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Failure Rates and Patterns of Recurrence in Patients With Resected N1 Non–Small-Cell Lung Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 2, pp. 353–359, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.05.022
CLINICAL INVESTIGATION
Lung
FAILURE RATES AND PATTERNS OF RECURRENCE IN PATIENTS WITH RESECTED N1 NON–SMALL-CELL LUNG CANCER JOHN M. VARLOTTO, M.D.,* LAURA NYSHEL MEDFORD-DAVIS, B.A.,y ABRAM RECHT, M.D.,yz JOHN C. FLICKINGER, M.D.,x ERIC SCHAEFER, M.S.,{ AND MALCOLM M. DECAMP, M.D.k *Penn State Hershey Cancer Institute, Hershey, PA; yHarvard Medical School; zDepartment of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA; xDepartment of Radiation Oncology, Pittsburgh Cancer Institute, Pittsburgh, PA; {Department of Public Health Sciences, Pennsylvania State University, Hershey, PA; and kDivision of Thoracic Surgery, Department of Surgery, Northwestern Memorial Hospital, Chicago, IL Purpose: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non–small-cell lung cancer. Methods and Materials: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence. Results: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site of local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure. Conclusions: Patients with resected non–small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy. Ó 2011 Elsevier Inc. Pattern of recurrence, N1 nodal involvement, Lung cancer, Surgical resection, Chemotherapy. Beth Israel Deaconess Medical Center, Boston; and the Denver and Boston Department of Veterans Affairs hospitals. Hospital and departmental tumor registries were used to identify all patients undergoing potentially curative resection of Stage I-IIIA NSCLC from 2000 to 2006. Patients were included in the study population if they had postoperative follow-up of at least 3 months, no second primary cancer diagnosed within 5 years of the index lung cancer, and no neoadjuvant or adjuvant radiotherapy. Medical records were reviewed for each patient to ensure eligibility. Of the total of 524 patients accrued, 60 patients had N1 disease and formed the study group for this report. Multiple factors potentially related to outcome were abstracted from the available medical records. Patient-related and staging factors were as follows: age; weight loss; preoperative hemoglobin; body mass index; presenting symptoms (cough, hemoptysis, dyspnea, or none); pulmonary function test results (FEV1–forced expiratory volume in one second, FEV1%–FEV1 percentage, and DLCO%–diffusing lung capacity for carbon monoxide percentage); smoking status (never, quit more than 2 years prior to surgery, quit 1–2 years prior to surgery, quit 6 months to 1 year prior to surgery, quit 30 days to 6 months before surgery, or smoking at present); drinking of alcoholic beverages (never, quit more than 2 years prior to surgery, quit between 1 and 2 years prior to surgery, quit 6 months
INTRODUCTION Several recent trials initially found that chemotherapy improved survival rates in patients with resected non–smallcell lung cancer (NSCLC) (1–4). However, with further follow-up this benefit was lost in some (5, 6) but not all studies (3, 7). Because all the initially positive trials suggested a benefit in patients with Stage II or Stage III disease, we chose to investigate whether patients with N1 nodal involvement might experience delayed local recurrence, which could overcome the initial impact of chemotherapy. We also explored the impact of clinical, pathologic, and treatment factors on the risk of both local and distant relapse. Finally, we used the Surveillance, Epidemiology and End Results (SEER) database to estimate what proportion of patients have resected N1 disease and hence might be affected by our results. METHODS AND MATERIALS This retrospective study was conducted with approval of the institutional review boards of the Penn State Hershey Cancer Institute; Reprint requests to: John M. Varlotto, M.D., Penn State Hershey Cancer Institute, Radiation Oncology–CH63, 500 University Drive, PO Box 850, Hershey, PA 17033-0850. Tel: (717) 531-8024; Fax: (717) 531-0882; E-mail: [email protected]
Conflict of interest: none. Received March 31, 2010, and in revised form May 11, 2010. Accepted for publication May 12, 2010. 353
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to 1 year prior to surgery, quit 30 days to 6 months prior to surgery, drinking at present); number of drinks per week; long-term use of steroids; history of intercurrent illnesses (diabetes, hypertension, myocardial infarction, coronary artery disease, cardiac rhythm disturbance, coronary artery bypass graft, cerebrovascular accidents, renal failure, thromboembolic disease); performance of staging positron emission tomography—computed tomography (PET-CT) at diagnosis; medication use at diagnosis (aspirin, statins, nonsteroidal antiinflammatory drugs); and hemoglobin and albumin values within 30 days prior to surgery. Surgery-related factors recorded included operative time; fluid balances during surgery (urine output, estimated blood loss, fluids infused, total excess intraoperative fluids (assuming one unit of packed red blood cells to be 300 cc); transfusions (total number of units required within 90 days of surgery, number of units required within the first day, number of units required within 2–4 days, and number of units after 4 days); type of resection (wedge resection, segmentectomy, lobectomy/bilobectomy, pneumonectomy); type of lymph node staging procedure; intraoperative and postoperative complications (pulmonary infection or pneumonia, adult respiratory distress syndrome, arrhythmias and their type (supraventricular tachycardia, ventricular tachycardia, or nonspecific), fistula formation, stump leak, prolonged air leak, anastomosis leak, mediastinitis/empyema, myocardial infarction, death, pulmonary embolus, deep venous thrombosis, and brachial plexus injury; length of hospital stay; and surgeon. Histopathologic factors recorded included tumor size; tumor grade (categorized as grade ‘‘1.5’’ when recorded as well to moderately differentiated and grade ‘‘2.5’’ when recorded as moderately to poorly differentiated); performance/positivity of previous fine-needle aspiration biopsy; lymphatic or vascular invasion (LVI); perineural invasion; margin status; extracapsular lymph node involvement; details of node resection (number resected, lymph node level resected, number of N1 nodes resected, number of N2 nodes resected, number of nodal stations sampled at mediastinoscopy, number of nodal stations examined during resection); histology (NSCLC not otherwise specified, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, neuroendocrine carcinoma, bronchioloalveolar carcinoma, adenocarcinoma with bronchioloalveolar features); tumor lobe location; and invasion of the visceral pleura. Details of chemotherapy recorded included type of chemotherapy (carboplatin and paclitaxel, cisplatin and navelbine, cisplatin and etoposide, other cisplatincontaining regimens, gemcitabine-containing combinations, other regimen); treatment sequencing (giving chemotherapy preoperatively, postoperatively, or both); and number of cycles. Patterns of failure were determined using physician clinical assessment, radiographic reports, and/or review of imaging studies as previously reported (8, 9). Local failures were defined as those occurring in the ipsilateral lungs and the N1–N3 nodal basins; all other failures were defined as distant. Patients were scored as having a nodal recurrence when a new or enlarging node measured more than 1 cm in short axis on follow-up CT. For patients who underwent PET-CT at the time of recurrence, all sites of abnormal uptake that correlated with lymph node or soft tissue mass were scored regardless of size. When available, data from bronchoscopy, biopsy, or mediastinoscopy were used to supplement the radiographic findings. Only the initial sites of recurrence were scored. Patients with simultaneous local and distant failures were scored as having both types of failure. Information on failure sites was reviewed by two of the authors (J.M.V., L.M.D.) for consistency between the radiologic, bronchoscopic, and/or pathologic studies. Computerized tomography studies from the Boston Veterans Administration, Penn State Hershey Cancer Institute, and Beth Israel
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Deaconess Medical Center were available for review. CT or PETCT was performed at more than 98% of all follow-up visits at these specialized thoracic oncology programs. The median follow-up was 30 months (range, 3–96 months). Recurrence rates at 2, 3, and 5 years were calculated by the method of Kaplan and Meier. Cox proportional hazards regression was used to assess risk factors for local and distant recurrence. Because of the limited number of local and distant failures, only univariate analysis was conducted. The SEER Database-17 (10) was accessed for the years 1988– 2006 to assess the proportion of all patients with NSCLC with Stage II disease and the frequency of N1 disease in patients who underwent resection.
