British Journal of Radiology (2006) 79, e53-e58
© 2006 British Institute of Radiology
doi: 10.1259/bjr/27645093
Stable disease and improved health-related quality of life (HRQoL) following fractionated low dose 131I-metaiodobenzylguanidine (MIBG) therapy in metastatic paediatric paraganglioma: observation on false "reverse" discordance during pre-therapy work up and its implication for patient selection for high dose targeted therapy
S Basu, MBBS (Hons), DRM, DNB and
N Nair, MD
Radiation Medicine Centre, Tata Memorial Hospital Annexe, Jerbai Wadia Road, Parel, Bombay 400 012, India
Correspondence: Dr Sandip Basu, Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe, Jerbai Wadia Road, Parel, Bombay 400 012, India.
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Abstract
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The incidence of paraganglioma in the paediatric population is exceedingly rare, accounting for <0.1% of childhood cancers. We report here the response and toxicity profile in a case of malignant paraganglioma which was treated with what is currently perceived as an unconventional and non-standard approach, using three consecutive low doses of 131I-MIBG (a cumulative dose of 11 647.6 MBq). The patient had a stable disease at the end of 42 months follow-up following the first treatment with 131I-MIBG. Excellent symptomatic and hormonal responses were observed. The only adverse effect was mild nausea in the first 24 h after therapy. In addition to the potentially primary end point of radiological and biochemical response measurement, we, in this paper, endeavoured to look for a quality of life evaluation for this form of treatment. Given the rarity of this condition, the experience gained by this therapeutic approach is intriguing from response and toxicity standpoints and may be extrapolated to malignant pheochromocytoma as well. An apparent "reverse discordance" between 131I-MIBG scintigraphy and 99Tcm-MDP bone scan encountered during pre-therapy work up is also described with possible explanations. This draws attention to an important clinical issue in selecting patients for high dose targeted therapy.
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Introduction
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Whole body 131I-MIBG scintigraphy is a relatively simple yet highly accurate procedure that plays a pivotal role in the clinical algorithm of evaluation of neural crest tumours. The fascinating principle of radiopharmaceutical targeting in tumours has been successfully exploited in the application of MIBG in diagnosis and treatment of neuroendocrine tumours. Data comparing the bone scan and MIBG scan in identifying the skeletal lesions in the neural crest tumours are sparse. Few studies [1–3] addressing this issue, are mainly restricted to the cases of neuroblastoma, wherein greater numbers of skeletal lesions were consistently evident on MIBG scintigraphy. There has not been any convincing study comparing the two scintigraphies in documenting skeletal secondaries in pheochromocytoma or paraganglioma. Common experience, however, suggests that radiolabelled MIBG is particularly useful and superior to conventional bone scan in the localization of malignant pheochromocytoma at remote skeletal metastases. The authors, in this article, present an unusual finding in a case of malignant paraganglioma where skeletal scintigraphy demonstrated more metastatic sites than diagnostic 131I-MIBG scintigraphy, all of which were subsequently found to be true positive lesions by the subsequent 131I-MIBG post-treatment scan. This apparent "reverse discordance" in diagnostic scan, subsequently clarified by post-therapy scan, stresses the fact that one needs to exert caution before designating the skeletal lesions positive by bone scan but "negative" on the diagnostic MIBG scan as either non-specific or non 131I-MIBG concentrating, even though the MIBG diagnostic scintigraphy may have shown uptake in some of the bone scan positive sites. The patient was treated thrice at an interval of 12 weeks showing an excellent palliative response, assessed by the follow up scans at different time intervals and Functional Assessment of Cancer Therapy General (FACT-G) quality of life questionnaire. This report probably represents the first effort to prospectively evaluate health-related quality of life (HRQoL) in 131I MIBG therapy.
