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Keywords:

  • lung carcinoma;
  • staging assessment;
  • treatment response evaluation;
  • computed tomography;
  • 99mTC-tetrofosmin scintigraphy

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

99mTC-tetrofosmin recently has emerged as a new radiopharmaceutical for cancer visualization. In this study, the authors have investigated, for the first time in a comprehensive way, its ability to assess lung carcinoma dissemination and progression.

METHODS

A 99mTC-tetrofosmin scan was incorporated into the pretreatment and posttreatment diagnostic workup of all lung carcinoma patients seen in a second referral institution for a province of 500,000 inhabitants during the years 1998 and 1999. Sixty-one patients, strongly suspected of lung carcinoma were photon-scanned; 21 of them were rescanned after completion of their front-line treatment. Eleven patients eventually underwent surgery, and 3 others underwent mediastinoscopy. Both planar and single photoemission computed tomography thoracic views were obtained. Images for the whole body also were acquired.

RESULTS

All 57 patients whose lung carcinoma was pathologically confirmed showed accumulation of the radiotracer (100% sensitivity). However, three of the four nonmalignant lesions were also 99mTC-tetrofosmin positive. 99mTC-tetrofosmin scan was highly sensitive for the detection of the T0–T2 disease (97% sensitivity) and highly specific for the N0–N1 disease (83% specificity). In the 16 pathologically staged mediastina, sensitivity, specificity, and accuracy rates were 73%, 100%, and 81%, respectively. 99mTC-tetrofosmin scan correctly detected most skeleton (9 of 10) and brain (5 of 7) metastases. The treatment response evaluation made with 99mTC-tetrofosmin corresponded to the clinical estimate in almost half of the sample.

CONCLUSIONS

This study shows that 99mTC-tetrofosmin scan is a relatively accurate method for lung carcinoma evaluation. The authors' preliminary data exclude, however, that noninvasive diagnostic efficiency might be substantially increased by a scintigraphy with 99mTC-tetrofosmin. More studies are needed for a better understanding of the real value of this technique. Cancer 2002;94:1796–807. © 2002 American Cancer Society.

DOI 10.1002/cncr.10394

In lung carcinoma, like in any other human cancer, the techniques of nuclear medicine are based on various radiopharmaceuticals, capable of exploiting specific characteristics of the malignant cells.1 Radiopharmaceuticals may recognize diverse cell densities, growth rates, metabolic pathways, and antigenic or surface receptor expressions.1 It is generally admitted that both 57mCo-bleomycin and 67mGa scintigraphy are tumor sensitive and moderately accurate, but their use has been forsaken by more innovative and encouraging approaches (see Table 1).2–32 They include the use of nonspecific radiotracers (201mTl and 99mTC-MIBI), substances useful in particular clinical applications (the somatostatin analogs 123mI-tyr3 and the 111mIn octreotide for neuroendocrine tumors), radiolabeled monoclonal antibodies, and the recently introduced positron emission tomography (PET) scan.33, 34 With the possible exception of PET scan, the results obtained so far, albeit stimulating and in same case attractive, remain preliminary.35

Tetrofosmin is a lipophilic, cationic diphosphine initially developed for myocardial imaging.36 Like other myocardial perfusion agents,3399mTC-tetrofosmin accumulates in lung carcinoma,11, 37–41 but there is virtually no information concerning important clinical applications, such as lung carcinoma staging and treatment response evaluation.

With the current study, we aimed to compensate that lack of information. In particular, we were interested in 99mTC-tetrofosmin scan ability to detect primary and metastatic cancer deposits and to recognize their changes in response to treatment.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients and Study Design

Sixty new unselected patients, who were evaluated for surgical cure of a highly suspected lung carcinoma, were set as a minimum target sample for this study. This figure was achieved in less than 2 years (March 27, 1998 to August 20, 1999). Eligible patients either had histologically proved lung carcinoma or had undergone thoracotomy for a clinical diagnosis of lung carcinoma. All had been considered operable after a preliminary evaluation based on clinical history and physical examination, blood chemistry and hematologic counts, bronchoscopy, functional respiratory tests, chest X-rays, and any other examination required by the results of the basic staging workup. All registered patients underwent 99mTC-tetrofosmin scan (both planar and single photoemission computed tomography [SPECT] images), 99mTC-methilene diphosphonate bone scan, and computed tomography (CT) of the thorax, abdomen, and brain. Other imaging studies, such as bone radiograms and ultrasonographic studies of the abdomen, were performed to support diagnosis or to guide needle aspirations and biopsies. All staging tests were obtained within a 3-week period. Tumor cell type and stage of disease were classified according to internationally adopted criteria.42, 43

