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The Role of Whole-Body Bone Scanning and Clinical Factors in Detecting Bone Metastases in Patients With Non-Small Cell Lung Cancer*

Posted on: Wednesday, 23 February 2005, 03:00 CST

Study objectives: Correct detection of bone metastases in patients with non-small cell lung cancer (NSCLC) is crucial for prognosis and selection of an appropriate treatment regimen. The aim of this study was to investigate the role of whole-body bone scanning (WBBS) and clinical factors in detecting bone metastases in NSCLC.

Design and patients: One hundred twenty-five patients with a diagnosis made between 1998 and 2002 were recruited (squamous cell carcinoma, 54.4%; adenocarcinoma, 32.8%; non-small cell carcinoma, 8.8%; large cell carcinoma, 4%). Clinical factors suggesting bone metastasis (skeletal pain, elevated alkaline phosphatase, hypercalcemia) were evaluated. WBBS was performed in all patients, and additional MRI was ordered in 10 patients because of discordance between clinical factors and WBBS findings.

Measurements and results: Bone metastases were detected in 53% (n = 21) of 39 clinical factor-positive patients, 5.8% (n = 5) of 86 clinical factor-negative patients, and 20.8% of total patients. The existence of bone-specific clinical factors as indicators of metastasis presented 53.8% positive predictive value (PPV), 94.2% negative predictive value (NPV), and 81.6% accuracy. However, the findings of WBBS showed 73.5% PPV, 97.8% NPV, and 91.2% accuracy. Adenocarcinoma was the most common cell type found in patients with bone metastasis (39%). The routine bone scanning prevented two futile thoracotomies (8%) in 25 patients with apparently operable lung cancer.

Conclusions: In spite of the high NPV of the bone-specific clinical factors and the high value obtained in the false-positive findings in the bone scan, the present study indicates that in patients for whom surgical therapy is an option, preoperative staging using WBBS can be helpful to avoid misstaging due to asymptomatic bone metastases. (CHEST 2005; 127:449-454)

Key words: imaging; non-small cell lung cancer; skeletal metastases; staging

Abbreviations: ACCP = American College of Chest Physicians; CWU = conventional workup: FDG = F-18 fluorodeoxyglucose; NPV = negative predictive value; NSCLC = non-small cell lung cancer; PET = positron emission tomography; PPV = positive predictive value: WBBS = whole- body hone scanning

Lung cancer is the most common cause of cancer-related deaths in both men and women.1 Surgical resection of the lung mass with mediastinal lymph node sampling is the best treatment modality for non-small cell lung cancer (NSCLC) in patients without preoperative evidence of mediastinal invasion or distant metastasis. However, recurrence rates after curative surgical procedures are high.2 Many patients have undetected disseminated disease at the time of thoracotomy, and this is the most likely cause of treatment failure and ultimate death.

If history, physical examination, and initial laboratory screening results are negative, the likelihood of finding metastatic disease on subsequent staging procedures is low.3 The joint statement of the American Thoracic Society and the European Respiratory Society4 on pretreatment evaluation of NSCLC advocates no preoperative imaging of the distant metastases in patients who have no symptoms or other evidence of distant metastases. According to American College of Chest Physicians (ACCP) evidence-based guidelines,5 patients with clinical stage I and II lung cancer and normal results of a clinical evaluation require no further imaging for detection of extrathoracic disease. However, patients with stage IIIA and IIIB disease should undergo routine imaging studies. Some authors6,7 suggest a more aggressive approach to rule out clinically occult, but detectable metastases.

METHODS AND MATERIALS

In our clinic, Cerrahpasa Medical Faculty, Department of Pulmonology, between January 1998 and September 2002, 125 patients who had histologically proven NSCLC received treatment according to cancer stage. They were then retrospectively subjected to evaluation for hone metastases. The patients with radiographic evidence of extrathoracic metastases demonstrated prior to discovery and staging of the primary bronchogenic carcinoma were excluded from the study. These patients had either CNS abnormalities with a cranial CT showing metastases, or plain radiographic abnormalities considered malignant bone metastases.