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Case report
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A 13-year-old female presented with a history of recurrent episodes of sudden severe frontal headache, diaphoresis and palpitation, and documentation of high blood pressure recordings during the episodes. The last episode was 15 days previously when her blood pressure (BP) recording was 240/130 mm Hg. On examination, her basal pulse rate was 90 min–1 and BP was 160/110 mm Hg. Her fundus showed grade II hypertensive changes. An ultrasound as well as a CT of the abdomen revealed a large extra-adrenal mass measuring 6 cmx3 cmx4 cm between inferior vena cava and aorta adjacent to the hilum of right kidney. The 24 h urinary vanillylmandelic acid (VMA) was 149 mg g–1 of creatinine (normal: 1–9 mg g–1 of creatinine). The patient commenced phenoxybenzamine with good pre-operative control of hypertension, and the entire mass was excised. The histopathology revealed it to be extra-adrenal pheochromcytoma. A post-operative CT scan of the abdomen at 3 months confirmed complete excision of the mass. Post-operatively, her BP was normal and she remained asymptomatic for 1 year. Thereafter, she started experiencing episodes of giddiness, frontal headache and pain at the mid dorsal region, palpitation and occasional visual obscurations. Her BP was 190/110 mm Hg and there was tenderness over right 8th and 9th ribs and the dorsal spine. She was put on prazosin hydrochloride (5 mg thrice daily) and atenolol (25 mg once daily) for control of hypertension. She required analgesics (a combination of ibuprofen and paracetamol was prescribed) almost daily for the alleviation of pain. A repeat CT scan of the abdomen revealed an ill defined lesion with an enhancing component measuring 4 cmx3 cmx2.5 cm to the right of abdominal aorta at the level of T11–L2 vertebrae. A whole body skeletal survey with 16 mCi 99Tcm methylene diphosphonate (MDP) demonstrated abnormal focal uptake of tracer in the following (Figure 1
):
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Figure 1. 99Tcm-MDP bone scintigraphy showing abnormal focal uptake of tracer in the medial part of left supraorbital region, T4–T6 vertebrae, left shoulder, right 8th rib and right superolateral part of L3 vertebra.
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- Medial part of left supraorbital region
- T4–T6 vertebrae
- Left shoulder
- Right 8th rib
- Right superolateral part of L3 vertebra
A 1 mCi diagnostic 131I-metaiodobenzylguanidine (MIBG) whole body scan (Figure 2a) 48 h post-injection demonstrated a well defined focal area of increased tracer uptake in:
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Figure 2. (a) 1 mCi diagnostic 131I-metaiodobenzylguanidine (MIBG) whole body scan 48 h post-injection demonstrated a well defined focal area of increased tracer uptake in midthoracic region (more evident in posterior view) and at an area inferomedial to the right lobe of liver. (b) Pre-therapy repeat 131I-MIBG posterior chest scan showing focal tracer uptake only at the region of T4–T6 vertebral lesions. Rest of the whole body survey did not reveal any abnormal tracer uptake.
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- Mid thoracic region (more evident in posterior view); and
- At an area inferomedial to the right lobe of liver.
These uptakes corresponded to the T4–T6 vertebral lesion seen in bone scintigraphy and the mass lesion evident in CT scan abdomen, respectively. Excision of the para-aortic mass along with right 8th rib biopsy was carried out in the same sitting under general anaesthesia. The histopathology of the mass was consistent with the diagnosis of paraganglioma and the rib biopsy was reported as metastasis from malignant paraganglioma. So, a diagnosis of recurrent paraganglioma (which was excised) with skeletal metastases was made. The 24 h urinary VMA was 19.5 mg g–1 of creatinine (normal: 1–9 mg g–1 of creatinine). In view of the persistence of hypertension and pain at the metastatic sites, the patient was considered for 131I-MIBG therapy. As a part of the pre-therapy workup protocol a repeat 131I-MIBG whole body scan was performed, which showed focal tracer uptake only at the region of T4–T6 vertebral lesions (Figure 2b
). The other skeletal lesions evident in bone scan did not show any tracer uptake. The abdominal tracer uptake earlier was not evident this time (not shown in Figure 2b) consistent with history of complete removal of the mass. Her complete blood counts and serum urea and creatinine levels were all within normal limits and she was treated with 4025.6 MBq (108.8 mCi) 131I-MIBG by intravenous infusion over 3.5 h. Proper precautions like thyroid blockade and adequate hydration were utilized for thyroid and urinary bladder protection at each diagnostic scan and therapy. Before discharging, routine whole body imaging was undertaken, which showed focal concentration of 131I-MIBG at all the sites seen on skeletal scintigraphy (Figure 3), i.e.:
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Figure 3. Post131I-MIBG treatment scan showing focal concentration in the medial part of left supraorbital region, T4–T6 vertebrae, left shoulder, right 8th rib and right superolateral part of L3 vertebra.
