Evidence-based follow-up of lung cancer patients

Evidence-based follow-up care of the lung cancer patient is straightforward with periodic histories and physical examinations recommended to detect recurrence. Yearly chest radiographs to detect second primaries "may be reasonable" in small and non-small cell lung cancer patients. The routine use of computed axial tomography (CAT) scans, bone scans, brain imaging, and serum tumor markers is not recommended in lung cancer patients. Many patients receive more extensive and expensive follow-up after treatment, despite the lack of curative options for recurrent lung cancer or evidence that earlier treatment of recurrence leads to better medical outcomes. The reasons for this are not known at present but could involve patient or physician preference, with no disincentives for extra testing. Adherence to breast cancer follow-up clinical practice guidelines at one cancer center reduced cost by one third with no change in health outcomes, but no studies have been performed in lung cancer.     

Bone and liver imaging in regionally advanced melanoma

The clinical records of 94 patients with regionally advanced melanoma (nodal disease or regional satellites) were reviewed to determine the value of preoperative bone and liver imaging. Of 68 bone scans obtained, none were suggestive of metastases. of 97 liver imaging studies (computed tomography, scintiscan, or sonography) in 88 patients, only two were found to have demonstrable metastases. Liver enzyme elevation was present in both of these patients. Bone and liver imaging in the absence of signs or symptoms of dissemination by history, physical examination, chest x-ray, and enzyme determination for regionally advanced melanoma appears to be of little value unless the patient is involved in a protocol study.     

Imaging studies and the prognostic value of serum calcitonin in staging small-cell lung cancer

The controversial prognostic significance of serum calcitonin in small-cell lung cancer (SCC) prompted this retrospective study relating serum levels to (1) stage of disease [limited disease (LD) vs. extensive disease (ED)], (2) imaging studies of metastases to bone, liver, and brain, and (3) survival. Of the 127 previously untreated patients with SCC presenting from 1979 to 1984, calcitonin levels could be compared to the stage of the disease in 69 patients (25 LD and 44 ED) and to various staging procedures including 99mTc methylene diphosphonate bone scans (63 patients), 99mTc sulfur colloid liver-spleen scans (64 patients), computed tomography of the head (63 patients) and serum calcium (61 patients). 71% (49/69) of patients had elevated calcitonin of whom 65% (32/49) had ED. 29% (20/69) had normal levels of whom 60% (12/20) had ED. 40% (18/45) of patients with raised calcitonin had liver metastases. 100% (19/19) with normal calcitonin had no liver involvement. Two patients with hypercalcemia and increased calcitonin had extensive bony metastases. The survival experiences of patients with normal and elevated serum calcitonin levels were analyzed. No significant differences were found within each stage or in the group overall. The positive correlation of serum calcitonin to liver metastases was statistically significant. No such relationship could be demonstrated with stage of disease, bone metastases, brain metastases, or survival.     

Assessing response to treatment of bone metastases from breast cancer: what should be the standard of care?

Bone is the most common site for breast cancer metastases, occurring in up to 70% of those with metastatic disease. In order to effectively manage these patients, it is essential to have consistent, reproducible and validated methods of assessing response to therapy. We present current clinical practice of imaging response assessment of bone metastases. We also review the biology of bone metastases and measures of response assessment including clinical assessment, tumour markers and imaging techniques; bone scans (BSs), computed tomography (CT), positron emission tomography, magnetic resonance imaging (MRI) and whole-body diffusion-weighted MRI (WB DW-MRI). The current standard of care of BSs and CT has significant limitations and are not routinely recommended for the purpose of response assessment in the bones. WB DW-MRI has the potential to address this unmet need and should be evaluated in clinical trials.     

Yield of total body GA-67 scintigraphy in the staging of non-small cell lung cancer