Of the patients, 111 were men and 14 were women. The mean ( SD) age was 61 10 years (range, 34 to 79 years). Histologic diagnosis were as follows: squamous cell carcinoma, n = 68 (54.4%); adenocarcinoma, n = 41 (32.8%); large-cell carcinoma, n = 5 (4.0%); and non-small cell carcinoma, n = 11 (8.8%).

All patients included in the study had undergone the routine extrathoracic metastasis screening procedures of our clinic. All of them underwent a CT scan of the thorax including the liver and the adrenal glands. Staging factors T and N were performed by CT and fiberoptic bronchoscopy according to the International System for Staging Lung Cancer adopted by the American Joint Committee on Cancer and the International Union Against Cancer in 1997.2 Lymph nodes measuring < 1 cm in the short axis were considered normal. The retrospective evaluation of the patients was made after the last ACCP evidence-based guidelines were published.8 The patients were classified into two main groups. The first group was considered operable and consisted of T1-2-3 and radiologic N0-1 patients. Patients with radiologic N2-3,T4 made up the second, unfavorable group. The separate tumor nodule(s) in the ipsilateral nonprimary- tumor lobe(s) of the lung or contralateral lung and intra-abdominal metastases were classified as M1.

The medical records of patients were reviewed to determine the bone-specific clinical factors suggestive of bone metastases. These factors include bone pain or tenderness, and elevated serum alkaline phosphatase and scrum calcium levels.

All patients underwent whole-body bone scanning (WBBS) using ^sup 99m^Tc. If the abnormal findings were multiple and asymmetric, they were considered positive for metastatic disease. Study findings were classified as normal if there was no scintigraphic abnormality or if there was a definite benign explanation for the scintigraphic findings (osteoarthritis, osteomalacia, etc). The remaining study findings were classified as "probable."

Additional MRI was ordered due to disagreement between WBBS and bone-specific clinical factors (n = 10). Interpretation of WBBS and bone-specific clinical factors were assessed for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and accuracy.

RESULTS

In 26 of 125 patients (20.8%), hone metastases were detected with the use of clinical factors, by bone scan and/or MRI. Besides bone metastases, 12 patients (9.6%) also had metastatic disease in the liver (n = 4), the lung (n = 3), the brain (n = 3), the adrenal glands (n = 1), and the liver plus the adrenal glands (n = 1). Thirty-nine of the 125 patients (31.2%) presented at least one bone- specific clinical factor suspicious of metastasis. In 21 of them (53.8%), bone metastases were confirmed. There were no bone- specific clinical factors in five patients (5.8%) with metastases (Fig 1, Table 1). Therefore, the existence of bone-specific clinical factors as indicators of metastasis presented 80.8% sensitivity, 81.8% specificity, 53.8% PPV, 94.2% NPV, and 81.6% accuracy. Proportions were furnished with their 95% confidence intervals (Table 2).

Abnormal WBBS results were obtained in 34 of the 125 patients (27.2%). WBBS and bone-specific clinical factors were in agreement in 98 of 125 patients (Table 3). MRI was ordered in 10 of 27 patients with disagreement (Table 4). Fifteen of the 27 patients were inoperable due to chest CT scan results (T4, N2, N3, or M1); 1 patient was 78 years of age and refused any proposed treatment. The last patient of the 17 who was inoperable due to chest CT scan results and positive WBBS findings was followed up for 14 months without clinical or radiographic evidence of neoplastic bone involvement, and this patient's WBBS result was considered false- positive. In these 17 patients, radiologic confirmation of bone metastases via MRI or pathologic confirmation via bone biopsy were considered unnecessary, as the results would not change the treatment modality.

Any scans with positive and probable results were listed as true- positive, and scans with negative results were true-negative. Of the six abnormal WBBS results in patients free of clinical evidence of metastases, two were true-positive and the remaining four were false- positive according to MRI (Table 4).