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- In the medial part of left supraorbital region
- T4–T6 vertebrae
- Left shoulder
- Right 8th rib
- Right superolateral part of L3 vertebra
The intensity of the tracer uptake at the individual sites varied. She was treated with 131I-MIBG two times subsequently at an interval of 12 weeks with a dose of 3552 MBq (96 mCi) and 4070 MBq (110 mCi) and showed considerable symptomatic improvement and became normotensive. Her 24 h urinary VMA level was within normal limits at 3 months after the third therapy. All of the therapies were well tolerated, with mild nausea as the only adverse effect in the first 24 h of treatment. The follow-up haematological profiles were within normal limits on all occasions. The total leukocyte count was 7200 mm–3, haemoglobin 11.1 g%, total platelet count 180 000 mm–3 at the pre-treatment baseline investigation. The haemograms carried out weekly for 6 weeks following treatment and from during the pre-therapy workup of subsequent therapies did not reveal any appreciable change in the counts at any instant. The cumulative dose of 131I-MIBG used in this case was 11 647.6 MBq (314.8 mCi).
She is being assessed periodically, with the most recent at the end of 42 months after the first treatment. The 131I-MIBG whole body scan showed tracer uptake only at the region of T4–T6 vertebral lesions and was of the same size. The bone scan showed focal uptake at the same sites, with no new sites revealed. The lesional uptakes were of the same intensity and dimension as seen in the first scan. She was designated as having "stable disease". Considerable symptomatic improvement was documented, with only three to four paroxysmal hypertensive episodes since the first therapy. Since the last therapy, there was no single episode of headache, diaphoresis, palpitation or apprehension. Atenolol was discontinued and the prazosin dosage was reduced to 2.5 mg thrice daily while she was being evaluated for the 2nd therapy. She was weaned off prazosin while she was being evaluated at 3 months after the 3rd therapy. The only symptom was pain at the dorsal vertebrae and left shoulder consistent with known metastatic foci at those sites. However, pain in none of these sites was severe enough to warrant intake of analgesics. She did not have any symptom related absenteeism from school in the last 2 years and her school performance was excellent. Assessment of HRQoL using FACT-G questionnaire (version 4) saw improvement in all the subscales. This 27-item ordinal scoring [15] based on a five-point scale of categorical response choices, encompasses the four primary domains of quality of life (i.e. physical, social/family, emotional and functional well being). Several items have reverse anchors, and hence care was taken to code these items by reversing them while scoring those items. On presentation to us, her debility was related mainly to the hypertension related to the catecholamine surge and pain at the metastatic sites (especially at the dorsal vertebrae and the left supraorbital region). She had a reduced performance in several components (Table 1). This was probably, in the majority of the components, related to the catecholamine surge characteristic of neuroendocrine tumours and the improvement was consistent with the gradual fall of urinary VMA level to normal. Her subsequent urinary VMA levels were within normal limits on all occasions.
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Discussion
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The nomenclature for paraganglioma is inconsistent. Sometimes the term is used to designate any extra-adrenal tumour of the paraganglion system. In other instances, the term is reserved for non-functional tumours of the paraganglion system, with functional tumours referred to as "extra-adrenal pheochromocytomas". Tumours in the head, neck and paravagal region are usually non-functioning. Tumours around the aorta and sympathetic chain and visceral tumours, such as bladder tumours, usually elaborate catecholamines. Usually extra-adrenal pheochromocytomas (i.e. functional paragangliomas) occur in the abdomen along the great vessels, the most common site being the upper periaortic region from the diaphragm to the lower poles of the kidneys [5, 6]. The second most common site is the organs of Zuckercandl at the origin of the inferior mesenteric artery. The present case imparts two important messages and is discussed below with the possible explanations.
