- Multidisciplinary Symposium — Monitoring Response to Treatment: Tuesday 16 October 2001, 10.40–13.00
- Open Access
Radiopharmaceuticals in monitoring cancer
Cancer Imaging volume 2, pages36–39(2001)
Normal cells have three basic outcomes: differentiation, division and death. Cancer cells usually have reduced differentiation, increased division and mechanisms to avoid programmed cell death. apoptosis. These properties can be used to monitor cancer by nuclear medicine imaging.
Thyroid cancer cells show a reduced ability to take up radio-iodine compared with normal cells. Thus. all normal thyroid tissue has to be ablated surgically and with radio-iodine in order that the papillary or follicular thyroid cancers show uptake on radioiodine images and for thyroglobulin. Tg. to be a useful serum marker. Monitoring of thyroid cancer used to be done with a tracer amount of radioiodine 131I. It was found that administration of amounts greater than 185 MBq, 5 mCi may cause stunning, reducing the of effectiveness of the large dose of 131I given for therapy, (5–6 GBq, 150 mCi). However, 185 MBq (or less) 131I gives a poor count rate signal, so that weakly iodine-avid malignant disease may not be detected. If the Tg is raised, some authorities are giving 131I therapy in the absence of proof of iodine uptake. Some 50% of such patients show no uptake on the post-therapy dose scan. Those patients have received a large amount of unnecessary radiation, hospitalization and temporary hypothyroidism while off trioiodothyronine. Such practice is against the radiation rules for the justification of the administration of radioactive materials to patients. The answer is to monitor with a dose of the gamma remitting 123I (185 MBq, 5 mCi), which gives a similar count rate as a therapy dose of 131I, but half the radiation dose of 185 MBq, 5 mCi of 131I. Then there is no stunning, so that iodine-avid disease can be treated. With this dose of 123I, but not the trivial doses of 123I used previously of less than 20 MBq, 0.5 mCi, a patient who is negative on 123Iisnot treated by radioiodine in spite of a raised Tg. The ef ectiveness of this approach in deciding when 131I therapy is needed has been shown with a Tg-positive, 131I tracer scan-negative, 123I image-positive, 131I post-therapy scan-positive disease and a Tg-positive, 131I tracer-negative, 123I image-negative, 131I post-therapy scan-negative disease. Thus, 123I (185 MBq) and Tg combination protocols are being introduced to monitor thyroid cancer.
Many neural crest APUDoma tumours maintain their Uptake-1 mechanism for noradrenaline storage in chromaffin granules. 123I MIBG, metaiodobenzylguanadine, a noradrenaline analogue, may be used at an administered dose of 185 MBq, 5 mCi, to monitor malignant pheochromocytoma, paragangliomas and about 50% of abdominal carcinoids. However, usually once the diagnosis of MIBG-avid tumour is made then 131I MIBG therapy (7.4 GBq, 200 mCi) is given and the post-therapy scan at 4 days is used to show continuing MIBG avidity. This therapy is repeated every 6 months until 45 GBq, 1.2 Ci is given to the patient, or else a satisfactory response has occurred, or else loss of MIBG avidity is demonstrated.
Bone metastases usually induce osteoblastic activity, so serial bone scans may be used to monitor response or more usually failure of response to treatment. In which case, evidence of widespread painful bone metastases from prostate or breast cancer on the bone scan may indicate the need for therapy with 89Sr or 153Sm-EHTMP Beta-emitting radionuclides.
Cancer cells divide frequently and outgrow normal tissues partly through better nutrition and partly by inhibiting the normal environmental reaction to invasion. Better nutrition is achieved by upregulation of glucose and amino acid transporter proteins. For glucose upregulation of the hexokinase enzyme which phos-phorylates glucose also occurs. FDG 18F deoxyglycose is a non-metabolizable analogue of glucose used with Positron Emission Tomography (PET) imaging for the detection of cancer vs. benign lesions. This is through the greater visual and measured uptake (SUV, Standard Uptake Value) and by demonstrating increased glucose uptake in lymph nodes either that have not regressed to normal size on CT scan as after chemotherapy of Hodgkin’s disease, or else in normal size nodes (1 cm or less on CT or MRI). It is clear that cancer has to be present in a normal-sized node before it can enlarge it to a greater than 1 cm diameter. The specificity of FDG PET (and 67Gallium) is context-dependent, the presence of cancer (primary or recurrent) indicating uptake in a node is likely to be due to cancer.
The general approach is that a reduction of FDG uptake after chemotherapy indicates a response. Such a reduction in uptake usually precedes a reduction in tumour size seen radiologically. However, it has to be remembered that activated white cells are also hungry for glucose and that dying necrobiotic cells and the autolytic process are glucose-avid, as are granuloma. An abscess or glandular enlargement due to infection may be mistakenly called recurrence. Cancer cells in a tumour mass are not uniform in response. The more anaplastic the clone of cells, the greater the initial expected glucose utilization and probably the greater reduction of uptake after therapy. It is not yet clear whether the average response of the tumour or the maximum response should be taken. In monitoring the response of cancer to chemotherapy using FDG the problem is further compounded that just as sick patients do not eat, so sick cells do not feed. Lack of FDG uptake thus may not equate with death or response to chemotherapy but with dormancy. In summary, the reduction of FDG uptake may give a false sense of benefit and no change of uptake may be due to an active, potentially beneficial inflammatory response rather than a lack of response to the therapy.
