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Outcome predictors for 143 patients with superior sulcus tumors treated by multidisciplinary approach at the University of Texas M. D. Anderson Cancer Center
Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 2, pp. 347–354, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter
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CLINICAL INVESTIGATION
Lung
OUTCOME PREDICTORS FOR 143 PATIENTS WITH SUPERIOR SULCUS TUMORS TREATED BY MULTIDISCIPLINARY APPROACH AT THE UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER RITSUKO KOMAKI, M.D.,* JACK A. ROTH, M.D.,† GARRETT L.WALSH, M.D.,† JOE B. PUTNAM, JR., M.D.,† ARA VAPORCIYAN, M.D.,† JIN S. LEE, M.D.,‡ FRANK V. FOSSELLA, M.D.,‡ MARVIN CHASEN, M.D.,§ MARC E. DELCLOS, M.D.,* JAMES D. COX, M.D.*
AND
Departments of *Radiation Oncology, †Thoracic and Cardiovascular Surgery, ‡Thoracic/Head and Neck Medical Oncology, and § Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: Superior sulcus tumors (SST) of the lung are uncommon and constitute approximately 3% of non–small cell lung cancer (NSCLC). These tumors cause specific symptoms and signs, and are associated with patterns of failure that differ from those seen for NSCLC tumors in other nonapical locations. Prognostic factors and most effective treatments are controversial. We conducted a retrospective study at The University of Texas M. D. Anderson Cancer Center to identify outcome predictors for patients with SST treated by a multidisciplinary approach. Methods and Materials: This retrospective review of 143 patients without distant metastasis at presentation is a continuation of a previous M. D. Anderson study now updated to 1994. In this study, we examine the 5-year survival rate by pretreatment tumor and patient characteristics and by the treatments received. Strict criteria were used to define SST. Actuarial life-table analyses and Cox proportional hazard models were used to compare survival rates. Results: Overall predictors of 5-year survival were weight loss (p < 0.01), supraclavicular fossa (p ⴝ 0.03), or vertebral body (p ⴝ 0.05) involvement, stage of the disease (p < 0.01), and surgical treatment (p < 0.01). Five-year survival for patients with Stage IIB disease was 47% compared to 14% for Stage IIIA, and 16% for Stage IIIB. For patients with Stage IIB disease, surgical treatment (p < 0.01) and weight loss (p ⴝ 0.01) were significant independent predictors of 5-year survival. Among patients with Stage IIIA disease, the only predictor of survival was Karnofsky performance score (KPS) (p ⴝ 0.02). For patients with Stage IIIB disease, the only independent predictor of survival was a right superior sulcus location, which was associated with a worse 5-year survival rate than that for patients with tumors in the left superior sulcus (p ⴝ 0.02). More patients with adenocarcinoma than with squamous cell tumors experienced cerebral metastases within 5 years (p < 0.01). Patients without gross residual disease after surgical resection who received postoperative radiation therapy with total doses of 55 to 64 Gy had a 5-year survival rate of 82% as compared with the 5-year survival rate of 56% in patients who received 50 to 54 Gy. Twenty-three patients survived for longer than 3 years. Of these, 4 patients (17%) received radiation therapy alone or in combination with chemotherapy without surgical resection. The other 19 patients (83%) had resection combined with radiation therapy and/or chemotherapy. Conclusions: The findings from this study confirm the importance of the new staging system, separating T3 N0 M0 (Stage IIB) from Stage IIIA, since there was a significant difference in the 5-year survival (p < 0.01). Interestingly, there was no significant 5-year survival difference between Stage IIIA (N2) and Stage IIIB (T4 or N3). This study also suggests that surgery is an important component of the multidisciplinary approach to patients with SST if their nodes were negative. Disease that is minimally invading surrounding normal structures can be resected followed by radiation therapy in doses of 55 to 64 Gy. Further investigation of treatment strategies combining high-dose radiation therapy (>66 Gy) with chemotherapy is indicated for patients with unresectable and/or node-positive (N2) SST. © 2000 Elsevier Science Inc. Lung, Superior sulcus tumors, Multidisciplinary treatment, Predictors, Survival.
This work was supported in part by PO1 CA-06294, T32CA77050, and P30CA16672 awarded by the National Cancer Institute, U.S. Department of Health and Human Services. Accepted for publication 11 April 2000.
Reprint requests to: Ritsuko Komaki, M.D., Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 97, Houston, TX 77030. Presented at the 80th Annual Meeting of the American Radium Society, Monaco, April 1998. 347
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INTRODUCTION Superior sulcus tumors (SST), including Pancoast’s tumors (1), arise in the apex of the lung above the sulcus and cause specific symptoms and signs depending on the location and whether the tumor extends into the surrounding structures. Because of the closeness of critical structures to the tumor (e.g., the subclavian artery for anterior lesions; the brachial plexus for lesions in the middle location, and the sympathetic stellate ganglion causing Horner’s syndrome [Pancoast’s tumor], the vertebral bodies, nerve foramen, and spinal cord for posterior lesions), SST were often considered marginally resectable or unresectable. Therefore, for many years, preoperative radiation therapy was considered routine treatment for those tumors. However, with the evolution in our understanding of these tumors and modern imaging and surgical techniques, there is now considerable debate about the roles and timing of surgical resection, radiation therapy, and chemotherapy in the treatment of patients with these tumors. Published reports (2) have noted 5-year survival rates of 15% to 56% for patients receiving combinations of radiation therapy and surgical treatment. In some of these studies, patients received additional postoperative radiation therapy. Few studies, however, have had adequate numbers of patients to allow examination of the effects of distinct treatments such as varying doses of radiation with surgery, radiation therapy with chemotherapy, or radiation therapy alone. A further difficulty is that some studies have identified univariate predictors of survival (3– 8); but only one identified multivariate (independent) predictors of survival (4). None has examined independent predictors of survival by stage of disease. The identification of predictors of survival along the continuum of care could reveal subgroups of patients who require new combined treatment strategies. Findings from a previous retrospective medical record review from this institution published in 1990 (5) were obtained in 85 patients with SST without distant metastatic disease at presentation. Since that publication, the length of follow-up has increased and additional patients have been treated. The current study of 143 patients updates the previous study. It also analyzes treatment combinations and identifies univariate and multivariate predictors of 5-year survival. METHODS AND MATERIALS The methods used in The University of Texas M. D. Anderson retrospective studies of SST have been described elsewhere (5). The patients in this update were identified from individual physicians’ records of lung cancer patients with SST who were treated at M. D. Anderson from 1975 through 1994. All 143 patients had a cytologically or histologically verified diagnosis of non–small cell lung cancer (NSCLC). Patients with small cell lung cancer or sarcoma or whose disease was diagnosed on the basis of clinical grounds alone were excluded from this review. The Amer-
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ican Joint Committee on Cancer staging criteria were used for previous publications (9). Patients were later reclassified using the new staging system (10) in which T3 N0 M0 involvement is considered Stage IIB instead of Stage IIIA. Stage assignment was based on clinical findings because only a subset of patients had surgical exploration. Only patients with distant metastases were excluded from these analyses. Five-year survival rates were calculated and predictors of survival were identified using actuarial life table methods and Cox proportional hazard models. RESULTS Patient characteristics One hundred forty-three patients with SST were identified in this retrospective study. Patient characteristics are summarized in Table 1 by stage of disease. Median patient age at diagnosis was 56 years. Patients were predominantly white, and there was a 2:1 male-to-female ratio. Most patients had less than 5% weight loss, although the losses ranged from 0 to 24% of body weight. Karnofsky performance scores (KPS) (11) ranged from 50 to 100, but 94% of the patients had a KPS of 80 to 100. Patients with Stage IIIB disease had slightly lower KPS. Ninety-seven percent of the patients had a history of smoking, and 31% had consistently consumed alcohol. Most did not have a prior history of malignancy. The frequencies of presenting symptoms were as follows: arm/shoulder pain, 99 patients (69%); chest pain, 56 patients (39%); cough, 57 patients (40%); dyspnea, 37 patients (26%); Horner’s syndrome, 27 patients (19%); and arm swelling, 3 patients (2%). Tumor characteristics are summarized in Table 2. Maximum tumor diameter, as measured in the surgical patients, ranged from 2.0 to 13.5 cm (median 5.4 cm). All patients had pathologic confirmation of non–small cell histology with a 2:1 ratio of adenocarcinoma to squamous cell histology. The ratio of tumors in the right apex to those in the left apex was approximately 2:1. More patients had tumors that involved the ribs (T3) or vertebral bodies (T4) than the supraclavicular fossa (N3). In addition, more patients had Stage IIIB disease than Stage IIIA or IIB disease. Follow-up after diagnosis ranged from 1 month to 15 years with median 24 months. Overall survival rates at 2 and 5 years were 40% and 23%, respectively. Predictors of survival Overall predictors. Overall univariate predictors of 5-year survival and cumulative survival rates are presented in Table 3. Better survival was found among patients who presented with weight loss of less than 5%, no vertebral body involvement, no supraclavicular involvement, and Stage IIB disease. Patients who underwent surgery also survived for longer especially among patients with negative nodes. Five-year survival rates were 47% in patients with Stage IIB disease compared to 14% in those with Stage IIIA and 16% with Stage IIIB (p ⬍ 0.01). The 5-year survival
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Table 1. Characteristics of patients with superior sulcus tumors Stage
Characteristics* Age at diagnosis (yr) Median Range Ethnicity White African American Hispanic Sex Male Female Weight loss ⬍5% ⱖ5% KPS 90–100 80 70 ⬍70 Smoking history Current smoker Stopped smoking Never smoked Unknown Daily alcohol use No Yes Unknown Prior/concurrent malignancy None Prior Current
IIB(T3N0M0) (n ⫽ 36)
IIIA(T1–3N2) (n ⫽ 31)
IIIB(T4 or N3) (n ⫽ 76) (T4:59 & N3:17)
Total (n ⫽ 143)
58 38–74
58 37–73
55 29–82
56 29–82
34 0 2
28 2 1
64 6 6
126 (88%) 8 (6%) 9 (6%)
21 15
21 10
59 17
101 (71%) 42 (29%)
34 2
25 6
54 22
113 (79%) 30 (21%)
29 4 2 1
30 1 0 0
55 15 3 3
114 (80%) 20 (14%) 5 (3%) 4 (3%)
21 15 0 0
14 14 1 2
38 36 1 1
73 (51%) 65 (45%) 2 (1%) 3 (2%)
10 26 0
8 21 2
27 49 0
96 (67%) 45 (31%) 2 (1%)
29 7 0
23 6 0
68 8 2
120 (84%) 21 (15%) 2 (1%)
*Numbers of patients, unless otherwise noted.