One hundred and one patients with histologically proved non-small cell lung cancer underwent whole body gallium-67 (TB Ga-67) scintigraphy as a part of their routine pretreatment evaluation. Twenty-eight of these patients were subsequently operated and pathologically staged for hilar and mediastinal disease. Two other patients underwent mediastinoscopy, but were judged unresectable at that time. All had computed tomography (CT) of the thorax, as well as radionuclide or CT scans of suspicious metastatic areas, and were carefully followed-up. When possible, a biopsy was performed of each suspected metastasis. Primary lung tumors concentrated Ga-67 in 94 patients. Sensitivity, specificity, and accuracy for hilar and mediastinal node metastases were 58%, 89%, and 77%, respectively. There were no false-negative gallium scans as regards secondary involvement of both liver and bone, whereas only 1 of the 4 brain metastases was detected by the technique. Sensitivity, specificity, and accuracy for all metastatic sites were 82%, 38%, and 56%, respectively. Fifty-five patients were classified as having a more advanced stage of disease by TB Ga-67 scintigraphy than at the initial clinical evaluation. However, 42 gallium-staged patients were ultimately re-classified differently according to all available clinical data. Using TB Ga-67 scintigraphy, 21 patients were found to have occult metastases which would not otherwise have been recognized; for the above reason, an unnecessary intervention was avoided in 6 of them.     

Detection of bone marrow involvement in patients with cancer

Current methods for the study of bone marrow to evaluate possible primary or metastatic cancers are reviewed. Bone marrow biopsy, radionuclide scan, computed tomography and magnetic resonance imaging (MRI) are analyzed with regard to their clinical usefulness at the time of diagnosis and during the course of the disease. Bone marrow biopsy is still the examination of choice not only in hematologic malignancies but also for tumors that metastasize into the marrow. Radionuclide scans are indicated for screening for skeletal metastases, except for those from thyroid carcinoma and multiple myeloma. Computed tomography is useful for cortical bone evaluation. MRI shows a high sensitivity in finding occult sites of disease in the marrow but its use has been restricted by high cost and limited availability. However, the future of MRI in bone marrow evaluation seems assured. MRI is already the method of choice for diagnosis of multiple myeloma, when radiography is negative, and for quantitative evaluation of lymphoma when a crucial therapeutic decision (i.e. bone marrow transplantation) must be made. Finally, methods are being developed that will enhance the sensitivity and specificity of MRI studies of bone marrow.     

Radiological staging of colorectal liver metastases

Rapid advances in imaging technology have improved the detection, characterization and staging of colorectal liver metastases. Multi-modality imaging approach is usually the more useful in staging colorectal liver metastases. Multi-detector computed tomography (MDCT) remains the main imaging modality for preoperative planning, lesion detection and tumour surveillance. Magnetic resonance imaging (MRI) and contrast enhanced ultrasonography (US) are invaluable in problem solving for characterization indeterminate lesions, while contrast enhanced intra-operative ultrasound (CE-IOUS) may be the new gold standard staging tool prior to liver resection. Ultimately, the imaging strategy has to be tailored to the clinical situation to obtain the most relevant information for optimal use of available imaging resources.     

An immunotolerant HER-2/neu transgenic mouse model of metastatic breast cancer

PURPOSE: Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies. EXPERIMENTAL DESIGN: The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry. RESULTS: Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody. CONCLUSION: The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.     

Stellenwert der PET bzw. PET/CT mit F-18-FDG beim kleinzelligen Lungenkarzinom

To date, most of the (relatively few) clinical studies that have ascertained the role of fluorodeoxyglucose positron emission tomography (FDG-PET) or PET/computed tomography (CT) in small cell lung cancer have been directed at differentiating limited from extensive disease and thus at exploring the therapeutic impact. It has been shown that the addition of PET in the staging algorithm correctly upstaged up to 33% of patients from limited disease to extensive disease compared with conventional diagnostic procedures alone. PET was especially more sensitive for detecting distant metastases. This way, (unnecessary) radiotherapy or surgery could be avoided. Patients suspected of having distant metastases were correctly downstaged by PET/CT and thus could undergo potentially curative therapy. Also, for radiation therapy planning, PET is valuable because it was found to be more sensitive and specific for detecting lymph node metastases than morphologic imaging procedures. The aforementioned, still relatively small, studies proved that FDG-PET is more sensitive for the detection of skeletal metastases; therefore, skeletal scintigraphy and bone marrow biopsy can be abandoned. However, for detection of brain metastases, magnetic resonance imaging (or CT) was found to be indispensable. Further studies are needed to find out whether FDG PET/CT will be able to replace other specifically invasive diagnostic methods and to determine the clinical relevance of PET/CT for detecting residual disease and for restaging patients.     

