Annals of Oncology 3: 469-474, 1992. O 1992 Klutver Academic Publishers. Printed in the Netherlands.
Original article The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer F. R. Hirsch, K. 0sterlind, L. Ingemann Jensen, C Thomsen, K. Peters, F. Jensen & H. H. Hansen Dept. of Oncology, Dept. of Radiology and Dept. of Clinical Physiology, Rigshospitalet, Copenhagen,
Denmark
Summary. One hundred six patients with small cell lung cancer (SCLC) were prospectively evaluated with regard to the prognostic impact of abdominal CT-scan in the pretreatment staging when compared to ultrasonography of the abdomen. Staging based on abdominal ultrasonography (US) plus bilateral bone marrow examinations gave as a result that 47 patients had extensive disease (ED) (44%). Seventeen patients with proven ED at time of referral were not included in this study. Abdominal CT-scan was performed in 76 of the 106 patients. Thirty patients of these 76 patients (39%) were classified as having ED after staging including US, but abdominal metastases were disclosed in another ten patients at the subsequent CT-scan. Liver metastases seen in two patients at ultrasonography were overlooked on the CT-scans. Median survival of the 36 patients classified as having limited disease (LD) after both procedures was 458 days, which was significantly better compared to 330 days for the ten patients with stage migration from LD to ED based on CT-scan, (p < 0.05) and compared to 242 days in the 30 patients with ED demonstrated by both US and CT-scans (p < 0.05). The prognostic impact of the CT-scan was further investigated in
a multivariate analysis (Cox). Stage disease, performance status, LDH and alkaline phosphatase were significant prognostic factors in a proportional hazards model based on the original 106 patients. Patients in the best prognostic group were characterized by LD, good performance status (0—1) and normal LDH and alkaline phosphatase serum values. This group consisted of 22 patients (21%). Seventeen of these patients had a CT-scan, after which five patients (29%) were downgraded from LD to ED. This downgrading significantly increased the influence of stage in a new Cox model. Correspondingly, the 2-year survival rate rose from 31% to 41%. It is concluded that abdominal CT-scanning is a more sensitive staging procedure in SCLC than ultrasonography. In prognostication this superiority is most important for patients in the good prognostic category, and CT-scans could therefore be restricted to the 20 percent of the patients belonging to this category.
Introduction
Group (VALG) defined the system of 'limited' and 'extensive' disease, mainly on the background of its suitability for radiotherapy [3]. This staging system has been demonstrated to represent valuable prognostic information [4]. The median survival of patients with SCCL ranges from 10-15 months for patients with 'limited' disease, and 7-11 months for patients with 'extensive' disease [5]. The reported rates of long-term survival differ somewhat from study to study. Differences in staging procedures such as, e.g. bone scans, brain scans and liver scans, which have been performed routinely by some but not by others, might explain some of the differences in the results from center to center. In 1984 the International Association for the Study of Lung Cancer (IASLC) produced the first concensus report on staging and staging procedures for SCLC [6|. At that time CT-scanners were not generally available, and the technique had not been investigated sufficiently to be recommended routinely as a part of the staging system. Since then, a few retrospective studies have
With the increasing application of common internationally accepted staging systems for malignant diseases it has been possible for oncologists to assess and compare the results of therapy more accurately. It has also been possible to identify important prognostic factors in the treatment planning for the individual patient as well as for groups of patients. The staging system for malignant lung tumors has been developed mainly to determine resectability. The American Joint Commission for Staging and End Results Reporting has recently revised the TNM-system for staging lung cancer [1]. Small cell lung cancer (SCLC) differs from other histologjcal types of lung cancer by, e.g. earlier and more widespread dissemination. Studies in the late 1960s demonstrated that the classical TNM system was inappropriate for the staging of this disease [2]. Accordingly, other staging systems were developed. The Veterans' Administration Lung Cancer Study
Key words: small cell lung cancer, staging, CT-scan, prognosis
470
been published comparing CT with the other staging procedures in patients with SCLC. Harper et al. [7] evaluated the thorax of 50 consecutive patients with SCLC and found that CT gave information about the extent of disease in the chest which could not be obtained by conventional methods, which has also been reported by others [8-10]. Abdominal CT has been evaluated in SCLC retrospectively and found to be of great value [11, 12]. These studies have been reviewed elsewhere [13]. Ultrasonography of the abdomen is another sensitive procedure for the detection of liver metastases [14] and was in our institution used as the primary option in trials since the mid 1980s. A comparative diagnostic study (predictive values) of ultrasonography versus CTscan has been described recently from our institution [15]. The present study was undertaken in order to evaluate the impact of abdominal CT-scanning in comparison with ultrasonography on the staging and prognosis in a prospective series of patients with SCLC.