We obtained follow-up clinical reassessments at 3– 4-week intervals during chemotherapy, and every 3–6 weeks in case of palliation radiotherapy, or no active anticancer treatment. Patients treated with radical surgery were seen at longer intervals, ranging 3–6 months. In 21 patients, a complete restaging evaluation was obtained 3 months after the first initial evaluation. Such restaging evaluation included all the examinations performed at diagnosis (including the scintigraphy), along any other test as clinically indicated. At each follow-up reassessment, the status of disease was classified using the standard criteria of objective response.44 To account for any meaningful variation in tumor volume, we interposed a category of minor regression between partial response and stable disease. Minor regression was defined as any unequivocal tumor volume shrinkage that did not fulfill the criteria of partial regression.

Patients were informed of the nature, aim, potential risks, and benefits of both 99mTC-tetrofosmin scan and iodine-contrasted CT scan, and they gave their consent before entering the study. The local committee on human research approved this study. Anthropometric and clinical characteristics of the 61 registered and assessable patients are summarized in Table 2.

99mTC-Tetrofosmin Scan: Radio Pharmaceutical, Imaging, and Interpretation of the Images

Tetrofosmin was obtained commercially (Mioview Kit; Nycomed Sorin Amersham, Milan, Italy). The labeling and quality control procedures were performed according to the manufacturer's instruction. The radiochemical purity of 99mTC-tetrofosmin used in this study was consistently higher than 90%.

The subjects received 11.1 MBq/kg of 99mTC-tetrofosmin. Planar spot images were acquired by a large field of view gamma camera (GE 400 ACT; General Electric, Milwaukee, WI) fitted with a medium-low-energy high-resolution parallel-hole collimator. Planar images (5 minutes per images,128 × 128 matrix) of the chest (anterior and posterior) were acquired 5, 20, 60, and 120 minutes after injection to clinically validate the multidrug resistance hypothesis (data not reported in this article). Single photoemission computed tomography views of the thorax were obtained 30 minutes after injection, and SPECT views of the brain were obtained 60 minutes after injection. In both cases, 64 planar images were collected around 360° with a 64 × 64 word-mode matrix. Single photoemission computed tomography images were used for staging purposes and for comparison with CT. The acquisition time for each plane was 20 seconds. The 64 planar projections were reconstructed to transverse slices with the use of a Butterworth filter (cutoff frequencies, 0.4 cyclescm; power factor, 20) at a 2-pixel thickness for each transverse (12.8-mm-thick) slice. No attenuation correction was used. Transverse sections were reoriented into the sagittal and coronal planes.

Single photoemission computed tomography images of the chest or brain were regarded as positive when an abnormal 99mTC-tetrofosmin uptake that exceeded pulmonary or brain background was documented in at least two sequential planes (either transverse, or sagittal, or coronal). The abnormality was located into a pulmonary, hilar, or mediastinal region according to topographic criteria. Pulmonary uptakes adjacent to the chest wall were read as T3, whereas accumulations involving the mediastinal space were classified as T4 lesions. Mediastinal lesions were assigned to a definite lymph node station according to topographic criteria and the American Thoracic Society (ATS) lymph node mapping scheme.45

The data were visually evaluated by two experienced Nuclear Medicine Physicians (A.B. and A.F.) who had knowledge of the CT results and were blinded to the pathologic findings, according to the above definitions and the 1997 Revision of the International Staging System.43

Regions of interest were localized in the tumor mass and normal lung, both on planar (20 min and 120 min images) and SPECT images. From them, the tumor-to-normal lung ratio was obtained.