RESULTS Presenting characteristics, treatment factors, and histopathologic characteristics can be seen in Table 1. Chemotherapy was given preoperatively and postoperatively to 4 and 20 patients, respectively. Chemotherapeutic regimens included carboplatin/paclitaxel in 12 patients, cisplatin/navelbine in 1 patient, cisplatin/etoposide in 1 patient, other cisplatincontaining regimens in 3 patients, gemcitabine combinations in 2 patients, and other regimens in 5 patients. Eighteen patients experienced local failure, for a crude rate of 30%. The actuarial rates at 2, 3, and 5 years were 33%, 33%, and 46%. Table 2 shows the combinations seen of specific sites of local failure (one or more per patient). The most common was the mediastinum only (5 patients). Theipsilateral mediastinum was one of the failure sites in 12 patients, the ipsilateral lung in 3, the ipsilateral hilum in 2, the subcarinal area in 2, the contralateral mediastinum in 2, the bronchial stump in 3, and the ipsilateral supraclavicular area in 1 patient. Twelve of the18 patients (67%) had local recurrences that would have been included within postoperative radiotherapy fields, including the bronchial stump/staple line, subcarinal area, ipsilateral mediastinum, and contralateral mediastinum (Fig. 1). Factors included in the Cox model for their effect on local failure are shown in Table 3. Chemotherapy was the only treatment that was statistically significant (hazard ratio [HR] 3.25, p = 0.0192) (Fig. 2). The distribution of other variables in relationship to the use of chemotherapy was significantly different only for length of stay (p = 0.0033) and performance of PET-CT (p = 0.0069). That is, 65% of patients receiving chemotherapy had staging with PET-CT, compared to 28% of patients not receiving chemotherapy; the respective lengths of stay in these two groups were 5 days and 7 days. Fourteen patients, or 23%, experienced distant failure as a first site of failure. Rates at 2, 3, and 5 years were 26%, 26%, and 32%, respectively. Specific sites of distant recurrence (one or more per patient) were brain (n = 5), bone (n = 5), contralateral lung (n = 2), and other (n = 2). Three variables significantly affected the risk of distant failure (Table 4): the number of nodes resected (p = 0.0497, HR = 1.07); the number of positive nodes (p = 0.0029, HR = 1.32), and performance of a pneumonectomy (p =
Recurrence of surgically resected N1 non-small-cell lung cancer d J. M. VARLOTTO et al.
Table 1. Clinical, pathologic, and treatment characteristics of the study population Characteristic Age (y) Mean Median (range) Diabetes Body mass index Unknown Mean (SD) Median (range) Sex M F History of myocardial infarction History of coronary artery disease Tumor size (cm) Unknown Mean (SD) Median (range) Histology NSCLC, NOS Squamous Adenocarcinoma Large cell Bronchoalveolar Adenocarcinoma and bronchoalveolar T stage T1 T2 T3–4 Number of positive nodes Mean (SD) Median (range) Grade Unknown Mean (SD) Median (range) Lymphovascular invasion present Resection type Lobectomy/bilobectomy Pneumonectomy Number of resected nodes Mean (SD) Median (range) Length of post-op stay (days) Mean (SD) Median (range) PET-CT for initial staging Unknown Yes No Received chemotherapy
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Table 2. Patterns of local failure for each of the 18 patients Site
Frequency (n = 18)
Ipsilateral mediastinum Ipsilateral mediastinum and lung Bronchial stump/staple line Ipsilateral and contralateral mediastinum Ipsilateral mediastinum, hilum, and supraclavicular area Ipsilateral mediastinum and subcarinum Ipsilateral lung Ipsilateral mediastinum and bronchial stump/staple line Ipsilateral hilum Subcarinal area Chest wall
5 (28%) 2 (11%) 2 (11%) 2 (11%) 1 (6%)
Determination 64.8 65.5 (47–86) 10 (17%) 6 (10%) 27.6 (5.01) 26.7 (18.3–42.5) 75% 25% 5 (8%) 15 (25%) 2 (3%) 4.1 (2.42) 3.5 (1–12) 4 (7%) 28 (47%) 19 (32%) 3 (5%) 2 (3%) 4 (7%) 22 (37%) 31 (52%) 7 (12%) 2.3 (2.8) 2 (1.0–20) 4 (7%) 2.4 (0.63) 2.0 (1–4) 20 (33%) 48 (80%) 12 (20%) 10.9 (7.45) 10 (2–39)
1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%)
tively. Both local and distant failure rates were significantly worse for the N1 patients (p = 0.03 and 0.01, respectively). Death rates for patients with N1 disease at 2, 3, and 5 years were 34%, 46%, and 59%, respectively. Only the number of nodes resected (p = 0.0042, HR = 1.08), the number of nodes positive (p = 0.0071, HR = 1.20), and the presence of LVI (p = 0.0532, HR = 2.04) were significantly associated with a survival decrement in the Cox model (Table 5). Actuarial survival rates in relation to LVI are shown in Fig. 5. The incidence of Stage II NSCLC as a percentage of all presenting stages and the incidence of N1 nodal stage as a percentage of all patients undergoing resection of NSCLC in the SEER database from 1988 to 2006 (grouped into 2-year intervals) are shown in Fig. 6. Stage II NSCLC and N1 nodal disease were found in 2.7–5% and 11–18% of patients during these years, respectively. DISCUSSION Stage II NSCLC and N1 nodal disease are relatively uncommon, constituting 2.7–5% and 11–18% of patients, respectively, in the SEER database from 1988 to 2006. Similarly, patients with resected N1 disease represented 11.5% of our total patient population with surgically resected NSCLC. Nonetheless, these patients seem to be at substantial
8.3 (8.62) 6.5 (3–69) 1 (2%) 25 (42%) 34 (58%) 24 (40%)
Abbreviations: NOS = not otherwise specified; NSCLC = nonsmall cell lung cancer; SD = standard deviation; PET-CT = positron emission tomography—computed tomography.