The basic principle of bone scanning is dependent on local osteoblastic reaction or the bone remodelling response. Before the introduction of radiolabelled MIBG, bone scanning remained the cornerstone of the evaluation of skeletal secondaries in neuroendocrine tumours because it is a highly sensitive, cost effective and non-invasive means to evaluate the whole body skeleton in a single examination. However, several drawbacks of this modality were addressed after the regular use of diagnostic MIBG scanning. The few comparative studies between the two scintigraphies in detection of skeletal metastases from neural crest tumours are mainly restricted to that from neuroblastoma. The study by Shulkin et al in 77 patients of neuroblastoma found nearly twofold greater number of skeletal lesions evident in MIBG scintigraphy [1]. Gordon et al reported about 60% more lesions with MIBG scintigraphy than with bone scanning [2]. In another comparative study between 123I-MIBG and bone scan, more lesions were found with 123I-MIBG scan and there were several false-positive lesions on bone scintigraphy [3]. The reasons put forward for the depiction of more skeletal metastatic lesions in neuroblastoma with MIBG scintigraphy are the following: (a) as the metastatic lesions usually originate from within the bone marrow, skeletal scintigraphy may underestimate early spread. (b) The propensity of neuroblastoma to metastasise in the metaphysis adjacent to the epiphyseal plates (which themselves are sites of increased skeletal tracer uptake); metastatic involvement may be difficult to appreciate. (c) In symmetric metaphyseal lesions, especially with relatively little alteration in skeletal tracer uptake, some lesions escape detection by skeletal scintigraphy. On the other hand, few cases where more lesions are detected in bone scans are often found to be false positive due to the scanner's sensitivity to a wide range of pathological processes [3]. Common experience, as well as research [4], has convincingly proven that radiolabelled MIBG is clearly the scintigraphic procedure of choice in the detection of skeletal metastases at various sites as well as local recurrences in malignant pheochromcytoma.
The present case of malignant paraganglioma is unique in several aspects. Here the skeletal scintigraphy picked up more true positive secondaries compared with diagnostic MIBG scintigraphy and thereby demonstrating a "reverse discordance", which is contrary to the common experience. The lesions were evident in the post-therapeutic scan, but of varying intensity. The tracer uptake in the post-treatment scan proves that they were all true positive lesions as well as 131I-MIBG concentrating. The term "reverse discordance" is used to emphasise this unusual finding of bone scan identifying more true positive lesions than the MIBG scintigraphy in a malignant paraganglioma. To the best of our knowledge, no such case has been reported previously.
One of the important principles of the current version of "seed and soil" theory, originally hypothesised by Stephen Paget more than a century ago, is that the outcome of metastasis depends on multiple interactions (cross-talk) between metastatic cells with homeostatic mechanisms unique to organ microenvironments influencing the biology of cancer growth, angiogenesis and metastasis in several ways. As a tumour specific radiopharmaceutical, 131I-MIBG uptake is more reliable in estimating tumour activity than bone scan, which is an indirect measure of tumour activity, being mainly dependent on local osteoblastic reaction. In the present vignette, the varying intensity of 131I-MIBG concentration in the post-treatment scan (Figure 3) reflects a combination of tumour differentiation and tumour volume at individual sites, the highest uptake being at the T4–T6 vertebrae. The differential tumour cell proliferation might be due to the different local homeostatic factors that the tumour cells can usurp. The additional foci of metastases on post-therapeutic scan not visible on diagnostic images is consistent with the principle of dose responsive functional imaging [10] with a radiopharmaceutical and is mainly due to two reasons: higher photon flux due to higher activity and delayed imaging allowing better non-target tissue clearance after high dose therapy.
Despite the low dose possible due to the relatively unfavourable characteristics of 131I, it continues to be the most commonly used radiolabel in many institutions, because of its low cost and wide availability. 123I MIBG yields superior image quality due to higher count density resulting from its more favourable characteristics, allowing higher dose administration. It also permits SPECT imaging. However, both are excellent agents for imaging neuroendocrine tumours. In direct comparison between the two isotopes, one study showed the same number of lesions revealed by both, while another showed more lesions identified with 123I-MIBG [7, 8]. The present case opens up an important clinical issue to be addressed: When 123I radiolabel is not available, will a negative diagnostic 131I-MIBG scan, which is often the only yardstick in several centres for selecting patients for high dose 131I-MIBG therapy, actually be false negative as in this instance and thus deny therapy to the deserving patients? Or, should one disregard the results of diagnostic scans in the presence of an elevated biochemical marker (plasma or urinary catecholamines and urinary metabolites of catecholamines or plasma-free normetanephrine and metanephrine) and immediately treat with a high dose of 131I-MIBG and look for lesional uptake in the post-therapy scan? This, however, has the possible drawback of the administration of unnecessary therapy doses in a number of cases, as no other alternative appears available at present. Obviously, this is a dilemma on which a consensus needs to be built and it is hoped that this case presentation will fuel that process.