Thoracic CT: Technique and Reading

All patients included in this report were studied with a CT of the thorax, upper abdomen, and brain. Until October 1998, CT scans were performed on a conventional scanner (GE 9800, General Electric, Milwaukee, WI); then, a spiral-CT machine (CT twin flash; Elscint Ltd., Haifa, Israel) was used. Ten-millimeter-thick sections of the thorax were obtained at 1-cm intervals, during suspended inspiration, from the lung apices to the upper abdomen. In selected cases, 5-mm-thick sections at 5-mm-intervals were acquired through the region of interest. Iodinated intravenous contrast (150 mL bolus, plus 100 mL in slow infusion) was injected prior to all studies. Appropriate windows were used for viewing both lungs and soft tissues.

Mediastinal lymph nodes were labeled as abnormal if they were 1 cm or larger (short axis) and/or 1.5 cm or longer (long axis) on the transverse plan images. Enlarged mediastinal lymph nodes were ascribed to a definite lymph node station on the basis of the ATS classification.45 All CT scans were interpreted by two experienced radiologists, with no restriction to the clinical information available at the time of the exam.

Surgical Sampling and Pathologic Examination

In patients who underwent surgery, lymph node stations positive to either CT or SPECT were carefully inspected and sampled, even when lymph nodes appeared macroscopically normal. All enlarged, palpable, or visible lymph nodes were removed in their integrity. In apparently normal mediastina with negative preoperative studies, a minimum sampling of three lymph node stations was required to reject the hypothesis of N2 disease. Mediastinoscopies (and, in one case, left anterior mediastinotomy) were performed when CT or scintigraphy were positive for accessible lymph nodes in otherwise operable patients. Removed lymph nodes were fixed separately in 10% neutral buffered formalin, and labeled according to the ATS criteria.45

Statistical Analysis

All 99mTC-tetrofosmin scans (SPECT results) were designated true-positive, false-positive, true-negative, and false-negative for the T and N factor, using either the best clinical estimate, or the pathologic reference when available. In pathologically staged patients, CT scan results also were reviewed and labeled as true-positive, false-positive, true-negative, and false-negative. Values of sensitivity, specificity, accuracy, and predictive capabilities were calculated according to the formulas given by Galen.46 Proportions are presented along with their 95% confidence interval.47

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Characteristics of Patients

Sixty-one patients (11 females and 50 males) were registered onto this study and assessable. Of them, 27 had a lung tumor located peripherally in the lung parenchyma (tumor growth beyond the lobar bronchi or nonvisible at bronchoscopy), 30 had a central lesion. The final diagnosis was squamous cell carcinoma (21 patients), small cell carcinoma (8 patients), adenocarcinoma (18 patients), large cell anaplastic carcinoma (5 patients), undefined cell type or mixed histology lung carcinoma (5 patients), nonmalignant lung lesion (4 patients, including 1 sclerotic bronchiectasis and 3 radiologically atypical pneumonias). All patients, except two, had an Eastern Cooperative Oncology Group performance status48 of between 0 and 2. At the end of the pretreatment staging evaluation, 11 patients underwent surgery, 3 underwent mediastinoscopy, and 2 had cervical exploration of supraclavicular glands. As a result, 16 patients had a pathologically documented N classification. There were also 12 T pathologic classifications (i.e., the 11 patients who underwent surgery, plus 1 patient with a pleural effusion containing malignant cells). Table 2 summarizes the demographic, clinical, pathologic, and follow-up data of the 61 patients.

Table 1. A Working Classification of the Newest Nuclear Medicine Methods of Lung Carcinoma Imaging
RadiotracerRelevant studiesPatient no.Sensitivity (%)a
  • CEA: carcinoembryonic antigen; PET: positron emission tomography.

  • a

    Unless otherwise specified, (N = lymph node assessment), values refer to the primary tumor detection rate.