0.0041, HR = 4.66). The risk of distant failure in relation to the use of pneumonectomy is shown in Fig. 3. Local and distant failure rates for the 60 patients with N1 disease were compared to those of 440 patients with N0 disease in our database (Fig. 4). Local failure rates in the latter group at 2, 3, and 5 years were 15%, 20%, and 29%, respectively; distant failure rates were 11%, 13%, and 19%, respec-
Fig. 1. Proposed postoperative radiation therapy portals.
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Table 3. Cox proportional hazards regression model for local failure Variable Chemotherapy treatment Lymphovascular invasion Diabetes Histology, nonsquamous Tumor location Grade No. of nodes resected No. of positive nodes Tumor size Body mass index Age Resection type, pneumonectomy Length of stay Performance of PET scan T stage
p value Hazard ratio (95% CI) 0.0192 0.0790 0.1939 0.31 0.3081 0.9784 0.9160 0.5823 0.8571 0.3649 0.4313 0.9000 0.3698 0.1014 0.6879
3.248 (1.21–8.71) 2.318 (0.91–5.92) 1.993 (0.70–5.64) 0.62 (0.24–1.58) 1.6 (0.63–4.27) 0.990 (0.49–2.02) 1.01 (0.93–1.09) 0.90 (0.63–1.30) 0.98 (0.82–1.19) 0.95 (0.85–1.06) 0.98 (0.93–1.03) 1.08 (0.31–3.77) 0.93 (0.80–1.09) 2.30 (0.85–6.20) 1.21 (0.48–3.07)
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Table 4. Cox proportional hazards regression model for distant failure Variable Chemotherapy treatment Lymphovascular invasion Diabetes Histology, nonsquamous Tumor location Grade No. of nodes resected No. of positive nodes Tumor size Body mass index Age Resection type, pneumonectomy Length of stay Performance of PET scan T stage
p value Hazard ratio (95% CI) 0.9261 0.4599 0.3401 0.8547 0.2609 0.0777 0.0497 0.0029 0.4536 0.4868 0.2549 0.0041 0.6328 0.5978 0.1837
1.054 (0.35–3.20) 1.514 (0.50–4.55) 0.371 (0.05–2.84) 1.104 (0.38–3.19) 0.472 (0.13–1.75) 0.46 (0.19–1.09) 1.07 (1.00–1.15) 1.32 (1.10–1.58) 1.08 (0.89–1.30) 1.04 (0.89–1.30) 0.97 (0.91–1.03) 4.66 (1.63–13.34) 0.98 (0.90–1.07) 1.34 (0.46–3.93) 0.42 (0.12–1.51)
Abbreviations: HR = hazard ratio; CI = confidence interval; PET = positron emission tomography.
Abbreviations: HR = hazard ratio; CI = confidence interval; PET = positron emission tomography.
risk of local recurrence, and have higher rates of local recurrence than distant failure. Of interest, in our study, patients receiving chemotherapy were at higher risk of local failure than were other patients. This suggests that chemotherapy may be preventing or delaying the development of distant recurrences and thus allowing local failures to become clinically evident. However, given that chemotherapy was not assigned to patients in a randomized fashion in our study, it may have been used more often in patients with clinical and pathologic factors that predisposed them to a higher risk of local recurrence before the initiation of therapy. Both the Adjuvant Navelbine International Trialist Association (ANITA) and the International Adjuvant Lung Cancer Trial (IALT) trials showed fewer local recurrences in patients
receiving chemotherapy than in control patients (3, 6). However, patients in the ANITA trial were monitored for recurrence either by clinical examination or by radiographic studies, whereas it is not clear how the patients in the IALT trial were assessed for recurrence. Also, local recurrence was not defined explicitly in the IALT trial (1, 6). Our study used routine CT or PET-CT and hence was more likely to have detected asymptomatic intrathoracic recurrences than were these two randomized trials. Also, most patients in our study received carboplatin and paclitaxel, which may not have be as effective at preventing late local failures as other regimens (11–14) such as cisplatin-vinorelbine (15). However, it has not yet been shown that cisplatin-containing combinations, or more
Fig. 2. Local failure rates in relation to use of chemotherapy.
Fig. 3. Distant failure rates in relation to the extent of surgery.
Recurrence of surgically resected N1 non-small-cell lung cancer d J. M. VARLOTTO et al.
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Fig. 4. Local and distant failure rates for patients with N0 and N1 disease.
specifically cisplatin-vinorelbine, are more effective at preventing local recurrences than other regimens. A summary of the Phase III trials demonstrating a survival benefit with chemotherapy in Stage II/III NSCLC can be seen in Table 6. It is interesting to note that local recurrence is not defined for two of the trials and that none of the studies required close follow-up with CT scans. Therefore, the ability of these trials, which were investigating overall survival as their primary endpoint, to properly assess local recurrence may be limited. Two-thirds of all recurrences would be contained within a proposed postoperative radiation therapy portal encompassing the bronchial stump, the anastomosis, the hilum, the subcarinal area, and the ipsilateral and contralateral mediastinum
Fig. 6. (A) Incidence of Stage II NSCLC as a percentage of all presenting stages, 1988–2006. (B) Incidence of N1 nodal stage as a percentage of all resected NSCLC, 1988–2006.