rate in patients who had surgery was 37% compared with 11% in those who did not have surgical resection (p ⬍ 0.01). Age, sex, prior or concurrent malignancy, smoking status, alcohol consumption, KPS ⬍ 90 versus 90 to 100, Horner’s syndrome, rib involvement, tumor histology, and the location of tumor (right or left apex) were not significant predictors of overall 5-year survival. Surgical patients. Univariate predictors of 5-year survival among surgical patients were weight loss (⬍5% versus ⱖ5%) (p ⫽ 0.04), stage of disease (p ⫽ 0.01), and residual disease (positive surgical margins or gross disease remaining) (p ⬍ 0.01). Multivariate analyses revealed that there was an association between several factors (weight loss, stage of disease, and residual disease after surgery); therefore, none of the univariate predictors was an independent predictor of 5-year survival. The 5-year survival rate was 18% in the 29 patients with residual disease, compared with 55% in the 33 patients who underwent complete resection (p ⬍ 0.01). There was no difference in the 5-year survival by the type of surgery (segmental or wedge resection versus lobectomy). There
was also no difference by the type of surgery procedure in patients who had residual disease. Unresectable patients. The 81 patients who did not undergo resection had an overall 5-year survival rate of 11%. The only univariate predictor of 5-year survival in these patients was the KPS (⬍90 versus 90 to 100) (p ⫽ 0.04). Stage of disease (IIB, IIIA versus IIIB) was not a predictor of 5-year survival for unresectable patients. Stage of disease. In the 36 patients with Stage IIB disease, univariate predictors of 5-year survival were weight loss (⬍5% versus ⱖ5%) (p ⬍ 0.01) and surgical treatment (p ⬍ 0.01). In the Cox bivariate analysis, surgical treatment and weight loss remained significant independent predictors of survival. In the 31 patients with Stage IIIA disease (positive nodes), the only univariate predictor of 5-year survival was the KPS (⬍90 versus 90 –100) (p ⫽ 0.02). Surgery was not an important prognostic factor of outcome in this group. In the 76 patients with Stage IIIB disease (T4:59, N3:17), tumor location (right versus left apex) (p ⫽ 0.02) was the only significant univariate predictor of 5-year survival.
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Table 2. Superior sulcus tumor characteristics Stage Characteristics* Histology Non–small cell carcinoma Adenocarcinoma Squamous Adenosquamous Large cell Non–small cell Location Right lung Left lung Regional extension Rib Vertebral body Supraclavicular fossa or supraclavicular nodes Median tumor size (cm) (surgical patients, n ⫽ 60)†
IIB (n ⫽ 36)
IIIA (n ⫽ 31)
IIIB (n⫽ 76)
Total (n ⫽ 143)
23 8 0 2 3
17 8 1 3 2
40 23 1 7 5
80 (56%) 39 (27%) 2 (1%) 12 (8%) 10 (7%)
24 12
21 10
46 30
91 (64%) 52 (36%)
11 4 1
4 0 0
28 33 22
43 (30%) 37 (26%) 23 (16%)
5
6
5.8
5.4
*Number of patients, unless otherwise noted. † 60 surgical patients with tumor measurements, 2 patients no tumor measurements recorded.
Five-year survival in patients with Stage IIIB disease was 10% in those with right apical tumors and 25% in patients with left apical tumors (p ⫽ 0.02). Other factors were examined that could contribute to less favorable survival in patients with Stage IIIB disease and right apical tumors. These factors were sex; age; current smoker; alcohol consumption; KPS; weight loss; prior or
concurrent malignancy; Horner’s syndrome; vertebral body, supraclavicular, or rib involvement; adenocarcinoma versus squamous cell histology; wedge resection versus lobectomy; and residual disease after surgical resection. The only difference identified was that patients with Stage IIIB disease and right apical tumors were found less frequently to have Horner’s syndrome compared to the left apical tumors (p ⫽ 0.02).
Table 3. Cumulative survival to 5 years for patients with superior sulcus tumors by predictive factors
Results of treatment combinations Overall results. Treatments are presented in Table 4. Only 5 patients (3%) received surgery alone. Forty-five patients (31%) received radiation therapy alone. Thirty-two patients (22%) were treated with radiation therapy and chemotherapy equally distributed between Stage IIIA and
Weight loss 1-year 2-year 5-year Vertebral body 1-year 2-year 5-year Supraclavicular involvement 1-year 2-year 5-year Stage 1-year 2-year 5-year Surgery 1-year 2-year 5-year
IIB (n ⫽ 36) 76% 58% 47%
⬍5% (n ⫽ 113) 67% 47% 27% NO (n ⫽ 106) 73% 41% 26%
ⱖ5% (n ⫽ 30) 68% 16% 10% YES (n ⫽ 37) 51% 37% 17%
NO (n ⫽ 120) 69% 43% 26% IIIA (n ⫽ 31) 76% 37% 14% NO 63% 28% 11%
YES (n ⫽ 23) 57% 21% 7% IIIB (n ⫽ 76) 60% 33% 16% YES 74% 56% 37%
p ⬍ 0.01
Table 4. Treatments received* by stage of disease (n ⫽ 143) Stage
p ⫽ 0.05 Treatment
p ⫽ 0.03
p ⬍ 0.01
Resectable Surgery only Chemo ⫾ XRT 3 Surgery Surgery 3 XRT ⫾ Chemo Pre ⫹ Postop XRT ⫾ Chemo Unresectable or inoperable Radiation only Chemotherapy only XRT ⫹ Chemo Total
p ⬍ 0.01
IIB
IIIA
IIIB
Total
2 4 14 8
2 1 6 2
1 7 8 7
5 (3%) 12 (8%) 28 (20%) 17 (12%)
5 2 1
5 1 14
35 1 17
45 (31%) 4 (3%) 32 (22%)
36
31
76
143
*Actual treatment received. Patient may not have completed planned treatment.