Somatostatin (only used in small cellLeitha et al. (1993)22084; 73(N)
 lung carcinoma)Krenning et al. (1993)328100
O'Byme et al. (1994)413100
Kwekkeboom et al. (1994)540100
201ThalliumSalvatore et al. (1976)64390; 87(N)
Tonami et al. (1989)723100; 71(N)
Sehweil et al. (1990)814787; 17(N)
Tonami et al. (1991)92976(N)
Matsuno et al. (1992)103867(N)
Takekawa et al. (1997)114696
99mTc-sestamibiLeBouthiller et al. (1993)122496; 100(N)
Aktolun et al. (1994)133893; 100(N)
Chiti et al. (1996)144791
Tanaka et al. (1997)151989
Wang et al. (1997)161983
Takekawa et al. (1997)114689
Radiolabeled monoclonal antibodies andGoldenberg et al. (1982)172572
 anti-CEA immunoscintigraphyPerkins et al. (1992)181369
Riva et al. (1988)191080
Riva et al. (1988)203497
Krishnamurthy et al. (1990)211675
Biggi et al. (1991)226690
Buccheri et al. (1992)236390
Buccheri et al. (1993)244591
Buccheri et al. (1996) (SPECT)2513173(N)
PETPatz et al. (1993)265189
Saunders et al. (1999)279771
Tatsumi et al. (1999)282378
Kernstine et al. (1999)296470
Farrell et al. (2000)308482
Pieterman et al. (2000)3110291
Dunagan et al. (2001)3215295
Table 2. Demographic and Clinical Characteristics of the Study Cohort
CharacteristicNo.MedianRangeFrequency
  • ECOG PS: Eastern Cooperative Oncology Group performance status; y: yes; n: no. Tumor cell type, E: epidermoid squamous cell carcinoma; S: small cell carcinoma; A: adenocarcinoma; L: large cell anaplastic carcinoma; U: undetermined or mixed cell type. T: trachea; M: main bronchus; L: lobar bronchus; P: segmental or more peripheral bronchus. Primary treatment: P: palliative and supportive care; C: chemotherapy; R: radiochemotherapy; S: surgical resection; O: other main treatment; U: unknown (2 patients were lost to follow-up). Objective Response Category: CR: complete remission or postoperative disease free status; PR: partial remission; MR: minor regression; SD: stable disease; PD: progressive disease.

  • a

    In 4 patients, the diagnosis of malignancy was excluded either Pathologically (1 case of sclerotic pleuricy) or clinically after a minimum follow-up of 6 months (3 cases of pneumonias).

Age (yr)616644–82
Male gender (y/n)6150/11
ECOG PS (0/1/2/3)6111/33/15/2
Tumor cell type (E/S/A/L/U)a5721/8/18/5/5
Tumor endobronchial location (T/M/L/P)571/10/19/27
Maximum tumor dimension, best estimate (cm)4651.2–13
Stage classification (IA/IB/IIA/IIB/IIIA/IIIB/IV)570/7/1/0/10/12/27
TNM best estimate (either pathologic or clinical)
 T factor (1/2/3/4)576/25/9/17
 N factor (0/1/2/3)5717/4/27/9
 M factor (0/1)5730/27
 Bone metastases (y/n)5711/46
 Lung metastases (y/n)5710/47
 Brain metastases (y/n)579/48
 Liver metastases (y/n)576/51
 Adrenal gland metastases (y/n)572/55
TNM pathologic evaluation
 T factor (0/1/2/3/4)121/1/6/0/4
 N factor (0/1/2/3)169/2/3/2
 M factor (0/1)31/2
Primary Treatment (P/C/R/S/O/U)575/31/6/11/2/2
Objective Response assessment (CR/PR/MR/SD/PD)4910/16/7/7/9

Imaging the Primary Tumor

Table 3 summarizes 99mTC-tetrofosmin scan data, reporting the total number of acquired planar and SPECT images, the tumor/background ratio, and the evaluations of disease extent, and treatment response. In all, we obtained 85 planar and SPECT views from 64 subjects. However, three patients were scanned only after treatment and lacked of a baseline evaluation. For this reason, they were excluded from study. All lung carcinoma patients showed an accumulation of tetrofosmin in their lesion. As expected, tumor/background ratio was, on average, higher in SPECT than in planar views, and tended to be lower after treatment. No difference in tumor/background ratio was evident comparing early and late planar images.

Table 3. Scintigrafic Data
CharacteristicNo.MedianRangeFrequency
  • D: performed at diagnosis; F: performed during follow-up; y: yes; n: no; SPECT: single photon emission computed tomography; CR: complete remission or postoperative disease free status; PR: partial remission; MR: minor regression; SD: stable disease; PD: progressive disease.

  • a

    Three subjects had only a posttreatment scintigraphy and were unassessable for this study.

