COSA:NETs guidelines/Radionuclide Therapy

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Radionuclide Therapy

Introduction

The heterogeneity of gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs) mandates a personalised approach to treatment with radionuclides. The following guidelines formulated for Australasian clinical practice are the first to advocate radionuclide therapy of GEP-NET patients as a standard treatment option. In the United States, National Comprehensive Cancer Network NCCN Clinical Practice Guidelines for NETs (Version 1, 2008) do not address radionuclide therapy. The European Neuroendocrine Tumour Society (ENETS) Guidelines,[1] do not currently recommend radiopeptide therapy, since it is practised only in a few specialised centres and is regarded as not yet being accessible to NET patients throughout Europe.

Largely retrospective series of 177Lu-octreotate radiopeptide therapy in a total of over 500 patients with GEP-NETs report response rates of almost 50%.[2] However, no multicentre randomised controlled trials have been published.

Small clinical trials in Australasia using therapeutic activities of the primarily diagnostic agent 111In-octreotide (Octreoscan®) showed some stabilisation of progressive metastatic NETs, but the response was relatively short-lived and the agent expensive.[3] The therapeutic use of 111In-octreotide is now restricted to highly selected patients with predominant NET bone marrow infiltration.

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Lutetium-177 octreotate radiopeptide therapy of GEP-NETS

The preferred radiopharmaceutical for radiopeptide therapy at the time of writing is 177Lu-octreotate. The major Australian clinical experience with 177Lu-octreotate to date comprises approximately 200 GEP-NET patients treated at Peter MacCallum Cancer Centre, Melbourne and Fremantle Hospital, Perth since 2005. Experience at these centres is consistent with outcomes of the large retrospective series from Europe. The major obstacle to the wider availability of 177Lu-octreotate is lack of an established path for formal registration and funding of what is effectively a clinician-sponsored therapy for an orphan disease.

If the funding issues can be resolved, it is envisaged that this treatment will be available in approximately six designated reference centres across Australia. It is planned that patients with progressive, disseminated, unresectable, low grade GEP-NETs, with appropriate somatostatin receptor avidity demonstrated on diagnostic somatostatin receptor imaging, including 111In-Octreotide SPECT or 68Ga-somatostatin analogue PET studies, will be referred to the State reference centre for radiopeptide treatment. 177LuCl3 is commercially available to Australasian patients directly imported from Europe (IDB, Baarle-Nassau, NL). It is hoped that 177Lu-octreotate may become available through the Australian Nuclear Science and Technology Organisation (ANSTO). The use of identified reference centres will facilitate both gathering of data and national randomised controlled trials using 177Lu-octreotate, with or without radiosensitising chemotherapy.

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Alternative radionuclides for therapy

In NETs not expressing sst2 – receptors, or where radiolabelled octreotide analogues are unavailable, alternative radionuclide therapeutic approaches may be considered. These include palliative treatment with 131I-MIBG therapy, usually reserved for neural crest NETs such as phaeochromocytoma, paraganglioma and neuroblastoma.[4]

If somatostatin receptor-negative GEP-NET metastases are limited to liver, then hepatic arterial administration of 90Y-SIRspheres® may be contemplated.[5] However, the potential interaction between hepatocellular toxicities due to ischaemia (due to vascular occlusion) and radiation has not been studied.

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Toxicity of 177Lu-octreotate

The toxicity of 177Lu-octreotate radiopeptide therapy is modest, generally being limited to mild, transient myelosuppression, nausea, transient flare in tumour hormonal activity, and transient reduction in male fertility. Radiation hepatitis is infrequently seen, usually in patients with diffuse extensive hepatic involvement.[2][6] Nephrotoxicity is reduced by concomitant amino acid infusion to decrease renal uptake of the radiopeptide. The addition of radiosensitising chemotherapy to standard dose 177Lu-octreotate, such as 5FU[7] or capecitabine[8] does not appear to increase the toxicity of radiopeptide monotherapy.