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IIIB. Twenty-four (17%) were treated with surgery followed by radiation therapy, 17 (12%) were treated with preoperative or postoperative radiation therapy in combination with various types and regimens of chemotherapy, and 10 (7%) were treated with radiation therapy followed by surgery. The remaining 10 patients received other combinations of treatment. Among the 4 patients who received chemotherapy only, 3 patients were on a treatment protocol for resectable disease; however, at the completion of chemotherapy, disease had progressed, which excluded surgery as a further treatment option. Among the 32 patients who received radiation therapy and chemotherapy without surgery, 23 patients (72%) were enrolled in various treatment protocols. Seventeen of the 23 patients were enrolled in broad protocols for unresectable NSCLC. Results in patients with Stage IIB disease (T3 N0 M0). Among 36 patients with Stage IIB disease (T3 N0 M0), the largest treatment groups consisted of 14 patients who had surgery followed by radiation treatment with or without chemotherapy (n ⫽ 14), and 8 patients who had surgery and both preoperative and postoperative combinations of radiation therapy and chemotherapy. The 5-year survival rate was 56% in the 11 patients who received surgery followed by radiation therapy, whereas it was 87% in the 8 patients who received both preoperative and postoperative combination radiation therapy and chemotherapy (p ⬎ 0.05). Treatment in the preoperative and postoperative treatment combination group (n ⫽ 8) consisted of the following: chemotherapy then surgery then radiation therapy (3 patients); radiation therapy then chemotherapy then surgery followed by radiation therapy (2 patients); radiation therapy then chemotherapy then surgery followed by chemotherapy (2 patients); and radiation therapy then surgery followed by radiation therapy (1 patient). Results in patients with Stage IIIA disease. Surgery was not a predictor of survival in patients with Stage IIIA disease (positive nodes). The largest treatment group (Table 4) consisted of patients who received combinations of radiation therapy and chemotherapy without surgery. The 5-year survival rate in the 20 patients without surgery was 20%. This rate was similar to that (14%) in the 11 patients with Stage IIIA disease who underwent surgery, either alone or in combination with chemotherapy or radiation therapy. Results in patients with Stage IIIB disease. There was no significant difference in overall 5-year survival rates between 59 patients with T4 and 17 patients with N3 disease; 17% vs. 7%, respectively (p ⫽ 0.28). Surgery was also not a predictor of survival in patients with Stage IIIB disease. The two largest treatment groups consisted of patients who received radiation therapy alone (n ⫽ 36) and radiation therapy plus chemotherapy (n ⫽ 17) (T4:38 and N3:15). The 5-year survival rate was 11% in patients treated with radiation therapy alone and 14% in patients treated with radiation therapy and chemotherapy. The 5-year survival rate in the 23 patients with Stage IIIB disease (T4:21 and
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Fig. 1. Overall survival after treatment depending on new AJCC staging system.
N3:2) who received surgery was 25%. The differences in the survival rates among the three treatment groups were not statistically significant. The 5-year survival rates for patients with Stage IIIB disease in smaller treatment groups were as follows: it was 19% in 7 patients who received preoperative radiation therapy with or without chemotherapy, which was similar to the 18% of patients who received both preoperative and postoperative combinations of radiation therapy or chemotherapy. The 5-year survival rate was 38% in the 8 patients with Stage IIIB disease (minimal T4 N0) who did not receive preoperative treatment but underwent operation first followed by postoperative radiation therapy with or without chemotherapy (p ⫽ 0.78) (Fig. 1). Radiation therapy doses Postoperative radiation therapy group. Among the surgical patients who had no residual disease (negative surgical margins or no gross residual disease), the 5-year survival rate was 51% in the 7 patients who received postoperative radiation therapy in doses of 50 to 54 Gy and 82% in the patients who received 55 to 64 Gy (Fig. 2). The 5-year survival rate was 22% in the 13 patients who had residual disease at surgery and who received 55 to 64 Gy of radiation postoperatively. Only 2 patients received the lower dose of 50 to 54 Gy. There were too few patients who received surgery alone or chemotherapy combined with radiation therapy postoperatively to examine other treatment effects. Radiation therapy only group. Among the 45 unresectable or inoperable patients who received radiation therapy alone, the total dose ranged from 16 to 69.6 Gy and the median dose was 60 Gy. The overall 5-year survival rate in these patients was 9%. Local control at 5 years was achieved in 32% of the patients. Distant metastasis occurred in 51% within 5 years. Radiation therapy doses with chemotherapy. Among the 32 nonsurgical patients who received radiation therapy with either concurrent or sequential chemotherapy, the total radiation dose ranged from 19.68 to 69.6 Gy (median 64 Gy).
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and 22% had Stage IIIB disease. Most had no weight loss (96%) and a KPS of 80 to 100 (91%) at diagnosis. Four of the 23 patients (17%) had radiation therapy or radiation therapy and chemotherapy without surgical resection. The other 19 patients (83%) received surgery in combination with radiation therapy, or chemotherapy, or both. DISCUSSION
Fig. 2. Five-year survival by postoperative radiation treatment dose.
The 12 nonsurgical patients who received a higher dose of radiation of ⱖ66 Gy, with either sequential or concurrent chemotherapy, showed a 5-year survival rate of 33% compared with 7% in the 20 patients who received a total dose ⬍ 66 Gy. The 5-year survival rate was 36% in the patients who received ⱖ66 Gy of radiation with concurrent chemotherapy. Local control at 5 years was achieved in 44% of the patients. Distant metastasis occurred in 53% within 5 years. Distant metastatic sites The brain was the most frequent site of distant metastasis. Cerebral metastasis occurred in 24 of 143 patients (17%) within 5 years of diagnosis. Three out of 14 patients who received prophylactic cranial irradiation (PCI) eventually developed brain metastasis, while 21 of 129 patients who did not receive PCI developed brain metastasis in 5 years. There was no statistical difference in the frequency of cerebral metastasis within 5 years between these 2 groups (p ⫽ 0.62). The stage of disease at diagnosis, location of tumor (right or left lung), type of surgical treatment, and type of adjuvant treatment were also not associated with cerebral metastasis. Tumor histology was the only significant factor associated with cerebral metastasis: cerebral metastasis occurred within 5 years in 21% of the 80 patients with adenocarcinoma compared with only 3% of the 39 patients with squamous cell histology (p ⬍ 0.01). The percentage of patients with distant metastasis to other sites was as follows: bone (15%), contralateral lung (10%), adrenal (8%), liver (6%), and soft tissue (4%). Less frequently, patients had metastases to the trachea, esophagus, heart, kidney, pelvis, and leptomeninges. One patient was found at autopsy to have metastases to the stomach, spleen, kidney, pancreas, small bowel, mesentery, omentum, and retroperitoneal nodes. Long-term survivors Twenty-three of the 143 patients (16%) survived 3 to 15 years after treatment. Age at diagnosis ranged from 29 to 67; 52% had Stage IIB disease, 22% had Stage IIIA disease,
Some factors that are generally used to predict outcome in lung cancer patients are closely related to the stage of disease and may help determine whether a patient is selected for surgery. Univariate analyses do not control for other factors that may influence the results. Multivariate analyses allow the examination of all recognized predictors of outcome to determine which ones are independent or are merely a component of another factor. Our analyses demonstrated that predictors of survival in patients with SST differ depending on the stage of disease. For example, lack of surgical treatment and a 5% or greater weight loss were the only negative independent predictors of 5-year survival for patients who had Stage IIB disease. Surgical treatment was not, however, a significant predictor of 5-year survival in patients with Stage IIIA (positive nodes) or IIIB disease. In patients with Stage IIIA disease, the only predictor of survival was the KPS, whereas in patients with Stage IIIB disease, the location of the tumor (right or left apex) was the only predictor of 5-year survival. Because tumors in the superior sulcus are less common than those at other sites within the thorax, there have been few studies with sufficient patients to examine data other than by univariate methods. Only two studies have had over 100 patients. In the study from Hilaris et al. (4) from Memorial Sloan-Kettering Cancer Center, which consisted of 129 patients, mediastinal node involvement and preoperative radiation therapy were found to be significant multivariate predictors of survival. Martini et al. (12), also at Memorial Sloan-Kettering, reported treatment results in 170 patients with Stage IIIA disease only. Millar et al. (6) at the Peter A. McCallum Cancer Institute in Australia observed that any nodal involvement adversely affected survival in their patient population of 131. In none of these studies were results stratified by stage of disease. Ours was the first study that examined survival predictors for patients with SST by stage of disease. There have been many reports of treatment outcome in small numbers of patients with SST. For example, researchers at the University of Navarra in Spain (13) studied 18 patients who received preoperative radiation therapy. The 4-year survival in the patients who received 10 to 15 Gy of radiation in addition to chemotherapy and were without residual disease after surgery was 88%, as opposed to 20% in 4-year survival for those with residual disease. In a study at the National Tumor Institute in Milan, Muscolino et al. (14) noted a 5-year survival of 57% in 7 patients with Stage III disease, who received preoperative radiation therapy, had less than N2 disease,