Planar scintigraphies, total (D/F)8561/24
 No. of assessable (D/F)a8261/21
SPECT, total (D/F)8561/24
 No. of assessable (D/F)a8261/21
Pretreatment tumor background ratio
 Early planar views581.311.01–2.22
 Late planar views581.310.96–2.55
 SPECT592.241.30–5.26
Posttreatment tumor background ratio
 Early planar views161.221.03–2.10
 Late planar views161.231.03–1.89
 SPECT202.091.25–3.53
Pretreatment evaluation of the extent of disease
 Central uptake (y/n)6116/45
 T factor (0/1/2/3/4)611/5/44/1/10
 N factor (0/1/2/3)6110/10/29/12
 Lung metastases (y/n)615/56
 Brain metastases (y/n)615/56
 Bone metastases (y/n)6110/51
Posttreatment evaluation of the extent of disease
 T factor (0/1/2/3/4)212/7/10/0/2
 N factor (0/1/2/3)218/3/3/7
Response to treatment (CR/PR/MR/SD/PD)212/12/0/6/1

99mTC-tetrofosmin scan was incorrectly positive in three subjects whose initial diagnosis of lung carcinoma was excluded at the completion of their diagnostic process. In these patients, the follow-up observation and the demonstration of a partial (or complete) resolution of the radiologic densities suggested the final diagnosis of pneumonia. Figure 1 depicts the increased uptake of 99mTC-tetrofosmin in a supposed malignant lesion (Patient 42) that showed a complete CT clearing after antibiotics. As already stated, 99mTC-tetrofosmin scan was correctly positive in all the 57 patients with lung carcinoma (100% sensitivity). The minimum size of tumor that could be detected was 1.2 × 1 cm.

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Figure 1. Transaxial, coronal, and sagittal images of the thorax (Patient 42) generated from single photoemission computed tomography and obtained 30 minutes after injection. Note the intense, inhomogeneous uptake of 99mTC-tetrofosmin into the right lung and the focal uptake into a mediastinal lymph node. The lesion, initially supposed malignant, eventually was considered benign based on a strict clinical and radiologic follow-up (radiologically atypical pneumonia).

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Staging the Intrathoracic Disease

Table 4 put in correlation 99mTC-tetrofosmin findings with either the best clinical estimate or the pathologic diagnosis. In 54% of the cases, 99mTC-tetrofosmin estimates corresponded to the best clinical assessment (T factor evaluation), which was underestimated in another 31% of the patients. In the subgroup of 12 patients with a pathologic T assessment, a slightly inferior accuracy rate (42%) and an increased error of underestimation (50%) were observed. 99mTC-tetrofosmin SPECT readings were fairly more accurate in pathologically documented lymph node disease (accuracy rate, 69%).

Table 4. Cross-tabulation between SPECT Estimates and the Final Diagnosisa
 T factor, final diagnosis
 01234Total
T factor, SPECT
 01 (1)1 (1)
 123 (2)5 (2)
 234 (1)21 (4)88 (4)44 (9)
 311
 41910
 Total4 (1)6 (1)25 (6)917 (4)61 (12)
 N factor, final diagnosis
0123Total
  • SPECT = single photoemission computed tomography (technectium-99m-tetrofosmin scintigraphy).

  • a

    The final diagnosis was based on either clinical or pathologic assessment (the cases with a pathologic reference are shown in parentheses).

N factor, SPECT
 09 (6)110 (6)
 13 (1)2 (1)510 (2)
 28 (2)2 (1)15 (2)429 (5)
 316 (1)5 (2)12 (3)
 Total21 (9)4 (2)27 (3)9 (2)61 (16)

Based on the above data, formulas for the diagnosis of “locally limited disease” (T1–T2 disease) or “regionally limited disease” (N0–N1) could be calculated. Table 5 provides the precise estimates and the 95% confidence intervals of sensitivity, specificity, accuracy, positive, and negative predictability for the 99mTC-tetrofosmin scan diagnosis of “limited disease.” Calculations are made using both the clinical and the pathologic reference. With limitation to the pathologically documented cases, a comparison with CT scan, assumed to be the gold standard for presurgical evaluation, is provided. Such a comparison showed an apparently equivalence of the two techniques (a 9% accuracy advantage of 99mTC-tetrofosmin scan, in assessing the T factor, was compensated by a 13% disadvantage in the N factor evaluation). Remarkably, 99mTC-tetrofosmin scan shared with CT a positive predictive value of 100% (diagnosis of N2 disease, Table 5).