Nyco, Oslo, Norway) or sodium-meglumin diatrizoate, 370 mg I/ml (Urografin, Schering, Berlin, W Germany). The postcontrast scanning included the liver, the adrenals and the pancreas. The examinations were evaluated on hard copies with suitable window-settings. In the evaluation of the CT-scans, lymph node involvement was defined as enlargement of a node to more than 1 cm. Involvement of the adrenals, pancreas, kidneys and spleen was defined as changes in the size and morphology and/or of the attenuation. Ultrasonography All examinations were performed with a dynamic ultrasonic scanner (Aloka SDD 256, Aloka Co. Ltd., Tokyo, Japan) with a linear array 3.5 MHz transducer equipped with a needle-steering device. A ventral and intercostal admittance was used with the patient in a supine position. Percutaneous biopsies of suspected hepatic lesions were taken immediately under ultrasonic guidance. If the liver appeared normal, random biopsies were taken from a right subcostal site directed centrally into the liver. An 0.8 mm diameter sure-cut needle was used to obtain histological material. Three needle passes were performed routinely. The US examination was always done by the same person (F. J.), and a report was written immediately after each examination. The results of the CT were not known when the US was evaluated, and vice versa.
Material and methods Statistics The study included consecutive patients 1.6). Eight of the nine downgraded patients moved to an inferior prognostic stratum (Table 7). The influence of downgrading on survival in the three prognostic strata was most apparent in the good prognostic category (Fig. 4). Tabled. Multivariate analysis (Cox) of pretreatment factors with influence on survival in 105 small cell lung cancer patients staged by ultrasonography (US) (model 1) plus subsequent abdominal CTscan (model 2).
Years Fig. 2. Survival curves for limited (-) and extensive stage ( ) disease of 76 patients staged by ultrasonography.
Variable
Coefficient 1
RR 1
Coefficient 2
RR2
Score
Stage Alkaline phosphatase
0.58
1.79
0.79
2.20
1.0
0.42 0.53 0.61
1.52 1.69 1.83
0.43 0.54 0.63
1.54 1.72 1.87
0.7 0.9 1.0
LDH PS
p < 0.05 for all four factors in both models and for an overall comparison of the two models (likelihood ratio test). 1: Abdominal disease staged by US. 2: Abdominal disease staged by US + CT-scan (in 75 patients). RR: Relative risk of dying. Score - RR/RR for PS. Table 7. Prognostic category migration and CT-scan findings in nine downgraded patients.
Years
Fig. 3. Survival curves for limited ( ) and extensive stage ( ) disease of 76 patients staged by CT-scan.
Prognostic impact of abdominal CT-scan Ultrasonography has been used routinely as a staging procedure in our trials since 1985. The results of a proportional hazards (Cox) analysis of survival data on the 106 patients staged by this procedure are shown in Table 6. One patient was excluded because of missing data (LDH and alkaline phosphatase). This patient was one of the ten with abdominal metastases at CT-scan (Table 2). 'Stage' was updated by data from the CTscans, nine patients were downgraded from LD to ED, and a new Cox analysis was done (Table 2). The prognostic influence of 'stage' increased, and model 2 fit the data significantly better than model 1 (p < 0.05 in a likelihood ratio test). A prognostic score was obtained by a minor transformation of the coefficients in model 1 (Table 6), and three prognostic categories were defined. The good prognostic category was characterized by limited disease, normal LDH and alkaline phosphatase, and performance status 0 or 1. Extensive disease alone or one abnormal blood test or PS > 1 qualified for the intermediate prognostic group, while two or more adverse
Migration
Adverse features
CT-findings
G-l G-I G-I G-I G-I
None None None None None
Liver metastases Adrenal metastases Adrenal metastases Pancreatic metastases Pancreatic + retroperitoneal mets.
I-P I- P 1-P
Alk. phosph. t LDHt PS> 1
Retroperitoneal metastases Adrenal metastases Adrenal + retroperitoneal metastases
P-P
Alk. Phosph. I &PS> 1
Liver metastases
Prognostic strata — G: Good; I: Intermediate; P: Poor.