MRI was ordered in three patients with bone-specific clinical factors, and positive WBBS results and bone metastases were confirmed in two of them. The third patient's MRI was evaluated as false-positive. Another patient with bone-specific clinical factors and a positive bone scan finding revealed osteoid osteoma by bone CT scan.

In one patient without clinical and scintigraphic evidence of bone metastases, WBBS and MRI were performed because of bone pain in the third month after thoracotomy. Needle aspiration biopsy revealed pathologically proven bone metastases. The presence of abnormal WBBS as an indication of metastasis presented 92.6% sensitivity, 90.8% specificity, 7.3.5% PPV, 97.8% NPV, and91.2% accuracy (Table 2).

FIGURE 1. Staging of patients based on CT scan of the chest. Two major groups are formed in regard of curative surgical option: (1) stage I, II and partially IIIA; (2) stage IIIB and stage IV. These groups are further subclassified according to the presence or absence of bone-specific clinical factors. After WBBS and skeletal MRI, the status of bone metastasis was confirmed.

The histologic analysis revealed bone metastases in 39% of the adenocarcinomas, and 11.8% of the squamous cell carcinomas. Patients with adenocarcinoma were at significantly greater risk for bone metastasis than those with squamous cell carcinoma (p = 0.004). The routine bone scanning prevented two futile thoracotomies (8%) in 25 patients with apparently operable lung cancer.

DISCUSSION

After NSCLC is diagnosed, a patient must be accurately staged. The only rationale for staging is to select patients who will benefit from surgical resection. If metastases are discovered, an unnecessary surgical procedure may he withheld.

Table 1-Clinical Characteristics of Patients With Bone Metastases But Without Bone-Specific Clinical factors

Imaging may reveal metastatic disease at the time of presentation in up to 50% of patients with abnormalities in history, physical examination, or simple laboratory tests,9 and prevent unnecessary surgical procedures. In patients with a negative history, a negative physical examination, and a negative initial laboratory screening, the incidence of metastatic disease is much lower (eg, 3% for hone metastases).3 In this subset of patients, clinicians disagree whether to continue searching for extrathoracic metastases. Additional extrathoracic staging with cranial CT, MRI, or WBBS despite normal results of the clinical evaluation can lead to unnecessary and invasive testing with a delay of operation, and is not cost-effective. However, this approach can detect clinically occult metastases and thus prevent an unnecessary thoracotomy.

The liver, bone, brain, and adrenal glands are the most frequent sites of metastases. It is currently recommended that all patients should undergo a CT scan of the thorax including the liver and adrenal glands.10 This approach provides a convenient method of imaging for the liver, the adrenal glands, and chest at no extra cost and requiring a little extra time.

Table 2-Accuracy of Bone-Specific Clinical Factors vs WBBS in Finding Bone Metastases*

We detected metastatic disease in 36 of 125 patients (28.8%). Twenty-six patients (20.8%) had bone metastases, hut only 14 of them had metastatic disease limited only to the skeletal system. Bone metastases are frequent in lung cancer and may be demonstrated by a radionuclide bone scan. The reported incidence of bone metastases varies from 10 to 18.9%.11-13

Clinical factors suggestive of bone metastasis include bone pain or tenderness, elevated serum alkaline phosphatase levels, and elevated serum calcium levels. In a study of 53 patients with NSCLC, bone metastases were detected in 7 patients (21.2%) of the 33 patients presenting at least one of the bone-specific clinical factors.13 In our study, this incidence was 53.8%.

The chance of finding bone metastases, where clinical factors fail, is reported in a range of 2.5 to 15%. In a meta-analysis3 the incidence of bone metastasis was reported to be 3% in asymptomatic patients. Similarly, Salvatierra et al12 detected bone metastases in 3.4% (4 of 116 patients) and Ramsdell et al14 in 2.5% of their patients. However, Bilgin et al11 detected skeletal metastases in 9.8% of patients who had no bone-specific clinical factors. Quinn et al13 had 20 clinically negative patients and detected bone metastases in 3 of them (15%). In our study, the NPV was 94.2% for bone-specific clinical factors, whereas silent metastases were 5.8%. Similarly, the study of Salvatierra et al12 revealed a NPV of 96.6%.