The standard course of 4 cycles of approximately 8GBq 177Lu-octreotate at 6–10 weekly intervals may be repeated, in selected patients, at least once for maintenance or consolidation therapy of residual disease after initial response. Safety and efficacy data on this approach is being collected. Whilst cure of GEP-NETs by radiopeptide therapy is unlikely, treatment with 177Lu-octreotate appears to be effective in controlling the disease and reducing symptoms related to hormonal effects of NET. Although more than a minor response by traditional imaging criteria to radiopeptide treatment is relatively uncommon, 177Lu-octreotate is effective in stabilising previously progressive disease in the majority of patients, without hospitalisation or impairment of quality of life.[6] Multi-modality radiopeptide therapy has the potential to improve objective response rates of GEP NETS.[8]

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Patient selection

Optimal selection of patients for 177Lu-octreotate radiopeptide therapy will be facilitated through referral to NET multidisciplinary teams established in each state. A prerequisite is the need to demonstrate that known tumour sites have sufficient uptake of diagnostic 111In-Octreotide or 68Ga-labelled somatostatin analogues, to indicate that therapeutic levels of internal radiation could be potentially delivered by administration of 177Lu-octreotate radiopeptide therapy. This is traditionally assessed qualitatively and considered adequate if lesion uptake is of greater intensity than that of normal liver. Other selection criteria include disseminated, histopathologically proven, relatively well differentiated NET with Ki-67 score <10%, which has been deemed by a specialist surgeon to be unresectable, and documented to be progressive either clinically or on serial imaging. In general, radiopeptide therapy is more effective if given at an early stage of disease progression, rather than being considered as an end-stage salvage therapy. Debulking prior to therapy may be recommended, as the efficacy of 177Lu-octreotate is potentially compromised by large disease burden. Large lesions act as a sink for the administered radiopeptide activity, limiting bioavailability and therefore reducing dose to smaller lesions. Dosimetric models also suggest that radiation dose delivery to large lesions is less efficient than to smaller lesions. Furthermore, poor vascularity, hypoxia and internal fibrosis may limit the radiobiological response of large tumour masses.

Given that standard chemotherapy has not been shown to be of significant benefit in control of disseminated progressive well-differentiated NET,[9] prior chemotherapy is not a pre-requisite for radiopeptide therapy. If first-line chemotherapy is deemed appropriate (for example, where Ki-67 is >10% despite good uptake of 111In-Octreotide or 68Ga-somatostatin analogue) then to avoid cumulative myelotoxicity, an interval of at least 8 weeks is required before administration of 177Lu-octreotate radiopeptide therapy. The decision regarding the regimen and timing of chemotherapy in relationship to radiopeptide therapy should be performed in a multidisciplinary environment and can be guided by 18F-FDG PET/CT scanning.

Symptomatic GEP-NET patients are likely to be on somatostatin analogue medication. In addition to symptom control in patients on regular receptor-targeted therapy there is anecdotal evidence of infrequent (1-2%) response to such treatment.[10] Long-acting somatostatin analogues [such as Sandostatin LAR® (Novartis) and Somatuline Autogel® (Ipsen)] therapy may be continued in patients undergoing radiopeptide therapy, but they should be ceased at least six weeks prior, to each dose of 177Lu-octreotate therapy to allow return of receptor binding and provide effective irradiation of the tumour. Soluble short-acting octreotide injections may be used to provide symptomatic control in patients with debilitating symptoms, such as profound hypoglycaemia consequent on functioning insulinoma or severe carcinoid syndrome up to 12 hours or in extreme cases up to a minimum of 6 hours prior to 177Lu-octreotate administration.

If symptoms prevent interruption of synthetic somatostatin analogues for these periods, imaging studies should be performed to demonstrate the likelihood of satisfactory targeting of therapeutic radiopharmaceutical at practically achievable timepoints.

Currently, treatment with radiolabeled somatostatin analogues is not considered curative in patients with metastatic disease. Patients with clinically symptomatic residual disease following surgical debulking can reasonably be offered radiopeptide therapy. However, in the absence of symptoms or progressive disease, such treatment should only be offered in the setting of a clinical trial.[7][8][11]

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Monitoring of response

Radiopeptide therapy currently comprises 4 cycles of 8 GBq 177Lu-octreotate at intervals of 6–8 weeks, and definitive objective response is determined 6 months after completion, since reduction in tumour size is characteristically delayed. Monitoring of response should be performed according to established research protocols at the designated radiopeptide therapy referral centre. At baseline, mid-course, end of course and at 6 months after radiopeptide therapy, CT or MRI studies, employing identical protocols are mandated for documentation of objective response by RECIST criteria with potential quantitation on functional MRI using DWI/ADC measurements. 68Ga-octreotate PET/CT follow-up combines evaluation of metabolic and objective response and is highly recommended.