Impact of somatic mutations on patterns of metastasis in colorectal cancer

Somatic mutation status in metastatic colorectal cancer (mCRC) is becoming increasingly clinically relevant as it may be correlated not only with response to biologic therapies, but also with site-specific pattern of metastatic spread and outcome. In this review, we describe our current understanding of associations between mutational activation of the KRAS, BRAF, PIK3CA, and NRAS oncogenes and clinical outcomes and metastatic patterns of mCRC. The presence of a KRAS mutation is associated with a distinct pattern of metastatic spread with decreased liver metastases and increased lung, brain, and bone metastases. In patients who undergo resection of colorectal liver metastases (CLM) with curative intent, KRAS mutation is associated increased risk of recurrence, worse survival, and increased recurrence outside of the liver, particularly in the lung, but also in the brain and bone. BRAF mutation, a poor prognostic factor in mCRC, is associated with decreased liver-limited metastasis and increased peritoneal and distant lymph node metastases. PIK3CA mutation does not clearly affect outcomes in the metastatic setting, but is associated with concurrent KRAS mutations, and has been associated with an increased incidence of lung and brain metastases, metastatic sites preferentially involved in KRAS mutant mCRC. NRAS mutation may confer worse survival and early studies suggest NRAS mutation may promote tumorigenesis in the setting of colorectal inflammation. As metastasectomy with curative intent is increasingly considered in patients with mCRC, understanding patterns of metastasis associated with tumor mutations may help focus medical treatment, surgical management, and surveillance in patients with mCRC.     

Routine brain imaging is unwarranted in asymptomatic patients with rhabdomyosarcoma arising outside of the head and neck region that is metastatic at diagnosis: a report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: To the authors' knowledge, the incidence of brain metastases at the time of diagnosis in children with metastatic rhabdomyosarcoma (RMS) arising outside the head and neck region is unknown, and routine imaging to identify metastatic brain involvement is costly. METHODS: The authors retrospectively reviewed the results of computed tomography (CT) or magnetic resonance imaging (MRI) scans of the head, which was mandated by protocol, in patients with metastatic RMS arising outside the head and neck region who were enrolled on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV; 1991--1997). RESULTS: Of 100 eligible patients with metastatic RMS arising outside the head and neck region, 56 (56%) underwent head CT (n = 51) and/or MRI (n = 11) scans. Seven of these 56 patients (12.5%) had abnormal scans. Three patients with physical findings suggesting head or neck pathology underwent imaging that confirmed the presence of metastases in bone (one patient), orbit (one patient), or lymph nodes (one patient). One patient who presented with seizures had imaging findings consistent with cerebral embolic infarctions. Of three asymptomatic patients, one had bone metastases that also were identified on skeletal survey and one had bone metastases in the base of the skull that were not identified on bone scan. The remaining asymptomatic patient had a retroperitoneal paraspinal tumor with spinal canal extension and subsequently developed leptomeningeal disease dissemination. CONCLUSIONS: Brain metastases are uncommon at the time of initial diagnosis of metastatic RMS arising outside the head and neck region, and the majority of abnormalities detected on head CT or MRI scans are evident clinically or on other imaging studies. Patients with clinical findings suggesting intracranial pathology and those with paraspinal tumors may benefit from brain imaging, but cost savings may be realized by foregoing imaging in patients without these features.     

Bone imaging in metastatic breast cancer.

Bone is the most common site to which breast cancer metastasizes. Imaging-by skeletal scintigraphy, plain radiography, computed tomography, or magnetic resonance imaging-is an essential part, and positron emission tomography or single-photon emission computed tomography have a potential of evaluating bone metastases, but no consensus exists as to the best modality for diagnosing the lesion and for assessing its response to treatment. Imaging bone metastases is problematic because the lesions can be osteolytic, osteoblastic, or mixed, and imaging modalities are based on either direct anatomic visualization of the bone or tumor or indirect measurements of bone or tumor metabolism. Although bone metastases can be treated, their response to treatment is considered "unmeasurable" according to existing response criteria. Therefore, the process by which oncologists and radiologists diagnose and monitor the response of bone metastases needs revision, and the current inability to assess the response of bone metastases excludes patients with breast cancer and bone disease from participating in clinical trials of new treatments for breast cancer. In this review of the MEDLINE literature, we discuss the pros and cons of each modality for diagnosing bone metastases and for assessing their response to treatment and we present a practical approach for diagnosis and assessment of bone metastasis.     