Another point of debate is whether or not to investigate for metastatic disease in patients with operable, early-stage lung cancer according to chest scan. Sider and Horejs15 investigated 95 patients who had NSCLC without evidence of hilar or mediastinal lymphadenopathy, pleural effusion, or definite chest wall involvement on CT. In this study, extrathoracic and bone metastases were detected in 24 patients and 8 patients, respectively. The authors suggested that a thorax that shows all mediastinal nodes to be < 1 cm should not preclude a search for extrathoracic metastases. In a study of 27 patients with NSCLC and a lung mass > 3 cm, with no clinical evidence of metastases and with no evidence of mediastinal invasion or abdominal metastases, 5 patients were found to have bone metastases.16

Table 3-Bone-Specific Clinical Factors vs Bone Scan Results*

Table 4-Results of Clinical Factors and WBBS in MRI-Ordered Patients*

Bilgin et al11 found no relationship between the clinical TN stage and the frequency of extrathoracic metastases in either squamous cell carcinoma or adenocarcinoma. In our study, 3 of the 18 patients (16.6%) in T2N0M0 according to thorax CT had bone metastases. One of them did not have suggestive clinical signs or symptoms. We did not detect bone metastases in two patients with T1N0M0. Of the 32 patients with operable lung cancer according to CT scan of the chest, 5 patients (15.6%) had bone metastases (Fig 1). Similarly, Salvatierra et al12 did not detect any relationship between the TN stage and the existence of metastasis in the adenocarcinomas and large-cell carcinomas. They reported that no metastases were detected in intrathoracic stage I squamous cell carcinoma. We suggest that the investigation for bone metastases should also be done in patients with operable lung cancer according to CT scan of the chest.

The cell type of lung cancer may play a role in generating systemic metastasis. Salvatierra et al12 detected bone metastases in 20% of the large cell carcinomas, 16% of the adenocarcinomas, and 10% of the squamous cell carcinomas. Merrick et al17 reported that the prevalence of bone metastases was 63% for adenocarcinomas, 57% for large cell carcinomas, and 50% for squamous cell carcinomas. In the present study, patients with adenocarcinoma were at greater risk for bone metastases than those with squamous cell carcinoma (39% vs 11.8%, p = 0.004).

Although WBBS is considered the best technique in detecting skeletal metastasis, its routine use is controversial. Salvatierra et al12 obtained an abnormal WBBS result in 33 of the 146 patients (22%) and classified only 19 cases as true-positives (57.6%). Quinn et al13 reported 13 false-positive cases (41%) out of 32 positive bone scan findings in 53 patients. Ramsdell et al14 reported that of 14 patients free of clinical evidence of metastases but with positive bone scan findings, 1 was true-positive and the 13 remaining were false-positive scans.

The false-positive results are often due to osteoarthritis, trauma, surgery, or other benign bone diseases. If there is a disagreement between clinical findings and bone scan, additional investigations including plain radiography, CT scan, MRI and, in selected patients, needle aspiration biopsy to obtain a histologic diagnosis of suspected metastases must be performed. The presence of false-positive interpretations is particularly troublesome for screening examination. Such interpretation can unnecessarily cause a delay in therapy and introduce additional testing to preclude the false impression of metastases.

In the present study, of the six abnormal bone scan results (three positive and three probable) in patients free of bone- specific clinical factors, two were true-positive and the four remaining were false-positive. There were two false-negative bone scan results in 91 patients with normal WBBS. In our study, the NPV, PPV, and accuracy were 97.8%, 73.5%, and 91.2% for WBBS, respectively. Salvatierra et al12 also reported similar results: NPV, 96.6%; PPV, 50%; and accuracy, 87%.