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and underwent complete tumor resection. Okubo et al. (15) from the Chest Disease Research Institute at Kyoto University reported a 5-year survival rate of 56% for patients who received preoperative radiation therapy and underwent complete tumor resection. Shahian et al. (8) in Boston, Massachusetts also reported a 5-year survival rate of 56% for 18 patients who received preoperative radiation therapy followed by surgery. Beyer and Weisenberger (16) at the University of California reported that the 5-year survival rate was 48% among 15 of 30 patients without metastatic disease who received preoperative radiation therapy. Wright et al. (17) from Massachusetts General Hospital, surgically resected 21 patients after preoperative radiation. The 5-year survival rate was 27%, but not all of these patients underwent complete resection. Ricci et al. (18) from the University of Rome, treated patients with radiation therapy followed by surgery. The 5-year survival rate was 34% in the 22 patients who underwent radical resection of their tumors. Van Houtte et al. (19) from the University of Rochester, treated 31 patients with preoperative radiation therapy. The overall 5-year survival rate was 18% but the 13 patients without bone erosion or scalene lymph node involvement had a 5-year survival rate of 40%. In some of these studies, apparently because the patient populations were small, patients who received postoperative radiation therapy were also included in the preoperative radiation treatment groups. Therefore, it is difficult to determine the precise effect of postoperative radiation therapy in these patients. Other researchers have reported lower survival rates for patients who may not have had complete resections. For example, Neal et al. (20) from the University of Florida, treated 73 patients with M0 disease, with either radiation therapy alone or radiation therapy followed by surgery and reported no difference in the 5-year survival rate between the treatment groups. They included some patients, however, who had M1 disease (21). Satori et al. (22) from the University of Padua in Italy, reported a 5-year survival of 25% for patients who received preoperative radiation followed by surgery. The 5-year survival rate in the 24 patients in our study who received postoperative radiation therapy was 40%, compared with 23% in the 10 who received preoperative radiation therapy. Only one study was found, that of Attar et al. (21), that compared the survival by preoperative versus postoperative radiation therapy. These investigators from the University of Maryland Hospital reported a 3-year survival rate of 23% for patients who received preoperative radiation therapy, 7% for those who received radiation therapy alone, and 7% for patients who underwent surgery followed by radiation therapy. In our study, we were unable to compare the effects of preoperative or postoperative chemotherapy alone because of the small number of patients who received only chemotherapy and surgery. Chemotherapy was, however, included in the preoperative and postoperative treatment compari-
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sons. No other studies were found that compared the effects of chemotherapy among patients with SST. Despite the difficulties in comparing outcome by treatment in our study, combinations of radiation therapy and chemotherapy plus surgery did appear to have the most favorable effect on 5-year survival in the patients in our study. In addition, clinical observations suggest that concurrent chemotherapy appears to be more effective than induction chemotherapy followed by radiation therapy to eliminate symptoms (23). Other investigators of operable (24 –27) and inoperable (28 –33) NSCLC have also reported the effects of chemoradiation therapy on survival. However, no studies were found that examined the effects of combined radiation therapy and chemotherapy in addition to surgery in patients with SST. The most common site of distant metastasis was in the brain. Twenty-one percent of the 80 patients with adenocarcinoma compared to 3% of the 39 patients with squamous histology developed brain metastasis. Our small number of patients who received prophylactic cranial irradiation (PCI) did not have a difference in the frequency of brain metastasis. A meta-analysis by Auperin (34) and his colleagues showed a significant improvement of overall survival among the patients who received PCI after complete response to the chemotherapy and thoracic radiation for small cell lung cancer. If we select patients with adenocarcinoma and give PCI within 4 months after the completion of treatment to the chest, it might benefit overall survival or at least reduce the rate of brain metastasis (31). CONCLUSIONS Among patients with Stage IIB SST (T3 N0 M0), less than 5% weight loss and surgical treatment as a part of a multidisciplinary approach were significant independent predictors of a better 5-year survival. Among patients with Stage IIIA (positive nodes) SST, the only predictor of survival was the KPS. For patients with Stage IIIB SST, the only predictor of survival was a right-sided SST which predicted a worse 5-year survival rate than a left-sided SST. More patients with adenocarcinoma than with squamous cell histology experienced cerebral metastases within 5 years. The 5-year survival rate in patients without gross residual disease after surgical resection who received postoperative radiation therapy in doses of 50 to 54 Gy was 51%, compared with 82% in those who received 55 to 64 Gy. There were 23 patients, out of a total of 143 (16%), who survived more than 3 years after diagnosis. Nineteen of the 23 patients (83%) underwent surgery in combination with radiation therapy or chemotherapy, or both. However, surgery did not improve the outcome if patients had positive nodes (N2). The overall results of this study suggest the need for new treatment strategies consisting of multidisciplinary treatments dictated by the new staging system (Stage IIIB vs. Stage IIIA), and histology of disease (adenocarcinoma vs. squamous carcinoma) for patients with SST. Prophylactic cranial irradiation might be warranted for patients with adenocarcinoma.
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REFERENCES 1. Pancoast HK. Superior pulmonary sulcus tumor. JAMA 1932; 99:1391–1396. 2. Detterbeck FC. Pancoast (superior sulcus) tumors. Ann Thorac Surg 1997;63:1810 –1881. 3. Anderson TM, May PM. Factors affecting survival in superior sulcus tumors. J Clin Oncol 1986;4:1598 –1603. 4. Hilaris BS, Martini N, Wong GY, Nori D. Treatment of superior sulcus tumor (Pancoast tumor). Surg Clin North Am 1987;67:965–977. 5. Komaki R, Mountain CF, Holbert JM, Garden AS, Shallenberger R, Cox JD, et al. Superior sulcus tumors: Treatment selection and results for 85 patients without metastasis (M0) at presentation. Int J Radiat Oncol Biol Phys 1990;19:31–36. 6. Millar J, Ball D, Worotniuk V, Smith J, Crennan E, Bishop M. Radiation treatment of superior sulcus lung carcinoma. Austral Radiol 1996;40:55– 60. 7. Reddy S, Faber LP, Baumann LA, Lee M-S, Jensik RJ, Kittle FC, et al. Preoperative radiation therapy in regionally localized stage III non–small cell lung carcinoma: Long-term results and patterns of failure. Int J Radiat Oncol Biol Phys 1990;19:287–292. 8. Shahian DM, Neptune WB, Ellis FH. Pancoast tumors: Improved survival with preoperative and postoperative radiotherapy. Ann Thorac Surg 1987;43:32–38. 9. American Joint Committee on Cancer (AJCC). Manual for staging of cancer. 4th ed. Philadelphia: J.B. Lippincott; 1992. p. 117–122. 10. American Joint Committee on Cancer (AJCC). Manual for staging of cancer. 5th ed. Philadelphia: J.B. Lippincott, 1997. p. 127–137. 11. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: McCloud CM, editor. Evaluation of chemotherapeutic agents. Symposium, Microbiology Section, New York Academy of Medicine. New York: Columbia University Press; 1949. p. 191– 205. 12. Martini N, McCormack P. Therapy on stage III (non metastatic disease). Semin Oncol 1983;10:95–110. 13. Martinez-Monge R, Herreros J, Aristu JJ, Aramendia JM, Azinovic I. Combined treatment in superior sulcus tumors. Am J Clin Oncol (CCT) 1994;17:317–322. 14. Muscolino G, Valente M, Andreani S. Pancoast tumours: Clinical assessment and long term results of combined radiosurgical treatment. Thorax 1997;52:284 –286. 15. Okubo K, Wada H, Fukuse T, Yokomise H, Inui K, Ike O, et al. Treatment of Pancoast tumors. Thorac Cardiovasc Surg 1995;43:284 –286. 16. Beyer DC, Weisenberger T. Superior sulcus tumors. Am J Clin Oncol (CCT) 1986;9:156 –161. 17. Wright CD, Moncure AC, Shepard J-AO, Wilkins EW, Mathisen DJ, Grillo HC. Superior sulcus lung tumors: Results of combined treatment (irradiation and radical resection). J Thorac Cardiovasc Surg 1987;94:69 –74. 18. Ricci C, Rendina EA, Venuta F, Francioni F, DeGiacomo T, Pescarmona EO, et al. Superior pulmonary sulcus tumors: Radical resection and palliative treatment. Int Surg 1989;74: 175–179. 19. van Houtte P, MacLennan I, Poulter C, Rubin P. External radiation in the management of superior sulcus tumor. Cancer 1984;54:223–227.