Fig. 5. Overall survival rates in relation to lymphovascular invasion.
(Fig. 1). Would such treatment be safe? The Postoperative Radiotherapy (PORT) meta-analysis demonstrated a survival decrement in patients with resected N1 disease who received adjuvant radiotherapy (16). Although the allocation of radiotherapy was not randomized in the ANITA trial, a similar survival decrement was noted in N1 patients treated with adjuvant radiotherapy, despite a survival benefit being found in irradiated patients with N2 disease (17). However, the IALT trial (which also did not randomly assign patients to radiotherapy) found that radiotherapy had no effect on the incidence of cardiopulmonary death (HR = 0.86) or second cancers (HR = 0.82). Likewise, there was no increase in deaths from intercurrent disease noted in patients receiving adjuvant radiotherapy for Stages II and III NSCLC in Eastern
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Table 5. Cox proportional hazards regression model for survival
Cooperative Oncology Group trial E3590, compared to agematched and gender-matched control participants (18). It is important to remember that the survival decrement from postoperative radiotherapy noted in patients with surgically resected N1and N0 disease in the PORT meta-analysis may have been due to outdated radiation techniques such as opposed lateral portals, 60Co radiation, hypofractionated treatments, and excessive radiation volumes (9, 16). It is of great interest to note that by using modern techniques, investigators from Universita Cattolica del S. Cuore in Rome found that adjuvant radiotherapy for patients with surgically-resected N0 patients was associated with significantly higher rates of local control, disease-free survival, and overall survival (19). Figure 4 demonstrates that both patient groups with surgically resected N0 and N1 NSCLC had higher rates of local rather than distant failure. We believe that it may be beneficial for all patients undergoing surgical resection of NSCLC to undergo a prospective evaluation to assess who is at risk for local failure. As noted in one of our previous publications (8), nodal stage may not be associated with local recurrence.
p value Hazard ratio (95% CI)
Variable Chemotherapy treatment Lymphovascular invasion Diabetes Histology, nonsquamous Tumor location Grade No. of nodes resected No. of positive nodes Tumor size Body mass index Age Resection type, pneumonectomy Length of stay Performance of PET scan T stage Past myocardial infarction History of coronary artery disease
0.5564 0.0532 0.3204 0.6195 0.2643 0.4145 0.0042 0.0071 0.4589 0.3526 0.8422 0.2392 0.5187 0.5266 0.5404 0.9965 0.5472
1.25 (0.60–2.61) 2.04 (0.99–4.22) 0.544 (0.16–1.81) 0.83 (0.41–1.71) 0.63 (0.28–1.41) 0.78 (0.43–1.41) 1.08 (1.02–1.14) 1.20 (1.05–1.38) 0.95 (0.82–1.10) 0.96 (0.89–1.05) 0.99 (0.96–1.04) 1.63 (0.72–3.69) 0.99 (0.94–1.03) 1.28 (0.60–2.75) 0.79 (0.37–1.69) 0.99 (0.30–3.36) 1.274 (0.58–2.80)
Abbreviations: HR = hazard ratio; CI = confidence interval; PET = positron emission tomography.
Table 6. Phase III trials demonstrating a survival benefit for chemotherapy in patients with surgically resected NSCLC
Trial
Mdn F/U n (y)
Stage
ANITA (3) 840
6.4
IB–IIIA IB 36% II 24% IIIA 39%
JBR10 (7) 482
9.3
IB–II IB 45% II 55%
1867 7.5
I–III I 36% II 24% III 40%
IALT (6)
RT Policy
Type of F/U
Recom LR, DR by for clinical node +; exam or CT, 33% Obs CXR 22% chemo
No RT
Clinical exam and CXR
Postop ? RT policy per center 1.9% Stage I, 33.7% Stage II, 64.3% Stage III, 30.4% Chemo, 30.8% Obs
Def-LR
% LR
% Pneumo
Ispilat mediast
12% Chemo 38% vs Chemo, 18% 36% Obs Obs
?
?
?
22% Obs, 25% Chemo
4.4% and 6.2% LR, benefit at 5- & 8-y Chemo
34.8% Chemo 34.6% Obs
Type of Chemo
Results
Cisplat, Vinorel
5-y and 7y S better with chemo by 8.6%, 8.4% Subgroup II, IIA benefit, not IB Cisplat/ Survival Vinorel benefit Chemo, confined to N1 11% 5 yr S Cisplat Improved with S and vinca alk DSS for or etopofirst 5 y, side, but both 26.8% decreased Cisplat/ after 5 y Vinorel
Abbreviations: NSCLC = non–small-cell lung cancer; ANITA = adjuvant navelbine international trialist association; JBR10 = National Cancer Institute of Canada Clinical Trials Group JBR.10 trial; IALT = international adjuvant lung cancer trial; F/U = follow-up; RT = radiotherapy; Def = definition; Pneumo = patients receiving a pneumonectomy; Obs = patients observed after resection and not treated with chemotherapy; Chemo = patients receiving chemotherapy; CXR = chest X-ray; Ipsilat = ipsilateral; Mediast = mediastinum; Cisplat = cisplatinum; Vinorel = vinorelbine; Vinca alk = vinca alkaloid; S = survival; LR = local recurrence; DR = distant recurrence; DSS = disease-specific survival.
Recurrence of surgically resected N1 non-small-cell lung cancer d J. M. VARLOTTO et al.
We found that, as in our larger dataset (8), patients undergoing pneumonectomy were at higher risk of distant recurrence. Deleterious effects of pneumonectomy on recurrence and survival have also been previously described by others (20). The negative prognostic influence of LVI (21) and nodal positivity have also been previously described (22, 23).
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CONCLUSIONS Patients with resected N1 NSCLC are uncommon, but they have a substantial risk of local failure, which exceeds that of distant failure. This risk is particularly high in individuals treated with adjuvant chemotherapy. The role of PORT in such patients should therefore be revisited.