Some authors12,14,18 and the joint statement of the American Thoracic Society and the European Respiratory Society4 advocate no preoperative imaging of skeleton and brain in patients with NSCLC who have no symptoms or other evidence of metastases. The recommendations of ACCP evidence-based guidelines5 with a grade of evidence A are as follows: for patients with either known or suspected lung cancer, a thorough clinical evaluation should be performed; patients with abnormal clinical evaluations should undergo imaging for extrathoracic metastases. Site-specific symptoms warrant directed evaluation of that site with the most appropriate study (eg, head CT scan, bone scan or abdominal CT scan); patients with clinical stage I or II lung cancer and normal results of a clinical evaluation require no further imaging for detection of extrathoracic disease; patients with abnormal imaging study results should not be excluded from potentially curative surgery without tissue confirmation or overwhelming clinical and radiographic evidence of metastases.

The high NPV of the bone-specific clinical factors and the high value obtained in the false-positive WBBS results do not seem to support the routine use of WBBS in extrathoracic staging of NSCLC because every additional investigation causes a significant cost. On the contrary, the study by the Canadian Lung Oncology Group6 showed the staging strategy of searching for occult metastases in every patient before surgical intervention to be cost-effective. Kelly et al7 also suggested that bone scans seem to be the most cost- effective means of examination.

Whole-body FDG PET allows screening of the entire body for metastatic disease in a single examination. Weder et al19 detected skeletal metastases with F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in 13 of 94 patients (14%) with stage IIIa NSCLC or less; 10 of these patients were clinically asymptomatic. Metastatic disease was confirmed using histology or MRI s\canning or bone scan or spot film radiograph. They obtained no false-positive results. Pieterman et al20 suggested that a positive PET result requires additional procedures, as in their study 17% of patients would have been denied potentially curative surgery because of false- positive mediastinal or distant hot spots or both, while our usage of the routine bone scanning prevented two futile thoracotomies (8%) in 25 patients with apparently operable lung cancer. Whole-body FDG PET, which is a more sensitive method in detecting metastatic disease, can yield higher ratios. In the study of van Tinteren et al,21 conventional workup (CWU), which consisted of invasive diagnostic and therapeutic procedures, and PET followed by CWU were compared to test whether PET would reduce the number of futile thoracotomies. Addition of PET to CWU prevented unnecessary surgery in one of five patients with suspected NSCLC.

We recognize some limitations of our study, particularly originating from its retrospective design. First, every abnormal WBBS result was not followed by MRI in order to confirm metastatic disease. Similarly, only one MRI indicating bone disease was supported pathologically by needle aspiration biopsy. Second, as a consequence of the social security system policy in our country, not all bone scans of the patients could be done in the same institution. Whole-body FDG PET was unfortunately not available for routine use in our country during the recruitment of the cases for the study.

CONCLUSION

The present study indicates high NPV of bone-specific clinical factors. However, whole-body bone scanning is a screening method with high false-positive results. Despite these facts, routine whole- body bone scanning prevented two futile thoracotomies (8%) in 25 of our patients with apparently operable lung cancer. As lung cancer is most often a systemic disease, aggressive search for locoregional and distant spread of disease is important. We conclude that in patients with clinical stages of NSCLC in whom surgical treatment can be offered as an option, routine bone scanning should be performed even in the absence of bone-specific clinical factors.

ACKNOWLEDGMENT: We wish to thank to Gkhan Demir, MD, for editing assistance.

* From the Departments of Pulmonology (Drs. Erturan, Yaman, Aydin, Uzel, and Msellim) and Thoracic Surgery (Dr. Kaynak), Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

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Serdar Erturan, MD; Mustafa Yaman, MD, FCCP; Gnay Aydin, MD; Isil Uzel MD; Benan Msellim, MD; and Kamil Kaynak, MD

Manuscript received August 13, 2003; revision accepted August 27, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Serdar Erturan, MD, Nevsehirli Ibrahim Pasa Cad. 26/4 Faith, 34230 Istanbul, Turkey; e-mail: serdarerturan@mynet.com

Copyright American College of Chest Physicians Feb 2005

Source: Chest

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