20. Neal CR, Amdur RJ, Mendenhall WM, Knauf DG, Black AJ, Million RR. Pancoast tumor: Radiation therapy alone versus preoperative radiation therapy and surgery. Int J Radiat Oncol Biol Phys 1991;21:651– 660. 21. Attar S, Miller JE, Satterfield J, Ho CK, Slawson RG, Hankins J, et al. Pancoast’s tumor: Irradiation or surgery? Ann Thorac Surg 1979;28:580 –584. 22. Satori F, Rea F, Calabro F, Mazzucco C, Bortolotti L, Tomio L. Carcinoma of the superior pulmonary sulcus: Results of irradiation and radical resection. J Thorac Cardiovasc Surg 1992;104:679 – 683. 23. Furuse K, Fukuoka KM, Takada Y, Nishikawa H, Katagami N, Kudoh S, et al. Phase III study of concurrent vs. sequential thoracic radiotherapy (TRT) in combination with mitomycin (M), vindesine and cisplatin (P) in unresectable stage III non–small cell lung cancer (NSCLC): Five-year median follow-up results. Proc ASCO 1999;18:458a. 24. Pincus M, Reddy S, Lee MS, Bonomi P, Taylor S, Rowland K, et al. Preoperative combined modality therapy for stage III MO non–small cell lung carcinoma. Int J Radiat Oncol Biol Phys 1988;15:189 –195. 25. Rusch VW, Albain KS, Crowley JJ, Rice TW, Lonchyna V, McKenna R, et al. Surgical resection of stage IIIA and stage IIIB non–small-cell lung cancer after concurrent induction chemoradiotherapy. J Thorac Cardiovasc Surg 1993;105:97– 106. 26. Dartevelle PG, Chapelier AR, Macchiarini P, Lenot B, Cerrina J, Ladurie FLR, et al. Anterior transcervical–thoracic approach for radical resection of lung tumors invading the thoracic inlet. J Thorac Cardiovasc Surg 1993;105:1025–1034. 27. Devine JW, Mendenhall WM, Million RR, Carmichael MJ. Carcinoma of the superior pulmonary sulcus treated with surgery and/or radiation therapy. Cancer 1986;57:941–943. 28. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non–small cell lung cancer. N Engl J Med 1992;326:524 –530. 29. Hebert SH, Curran WJ, Stafford PM, Rosenthal SA, McKenna WG, Hughes EN. Comparison of outcome between clinically staged, unresected superior sulcus tumors and other stage III non–small cell lung carcinomas treated with radiation therapy alone. Cancer 1992;69:363–369. 30. Johnson DE, Goldberg M. Management of the carcinoma of the superior pulmonary sulcus. Oncology 1997;11:781– 784. 31. Komaki R, Cox JD, Hartz AJ, Byhardt RW, Perez-Tamayo C, Clowry L, et al. Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol (CCT) 1985;8:362–370. 32. Komaki R, Derus SB, Perez-Tamayo C, Byhardt RW, Hartz A, Cox JD. Brain metastasis in patients with superior sulcus tumors. Cancer 1987;59:1649 –1653. 33. Komaki R, Roth J, Cox JD, Lopes da Conceicao A. Superior sulcus tumors: Results of irradiation of 36 patients. Cancer 1981;48:1563–1568. 34. Auperin A, Arriagada R, Pignon J-P, LeP C, Gregor A, Stephens RJ, Kristjansen PEG, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999;476:476 – 484.
PII S0360-3016(00)00736-7
CLINICAL INVESTIGATION
Lung
OUTCOME PREDICTORS FOR 143 PATIENTS WITH SUPERIOR SULCUS TUMORS TREATED BY MULTIDISCIPLINARY APPROACH AT THE UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER RITSUKO KOMAKI, M.D.,* JACK A. ROTH, M.D.,† GARRETT L.WALSH, M.D.,† JOE B. PUTNAM, JR., M.D.,† ARA VAPORCIYAN, M.D.,† JIN S. LEE, M.D.,‡ FRANK V. FOSSELLA, M.D.,‡ MARVIN CHASEN, M.D.,§ MARC E. DELCLOS, M.D.,* JAMES D. COX, M.D.*
AND
Departments of *Radiation Oncology, †Thoracic and Cardiovascular Surgery, ‡Thoracic/Head and Neck Medical Oncology, and § Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: Superior sulcus tumors (SST) of the lung are uncommon and constitute approximately 3% of non–small cell lung cancer (NSCLC). These tumors cause specific symptoms and signs, and are associated with patterns of failure that differ from those seen for NSCLC tumors in other nonapical locations. Prognostic factors and most effective treatments are controversial. We conducted a retrospective study at The University of Texas M. D. Anderson Cancer Center to identify outcome predictors for patients with SST treated by a multidisciplinary approach. Methods and Materials: This retrospective review of 143 patients without distant metastasis at presentation is a continuation of a previous M. D. Anderson study now updated to 1994. In this study, we examine the 5-year survival rate by pretreatment tumor and patient characteristics and by the treatments received. Strict criteria were used to define SST. Actuarial life-table analyses and Cox proportional hazard models were used to compare survival rates. Results: Overall predictors of 5-year survival were weight loss (p < 0.01), supraclavicular fossa (p ⴝ 0.03), or vertebral body (p ⴝ 0.05) involvement, stage of the disease (p < 0.01), and surgical treatment (p < 0.01). Five-year survival for patients with Stage IIB disease was 47% compared to 14% for Stage IIIA, and 16% for Stage IIIB. For patients with Stage IIB disease, surgical treatment (p < 0.01) and weight loss (p ⴝ 0.01) were significant independent predictors of 5-year survival. Among patients with Stage IIIA disease, the only predictor of survival was Karnofsky performance score (KPS) (p ⴝ 0.02). For patients with Stage IIIB disease, the only independent predictor of survival was a right superior sulcus location, which was associated with a worse 5-year survival rate than that for patients with tumors in the left superior sulcus (p ⴝ 0.02). More patients with adenocarcinoma than with squamous cell tumors experienced cerebral metastases within 5 years (p < 0.01). Patients without gross residual disease after surgical resection who received postoperative radiation therapy with total doses of 55 to 64 Gy had a 5-year survival rate of 82% as compared with the 5-year survival rate of 56% in patients who received 50 to 54 Gy. Twenty-three patients survived for longer than 3 years. Of these, 4 patients (17%) received radiation therapy alone or in combination with chemotherapy without surgical resection. The other 19 patients (83%) had resection combined with radiation therapy and/or chemotherapy. Conclusions: The findings from this study confirm the importance of the new staging system, separating T3 N0 M0 (Stage IIB) from Stage IIIA, since there was a significant difference in the 5-year survival (p < 0.01). Interestingly, there was no significant 5-year survival difference between Stage IIIA (N2) and Stage IIIB (T4 or N3). This study also suggests that surgery is an important component of the multidisciplinary approach to patients with SST if their nodes were negative. Disease that is minimally invading surrounding normal structures can be resected followed by radiation therapy in doses of 55 to 64 Gy. Further investigation of treatment strategies combining high-dose radiation therapy (>66 Gy) with chemotherapy is indicated for patients with unresectable and/or node-positive (N2) SST. © 2000 Elsevier Science Inc. Lung, Superior sulcus tumors, Multidisciplinary treatment, Predictors, Survival.
This work was supported in part by PO1 CA-06294, T32CA77050, and P30CA16672 awarded by the National Cancer Institute, U.S. Department of Health and Human Services. Accepted for publication 11 April 2000.