  1. Metabolic response is defined by comparative 177Lu-octreotate tumour uptake on referenced 24 hour scintiscans after each therapy administration.
  2. Objective response is defined by RECIST criteria on standardised CT or MR studies at 3–6 month intervals.
  3. Biochemical response is defined by serial chromogranin A titre, preferably with urinary 5HIAA levels (observing appropriate dietary restrictions). This should be performed at approximately 3-monthly intervals.
  4. Symptomatic (clinical) response is defined on standardised QOL EORTC QLQ C-30 version 3 instruments as appropriate for NET tumours (EORTC QLQ-G.I. NET21).
  5. Adverse events are identified on standard instruments (CTCAE version 2 or 3).


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Access to radiopeptide therapy in Australia and New Zealand

It is currently anticipated that 177Lu-octreotate radiopeptide therapy of GEP-NETs will be made available to patients throughout Australia on research protocols at designated regional referral centres as described above. Compassionate use programs may continue to be offered for patients failing to fulfil eligibility criteria for clinical trials or electing not to enter such a trial.

Lutetium-177 octreotate is not available in New Zealand but it is accessible in Australian centres if a patient is willing to self-fund the treatment or as a part of a compassionate use program.

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Conclusion

It is recommended that referral of GEP-NET patients for radiopeptide therapy be facilitated through consultation at NET multidisciplinary team meetings to establish appropriate indications for radiopeptide therapy of GEP-NETs and to define outcomes in the Australian patient population.

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References

  1. Klöppel G, Couvelard A, Perren A, Komminoth P, McNicol A, Nilsson O, et. al. ENETs guidelines for the standards of care in patients with neuroendocrine tumors: Towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Germany: Neuroendocrinology; 2008 [cited 2014 Jun 12]. Report No.: 90:162–166. Available from: http://www.enets.org/d.f.50.pdf.
  2. 2.0 2.1 Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008 May 1;26(13):2124-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18445841.
  3. Hubble DJ, Johnson V, Ramdave S, Hicks RJ. Safety of therapeutic Lu-177 octreotate (LuTate) administration in patients previously treated with high-dose In-111 octreotide (HD-Oc) for neuroendocrine tumour (NET). Internal Medicine Journal 2008 [cited 2014 Jun 12];38(Suppl 3):A50.
  4. Dittmann H, Brendle J, Dietz K, Bares R. Treatment of advanced neuroendocrine tumors (NET) with Iodine-131-mIBG or Yttrium-90-DOTATOC – Results and side effects. J Nucl Med 2014 Jun 12 [cited 2014 Jun 12];48 (Supplement 2):393P Abstract available at http://jnumedmtg.snmjournals.org/cgi/content/short/48/MeetingAbstracts_2/393P-c.
  5. King J, Quinn R, Glenn DM, Janssen J, Tong D, Liaw W, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer 2008 Sep 1;113(5):921-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18618495.
  6. 6.0 6.1 Claringbold PG, Brayshaw PA, Krenning EP, Kwekkeboom DJ, Turner JH. Radiopeptide control of endocrine cancer: A Phase IIA study of 177Lu-octreotate/ capecitabine therapy of disseminated neuroendocrine tumours. Stockholm: Abstract Annal Oncol European Society for Medical Oncology (ESMO); 2008 [cited 2014 Jun 12].
  7. 7.0 7.1 Kong G, Johnston V, Ramdave S, Lau E, Rischin D, Hicks RJ. High-administered activity In-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience. Cancer Biother Radiopharm 2009 Oct;24(5):527-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19877882.
  8. 8.0 8.1 8.2 Claringbold PG, Brayshaw PA, Price RA, Turner JH. Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2011 Feb;38(2):302-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21052661.
  9. Delaunoit T, Ducreux M, Boige V, Dromain C, Sabourin JC, Duvillard P, et al. The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option? Eur J Cancer 2004 Mar;40(4):515-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14962717.
  10. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009 Oct 1;27(28):4656-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19704057.
  11. Hubble D, Kong G, Michael M, Johnson V, Ramdave S, Hicks RJ. 177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide. Eur J Nucl Med Mol Imaging 2010 Oct;37(10):1869-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20445977.


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