Skeletal Metastases In Apparently Operable Lung Cancer Evaluated With Whole Body Bone Scan – A Pilot Study In South India.
A Shinto, L Pachen, S T K, C Joseph
A Shinto, L Pachen, S T K, C Joseph. Skeletal Metastases In Apparently Operable Lung Cancer Evaluated With Whole Body Bone Scan – A Pilot Study In South India.. The Internet Journal of Thoracic and Cardiovascular Surgery. 2009 Volume 14 Number 2.
Study objectives: The management of patients diagnosed with non-small cell lung cancer is dependant on the stage of disease, which is also crucial for prognosis and selection of an appropriate treatment regimen. Historically a whole body bone scan has been used to identify skeletal metastases. The aim of this study was to investigate the usefulness of whole-body bone scanning (BS) in detecting bone metastases in newly diagnosed and apparently operable cases of lung cancer. Design and patients: Ninety two patients with a diagnosis made between 2008 and 2010 were recruited (squamous cell carcinoma, n =29; adenocarcinoma, n=36 ; non-small cell carcinoma, n= 22; others n=5). None of these patients had clinical factors suggesting bone metastasis (skeletal pain, elevated alkaline phosphatase, hypercalcemia). BS was performed in all patients, and additional imaging or biopsy was ordered in patients where there were doubtful lesions. Measurements and results: Bone metastases were detected in 14.13 % (n =13 ) of 92 clinical factor-negative patients. Of the eighteen abnormal bone scan results (eleven positive and seven probable), thirteen were true-positive and the five remaining were false-positive. In our study, PPV of the BS was 72.2%. Skeletal metastases was found more commonly in adenocarcinoma (46.15%, n=6 ) than other cell types. In 13 patients diagnosed with metastases, 53.8 % (n=7) were patients with non-small cell lung cancer and 38.4% (n=5) with small cell lung cancer. 4 of the 18 patients (22.2%) in T2N0M0 clinical stage had bone metastases. The routine bone scanning prevented thirteen futile thoracotomies (14%) in 92 patients with apparently operable lung cancer. Conclusions: Though clinical factors have a high NPV and the bone scans have less than desired specificity in diagnosing metastases, BS could be considered in those asymptomatic patients as a part of their work up and staging, in whom operative intervention is contemplated.
One of the major controversies a thoracic surgeon faces in a newly diagnosed case of apparently operable NSCLC is the degree of investigations to which the patient needs to be subjected. This is due to the significant recurrence rates after “curative” surgical procedures have been attempted. [1–3]. Thus many patients have extra thoracic or disseminated disease at the time of surgery, which had been missed or had not been investigated. This is the most likely cause of treatment failure and ultimate death. In patients with a suggestive history, physical examination or biochemical investigations further imaging tests reveal metastases in approximately half the patient population .As a significant proportion of these patients are not surgical candidates, it is justified to subject this subgroup of patients to additional staging evaluations and imaging.
However the controversy emerges in a patient with no history, physical examination or biochemical abnormalities suggestive of metastases. In these patients the incidence of metastatic disease is much lower and hence the need to further investigate can be questioned.Reports are varied , with some centers advocating immediate surgery [6–9] , while others follow an imaging algorithm to rule out sub clinical but detectable metastases. Hence various imaging procedures have been utilized before surgery, which have been discussed at length elsewhere.[10-16].However there is no consensus on the exact imaging procedure or combination of imaging procedures and the extent to which the patient should be subjected to detect these occult or sub clinical metastases in these patients with apparently operable disease. The arguments against additional investigations is based on the premise that skeletal metastases in lung cancer are usually symptomatic and incidence of metastases in the early stages is low with reports of less than 10 % in this subgroup of patients.
The aim of this study was to investigate with a BS, those patients who were freshly diagnosed with non–small cell lung cancer and in whom initial systematic history, physical examination, laboratory tests and examination for mediastinal disease failed to suggest metastatic disease. Thus we wanted to assess the percentage of apparently operable NSCLC cases which were upstaged, thereby preventing a futile thoracotomy or a potential thoracotomy with subsequent recurrence.
Patients and Methods
We considered all newly diagnosed patients with apparently operable non–small cell lung cancer referred to the department of onco- surgery and thoracic surgery at our institute. We excluded patients with findings on history, physical examination, laboratory testing, or imaging that suggested skeletal metastases. These findings included symptoms or signs suggesting bony involvement distant from the site of the primary lesion (including persistent pain or tenderness localized over a bony surface ), serum alkaline phosphatase value greater than the laboratory’s upper limit of normal, and other findings on history or physical examination, chest radiograph, or CT of the chest suggesting unresectable disease.
We excluded patients who were medically unfit or unwilling for operation.
To standardize their approach to the threshold of history and physical examination findings that would exclude patients from the study, participating surgeons and nuclear medicine physicians met before the start of the study. They agreed to take a conservative approach and to exclude patients with any more than minimal symptoms or signs that might suggest extra pulmonary metastatic disease.
All patients gave written informed consent to participate in this study.
We did bone scans blinded to the history, histopathology and TNM stage of disease.
All patients underwent whole-body bone scanning (BS) using standard imaging protocol of 99mTc-MDP. 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 including suspicious solitary lesions were classified as “probable.”
In case of doubtful or solitary or probable lesions additional imaging tests like MRI or bone marrow aspiration/biopsy for inaccessible sites were done to confirm metastases. (n = 7).
The combined results of a positive bone scan and patients' subsequent clinical course were the ideal for identification of bony metastases.
We found skeletal metastases in 13 patients (14.1%) of the 92 patients recruited into the study. Asymptomatic and clinical factor negative skeletal metastases was found more commonly in adenocarcinoma (46.15%, n=6) than other cell types. Incidence of metastases was 53.8 % (n=7) in patients with non-small cell lung cancer and 38.4% (n=5) in those with small cell lung cancer. 4 of the 18 patients (22.2%) in T2N0M0 clinical stage according to thorax CT had bone metastases.