Discussion The liver is one of the most frequent sites of metastases of SCLC at the time of primary diagnosis and during treatment. A variety of diagnostic modalities has been used for the work-up of patients with SCLC: biochemical tests by means of liver associated enzymes, liver scintigraphy with isotopes, peritoneoscopy (PS) with guided biopsy, ultrasonography (US) with concomitant biopsy, and CT. Prospective, comparative studies have been carried out in our institution comparing the diagnostic value of liver associated enzymes to that of peritoneoscopy (PS) [21], and PS versus US [14]. According to the results of these studies, US with guided biopsy was found to be
473
The present study shows that the CT-scan downgraded about 20% of the patients from the limited to the extensive disease stage, and these patients had a significantly shorter survival than patients in the limited disease category. A characteristic Will-Rogers phenomenon was thus demonstrated. CT-scans clearly improve our ability to point out the best prognostic subgroup of patients with SCLC, and the procedure is highly recommended in trials of more aggressive treatment modalities such as surgery and high dose chemotherapy. 25Today, newer diagnostic tools are increasingly available at several institutions, such as magnetic resonance scanners and imaging by the use of monoclonal antibodies. Whether these diagnostic methods will improve the staging system and/or have any clinical importance Years Fig. 4. Survival curves for patients in three prognostic strata based must be evaluated prospectively in future studies. 100
on Cox model 1 ( ). The groups include 22, 33 and 50 patients, respectively. The three hatched curves ( ) were obtained after downgrading eight patients, based on CT findings (cf. Table 7).
References
the most valuable examination. The superiority of US compared to peritoneoscopy was again demonstrated in this investigation. The present study has compared CT-scan with USscan and guided liver biopsy. In the present study CTscan demonstrated that 50% of the patients had extensive disease compared to only 39% by the US-scan, while almost no additional information regarding metastases resulted from the use of both procedures. If both procedures are available CT-scan should therefore be recommended. When capacity problems restrict the use of the CT-scanner, as in our institution, staging could be initiated with ultrasonography, and CT-scan restricted to limited stage patients. Considering the results of the present Cox analyses, CT-scans could be further restricted to patients with normal LDH and alkaline phosphatase and good performance status, thereby reducing requirements to
Original article The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer F. R. Hirsch, K. 0sterlind, L. Ingemann Jensen, C Thomsen, K. Peters, F. Jensen & H. H. Hansen Dept. of Oncology, Dept. of Radiology and Dept. of Clinical Physiology, Rigshospitalet, Copenhagen,
Denmark
Summary. One hundred six patients with small cell lung cancer (SCLC) were prospectively evaluated with regard to the prognostic impact of abdominal CT-scan in the pretreatment staging when compared to ultrasonography of the abdomen. Staging based on abdominal ultrasonography (US) plus bilateral bone marrow examinations gave as a result that 47 patients had extensive disease (ED) (44%). Seventeen patients with proven ED at time of referral were not included in this study. Abdominal CT-scan was performed in 76 of the 106 patients. Thirty patients of these 76 patients (39%) were classified as having ED after staging including US, but abdominal metastases were disclosed in another ten patients at the subsequent CT-scan. Liver metastases seen in two patients at ultrasonography were overlooked on the CT-scans. Median survival of the 36 patients classified as having limited disease (LD) after both procedures was 458 days, which was significantly better compared to 330 days for the ten patients with stage migration from LD to ED based on CT-scan, (p < 0.05) and compared to 242 days in the 30 patients with ED demonstrated by both US and CT-scans (p < 0.05). The prognostic impact of the CT-scan was further investigated in
a multivariate analysis (Cox). Stage disease, performance status, LDH and alkaline phosphatase were significant prognostic factors in a proportional hazards model based on the original 106 patients. Patients in the best prognostic group were characterized by LD, good performance status (0—1) and normal LDH and alkaline phosphatase serum values. This group consisted of 22 patients (21%). Seventeen of these patients had a CT-scan, after which five patients (29%) were downgraded from LD to ED. This downgrading significantly increased the influence of stage in a new Cox model. Correspondingly, the 2-year survival rate rose from 31% to 41%. It is concluded that abdominal CT-scanning is a more sensitive staging procedure in SCLC than ultrasonography. In prognostication this superiority is most important for patients in the good prognostic category, and CT-scans could therefore be restricted to the 20 percent of the patients belonging to this category.