Table 5. Tumor Resectability: Diagnostic Formulas
Scintigraphic results (clinicopathologic reference)
 TPTNFPFNtotalSE  SP  AC  PPV  NPV  
Diagnosis of limited disease(SE ± CI)(SE ± CI)(AC ± CI)(PPV ± CI)(NPV ± CI)
 T0-T2 (any reference)34101616197%92%103%38%20%57%72%61%83%68%55%61%81%74%108%
 N0-N1 (any reference)14306116156%37%75%83%71%96%72%61%83%70%50%90%73%60%87%
Scintigraphic results vs. CT findings (pathologic reference)
TPTNFPFNtotalSESPACPPVNPV
  1. TP: true-positive; TN: true-negative; FP: false-positive; FN: false-negative; SE: sensitivity; SP: specificity; AC: accuracy; PPV: positive predictive value; NPV: negative predictive value; CI: confidence interval; CT: computed tomography; IC: incalculable.

Diagnosis of locally limited disease (pathologic T0–T2)(SE ± CI)(SP ± CI)(AC ± CI)(PPV ± CI)(NPV ± CI)
 Scintigraphy804012100%100%100%0%0%0%67%40%93%67%40%93%ICICIC
 CT scanning70411288%65%110%0%0%0%58%30%86%64%35%92%0%0%0%
Diagnosis of regionally limited disease (pathologic N0–N1)
 Scintigraphy85031673%46%99%100%100%100%81%62%100%100%100%100%63%29%96%
 CT scanning105011691%74%108%100%100%100%94%82%106%100%100%100%83%54%113%

Detecting Distant Metastases

Table 6 allows a summary of the 99mTC-tetrofosmin scan diagnostic capability for the metastatic disease. Note that given the physiologic distribution of tetrofosmin, only a few sites of possible metastatic spread (i.e., brain, lung, and the skeleton) were assessable. Table 6 provides data concerning 27 metastatic patients and another nonmetastatic subject, who had an unconfirmed scintigraphic diagnosis of bone metastasis. In particular, the site(s) of metastasis, the method(s) used for their confirmation, and the results of 99mTC-tetrofosmin scan are listed.

Table 6. Distant Metastases: Diagnostic Correlates
Patient no.Confirmed site(s) of metastasisMethod(s) of diagnosis or exclusionScintigraphic resultsa
  • CT: computed tomography; MRI: magnetic resonance imaging; NA: nonassessable; FU: follow-up (occurence of specific symptoms and signs of a later time).

  • a

    Brain, lung, and bone were the only assessable sites of metastasis.

  • b

    The diagnosis of lung carcinoma and the execution of the technectium-99m-tetrofosmin scintigraphy followed the cerebral mass removal and its pathologic examination.

  • c

    The pathologic diagnosis was obtained during surgery of osteosynthesis for fractured humerus.

2BrainCT, FUPositive
3LungCT, FUPositive
6LungCTPositive
10Lung, liverCTNegative (lung)
15BrainNeurosurgical escissionNA (b)
16BrainCT, neurologic symptomsPositive
17Lung, adrenal glandsCTNegative (lung)
18BoneBone scan, CT, clinical signesPositive
19BrainCT, MRI, FUPositive
20BonePathologic diagnosiscPositive
21LungCTPositive
23Bone, liverBone scan, abdomen CTNegative (bone)
25Bone, liverBone scan, CT, FUPositive (bone)
26BoneBone scan, CT, FUPositive
28LungCTNegative
31Brain, boneCT, bone scan, bone X-rays, FUPositive
34BoneBone scanPositive (bone and lung)
43Lung, brainCT, FUNegative
47Lung, boneCT, bone scan, bone x-raysPositive (bone)
52Bone, liverBone scan, CTPositive (bone)
53Brain, liver, bone, adrenal glandsBone scan, CTPositive (bone)
54BoneBone scanNegative
55BrainCT, neurologic symptomsNegative
56BrainCTPositive
57Pancreas, abdominal nodesCTPositive (lung)
58LungCTNegative
60Lung, liverCTNegative
32noneCT, bone scan, FUPositive (bone)

Overall, 99mTC-tetrofosmin scan was true-positive, for at least 1 metastatic site, in 17 patients and truly negative in another 29 cases; it was false-positive in 1 subject and false-negative in another 9. This means an overall accuracy rate of 82% and a rewarding specificity of 97%. Figure 2 shows the intense brain accumulation of 99mTC-tetrofosmin in Patient 16.