There are technical problems in evaluating response by quantitative imaging, reviewed by Hoekstra et al.. There are no rigorous methods to determine the threshold to use to draw a region of interest around the tumour on the image. Say it is 37% of the peak tumour counts on the pre-treatment image. Should it be 37% on the post-treatment image, which may be inappropriate as therapy may have changed the environment as well as the tumour, or should it be what looks best? In the latter the subjective element creeps in. Furthermore, the reconstruction process, whether iterative or back-projection, relates the count content of each pixel to every other pixel. The statistical independence of each pixel is lost and thus the statistical requirement that a comparison must be made of independent variables is lost. An active environment, e.g. blood or heart activity will reduce the count rate in a neighbouring tumour, a stomach bubble or air in the gut will increase the apparent count rate in the neighbouring tumour. In principle quantification should be undertaken before reconstruction, as in the method called ‘image surgery’. The actual timing of the second PET scan is a problem in relation to chemotherapy and the optimum time to attempt to predict responsiveness may be dif erent for dif erent tumours, dif erent regions and dif erent patients. It appears that 18F amino acids such as methyl tyrosine (also as 123I methyl tyrosine) may be more specific, as may radiolabelled purines and pyramidines, through being less affected by the inflammatory response when predicting and monitoring the effect of chemotherapy[6,7]. Nevertheless, FDG PET is being used to monitor breast cancer therapy successfully and sarcoma. General recommendations are made by EORTC (Table 1), but the above caveats need to be noted.
Both Tc-99m SestaMIBI (methoxy-isobutyl isonitrile), perhaps representing mitochondrial activity, and 201Thallium, relating to cellular potassium uptake, have been used to monitor therapeutic response in small cell lung cancer and in bone and soft tissue tumours.
The upregulation of receptors to take advantage of autocrine growth factors may be imaged with 111In Octreotide analogues and more recently Tc-99m Octreotide analogues to monitor somatostatin receptor avidity in neuro-endocrine tumours. Absence of receptors on imaging will indicate absence of response to cold Octreotide and to 90Y Dotatoc. The five somatostatin receptors confound the issue so that an 111Indium Octreotide-negative scan may be 111Indium Lanreotide-positive and such a tumour may respond to 90Y Lanreotide. As there are over 100 biologically active peptides in the regulation of cell growth and division, many new radiolabelled peptides are being evaluated for monitoring cancer.
The architectural disruption of the malignant process brings antigens normally not exposed to blood to be upregulated and available for detection by imaging. Examples are murine and more recently humanized HMFG, a monoclonal antibody against the human milk fat globule, and murine and more recently humanized PR1A3, a monoclonal antibody that binds to colorectal cancer. Both may be radiolabelled with Tc-99m for determining recurrent disease and the response to radio or chemotherapy. Other tumour antigens are upregulated, such as prostate-specific membrane antigen (PSMA) in prostate cancer which remains fixed to the cell, unlike the prostate-specific antigen (PSA) which is increased in the serum. As well as for judging the operability of primary prostate cancer, antibodies against PSMA-labelled either with 111Indium (Prostascint) or with Tc-99m may be used after surgery to judge whether a small change in PSA is significant, or, if the PSA is rising, the site of the soft tissue recurrences when the bone scan and other radiology are negative. Receptor imaging and monoclonal antibody imaging of antigens present on the cancer cell have the advantage that these are still present in the dormant cancer cell during therapy but disappear with successful treatment. Furthermore, post-surgical or radiotherapy fibrosis can be distinguished from active or viable tumour using these agents, which may be difficult with CT or MRI. When cancer recurs as sheets, ribbons or plaques with very little mass it is very difficult to detect it radiologically. The nuclear medicine techniques identify the presence of cancer through differences between the cancer cells and their normal counterparts. Such identification does not depend on its physical mass. However, when a more malignant clone of cancer develops it may lose some receptors and antigens.
Cancers have developed techniques to avoid apoptosis so that the p53 and related mechanisms fail to recognize the damaged DNA of the oncogene and thus fail to switch on the apoptotic mechanism. Treatment of cancer with chemotherapy and radionuclide therapy may trigger apoptosis in contrast to high dose external beam radiotherapy which breaks DNA strands and tends to cause necrosis. Tc-99m annexin is a marker of apoptosis. On the onset of apoptosis, phosphatidylserine which is on the inner side of the cell membrane, becomes exposed to the outer surface where it can combine with the peptide annexin. Trials have shown that this imaging agent can demonstrate immunologically induced apoptosis, for example in cardiac transplant rejection, but so far has been less successful in demonstrating whether chemotherapy is likely to be effective or not by imaging before and after the onset of the first course of chemotherapy. The principle, however, is a good one and it may be the key to determining the effectiveness of chemotherapy by demonstrating activation of apoptosis early in its course.
Other approaches include: the demonstration of hypoxia, for example with radiolabelled nitroimidazoles[15,16]; by showing multiple drug resistance or not as is in Tc-99m-sestaMIBI imaging; and monitoring gene therapy with 123I FIAU or 18F FIAU, a uracil derivative.
The regular and reliable monitoring of cancer therapy using radiopharmaceutical-based imaging techniques is still in its infancy, nevertheless, understanding the biological behaviour of cancer cells undergoing treatment will lead to one or more of the above approaches becoming successful.
Monitoring cancer questions
How to detect cancer in lymph nodes less than 1 cm diameter?
How to relate nuclear medicine imaging and measurements before, during and after therapy when the technical assumptions at each image time differ?
What is the best measure for response to therapy before morphological change?
Is it apoptosis induction or loss of viability, as reduction in glucose utilisation appears insufficient?
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We thank the Imperial Cancer Research Fund for their continuing support.
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Britton, K.E., Granowska, M. Radiopharmaceuticals in monitoring cancer. cancer imaging 2, 36–39 (2001) doi:10.1102/1470-7330.2001.020
- Thyroid Cancer
- 131I Therapy
- 123I MIBG