Introduction
Group (VALG) defined the system of 'limited' and 'extensive' disease, mainly on the background of its suitability for radiotherapy [3]. This staging system has been demonstrated to represent valuable prognostic information [4]. The median survival of patients with SCCL ranges from 10-15 months for patients with 'limited' disease, and 7-11 months for patients with 'extensive' disease [5]. The reported rates of long-term survival differ somewhat from study to study. Differences in staging procedures such as, e.g. bone scans, brain scans and liver scans, which have been performed routinely by some but not by others, might explain some of the differences in the results from center to center. In 1984 the International Association for the Study of Lung Cancer (IASLC) produced the first concensus report on staging and staging procedures for SCLC [6|. At that time CT-scanners were not generally available, and the technique had not been investigated sufficiently to be recommended routinely as a part of the staging system. Since then, a few retrospective studies have
With the increasing application of common internationally accepted staging systems for malignant diseases it has been possible for oncologists to assess and compare the results of therapy more accurately. It has also been possible to identify important prognostic factors in the treatment planning for the individual patient as well as for groups of patients. The staging system for malignant lung tumors has been developed mainly to determine resectability. The American Joint Commission for Staging and End Results Reporting has recently revised the TNM-system for staging lung cancer [1]. Small cell lung cancer (SCLC) differs from other histologjcal types of lung cancer by, e.g. earlier and more widespread dissemination. Studies in the late 1960s demonstrated that the classical TNM system was inappropriate for the staging of this disease [2]. Accordingly, other staging systems were developed. The Veterans' Administration Lung Cancer Study
Key words: small cell lung cancer, staging, CT-scan, prognosis
470
been published comparing CT with the other staging procedures in patients with SCLC. Harper et al. [7] evaluated the thorax of 50 consecutive patients with SCLC and found that CT gave information about the extent of disease in the chest which could not be obtained by conventional methods, which has also been reported by others [8-10]. Abdominal CT has been evaluated in SCLC retrospectively and found to be of great value [11, 12]. These studies have been reviewed elsewhere [13]. Ultrasonography of the abdomen is another sensitive procedure for the detection of liver metastases [14] and was in our institution used as the primary option in trials since the mid 1980s. A comparative diagnostic study (predictive values) of ultrasonography versus CTscan has been described recently from our institution [15]. The present study was undertaken in order to evaluate the impact of abdominal CT-scanning in comparison with ultrasonography on the staging and prognosis in a prospective series of patients with SCLC.
Nyco, Oslo, Norway) or sodium-meglumin diatrizoate, 370 mg I/ml (Urografin, Schering, Berlin, W Germany). The postcontrast scanning included the liver, the adrenals and the pancreas. The examinations were evaluated on hard copies with suitable window-settings. In the evaluation of the CT-scans, lymph node involvement was defined as enlargement of a node to more than 1 cm. Involvement of the adrenals, pancreas, kidneys and spleen was defined as changes in the size and morphology and/or of the attenuation. Ultrasonography All examinations were performed with a dynamic ultrasonic scanner (Aloka SDD 256, Aloka Co. Ltd., Tokyo, Japan) with a linear array 3.5 MHz transducer equipped with a needle-steering device. A ventral and intercostal admittance was used with the patient in a supine position. Percutaneous biopsies of suspected hepatic lesions were taken immediately under ultrasonic guidance. If the liver appeared normal, random biopsies were taken from a right subcostal site directed centrally into the liver. An 0.8 mm diameter sure-cut needle was used to obtain histological material. Three needle passes were performed routinely. The US examination was always done by the same person (F. J.), and a report was written immediately after each examination. The results of the CT were not known when the US was evaluated, and vice versa.
Material and methods Statistics The study included consecutive patients 1.6). Eight of the nine downgraded patients moved to an inferior prognostic stratum (Table 7). The influence of downgrading on survival in the three prognostic strata was most apparent in the good prognostic category (Fig. 4). Tabled. Multivariate analysis (Cox) of pretreatment factors with influence on survival in 105 small cell lung cancer patients staged by ultrasonography (US) (model 1) plus subsequent abdominal CTscan (model 2).
Years Fig. 2. Survival curves for limited (-) and extensive stage ( ) disease of 76 patients staged by ultrasonography.