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doi:10.1016/j.ijrobp.2010.05.022
CLINICAL INVESTIGATION
Lung
FAILURE RATES AND PATTERNS OF RECURRENCE IN PATIENTS WITH RESECTED N1 NON–SMALL-CELL LUNG CANCER JOHN M. VARLOTTO, M.D.,* LAURA NYSHEL MEDFORD-DAVIS, B.A.,y ABRAM RECHT, M.D.,yz JOHN C. FLICKINGER, M.D.,x ERIC SCHAEFER, M.S.,{ AND MALCOLM M. DECAMP, M.D.k *Penn State Hershey Cancer Institute, Hershey, PA; yHarvard Medical School; zDepartment of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA; xDepartment of Radiation Oncology, Pittsburgh Cancer Institute, Pittsburgh, PA; {Department of Public Health Sciences, Pennsylvania State University, Hershey, PA; and kDivision of Thoracic Surgery, Department of Surgery, Northwestern Memorial Hospital, Chicago, IL Purpose: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non–small-cell lung cancer. Methods and Materials: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence. Results: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site of local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure. Conclusions: Patients with resected non–small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy. Ó 2011 Elsevier Inc. Pattern of recurrence, N1 nodal involvement, Lung cancer, Surgical resection, Chemotherapy. Beth Israel Deaconess Medical Center, Boston; and the Denver and Boston Department of Veterans Affairs hospitals. Hospital and departmental tumor registries were used to identify all patients undergoing potentially curative resection of Stage I-IIIA NSCLC from 2000 to 2006. Patients were included in the study population if they had postoperative follow-up of at least 3 months, no second primary cancer diagnosed within 5 years of the index lung cancer, and no neoadjuvant or adjuvant radiotherapy. Medical records were reviewed for each patient to ensure eligibility. Of the total of 524 patients accrued, 60 patients had N1 disease and formed the study group for this report. Multiple factors potentially related to outcome were abstracted from the available medical records. Patient-related and staging factors were as follows: age; weight loss; preoperative hemoglobin; body mass index; presenting symptoms (cough, hemoptysis, dyspnea, or none); pulmonary function test results (FEV1–forced expiratory volume in one second, FEV1%–FEV1 percentage, and DLCO%–diffusing lung capacity for carbon monoxide percentage); smoking status (never, quit more than 2 years prior to surgery, quit 1–2 years prior to surgery, quit 6 months to 1 year prior to surgery, quit 30 days to 6 months before surgery, or smoking at present); drinking of alcoholic beverages (never, quit more than 2 years prior to surgery, quit between 1 and 2 years prior to surgery, quit 6 months
INTRODUCTION Several recent trials initially found that chemotherapy improved survival rates in patients with resected non–smallcell lung cancer (NSCLC) (1–4). However, with further follow-up this benefit was lost in some (5, 6) but not all studies (3, 7). Because all the initially positive trials suggested a benefit in patients with Stage II or Stage III disease, we chose to investigate whether patients with N1 nodal involvement might experience delayed local recurrence, which could overcome the initial impact of chemotherapy. We also explored the impact of clinical, pathologic, and treatment factors on the risk of both local and distant relapse. Finally, we used the Surveillance, Epidemiology and End Results (SEER) database to estimate what proportion of patients have resected N1 disease and hence might be affected by our results. METHODS AND MATERIALS This retrospective study was conducted with approval of the institutional review boards of the Penn State Hershey Cancer Institute; Reprint requests to: John M. Varlotto, M.D., Penn State Hershey Cancer Institute, Radiation Oncology–CH63, 500 University Drive, PO Box 850, Hershey, PA 17033-0850. Tel: (717) 531-8024; Fax: (717) 531-0882; E-mail: [email protected]
Conflict of interest: none. Received March 31, 2010, and in revised form May 11, 2010. Accepted for publication May 12, 2010. 353
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to 1 year prior to surgery, quit 30 days to 6 months prior to surgery, drinking at present); number of drinks per week; long-term use of steroids; history of intercurrent illnesses (diabetes, hypertension, myocardial infarction, coronary artery disease, cardiac rhythm disturbance, coronary artery bypass graft, cerebrovascular accidents, renal failure, thromboembolic disease); performance of staging positron emission tomography—computed tomography (PET-CT) at diagnosis; medication use at diagnosis (aspirin, statins, nonsteroidal antiinflammatory drugs); and hemoglobin and albumin values within 30 days prior to surgery. Surgery-related factors recorded included operative time; fluid balances during surgery (urine output, estimated blood loss, fluids infused, total excess intraoperative fluids (assuming one unit of packed red blood cells to be 300 cc); transfusions (total number of units required within 90 days of surgery, number of units required within the first day, number of units required within 2–4 days, and number of units after 4 days); type of resection (wedge resection, segmentectomy, lobectomy/bilobectomy, pneumonectomy); type of lymph node staging procedure; intraoperative and postoperative complications (pulmonary infection or pneumonia, adult respiratory distress syndrome, arrhythmias and their type (supraventricular tachycardia, ventricular tachycardia, or nonspecific), fistula formation, stump leak, prolonged air leak, anastomosis leak, mediastinitis/empyema, myocardial infarction, death, pulmonary embolus, deep venous thrombosis, and brachial plexus injury; length of hospital stay; and surgeon. Histopathologic factors recorded included tumor size; tumor grade (categorized as grade ‘‘1.5’’ when recorded as well to moderately differentiated and grade ‘‘2.5’’ when recorded as moderately to poorly differentiated); performance/positivity of previous fine-needle aspiration biopsy; lymphatic or vascular invasion (LVI); perineural invasion; margin status; extracapsular lymph node involvement; details of node resection (number resected, lymph node level resected, number of N1 nodes resected, number of N2 nodes resected, number of nodal stations sampled at mediastinoscopy, number of nodal stations examined during resection); histology (NSCLC not otherwise specified, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, neuroendocrine carcinoma, bronchioloalveolar carcinoma, adenocarcinoma with bronchioloalveolar features); tumor lobe location; and invasion of the visceral pleura. Details of chemotherapy recorded included type of chemotherapy (carboplatin and paclitaxel, cisplatin and navelbine, cisplatin and etoposide, other cisplatincontaining regimens, gemcitabine-containing combinations, other regimen); treatment sequencing (giving chemotherapy preoperatively, postoperatively, or both); and number of cycles. Patterns of failure were determined using physician clinical assessment, radiographic reports, and/or review of imaging studies as previously reported (8, 9). Local failures were defined as those occurring in the ipsilateral lungs and the N1–N3 nodal basins; all other failures were defined as distant. Patients were scored as having a nodal recurrence when a new or enlarging node measured more than 1 cm in short axis on follow-up CT. For patients who underwent PET-CT at the time of recurrence, all sites of abnormal uptake that correlated with lymph node or soft tissue mass were scored regardless of size. When available, data from bronchoscopy, biopsy, or mediastinoscopy were used to supplement the radiographic findings. Only the initial sites of recurrence were scored. Patients with simultaneous local and distant failures were scored as having both types of failure. Information on failure sites was reviewed by two of the authors (J.M.V., L.M.D.) for consistency between the radiologic, bronchoscopic, and/or pathologic studies. Computerized tomography studies from the Boston Veterans Administration, Penn State Hershey Cancer Institute, and Beth Israel
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Deaconess Medical Center were available for review. CT or PETCT was performed at more than 98% of all follow-up visits at these specialized thoracic oncology programs. The median follow-up was 30 months (range, 3–96 months). Recurrence rates at 2, 3, and 5 years were calculated by the method of Kaplan and Meier. Cox proportional hazards regression was used to assess risk factors for local and distant recurrence. Because of the limited number of local and distant failures, only univariate analysis was conducted. The SEER Database-17 (10) was accessed for the years 1988– 2006 to assess the proportion of all patients with NSCLC with Stage II disease and the frequency of N1 disease in patients who underwent resection.