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Figure 2. Transaxial, coronal, and sagittal images of the brain (Patient 16) generated from single photoemission computed tomography and obtained 60 minutes after injection. The arrows indicate the focal uptake of 99mTc-tetrofosmin in a lesion located into the right occipital lobe. Note the “normal” uptake of the tracer into the choroid plexuses.

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Assessing the Response to Treatment

Twenty-one patients underwent a full restaging evaluation, including a repetition of 99mTC-tetrofosmin scan 3 months after starting treatment. In three of them, the restaging evaluation followed an apparently radical tumor resection (two right superior bilobectomies and one left pneumonectomy). In the remaining 18 subjects, the main treatment was chemotherapy with or without thoracic irradiation. Based on the standard assessment, all surgical subjects were judged disease free (or complete responders). In addition, there were other two complete, nine partial, four minor responders, and three progressing patients in the chemotherapy group. 99mTC-tetrofosmin scan response assessment was identical in 47% of the sample and reasonably similar in another 38%. It differed markedly in three patients, where tetrofosmin uptake remained unchanged, whereas radiologic findings were consistent with a substantial reduction or even a disappearance of the cancerous lesion. Figure 3 gives an example of nonconcordant diagnosis of response (i.e., modest 99mTC-tetrofosmin response, with dramatic CT scan improvement).

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Figure 3. (a–b) Pretreatment (2/15/99) and posttreatment (6/4/99) transaxial, coronal, and sagittal SPECT images of the thorax (a). The arrows indicate the abnormal uptake of the hilar (bilaterally) and mediastinal lymph nodes. Corresponding CT images are given for comparison (b). After chemotherapy (three cycles with cisplatin and etoposide), the lymph node uptake is almost unchanged, whereas a marked reduction of the mediastinal disease is evident on CT (Patient 24).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In lung carcinoma, surgery remains the only chance of cure.49 An accurate noninvasive evaluation of the real extent of disease is the premise for a successful operation.49 Ideally, the preoperative staging maneuvers should be able to save patients futile surgery, guaranteeing the surgical cure if this is appropriate. Often, the final evaluation of resectability depends on invasive staging procedures, such as mediastinoscopy and anterior mediastinotomy.49, 50 A reliable noninvasive test might be useful in limiting the recourse to these procedures, by selecting subgroups of patients with various probabilities of mediastinal involvement. Computed tomography scan normally is used in this context.51 A classic meta-analytic review of 42 early studies documented, on average, a CT accuracy rate of 80%.52 Recent estimates suggest more prudent figures, in the 50–60% range in the United States and in the 60–70% range in Europe and Japan.53, 54 According to these last data, thoracic CT might be insufficiently accurate for being the ideal preoperative staging test.

Nuclear medicine continues to introduce novel techniques for cancer imaging. New scintigraphic methods have been introduced for the detection, pretreatment staging workup and posttreatment response evaluation of bronchial carcinoma.33 Unfortunately, no scintigraphic technique has been found sufficiently effective and feasible to replace the routine use of CT.33 For example, when we studied 67mGa scintigraphy and, later, the anticarcinoembryonic antigen monoclonal antibody scintigraphy, we obtained results that were often noteworthy but never really satisfactory.22, 23, 25, 55–59