Reprint requests to: Ritsuko Komaki, M.D., Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 97, Houston, TX 77030. Presented at the 80th Annual Meeting of the American Radium Society, Monaco, April 1998. 347
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INTRODUCTION Superior sulcus tumors (SST), including Pancoast’s tumors (1), arise in the apex of the lung above the sulcus and cause specific symptoms and signs depending on the location and whether the tumor extends into the surrounding structures. Because of the closeness of critical structures to the tumor (e.g., the subclavian artery for anterior lesions; the brachial plexus for lesions in the middle location, and the sympathetic stellate ganglion causing Horner’s syndrome [Pancoast’s tumor], the vertebral bodies, nerve foramen, and spinal cord for posterior lesions), SST were often considered marginally resectable or unresectable. Therefore, for many years, preoperative radiation therapy was considered routine treatment for those tumors. However, with the evolution in our understanding of these tumors and modern imaging and surgical techniques, there is now considerable debate about the roles and timing of surgical resection, radiation therapy, and chemotherapy in the treatment of patients with these tumors. Published reports (2) have noted 5-year survival rates of 15% to 56% for patients receiving combinations of radiation therapy and surgical treatment. In some of these studies, patients received additional postoperative radiation therapy. Few studies, however, have had adequate numbers of patients to allow examination of the effects of distinct treatments such as varying doses of radiation with surgery, radiation therapy with chemotherapy, or radiation therapy alone. A further difficulty is that some studies have identified univariate predictors of survival (3– 8); but only one identified multivariate (independent) predictors of survival (4). None has examined independent predictors of survival by stage of disease. The identification of predictors of survival along the continuum of care could reveal subgroups of patients who require new combined treatment strategies. Findings from a previous retrospective medical record review from this institution published in 1990 (5) were obtained in 85 patients with SST without distant metastatic disease at presentation. Since that publication, the length of follow-up has increased and additional patients have been treated. The current study of 143 patients updates the previous study. It also analyzes treatment combinations and identifies univariate and multivariate predictors of 5-year survival. METHODS AND MATERIALS The methods used in The University of Texas M. D. Anderson retrospective studies of SST have been described elsewhere (5). The patients in this update were identified from individual physicians’ records of lung cancer patients with SST who were treated at M. D. Anderson from 1975 through 1994. All 143 patients had a cytologically or histologically verified diagnosis of non–small cell lung cancer (NSCLC). Patients with small cell lung cancer or sarcoma or whose disease was diagnosed on the basis of clinical grounds alone were excluded from this review. The Amer-
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ican Joint Committee on Cancer staging criteria were used for previous publications (9). Patients were later reclassified using the new staging system (10) in which T3 N0 M0 involvement is considered Stage IIB instead of Stage IIIA. Stage assignment was based on clinical findings because only a subset of patients had surgical exploration. Only patients with distant metastases were excluded from these analyses. Five-year survival rates were calculated and predictors of survival were identified using actuarial life table methods and Cox proportional hazard models. RESULTS Patient characteristics One hundred forty-three patients with SST were identified in this retrospective study. Patient characteristics are summarized in Table 1 by stage of disease. Median patient age at diagnosis was 56 years. Patients were predominantly white, and there was a 2:1 male-to-female ratio. Most patients had less than 5% weight loss, although the losses ranged from 0 to 24% of body weight. Karnofsky performance scores (KPS) (11) ranged from 50 to 100, but 94% of the patients had a KPS of 80 to 100. Patients with Stage IIIB disease had slightly lower KPS. Ninety-seven percent of the patients had a history of smoking, and 31% had consistently consumed alcohol. Most did not have a prior history of malignancy. The frequencies of presenting symptoms were as follows: arm/shoulder pain, 99 patients (69%); chest pain, 56 patients (39%); cough, 57 patients (40%); dyspnea, 37 patients (26%); Horner’s syndrome, 27 patients (19%); and arm swelling, 3 patients (2%). Tumor characteristics are summarized in Table 2. Maximum tumor diameter, as measured in the surgical patients, ranged from 2.0 to 13.5 cm (median 5.4 cm). All patients had pathologic confirmation of non–small cell histology with a 2:1 ratio of adenocarcinoma to squamous cell histology. The ratio of tumors in the right apex to those in the left apex was approximately 2:1. More patients had tumors that involved the ribs (T3) or vertebral bodies (T4) than the supraclavicular fossa (N3). In addition, more patients had Stage IIIB disease than Stage IIIA or IIB disease. Follow-up after diagnosis ranged from 1 month to 15 years with median 24 months. Overall survival rates at 2 and 5 years were 40% and 23%, respectively. Predictors of survival Overall predictors. Overall univariate predictors of 5-year survival and cumulative survival rates are presented in Table 3. Better survival was found among patients who presented with weight loss of less than 5%, no vertebral body involvement, no supraclavicular involvement, and Stage IIB disease. Patients who underwent surgery also survived for longer especially among patients with negative nodes. Five-year survival rates were 47% in patients with Stage IIB disease compared to 14% in those with Stage IIIA and 16% with Stage IIIB (p ⬍ 0.01). The 5-year survival
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Table 1. Characteristics of patients with superior sulcus tumors Stage
Characteristics* Age at diagnosis (yr) Median Range Ethnicity White African American Hispanic Sex Male Female Weight loss ⬍5% ⱖ5% KPS 90–100 80 70 ⬍70 Smoking history Current smoker Stopped smoking Never smoked Unknown Daily alcohol use No Yes Unknown Prior/concurrent malignancy None Prior Current
IIB(T3N0M0) (n ⫽ 36)
IIIA(T1–3N2) (n ⫽ 31)
IIIB(T4 or N3) (n ⫽ 76) (T4:59 & N3:17)
Total (n ⫽ 143)
58 38–74
58 37–73
55 29–82
56 29–82
34 0 2
28 2 1
64 6 6
126 (88%) 8 (6%) 9 (6%)
21 15
21 10
59 17
101 (71%) 42 (29%)
34 2
25 6
54 22
113 (79%) 30 (21%)
29 4 2 1
30 1 0 0
55 15 3 3
114 (80%) 20 (14%) 5 (3%) 4 (3%)
21 15 0 0
14 14 1 2
38 36 1 1
73 (51%) 65 (45%) 2 (1%) 3 (2%)
10 26 0
8 21 2
27 49 0
96 (67%) 45 (31%) 2 (1%)
29 7 0
23 6 0
68 8 2
120 (84%) 21 (15%) 2 (1%)
*Numbers of patients, unless otherwise noted.
rate in patients who had surgery was 37% compared with 11% in those who did not have surgical resection (p ⬍ 0.01). Age, sex, prior or concurrent malignancy, smoking status, alcohol consumption, KPS ⬍ 90 versus 90 to 100, Horner’s syndrome, rib involvement, tumor histology, and the location of tumor (right or left apex) were not significant predictors of overall 5-year survival. Surgical patients. Univariate predictors of 5-year survival among surgical patients were weight loss (⬍5% versus ⱖ5%) (p ⫽ 0.04), stage of disease (p ⫽ 0.01), and residual disease (positive surgical margins or gross disease remaining) (p ⬍ 0.01). Multivariate analyses revealed that there was an association between several factors (weight loss, stage of disease, and residual disease after surgery); therefore, none of the univariate predictors was an independent predictor of 5-year survival. The 5-year survival rate was 18% in the 29 patients with residual disease, compared with 55% in the 33 patients who underwent complete resection (p ⬍ 0.01). There was no difference in the 5-year survival by the type of surgery (segmental or wedge resection versus lobectomy). There
was also no difference by the type of surgery procedure in patients who had residual disease. Unresectable patients. The 81 patients who did not undergo resection had an overall 5-year survival rate of 11%. The only univariate predictor of 5-year survival in these patients was the KPS (⬍90 versus 90 to 100) (p ⫽ 0.04). Stage of disease (IIB, IIIA versus IIIB) was not a predictor of 5-year survival for unresectable patients. Stage of disease. In the 36 patients with Stage IIB disease, univariate predictors of 5-year survival were weight loss (⬍5% versus ⱖ5%) (p ⬍ 0.01) and surgical treatment (p ⬍ 0.01). In the Cox bivariate analysis, surgical treatment and weight loss remained significant independent predictors of survival. In the 31 patients with Stage IIIA disease (positive nodes), the only univariate predictor of 5-year survival was the KPS (⬍90 versus 90 –100) (p ⫽ 0.02). Surgery was not an important prognostic factor of outcome in this group. In the 76 patients with Stage IIIB disease (T4:59, N3:17), tumor location (right versus left apex) (p ⫽ 0.02) was the only significant univariate predictor of 5-year survival.
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Table 2. Superior sulcus tumor characteristics Stage Characteristics* Histology Non–small cell carcinoma Adenocarcinoma Squamous Adenosquamous Large cell Non–small cell Location Right lung Left lung Regional extension Rib Vertebral body Supraclavicular fossa or supraclavicular nodes Median tumor size (cm) (surgical patients, n ⫽ 60)†
IIB (n ⫽ 36)
IIIA (n ⫽ 31)
IIIB (n⫽ 76)
Total (n ⫽ 143)
23 8 0 2 3
17 8 1 3 2
40 23 1 7 5
80 (56%) 39 (27%) 2 (1%) 12 (8%) 10 (7%)
24 12
21 10
46 30
91 (64%) 52 (36%)
11 4 1
4 0 0
28 33 22
43 (30%) 37 (26%) 23 (16%)
5
6
5.8
5.4
*Number of patients, unless otherwise noted. † 60 surgical patients with tumor measurements, 2 patients no tumor measurements recorded.