RESULTS Presenting characteristics, treatment factors, and histopathologic characteristics can be seen in Table 1. Chemotherapy was given preoperatively and postoperatively to 4 and 20 patients, respectively. Chemotherapeutic regimens included carboplatin/paclitaxel in 12 patients, cisplatin/navelbine in 1 patient, cisplatin/etoposide in 1 patient, other cisplatincontaining regimens in 3 patients, gemcitabine combinations in 2 patients, and other regimens in 5 patients. Eighteen patients experienced local failure, for a crude rate of 30%. The actuarial rates at 2, 3, and 5 years were 33%, 33%, and 46%. Table 2 shows the combinations seen of specific sites of local failure (one or more per patient). The most common was the mediastinum only (5 patients). Theipsilateral mediastinum was one of the failure sites in 12 patients, the ipsilateral lung in 3, the ipsilateral hilum in 2, the subcarinal area in 2, the contralateral mediastinum in 2, the bronchial stump in 3, and the ipsilateral supraclavicular area in 1 patient. Twelve of the18 patients (67%) had local recurrences that would have been included within postoperative radiotherapy fields, including the bronchial stump/staple line, subcarinal area, ipsilateral mediastinum, and contralateral mediastinum (Fig. 1). Factors included in the Cox model for their effect on local failure are shown in Table 3. Chemotherapy was the only treatment that was statistically significant (hazard ratio [HR] 3.25, p = 0.0192) (Fig. 2). The distribution of other variables in relationship to the use of chemotherapy was significantly different only for length of stay (p = 0.0033) and performance of PET-CT (p = 0.0069). That is, 65% of patients receiving chemotherapy had staging with PET-CT, compared to 28% of patients not receiving chemotherapy; the respective lengths of stay in these two groups were 5 days and 7 days. Fourteen patients, or 23%, experienced distant failure as a first site of failure. Rates at 2, 3, and 5 years were 26%, 26%, and 32%, respectively. Specific sites of distant recurrence (one or more per patient) were brain (n = 5), bone (n = 5), contralateral lung (n = 2), and other (n = 2). Three variables significantly affected the risk of distant failure (Table 4): the number of nodes resected (p = 0.0497, HR = 1.07); the number of positive nodes (p = 0.0029, HR = 1.32), and performance of a pneumonectomy (p =
Recurrence of surgically resected N1 non-small-cell lung cancer d J. M. VARLOTTO et al.
Table 1. Clinical, pathologic, and treatment characteristics of the study population Characteristic Age (y) Mean Median (range) Diabetes Body mass index Unknown Mean (SD) Median (range) Sex M F History of myocardial infarction History of coronary artery disease Tumor size (cm) Unknown Mean (SD) Median (range) Histology NSCLC, NOS Squamous Adenocarcinoma Large cell Bronchoalveolar Adenocarcinoma and bronchoalveolar T stage T1 T2 T3–4 Number of positive nodes Mean (SD) Median (range) Grade Unknown Mean (SD) Median (range) Lymphovascular invasion present Resection type Lobectomy/bilobectomy Pneumonectomy Number of resected nodes Mean (SD) Median (range) Length of post-op stay (days) Mean (SD) Median (range) PET-CT for initial staging Unknown Yes No Received chemotherapy
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Table 2. Patterns of local failure for each of the 18 patients Site
Frequency (n = 18)
Ipsilateral mediastinum Ipsilateral mediastinum and lung Bronchial stump/staple line Ipsilateral and contralateral mediastinum Ipsilateral mediastinum, hilum, and supraclavicular area Ipsilateral mediastinum and subcarinum Ipsilateral lung Ipsilateral mediastinum and bronchial stump/staple line Ipsilateral hilum Subcarinal area Chest wall
5 (28%) 2 (11%) 2 (11%) 2 (11%) 1 (6%)
Determination 64.8 65.5 (47–86) 10 (17%) 6 (10%) 27.6 (5.01) 26.7 (18.3–42.5) 75% 25% 5 (8%) 15 (25%) 2 (3%) 4.1 (2.42) 3.5 (1–12) 4 (7%) 28 (47%) 19 (32%) 3 (5%) 2 (3%) 4 (7%) 22 (37%) 31 (52%) 7 (12%) 2.3 (2.8) 2 (1.0–20) 4 (7%) 2.4 (0.63) 2.0 (1–4) 20 (33%) 48 (80%) 12 (20%) 10.9 (7.45) 10 (2–39)
1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%) 1 (6%)
tively. Both local and distant failure rates were significantly worse for the N1 patients (p = 0.03 and 0.01, respectively). Death rates for patients with N1 disease at 2, 3, and 5 years were 34%, 46%, and 59%, respectively. Only the number of nodes resected (p = 0.0042, HR = 1.08), the number of nodes positive (p = 0.0071, HR = 1.20), and the presence of LVI (p = 0.0532, HR = 2.04) were significantly associated with a survival decrement in the Cox model (Table 5). Actuarial survival rates in relation to LVI are shown in Fig. 5. The incidence of Stage II NSCLC as a percentage of all presenting stages and the incidence of N1 nodal stage as a percentage of all patients undergoing resection of NSCLC in the SEER database from 1988 to 2006 (grouped into 2-year intervals) are shown in Fig. 6. Stage II NSCLC and N1 nodal disease were found in 2.7–5% and 11–18% of patients during these years, respectively. DISCUSSION Stage II NSCLC and N1 nodal disease are relatively uncommon, constituting 2.7–5% and 11–18% of patients, respectively, in the SEER database from 1988 to 2006. Similarly, patients with resected N1 disease represented 11.5% of our total patient population with surgically resected NSCLC. Nonetheless, these patients seem to be at substantial
8.3 (8.62) 6.5 (3–69) 1 (2%) 25 (42%) 34 (58%) 24 (40%)
Abbreviations: NOS = not otherwise specified; NSCLC = nonsmall cell lung cancer; SD = standard deviation; PET-CT = positron emission tomography—computed tomography.