We feel the philosophy, the intent and the protocol of 131I-MIBG therapy needs to be re-explored in different clinical settings and investigated accordingly. The treating nuclear medicine physician should clearly set before him the goal of treatment in each individual case scenario before he decides upon the individual dose, the interval between therapies and the number of therapies. The contexts differ between tumour types in the neuroendocrine malignancies, mainly due to the varying tumour biology, and even within the same malignancy from case to case. While paragangliomas or pheochromoctomas in general grow slowly, the neuroblastomas usually behave aggressively with more than 50% of the patients presenting with metastatic disease at the time of diagnosis. The treatment of an inoperable neuroblastoma in the neoadjuvant setting is aimed at making the mass operable at the earliest opportunity with an aggressive therapy, while a relatively slow growing multiple metastatic paraganglioma or a pheochromocytoma as in the present case should be treated with a palliative intent with an aim to stabilize the disease. Continued tumour cell proliferation in a fast growing malignancy at very low dose rates can contribute to the reduced effectiveness of low dose rate radiation. This stems from the fact that tumours with poor repair capabilities usually exhibit less of a dose rate effect than tumours with good repair capabilities. This means, theoretically, a treatment with a curative intent or with an aim to make an inoperable mass operable will require a small number of treatment cycles with a high amount of radiopharmaceutical, whereas a case with multiple metastases from a slow growing tumour should preferably be dealt with repetitive treatments with smaller doses.
The current convention for treating neural crest tumours is to adopt a standardized dose ranging from 7.4 GBq (200 mCi) to 11.1 GBq of 131I-MIBG administered by slow intravenous infusion [9]. There is, at present, no clear guideline regarding the individual and cumulative dose to be administered for a particular tumour and therefore depends upon the patient profile, institutional policy and the treating physician. The role of repetitive treatments with lower doses is not well defined in the case of 131I-MIBG therapy. To date, there has not been any head-to-head prospective comparison to investigate whether better responses can be obtained with multiple lower doses than with single larger doses. A number of studies [11–14] addressing the low-dose-rate (LDR) radiobiology of targeted radiopharmaceutical therapy in radioimmunotherapy of lymphoma have been published. The unproportionally high clinical responsiveness sometimes observed after radioimmunoconjugate therapy has been ascribed to various factors, e.g. cytotoxic enhancement or sensitization to protracted courses of low-dose-rate radiation exposure, radiation-associated apoptosis [11, 12] etc. It is well imaginable that the LDR effect can be extrapolated to the treatment of neural crest tumours. In addition, treatment-related toxicity can be reduced with repetitive lower doses. The authors, here, used lower levels of activity of 131I-MIBG than previously reported. If dose kg–1 of body weight is considered, the use of around 2.5 mCi kg–1 of 131I MIBG each time is much lower compared with the 10–18 mCi kg–1 currently used in neuroblastoma therapy. In advanced stage cases, the principal aim of 131I-MIBG therapy is symptom palliation and tumour function reduction as well as at tumour arrest and thereby allowing prolonged survival and good quality of life. The excellent patient response and negligible toxicity with this therapeutic approach subserved the above purpose and warrants further study in larger number of patients. Although not used in this case, we conjecture that the interval between the therapies can be reduced using this approach but requires critical examination. As total eradication is usually not possible and hence not the intent of therapy in the multiple metastatic advanced cases, this strategy will allow the treating physician to reserve the dose for treatment of future recurrences.
Received for publication November 18, 2004.
Revision received July 16, 2005.
Accepted for publication September 2, 2005.
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References
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Abstract
Introduction