Five-year survival in patients with Stage IIIB disease was 10% in those with right apical tumors and 25% in patients with left apical tumors (p ⫽ 0.02). Other factors were examined that could contribute to less favorable survival in patients with Stage IIIB disease and right apical tumors. These factors were sex; age; current smoker; alcohol consumption; KPS; weight loss; prior or
concurrent malignancy; Horner’s syndrome; vertebral body, supraclavicular, or rib involvement; adenocarcinoma versus squamous cell histology; wedge resection versus lobectomy; and residual disease after surgical resection. The only difference identified was that patients with Stage IIIB disease and right apical tumors were found less frequently to have Horner’s syndrome compared to the left apical tumors (p ⫽ 0.02).
Table 3. Cumulative survival to 5 years for patients with superior sulcus tumors by predictive factors
Results of treatment combinations Overall results. Treatments are presented in Table 4. Only 5 patients (3%) received surgery alone. Forty-five patients (31%) received radiation therapy alone. Thirty-two patients (22%) were treated with radiation therapy and chemotherapy equally distributed between Stage IIIA and
Weight loss 1-year 2-year 5-year Vertebral body 1-year 2-year 5-year Supraclavicular involvement 1-year 2-year 5-year Stage 1-year 2-year 5-year Surgery 1-year 2-year 5-year
IIB (n ⫽ 36) 76% 58% 47%
⬍5% (n ⫽ 113) 67% 47% 27% NO (n ⫽ 106) 73% 41% 26%
ⱖ5% (n ⫽ 30) 68% 16% 10% YES (n ⫽ 37) 51% 37% 17%
NO (n ⫽ 120) 69% 43% 26% IIIA (n ⫽ 31) 76% 37% 14% NO 63% 28% 11%
YES (n ⫽ 23) 57% 21% 7% IIIB (n ⫽ 76) 60% 33% 16% YES 74% 56% 37%
p ⬍ 0.01
Table 4. Treatments received* by stage of disease (n ⫽ 143) Stage
p ⫽ 0.05 Treatment
p ⫽ 0.03
p ⬍ 0.01
Resectable Surgery only Chemo ⫾ XRT 3 Surgery Surgery 3 XRT ⫾ Chemo Pre ⫹ Postop XRT ⫾ Chemo Unresectable or inoperable Radiation only Chemotherapy only XRT ⫹ Chemo Total
p ⬍ 0.01
IIB
IIIA
IIIB
Total
2 4 14 8
2 1 6 2
1 7 8 7
5 (3%) 12 (8%) 28 (20%) 17 (12%)
5 2 1
5 1 14
35 1 17
45 (31%) 4 (3%) 32 (22%)
36
31
76
143
*Actual treatment received. Patient may not have completed planned treatment.
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IIIB. Twenty-four (17%) were treated with surgery followed by radiation therapy, 17 (12%) were treated with preoperative or postoperative radiation therapy in combination with various types and regimens of chemotherapy, and 10 (7%) were treated with radiation therapy followed by surgery. The remaining 10 patients received other combinations of treatment. Among the 4 patients who received chemotherapy only, 3 patients were on a treatment protocol for resectable disease; however, at the completion of chemotherapy, disease had progressed, which excluded surgery as a further treatment option. Among the 32 patients who received radiation therapy and chemotherapy without surgery, 23 patients (72%) were enrolled in various treatment protocols. Seventeen of the 23 patients were enrolled in broad protocols for unresectable NSCLC. Results in patients with Stage IIB disease (T3 N0 M0). Among 36 patients with Stage IIB disease (T3 N0 M0), the largest treatment groups consisted of 14 patients who had surgery followed by radiation treatment with or without chemotherapy (n ⫽ 14), and 8 patients who had surgery and both preoperative and postoperative combinations of radiation therapy and chemotherapy. The 5-year survival rate was 56% in the 11 patients who received surgery followed by radiation therapy, whereas it was 87% in the 8 patients who received both preoperative and postoperative combination radiation therapy and chemotherapy (p ⬎ 0.05). Treatment in the preoperative and postoperative treatment combination group (n ⫽ 8) consisted of the following: chemotherapy then surgery then radiation therapy (3 patients); radiation therapy then chemotherapy then surgery followed by radiation therapy (2 patients); radiation therapy then chemotherapy then surgery followed by chemotherapy (2 patients); and radiation therapy then surgery followed by radiation therapy (1 patient). Results in patients with Stage IIIA disease. Surgery was not a predictor of survival in patients with Stage IIIA disease (positive nodes). The largest treatment group (Table 4) consisted of patients who received combinations of radiation therapy and chemotherapy without surgery. The 5-year survival rate in the 20 patients without surgery was 20%. This rate was similar to that (14%) in the 11 patients with Stage IIIA disease who underwent surgery, either alone or in combination with chemotherapy or radiation therapy. Results in patients with Stage IIIB disease. There was no significant difference in overall 5-year survival rates between 59 patients with T4 and 17 patients with N3 disease; 17% vs. 7%, respectively (p ⫽ 0.28). Surgery was also not a predictor of survival in patients with Stage IIIB disease. The two largest treatment groups consisted of patients who received radiation therapy alone (n ⫽ 36) and radiation therapy plus chemotherapy (n ⫽ 17) (T4:38 and N3:15). The 5-year survival rate was 11% in patients treated with radiation therapy alone and 14% in patients treated with radiation therapy and chemotherapy. The 5-year survival rate in the 23 patients with Stage IIIB disease (T4:21 and
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Fig. 1. Overall survival after treatment depending on new AJCC staging system.
N3:2) who received surgery was 25%. The differences in the survival rates among the three treatment groups were not statistically significant. The 5-year survival rates for patients with Stage IIIB disease in smaller treatment groups were as follows: it was 19% in 7 patients who received preoperative radiation therapy with or without chemotherapy, which was similar to the 18% of patients who received both preoperative and postoperative combinations of radiation therapy or chemotherapy. The 5-year survival rate was 38% in the 8 patients with Stage IIIB disease (minimal T4 N0) who did not receive preoperative treatment but underwent operation first followed by postoperative radiation therapy with or without chemotherapy (p ⫽ 0.78) (Fig. 1). Radiation therapy doses Postoperative radiation therapy group. Among the surgical patients who had no residual disease (negative surgical margins or no gross residual disease), the 5-year survival rate was 51% in the 7 patients who received postoperative radiation therapy in doses of 50 to 54 Gy and 82% in the patients who received 55 to 64 Gy (Fig. 2). The 5-year survival rate was 22% in the 13 patients who had residual disease at surgery and who received 55 to 64 Gy of radiation postoperatively. Only 2 patients received the lower dose of 50 to 54 Gy. There were too few patients who received surgery alone or chemotherapy combined with radiation therapy postoperatively to examine other treatment effects. Radiation therapy only group. Among the 45 unresectable or inoperable patients who received radiation therapy alone, the total dose ranged from 16 to 69.6 Gy and the median dose was 60 Gy. The overall 5-year survival rate in these patients was 9%. Local control at 5 years was achieved in 32% of the patients. Distant metastasis occurred in 51% within 5 years. Radiation therapy doses with chemotherapy. Among the 32 nonsurgical patients who received radiation therapy with either concurrent or sequential chemotherapy, the total radiation dose ranged from 19.68 to 69.6 Gy (median 64 Gy).
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and 22% had Stage IIIB disease. Most had no weight loss (96%) and a KPS of 80 to 100 (91%) at diagnosis. Four of the 23 patients (17%) had radiation therapy or radiation therapy and chemotherapy without surgical resection. The other 19 patients (83%) received surgery in combination with radiation therapy, or chemotherapy, or both. DISCUSSION
Fig. 2. Five-year survival by postoperative radiation treatment dose.