0.0041, HR = 4.66). The risk of distant failure in relation to the use of pneumonectomy is shown in Fig. 3. Local and distant failure rates for the 60 patients with N1 disease were compared to those of 440 patients with N0 disease in our database (Fig. 4). Local failure rates in the latter group at 2, 3, and 5 years were 15%, 20%, and 29%, respectively; distant failure rates were 11%, 13%, and 19%, respec-
Fig. 1. Proposed postoperative radiation therapy portals.
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Table 3. Cox proportional hazards regression model for local failure Variable Chemotherapy treatment Lymphovascular invasion Diabetes Histology, nonsquamous Tumor location Grade No. of nodes resected No. of positive nodes Tumor size Body mass index Age Resection type, pneumonectomy Length of stay Performance of PET scan T stage
p value Hazard ratio (95% CI) 0.0192 0.0790 0.1939 0.31 0.3081 0.9784 0.9160 0.5823 0.8571 0.3649 0.4313 0.9000 0.3698 0.1014 0.6879
3.248 (1.21–8.71) 2.318 (0.91–5.92) 1.993 (0.70–5.64) 0.62 (0.24–1.58) 1.6 (0.63–4.27) 0.990 (0.49–2.02) 1.01 (0.93–1.09) 0.90 (0.63–1.30) 0.98 (0.82–1.19) 0.95 (0.85–1.06) 0.98 (0.93–1.03) 1.08 (0.31–3.77) 0.93 (0.80–1.09) 2.30 (0.85–6.20) 1.21 (0.48–3.07)
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Table 4. Cox proportional hazards regression model for distant failure Variable Chemotherapy treatment Lymphovascular invasion Diabetes Histology, nonsquamous Tumor location Grade No. of nodes resected No. of positive nodes Tumor size Body mass index Age Resection type, pneumonectomy Length of stay Performance of PET scan T stage
p value Hazard ratio (95% CI) 0.9261 0.4599 0.3401 0.8547 0.2609 0.0777 0.0497 0.0029 0.4536 0.4868 0.2549 0.0041 0.6328 0.5978 0.1837
1.054 (0.35–3.20) 1.514 (0.50–4.55) 0.371 (0.05–2.84) 1.104 (0.38–3.19) 0.472 (0.13–1.75) 0.46 (0.19–1.09) 1.07 (1.00–1.15) 1.32 (1.10–1.58) 1.08 (0.89–1.30) 1.04 (0.89–1.30) 0.97 (0.91–1.03) 4.66 (1.63–13.34) 0.98 (0.90–1.07) 1.34 (0.46–3.93) 0.42 (0.12–1.51)
Abbreviations: HR = hazard ratio; CI = confidence interval; PET = positron emission tomography.
Abbreviations: HR = hazard ratio; CI = confidence interval; PET = positron emission tomography.
risk of local recurrence, and have higher rates of local recurrence than distant failure. Of interest, in our study, patients receiving chemotherapy were at higher risk of local failure than were other patients. This suggests that chemotherapy may be preventing or delaying the development of distant recurrences and thus allowing local failures to become clinically evident. However, given that chemotherapy was not assigned to patients in a randomized fashion in our study, it may have been used more often in patients with clinical and pathologic factors that predisposed them to a higher risk of local recurrence before the initiation of therapy. Both the Adjuvant Navelbine International Trialist Association (ANITA) and the International Adjuvant Lung Cancer Trial (IALT) trials showed fewer local recurrences in patients
receiving chemotherapy than in control patients (3, 6). However, patients in the ANITA trial were monitored for recurrence either by clinical examination or by radiographic studies, whereas it is not clear how the patients in the IALT trial were assessed for recurrence. Also, local recurrence was not defined explicitly in the IALT trial (1, 6). Our study used routine CT or PET-CT and hence was more likely to have detected asymptomatic intrathoracic recurrences than were these two randomized trials. Also, most patients in our study received carboplatin and paclitaxel, which may not have be as effective at preventing late local failures as other regimens (11–14) such as cisplatin-vinorelbine (15). However, it has not yet been shown that cisplatin-containing combinations, or more
Fig. 2. Local failure rates in relation to use of chemotherapy.
Fig. 3. Distant failure rates in relation to the extent of surgery.
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Fig. 4. Local and distant failure rates for patients with N0 and N1 disease.
specifically cisplatin-vinorelbine, are more effective at preventing local recurrences than other regimens. A summary of the Phase III trials demonstrating a survival benefit with chemotherapy in Stage II/III NSCLC can be seen in Table 6. It is interesting to note that local recurrence is not defined for two of the trials and that none of the studies required close follow-up with CT scans. Therefore, the ability of these trials, which were investigating overall survival as their primary endpoint, to properly assess local recurrence may be limited. Two-thirds of all recurrences would be contained within a proposed postoperative radiation therapy portal encompassing the bronchial stump, the anastomosis, the hilum, the subcarinal area, and the ipsilateral and contralateral mediastinum
Fig. 6. (A) Incidence of Stage II NSCLC as a percentage of all presenting stages, 1988–2006. (B) Incidence of N1 nodal stage as a percentage of all resected NSCLC, 1988–2006.