In the present study, of the eighteen abnormal bone scan results (eleven positive and seven probable) in patients free of bone-specific clinical factors, thirteen were true-positive and the five remaining were false-positive. In our study, PPV was 72.2% for BS. 31 % (n=4) of the patients with metastases had advanced spread as 3 or more sites of skeletal involvement.
Staging is an integral part of the work up in any newly diagnosed case of cancer and is applicable to NSCLC. The real impact of staging in malignancy is to assess for operability if the patient presents in the early stages. Hence, if metastases are discovered, the patient is spared of an unnecessary surgical procedure and attendant expense and morbidity.
In NSCLC, staging evaluations and imaging can reveal metastases in approximately half the number of patients in whom there is a suggestive history, physical examination or biochemical laboratory tests. (17). However in the subgroup of patients who are operable with a negative history, physical examination or biochemical laboratory tests, the incidence of skeletal metastases has been widely reported to be much lower ( range of 2.5% to 15%). It is in this subgroup of patients wherein the role of BS to identify sub clinical but detectable metastases is contested. Additional extra thoracic staging with a BS despite normal results of the clinical evaluation can lead to unnecessary and invasive testing with a delay of operation, is not cost-effective, the yield is too low to justify routine clinical usage and bones metastases if present, are usually symptomatic in NSCLC setting ; are the arguments professed. However, this approach can detect clinically occult metastases and thus prevent an unnecessary thoracotomy.
Ruling out skeletal involvement is usually done by the treating oncologist or surgeon on the basis of a history of regional bone pain or tenderness, elevated serum alkaline phosphatase level or serum calcium levels. The incidence of bone metastases in this subgroup with one or all of these factors present is usually much higher than when the clinical bone specific factors are all negative, which is reported as usually less than 15 %(18-20). We detected metastatic disease in 13 of 92 patients (14.1%), thus confirming that sub clinical or asymptomatic bone metastases are not infrequent in early stage lung cancer and may be demonstrated by a radionuclide bone scan. In our study, PPV was 72.2% for BS which is similar to other reports.(19).
Multiple reports have given valuable data supporting the rationale of investigating apparently operable lung cancer. In their study on 95 patients who had operable disease on chest CT, Sider et al found bone metastases in 8 patients (21). Thus the authors suggested that even with a CT showing no mediastinal involvement, it is worthwhile to rule out extra thoracic spread. Another similar study on 27 patients with apparently operable NSCLC and a lung mass > 3 cm, 5 patients were found to have bone metastases.(22)
Bilgin et al and Salvatierra et al(18,19) further stated that the initial clinical and imaging TN staging bore no impact on the frequency of extra thoracic metastases in either squamous cell carcinoma or adenocarcinoma. In our study, even 4 of the 18 patients (22.2%) in T2N0M0 according to thorax CT had bone metastases. None of them had suggestive clinical signs or symptoms. Our study also suggests the importance of further investigation with a BS to rule out skeletal in patients with small operable lung cancer without nodal involvement according to CT scan of the chest.
The histopathology or cell differentiation type of lung cancer could influence the frequency of skeletal involvement. Merrick et al and Salvatierra et al (19) have reported higher frequency of bone metastases in large cell carcinomas and adenocarcinomas, which is consistent with our study in which adenocarcinomas more frequently demonstrated bone involvement compared to squamous cell carcinoma (46.1% vs 7.7%, p < 0.005).
Although BS is considered the best technique in detecting skeletal metastasis, its routine use is controversial. Multiple reports have stressed on the high false positive rates on a routine BS.(18-20).Hence , authors have suggested further clarification with a regional CT/MRI / X-ray or bone biopsy when there is a discordance between clinical factors and bone scan findings. High false positive rates is the main reason why a BS is not currently used for screening operable lung cancers as they could entail additional testing, anxiety and waste of valuable time.
Standard guidelines issued by American Thoracic Society , the European Respiratory Society and ACCP suggest no requirement for additional BS evaluation in patients with clinical stage I and II and normal results of a standardized, thorough clinical evaluation. Bone scan is reserved for those patients who are symptomatic. (19, 6, 23, 24).
The rationale for this is that the bone specific clinical factors have been proven to have a high NPV and screening with a BS has a low yield, compounded by low specificity or high false positive rates. Thus further waste of time or money is not routinely warranted. However, the study by Canadian Lung Oncology Group (6) has suggested routine screening with a BS to be cost effective, a view supported by other authors.(7)
The introduction of NaF-18 or F18 FDG PET scans as an alternative to whole body skeletal and extra thoracic staging has gained significant momentum. However in developing nations or where the facility of PET is not available, BS would continue to play a significant role in screening for bony metastases in NSCLC. (25-27)
Limitations of the study and future scope:
We recognize some limitations of our study, particularly originating from its lack of MRI or biopsy correlation in all the patients with a positive bone scan. The patients who had a negative bone scan were not further assessed or followed up to evaluate missed lesions or the false negative rates. The total number of patients and the numbers of BS positive patients are small , to derive statistically satisfying conclusions. A randomized controlled study to evaluate the cost effectiveness of a screening bone scan in clinically negative and apparently operable lung cancer should be undertaken to study the impact of a screening BS definitively. Whole-body FDG PET is not easily available or affordable for routine use in our institute and should also be evaluated in this specific clinical setting.
The present study indicates high NPV of bone-specific clinical factors and whole-body bone scanning as a screening method, with high false-positive results. Despite these facts, routine whole-body bone scanning prevented thirteen futile thoracotomies (14.1%) in 92 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.