A diagnostic model to detect silent brain metastases in patients with non-small cell lung cancer

We aimed to discriminate subgroups according to the risk of brain metastases in patients with non-small cell lung cancer (NSCLC) lacking neurological symptoms. We performed a retrospective review of 433 patients with NSCLC who underwent chest computed tomography (CT), brain magnetic resonance imaging (MRI) and bone scans at an initial staging work-up between April 2003 and April 2007. Brain metastases were determined by MRI. Patients were stratified into groups according to the number of risk factors (0-3) identified by multivariate analysis. In multivariate analysis, histopathology with non-squamous cell carcinoma, nodal stage 2 on CT and presence of bone metastases were three risk factors for brain metastases. Patients were divided into four groups according to the number (0-3) of these predictive factors. The proportions of patients with brain metastases in the four groups were 2%, 3%, 17% and 35%, respectively, and these differences were significant (P<0.001). When analysis was performed in patients with localised disease, the number of risk factors was correlated with the prevalence of brain metastases (P=0.013) but stage was not (P=0.153). Although this diagnostic model should be validated through further studies, our data suggest that the number of risk factors might be a useful tool to identify silent brain metastases in patients with NSCLC.     

MRI findings of large low-grade angiosarcoma of the breast with subsequent bone metastases: a case report

We describe the magnetic resonance imaging (MRI) findings of 13 cm-sized low-grade angiosarcoma of the breast that occurred in a 23-year-old woman. Magnetic resonance examination revealed an ill-defined mass with marked high-signal intensity on T2-weighted images and persistent heterogeneous enhancement. Thirty months later she developed bone metastases, incidentally found on an MRI performed to evaluate the pelvis. There were well-defined bone lesions with high-signal intensity on T2-weighted images and persistent contrast enhancement on delayed phases. The metastases were not detected on previous computed tomography and fluoro-deoxyglucose positron emission tomography scans because the lesions were subtle osteoblastic type with a low proliferative index.     

Additional value of whole-body fluorodeoxyglucose positron emission tomography in the detection of distant metastases of non-small-cell lung cancer

The purpose of this work was to evaluate the additional value of whole-body positron emission tomography (WB-PET) in the distant staging of non-small-cell lung cancer (NSCLC). One hundred forty-four patients with NSCLC in whom conventional staging (CS) was negative or equivocal for metastases, and who underwent WB-PET as part of their initial work-up, were retrospectively analyzed. Conventional staging consisted of thoracic computed tomography (CT), upper abdominal ultrasound and/or CT, and bone scintigraphy or brain CT on indication. Final M stage was based on histology, additional imaging, or follow-up of = 18 months. An additional lesion suspect for metastasis was found on WB-PET in 11 patients. This was true positive in 7 (3 bone, 1 retroperitoneal lymph nodes, 1 lung, and 2 asymptomatic coexisting colorectal cancer) and false positive in 4 patients (3 bowel, 1 breast). Twenty-four lesions in 21 patients remained equivocal after CS. Whole- body PET correctly characterized 20 lesions in 18 patients as true positive (n = 1) or true negative (n = 19). Whole-body PET was false positive in one patient (adrenal adenoma) and false negative in 2 patients (2 bone, 1 lung lesion). Despite negative results of modern CS and WB-PET, 16 of 86 patients (19%) who underwent a curative resection, experienced a systemic relapse. After thorough modern CS, WB-PET correctly detected additional distant malignant lesions in only 5% of the patients, while the combined staging strategy probably still misses micrometastatic disease in one fifth of the patients. The most important contribution of WB-PET was its ability to exclude malignancy in the majority of distant lesions with equivocal CS.     

Monitoring therapeutic response in skeletal metastases using dual-energy x-ray absorptiometry: a prospective feasibility study in breast cancer patients

Response to systemic therapy in breast cancer patients with lytic skeletal metastases manifests as a shift from increased bone resorption to new bone formation. We hypothesized that dual-energy x-ray absorptiometry (DXA) could be used to prospectively quantitate changes in bone mineral density (BMD) in metastatic skeletal lesions in breast cancer patients receiving systemic therapy. Nine metastatic breast cancer patients with one or more assessable lytic skeletal metastases receiving systemic therapy were prospectively evaluated with DXA, skeletal radiographs, computed tomography (CT), and radionuclide bone scans at baseline (t = 0 months, 2 months, and 6 months). The median (range) percentage change in BMD in skeletal lesions among patients responding to systemic therapy was 10.7% (0.1-21.85), 5.0% (-1.3-23.8), and 16.7% (-2.0-50.8) at 0-2, 2-6, and 0-6 months, respectively. Changes in BMD between 0-2, and 0-6 months were significant (Wilcoxin signed rank test; p = 0.013 and p = 0.017, respectively). The percentage change in BMD skeletal lesions between 0-2 and 2-6 months correlated with the changes imaged on skeletal x-rays (Spearman rank order correlation coefficient [Rs] = 0.511, p = 0.011) and CTs (Rs = 0.416, p = 0.046) but less so with bone scans (Rs = 0.293, p = 0.189). It is technically feasible to use DXA to prospectively monitor changes in lytic skeletal metastases in breast cancer patients receiving systemic therapy. The BMD of skeletal metastases increases in patients responding to treatment and was significantly correlated with the changes imaged on skeletal x-rays and CTs. Additional studies of DXA to evaluate response in skeletal metastasis are warranted.     