Fig. 5. Overall survival rates in relation to lymphovascular invasion.
(Fig. 1). Would such treatment be safe? The Postoperative Radiotherapy (PORT) meta-analysis demonstrated a survival decrement in patients with resected N1 disease who received adjuvant radiotherapy (16). Although the allocation of radiotherapy was not randomized in the ANITA trial, a similar survival decrement was noted in N1 patients treated with adjuvant radiotherapy, despite a survival benefit being found in irradiated patients with N2 disease (17). However, the IALT trial (which also did not randomly assign patients to radiotherapy) found that radiotherapy had no effect on the incidence of cardiopulmonary death (HR = 0.86) or second cancers (HR = 0.82). Likewise, there was no increase in deaths from intercurrent disease noted in patients receiving adjuvant radiotherapy for Stages II and III NSCLC in Eastern
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Table 5. Cox proportional hazards regression model for survival
Cooperative Oncology Group trial E3590, compared to agematched and gender-matched control participants (18). It is important to remember that the survival decrement from postoperative radiotherapy noted in patients with surgically resected N1and N0 disease in the PORT meta-analysis may have been due to outdated radiation techniques such as opposed lateral portals, 60Co radiation, hypofractionated treatments, and excessive radiation volumes (9, 16). It is of great interest to note that by using modern techniques, investigators from Universita Cattolica del S. Cuore in Rome found that adjuvant radiotherapy for patients with surgically-resected N0 patients was associated with significantly higher rates of local control, disease-free survival, and overall survival (19). Figure 4 demonstrates that both patient groups with surgically resected N0 and N1 NSCLC had higher rates of local rather than distant failure. We believe that it may be beneficial for all patients undergoing surgical resection of NSCLC to undergo a prospective evaluation to assess who is at risk for local failure. As noted in one of our previous publications (8), nodal stage may not be associated with local recurrence.
p value Hazard ratio (95% CI)
Variable Chemotherapy treatment Lymphovascular invasion Diabetes Histology, nonsquamous Tumor location Grade No. of nodes resected No. of positive nodes Tumor size Body mass index Age Resection type, pneumonectomy Length of stay Performance of PET scan T stage Past myocardial infarction History of coronary artery disease
0.5564 0.0532 0.3204 0.6195 0.2643 0.4145 0.0042 0.0071 0.4589 0.3526 0.8422 0.2392 0.5187 0.5266 0.5404 0.9965 0.5472
1.25 (0.60–2.61) 2.04 (0.99–4.22) 0.544 (0.16–1.81) 0.83 (0.41–1.71) 0.63 (0.28–1.41) 0.78 (0.43–1.41) 1.08 (1.02–1.14) 1.20 (1.05–1.38) 0.95 (0.82–1.10) 0.96 (0.89–1.05) 0.99 (0.96–1.04) 1.63 (0.72–3.69) 0.99 (0.94–1.03) 1.28 (0.60–2.75) 0.79 (0.37–1.69) 0.99 (0.30–3.36) 1.274 (0.58–2.80)
Abbreviations: HR = hazard ratio; CI = confidence interval; PET = positron emission tomography.
Table 6. Phase III trials demonstrating a survival benefit for chemotherapy in patients with surgically resected NSCLC
Trial
Mdn F/U n (y)
Stage
ANITA (3) 840
6.4
IB–IIIA IB 36% II 24% IIIA 39%
JBR10 (7) 482
9.3
IB–II IB 45% II 55%
1867 7.5
I–III I 36% II 24% III 40%
IALT (6)
RT Policy
Type of F/U
Recom LR, DR by for clinical node +; exam or CT, 33% Obs CXR 22% chemo
No RT
Clinical exam and CXR
Postop ? RT policy per center 1.9% Stage I, 33.7% Stage II, 64.3% Stage III, 30.4% Chemo, 30.8% Obs
Def-LR
% LR
% Pneumo
Ispilat mediast
12% Chemo 38% vs Chemo, 18% 36% Obs Obs
?
?
?
22% Obs, 25% Chemo
4.4% and 6.2% LR, benefit at 5- & 8-y Chemo
34.8% Chemo 34.6% Obs
Type of Chemo
Results
Cisplat, Vinorel
5-y and 7y S better with chemo by 8.6%, 8.4% Subgroup II, IIA benefit, not IB Cisplat/ Survival Vinorel benefit Chemo, confined to N1 11% 5 yr S Cisplat Improved with S and vinca alk DSS for or etopofirst 5 y, side, but both 26.8% decreased Cisplat/ after 5 y Vinorel
Abbreviations: NSCLC = non–small-cell lung cancer; ANITA = adjuvant navelbine international trialist association; JBR10 = National Cancer Institute of Canada Clinical Trials Group JBR.10 trial; IALT = international adjuvant lung cancer trial; F/U = follow-up; RT = radiotherapy; Def = definition; Pneumo = patients receiving a pneumonectomy; Obs = patients observed after resection and not treated with chemotherapy; Chemo = patients receiving chemotherapy; CXR = chest X-ray; Ipsilat = ipsilateral; Mediast = mediastinum; Cisplat = cisplatinum; Vinorel = vinorelbine; Vinca alk = vinca alkaloid; S = survival; LR = local recurrence; DR = distant recurrence; DSS = disease-specific survival.
Recurrence of surgically resected N1 non-small-cell lung cancer d J. M. VARLOTTO et al.
We found that, as in our larger dataset (8), patients undergoing pneumonectomy were at higher risk of distant recurrence. Deleterious effects of pneumonectomy on recurrence and survival have also been previously described by others (20). The negative prognostic influence of LVI (21) and nodal positivity have also been previously described (22, 23).
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CONCLUSIONS Patients with resected N1 NSCLC are uncommon, but they have a substantial risk of local failure, which exceeds that of distant failure. This risk is particularly high in individuals treated with adjuvant chemotherapy. The role of PORT in such patients should therefore be revisited.
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