Tumor size 1.26 (1.07, 1.49) p (1.10, 1.65) p Angioinvasion 1.84 (0.73, 4.69) p (1.37, 8.20) p Histologic grade 4.05 (1.38, 11.90) p (0.73, 4.46) p GENERAL THORACIC a p 0.05 considered significant. All variables with a positive p value are associated with a worse prognosis. Overall survival and disease-free survival data presented as the hazard ratio with (95% confidence intervals). than would be expected for node-negative NSCLC. In an analysis of isolated stage IB patients, Padilla and colleagues [9] found that tumor size was the only predictive variable for a worse prognosis. The importance of tumor size in T2 lesions has also been emphasized by Carbone and colleagues [10] who have a shown 5-year survivals of 62% and 51% for T2NO lesions greater than 3.0 cm and less than or equal to 5.0 cm, and greater than 5.0 cm, respectively. Similarly several authors have identified visceral pleural invasion to be an independent negative prognosticator in stage IB patients as well as other stages [11 13]. Our study confirmed that both increasing tumor size (as a continuous variable) and histologic tumor grade were significant predictors of a decreased overall survival (Table 4). Moreover, tumor size and tumor angioinvasion were both predictors of a worse OS and DFS on multivariate analysis. These results suggest that the histopathologic analysis of tumor size, histologic grade, and angioinvasion may permit the identification of a suset of T2N0 patients that have a high likelihood of having recurrent disease develop. An examination of these variables and their association with either locoregional or distant recurrence reveals that more than 50% of patients with distant recurrence had high-grade tumor histology and larger tumors ( 5.0 cm) Table 5. Recurrence Patterns After Resection (Table 5). In addition, the presence of visceral pleural invasion or tumor angioinvasion was also found in 36% and 27%, respectively, of patients with distant recurrence. Evidence of the impact of these variables on overall survival is demonstrated in Figure 1 in which those patients with smaller tumors sizes ( 5.0 cm), no angioinvasion, and a low-grade histology had a significantly superior 4-year survival of 89% compared with a 56% survival for patients with one or more of these variables. Similar significant results were seen with disease-free survivals (data not shown). Identification of which patient is at high-risk for recurrence and cancer death after resection of their stage IB NSCLC is important. Historically, the use of adjuvant chemotherapy after an R 0 resection for patients with any stage NSCLC has not been a standard practice as there has been no demonstrated survival benefit [14]. Similarly there has been no demonstrable survival benefit for adjuvant radiation therapy in pathologic T2N0 lesions [15]. The treatment paradigm of post-resection observation has recently been challenged as the results of four, prospective, randomized, phase III studies have demonstrated a significant survival benefit with adjuvant chemotherapy after resection [3 5, 16]. Focusing only on stage IB disease, the Cancer and Leukemia Group B 9633 demonstrated a 4-year overall survival of 71% and 59% with adjuvant doublet chemotherapy and observation, respectively [4]. In addition, the Cancer and Leukemia N (%) Locoregional recurrence 6/119 (5) Tumor size 5 cm 3 (50) Angioinvasion 3 (50) Lymphatic invasion 2 (33) Visceral pleural involvement 2 (33) High-grade histology 3 (50) Distant recurrence a 22/119 (18) Location Brain 10 (45) Bone 5 (23) Other 7 (32) Tumor size 5 cm 13 (59) Angioinvasion 6 (27) Lymphatic invasion 4 (18) Visceral pleural involvement 8 (36) High-grade histology 14 (67) a One patient had combined locoregional and distant recurrences and is counted in the distant recurrence group. Fig 1. Kaplan-Meier graph of overall survival in patients with no high-risk variables (ie, increasing tumor size, angioinvasion, and higher histologic grade) compared with patients with one or more of these variables.

5 1962 JONES ET AL Ann Thorac Surg STAGE IB NSCLC 2006;81: Group B 9633 does have biologic data for their study, that once published, may offer additional insight into which variables may be important in predicting a response to adjuvant chemotherapy. Our 4-year survival of 62% is nearly identical to those results, although our lung cancer-specific mortality is only 13% compared with 26% in their study. In contrast, the International Adjuvant Lung Cancer Trial study demonstrated a 4.1% absolute overall survival benefit with adjuvant chemotherapy at 5 years for stages IB to IIIA. Although not adequately powered to detect differences between stages, it is interesting to note that there was no survival benefit for stages IA (n 183) and IB (n 498) disease [3]. This suggests certain subsets, but not all, of patients with NSCLC may benefit from adjuvant chemotherapy, and it highlights the need for appropriate risk stratification criteria. The limitations associated with our article include the fact that it is retrospective and it is from a single institution. Although these are valid criticisms, all patient data is entered into our general thoracic surgery database concurrent with their care, and by the very nature of this type of analysis, an initial retrospective analysis is required. In addition, the number of patients available for review is reasonably robust, although a larger cohort may have permitted the identification of other significant prognostic factors. Finally, our data do not permit any direct correlation of these histologic variables and any potential survival benefits to adjuvant chemotherapy. In conclusion, our data confirms the heterogeneous nature of the current stage IB classification and suggests that all stage IB NSCLC is not the same. We demonstrate that subset analysis of this stage, based on uniformly recognized and reported tumor histopathologic features, may better identify patients with T2N0 lesions who may benefit from adjuvant therapy. Specifically, these include tumor size, histologic grade, and the presence of angioinvasion. These findings need confirmation by either other large-scale retrospective reviews or prospective analyses, and when done, these should be considered for incorporation into future clinical trials for adjuvant therapy and in revisions of the staging system. References 1. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111: Molina R, Filella X, Auge JM, et al. Tumor markers (CEA, CA 125, CYFRA 21-1, SCC and NSE) in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis. Comparison with the main clinical and pathological prognostic factors. 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Randomized study of adjuvant chemotherapy for completely resected stage I, II or IIIA non-small cell lung cancer. J Natl Cancer Inst 2003;95: Lafitt J, Ribet M, Prevost B, Gosselin B, Copin M, Brichet A. Postresection irradiation for T2N0M0 non-small cell lung cancer: a prospective, randomized study. Ann Thorac Surg 1996;62: Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med_2004;350: DISCUSSION DR ROBERT J. CERFOLIO (Birmingham, AL): Dave, very, good work, excellent. I saw you said the majority of the patients had positron-emission tomography (PET), but I did not see that you showed the standard uptake value (SUV) data. And the reason I am interested in that is there is some data, and we have a paper coming out on over 300 patients in the Journal of Cardiothoracic Surgery in January that shows that the maximum SUV, which is now standardized in the software packages contained within the PET machine itself, which should be the same all over the world, is a predictor of lymphovascular invasion, lymph node involvement with cancer, and is a better predictor of survival and recurrence than the current TNM staging classification system. This is incredibly powerful data and I wonder if you have maximum SUV data that can corroborate this in your experience? DR JONES: Thank you, Dr Cerfolio. When we put together the manuscript and began to look at what is coming out in the literature about maximum SUV values with respect to prognostication, I wish we would have had those maximum SUV numbers, but we do not. One problem is that probably 50% of the patients had their PET scan at University of Virginia and the other 50% had outside studies. So even with a retrospective analysis, I could probably only identify an SUV value on maybe 60 or so of these patients.