Comparison between positron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-D-glucose,conventional imaging and computed tomography for staging of breast cancer

BackgroundThe presence, extent and localization of distant metastases are key prognostic factors in breast cancer patients and play a central role in therapeutic decision making. The aim of this study was to compare the diagnostic performance of positron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG–PET) with that of computed tomography (CT) and conventional imaging including chest radiography, abdominal ultrasound and bone scintigraphy.Patients and methodsA total of 119 consecutive patients with newly diagnosed locally advanced disease (n = 69) or previous history of breast cancer (n = 50) who had clinical suspicion of metastatic disease underwent FDG–PET, CT and conventional imaging procedures. Imaging results were retrospectively compared with histopathology and clinical follow-up which served as a reference standard.ResultsFDG–PET detected distant metastases with a sensitivity of 87% and a specificity of 83%. In contrast, the sensitivity and specificity of combined conventional imaging procedures were 43% and 98%, respectively. CT revealed a sensitivity of 83% and a specificity of 85%.ConclusionsIn breast cancer, FDG–PET is superior to conventional imaging procedures for detection of distant metastases. Although FDG–PET and CT provided similar diagnostic accuracy, the information was often found to be complementary. With increasing availability of FDG–PET/CT, prospective studies are needed to determine whether it could potentially replace the array of conventional imaging procedures used today.     

Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.     

Evaluation of chest computed tomography in the staging of patients with potentially resectable liver metastases from colorectal carcinoma.

BACKGROUND: Chest computed tomography (CT) often is used to rule out lung metastases in patients with potentially resectable liver metastases from colorectal carcinoma. In the current study the authors evaluated whether CT of the chest was necessary in patients with a negative chest radiograph. METHODS: The authors performed a retrospective analysis of 202 patients with negative initial chest X-rays who were undergoing evaluation for potentially resectable liver metastases from colorectal carcinoma. Patients with highly suspicious pulmonary lesions on the initial chest CT scan underwent a thoracoscopy and biopsy. All patients were monitored for the development of pulmonary metastases. RESULTS: Sixty patients (30%) had a positive initial chest CT scan. Two patients were found to have metastases by comparison with prior CT scans. Seventeen patients had highly suspicious lesions that were biopsied, but only 2 were found to have pulmonary metastases; the other lesions were benign. An additional 13 of these 60 patients developed lung metastases during follow-up, 6 of whom were diagnosed in retrospect. Of the 142 patients with a negative initial CT scan, 33 (23%) developed pulmonary metastases. The rate of pulmonary metastases in both groups was not significantly different, regardless of whether the CT scans were positive or negative. CONCLUSIONS: During routine preoperative workup for liver resection, the majority of lesions appearing on chest CT scans of patients with negative chest radiographs were not malignant. The positive yield of CT-guided workup was only 10 of 202 patients (5%). Based on this review the authors question the use of chest CT scans in this setting.     

Preoperative nuclear scans in patients with melanoma

One hundred forty-one liver scans, 137 brain scans, and 112 bone scans were performed in 192 patients with clinical Stage 1 melanoma. One liver scan was interpreted as abnormal; liver biopsy of that patient showed no metastasis. There were 11 suggestive liver scans; three of the patients with suggestive liver scans had negative liver biopsies. The remaining eight patients were followed from 4 to 6 years and none of those patients developed clinical evidence of hepatic metastases. All of the brain scans were normal. Five patients had suggestive bone scans and none of those patients had manifested symptoms of osseous metastases with a follow-up of 2 to 4.5 years. This study demonstrates that the use of preoperative liver, brain and bone scan in the evaluation of patients with clinical Stage 1 melanoma is virtually unproductive.