Variable
Coefficient 1
RR 1
Coefficient 2
RR2
Score
Stage Alkaline phosphatase
0.58
1.79
0.79
2.20
1.0
0.42 0.53 0.61
1.52 1.69 1.83
0.43 0.54 0.63
1.54 1.72 1.87
0.7 0.9 1.0
LDH PS
p < 0.05 for all four factors in both models and for an overall comparison of the two models (likelihood ratio test). 1: Abdominal disease staged by US. 2: Abdominal disease staged by US + CT-scan (in 75 patients). RR: Relative risk of dying. Score - RR/RR for PS. Table 7. Prognostic category migration and CT-scan findings in nine downgraded patients.
Years
Fig. 3. Survival curves for limited ( ) and extensive stage ( ) disease of 76 patients staged by CT-scan.
Prognostic impact of abdominal CT-scan Ultrasonography has been used routinely as a staging procedure in our trials since 1985. The results of a proportional hazards (Cox) analysis of survival data on the 106 patients staged by this procedure are shown in Table 6. One patient was excluded because of missing data (LDH and alkaline phosphatase). This patient was one of the ten with abdominal metastases at CT-scan (Table 2). 'Stage' was updated by data from the CTscans, nine patients were downgraded from LD to ED, and a new Cox analysis was done (Table 2). The prognostic influence of 'stage' increased, and model 2 fit the data significantly better than model 1 (p < 0.05 in a likelihood ratio test). A prognostic score was obtained by a minor transformation of the coefficients in model 1 (Table 6), and three prognostic categories were defined. The good prognostic category was characterized by limited disease, normal LDH and alkaline phosphatase, and performance status 0 or 1. Extensive disease alone or one abnormal blood test or PS > 1 qualified for the intermediate prognostic group, while two or more adverse
Migration
Adverse features
CT-findings
G-l G-I G-I G-I G-I
None None None None None
Liver metastases Adrenal metastases Adrenal metastases Pancreatic metastases Pancreatic + retroperitoneal mets.
I-P I- P 1-P
Alk. phosph. t LDHt PS> 1
Retroperitoneal metastases Adrenal metastases Adrenal + retroperitoneal metastases
P-P
Alk. Phosph. I &PS> 1
Liver metastases
Prognostic strata — G: Good; I: Intermediate; P: Poor.
Discussion The liver is one of the most frequent sites of metastases of SCLC at the time of primary diagnosis and during treatment. A variety of diagnostic modalities has been used for the work-up of patients with SCLC: biochemical tests by means of liver associated enzymes, liver scintigraphy with isotopes, peritoneoscopy (PS) with guided biopsy, ultrasonography (US) with concomitant biopsy, and CT. Prospective, comparative studies have been carried out in our institution comparing the diagnostic value of liver associated enzymes to that of peritoneoscopy (PS) [21], and PS versus US [14]. According to the results of these studies, US with guided biopsy was found to be
473
The present study shows that the CT-scan downgraded about 20% of the patients from the limited to the extensive disease stage, and these patients had a significantly shorter survival than patients in the limited disease category. A characteristic Will-Rogers phenomenon was thus demonstrated. CT-scans clearly improve our ability to point out the best prognostic subgroup of patients with SCLC, and the procedure is highly recommended in trials of more aggressive treatment modalities such as surgery and high dose chemotherapy. 25Today, newer diagnostic tools are increasingly available at several institutions, such as magnetic resonance scanners and imaging by the use of monoclonal antibodies. Whether these diagnostic methods will improve the staging system and/or have any clinical importance Years Fig. 4. Survival curves for patients in three prognostic strata based must be evaluated prospectively in future studies. 100
on Cox model 1 ( ). The groups include 22, 33 and 50 patients, respectively. The three hatched curves ( ) were obtained after downgrading eight patients, based on CT findings (cf. Table 7).
References
the most valuable examination. The superiority of US compared to peritoneoscopy was again demonstrated in this investigation. The present study has compared CT-scan with USscan and guided liver biopsy. In the present study CTscan demonstrated that 50% of the patients had extensive disease compared to only 39% by the US-scan, while almost no additional information regarding metastases resulted from the use of both procedures. If both procedures are available CT-scan should therefore be recommended. When capacity problems restrict the use of the CT-scanner, as in our institution, staging could be initiated with ultrasonography, and CT-scan restricted to limited stage patients. Considering the results of the present Cox analyses, CT-scans could be further restricted to patients with normal LDH and alkaline phosphatase and good performance status, thereby reducing requirements to