99mTC-tetrofosmin is a new myocardial imaging agent with high affinity for cancer tissues. The mechanism of tumor uptake for this radiopharmaceutical is not clearly understood. Hypotheses explicative of the phenomenon include a 99mTC-tetrofosmin binding to the cytosol of tumor cell, its intracytoplasmic retention due to a reduced activity of the 170-kilodalton P-glycoprotein, or an increased tumor blood flow or capillary permeability.36 Clinical studies that have confirmed the affinity of 99mTC-tetrofosmin for lung carcinoma are already numerous. In 1995, Basoglu and coworkers reported a pilot study of five patients with bronchial carcinoma, in different phases of treatment, four of which showed a localized tumor uptake of 99mTC-tetrofosmin.60 In their mature analysis,39 a clear accumulation of the radiotracer was visibly present in 26 of 34 malignant tumors, but also in 3 of the 11 benign lesions. Of the 26 patients with malignant tumors accumulating 99mTC-tetrofosmin, 9 had repeated imaging 6–8 weeks after radiochemotherapy. In five of the nine, the course of the 99mTC-tetrofosmin uptake in follow-up imaging was in accordance with the radiologic size of the tumor, used as the criteria of reference for response. Two of the four remaining subjects showed some degree of inconsistency between changes in 99mTC-tetrofosmin uptake and radiologic size. In another study, Atasever and colleagues imaged 30 patients with 99mTC-tetrofosmin.37 There were 21 cases of primary lung carcinoma (10 squamous cell, 5 small cell, 4 adenocarcinoma, and 2 large cell) and 9 benign lung lesions (4 pneumonia, 3 tuberculosis, 1 infected bronchiectasis, and 1 obliterating bronchiectasis). Of the 21 primary malignant lesions 19 showed a 99mTC-tetrofosmin accumulation. However, also 4 (44%) of the 9 benign lesions (3 cases of pneumonia and the 1 case of active tuberculosis) showed an increased uptake. In 1997, Kao and colleagues studied 49 patients with a single solid lung mass, to determine the capability of 99mTC-tetrofosmin SPECT to differentiate between malignant and benign lesions.41 In this study, only 61% of the lung tumors were detected by 99mTC-tetrofosmin SPECT of the chest. In addition, 50% of the benign lesions were falsely visualized. Tetrofosmin uptake was not related to the mass size. The authors concluded that, for differentiating malignant and benign lesions presenting as a single solid lung mass, 99mTC-tetrofosmin SPECT of the chest is of little or no value.41 In the study by Takekawa et al.,11 46 patients with lung carcinoma were photo-scanned after the intravenous injection of 740 MBq 99mTC- tetrofosmin and 111 MBq 201mT1-chloride. The authors reported that 99mTC-tetrofosmin visualized 89% of the primary lung carcinomas, 96% of which accumulated 201mT1. The difference between 201mTl and 99mTC-tetrofosmin uptake ratios was significantly greater in squamous cell carcinomas than in small cell carcinomas (P < 0.01) and tended to be greater in squamous cell carcinomas than in adenocarcinomas (P = 0.093), indicating that such a different biologic behavior of 99mTC-tetrofosmin and 201mT1 might provide useful information regarding the histologic type.11 In summary, the current literature indicates that 99mTC-tetrofosmin is accumulated in 60–90% of all lung carcinomas (with possible variation due to the cell type) and in roughly 50% of all benign lesions erroneously considered cancer in a first clinical evaluation. Also, our data (100% sensitivity and 25% specificity) underline the good affinity of 99mTC-tetrofosmin for both cancerous and noncancerous lesions of the lung.

Concerning the main scope of this study, almost no information is available. So far, to our knowledge, our investigation is the only organic, sufficiently large, piece of evidence. It already has been shown that 99mTC-tetrofosmin scan may be used effectively in both lung carcinoma staging and tumor response evaluation. However, the exact merit of this technique cannot be assessed on the sole basis of this report. The comparison with CT scan seems to suggest that 99mTC-tetrofosmin scan might be equivalent to CT in the study of mediastinum. The ability of 99mTC-tetrofosmin to visualize distant metastases in the brain and the skeleton is also attractive. The fair correlation between the standard assessment of response and the uptake of 99mTC-tetrofosmin already has been reported,39 and our study offers confirming evidence.

Unfortunately, surgical maneuvers remain essential for a correct staging classification, and the scintigraphy with 99mTC-tetrofosmin does not appear to have the potential to change the situation radically. Lacking better options, we believe thoracic CT is the standard test for pretreatment and posttreatment evaluation of lung carcinoma. More information is needed to correctly catalog 99mTC-tetrofosmin scan in the diagnostic armamentarium for lung carcinoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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