The 12 nonsurgical patients who received a higher dose of radiation of ⱖ66 Gy, with either sequential or concurrent chemotherapy, showed a 5-year survival rate of 33% compared with 7% in the 20 patients who received a total dose ⬍ 66 Gy. The 5-year survival rate was 36% in the patients who received ⱖ66 Gy of radiation with concurrent chemotherapy. Local control at 5 years was achieved in 44% of the patients. Distant metastasis occurred in 53% within 5 years. Distant metastatic sites The brain was the most frequent site of distant metastasis. Cerebral metastasis occurred in 24 of 143 patients (17%) within 5 years of diagnosis. Three out of 14 patients who received prophylactic cranial irradiation (PCI) eventually developed brain metastasis, while 21 of 129 patients who did not receive PCI developed brain metastasis in 5 years. There was no statistical difference in the frequency of cerebral metastasis within 5 years between these 2 groups (p ⫽ 0.62). The stage of disease at diagnosis, location of tumor (right or left lung), type of surgical treatment, and type of adjuvant treatment were also not associated with cerebral metastasis. Tumor histology was the only significant factor associated with cerebral metastasis: cerebral metastasis occurred within 5 years in 21% of the 80 patients with adenocarcinoma compared with only 3% of the 39 patients with squamous cell histology (p ⬍ 0.01). The percentage of patients with distant metastasis to other sites was as follows: bone (15%), contralateral lung (10%), adrenal (8%), liver (6%), and soft tissue (4%). Less frequently, patients had metastases to the trachea, esophagus, heart, kidney, pelvis, and leptomeninges. One patient was found at autopsy to have metastases to the stomach, spleen, kidney, pancreas, small bowel, mesentery, omentum, and retroperitoneal nodes. Long-term survivors Twenty-three of the 143 patients (16%) survived 3 to 15 years after treatment. Age at diagnosis ranged from 29 to 67; 52% had Stage IIB disease, 22% had Stage IIIA disease,
Some factors that are generally used to predict outcome in lung cancer patients are closely related to the stage of disease and may help determine whether a patient is selected for surgery. Univariate analyses do not control for other factors that may influence the results. Multivariate analyses allow the examination of all recognized predictors of outcome to determine which ones are independent or are merely a component of another factor. Our analyses demonstrated that predictors of survival in patients with SST differ depending on the stage of disease. For example, lack of surgical treatment and a 5% or greater weight loss were the only negative independent predictors of 5-year survival for patients who had Stage IIB disease. Surgical treatment was not, however, a significant predictor of 5-year survival in patients with Stage IIIA (positive nodes) or IIIB disease. In patients with Stage IIIA disease, the only predictor of survival was the KPS, whereas in patients with Stage IIIB disease, the location of the tumor (right or left apex) was the only predictor of 5-year survival. Because tumors in the superior sulcus are less common than those at other sites within the thorax, there have been few studies with sufficient patients to examine data other than by univariate methods. Only two studies have had over 100 patients. In the study from Hilaris et al. (4) from Memorial Sloan-Kettering Cancer Center, which consisted of 129 patients, mediastinal node involvement and preoperative radiation therapy were found to be significant multivariate predictors of survival. Martini et al. (12), also at Memorial Sloan-Kettering, reported treatment results in 170 patients with Stage IIIA disease only. Millar et al. (6) at the Peter A. McCallum Cancer Institute in Australia observed that any nodal involvement adversely affected survival in their patient population of 131. In none of these studies were results stratified by stage of disease. Ours was the first study that examined survival predictors for patients with SST by stage of disease. There have been many reports of treatment outcome in small numbers of patients with SST. For example, researchers at the University of Navarra in Spain (13) studied 18 patients who received preoperative radiation therapy. The 4-year survival in the patients who received 10 to 15 Gy of radiation in addition to chemotherapy and were without residual disease after surgery was 88%, as opposed to 20% in 4-year survival for those with residual disease. In a study at the National Tumor Institute in Milan, Muscolino et al. (14) noted a 5-year survival of 57% in 7 patients with Stage III disease, who received preoperative radiation therapy, had less than N2 disease,
Superior sulcus tumors: Outcome predictors for SST
and underwent complete tumor resection. Okubo et al. (15) from the Chest Disease Research Institute at Kyoto University reported a 5-year survival rate of 56% for patients who received preoperative radiation therapy and underwent complete tumor resection. Shahian et al. (8) in Boston, Massachusetts also reported a 5-year survival rate of 56% for 18 patients who received preoperative radiation therapy followed by surgery. Beyer and Weisenberger (16) at the University of California reported that the 5-year survival rate was 48% among 15 of 30 patients without metastatic disease who received preoperative radiation therapy. Wright et al. (17) from Massachusetts General Hospital, surgically resected 21 patients after preoperative radiation. The 5-year survival rate was 27%, but not all of these patients underwent complete resection. Ricci et al. (18) from the University of Rome, treated patients with radiation therapy followed by surgery. The 5-year survival rate was 34% in the 22 patients who underwent radical resection of their tumors. Van Houtte et al. (19) from the University of Rochester, treated 31 patients with preoperative radiation therapy. The overall 5-year survival rate was 18% but the 13 patients without bone erosion or scalene lymph node involvement had a 5-year survival rate of 40%. In some of these studies, apparently because the patient populations were small, patients who received postoperative radiation therapy were also included in the preoperative radiation treatment groups. Therefore, it is difficult to determine the precise effect of postoperative radiation therapy in these patients. Other researchers have reported lower survival rates for patients who may not have had complete resections. For example, Neal et al. (20) from the University of Florida, treated 73 patients with M0 disease, with either radiation therapy alone or radiation therapy followed by surgery and reported no difference in the 5-year survival rate between the treatment groups. They included some patients, however, who had M1 disease (21). Satori et al. (22) from the University of Padua in Italy, reported a 5-year survival of 25% for patients who received preoperative radiation followed by surgery. The 5-year survival rate in the 24 patients in our study who received postoperative radiation therapy was 40%, compared with 23% in the 10 who received preoperative radiation therapy. Only one study was found, that of Attar et al. (21), that compared the survival by preoperative versus postoperative radiation therapy. These investigators from the University of Maryland Hospital reported a 3-year survival rate of 23% for patients who received preoperative radiation therapy, 7% for those who received radiation therapy alone, and 7% for patients who underwent surgery followed by radiation therapy. In our study, we were unable to compare the effects of preoperative or postoperative chemotherapy alone because of the small number of patients who received only chemotherapy and surgery. Chemotherapy was, however, included in the preoperative and postoperative treatment compari-
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sons. No other studies were found that compared the effects of chemotherapy among patients with SST. Despite the difficulties in comparing outcome by treatment in our study, combinations of radiation therapy and chemotherapy plus surgery did appear to have the most favorable effect on 5-year survival in the patients in our study. In addition, clinical observations suggest that concurrent chemotherapy appears to be more effective than induction chemotherapy followed by radiation therapy to eliminate symptoms (23). Other investigators of operable (24 –27) and inoperable (28 –33) NSCLC have also reported the effects of chemoradiation therapy on survival. However, no studies were found that examined the effects of combined radiation therapy and chemotherapy in addition to surgery in patients with SST. The most common site of distant metastasis was in the brain. Twenty-one percent of the 80 patients with adenocarcinoma compared to 3% of the 39 patients with squamous histology developed brain metastasis. Our small number of patients who received prophylactic cranial irradiation (PCI) did not have a difference in the frequency of brain metastasis. A meta-analysis by Auperin (34) and his colleagues showed a significant improvement of overall survival among the patients who received PCI after complete response to the chemotherapy and thoracic radiation for small cell lung cancer. If we select patients with adenocarcinoma and give PCI within 4 months after the completion of treatment to the chest, it might benefit overall survival or at least reduce the rate of brain metastasis (31). CONCLUSIONS Among patients with Stage IIB SST (T3 N0 M0), less than 5% weight loss and surgical treatment as a part of a multidisciplinary approach were significant independent predictors of a better 5-year survival. Among patients with Stage IIIA (positive nodes) SST, the only predictor of survival was the KPS. For patients with Stage IIIB SST, the only predictor of survival was a right-sided SST which predicted a worse 5-year survival rate than a left-sided SST. More patients with adenocarcinoma than with squamous cell histology experienced cerebral metastases within 5 years. The 5-year survival rate in patients without gross residual disease after surgical resection who received postoperative radiation therapy in doses of 50 to 54 Gy was 51%, compared with 82% in those who received 55 to 64 Gy. There were 23 patients, out of a total of 143 (16%), who survived more than 3 years after diagnosis. Nineteen of the 23 patients (83%) underwent surgery in combination with radiation therapy or chemotherapy, or both. However, surgery did not improve the outcome if patients had positive nodes (N2). The overall results of this study suggest the need for new treatment strategies consisting of multidisciplinary treatments dictated by the new staging system (Stage IIIB vs. Stage IIIA), and histology of disease (adenocarcinoma vs. squamous carcinoma) for patients with SST. Prophylactic cranial irradiation might be warranted for patients with adenocarcinoma.
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