ASCO (American Society of Clinical Oncology) is one of the biggest cancer conferences in the world normally bringing together more than 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field. As Neuroendorine Tumors is on a roll in terms of new treatments and continued research, we appear to be well represented with over 20 ‘extracts’ submitted for review and display. This is fairly complex stuff but much of it will be familiar to many. I’ve filtered and extracted all the Neuroendocrine stuff into one list providing you with an easy to peruse table of contents, complete with relevant linkages if you need to read more. For many the extract title and conclusion will be sufficiently educational or at least prompt you to click the link to investigate further. Remember, these are extracts so do not contain all the details of the research or study. However, some are linked to bigger trials and linkages are shown where relevant. I’ve also linked to some of my blog posts to add context and detail.
I’m hoping to capture any presentations or other output from the meeting which appears to be relevant and this will follow after the meeting. I will also be actively tweeting any output from the live event (for many cancers, not just NETs).
There’s something for everyone here – I hope it’s useful.
Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.
Check out my recent blog discussing ‘Theranostic pairing” – click here
Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.
Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910
Conclusions: A pre-PRRT analysis of circulating NET genes, the predictive quotient index comprising “omic” analysis and grading, is validated to predict the efficacy of PRRT therapy in GEP and lung NETs.
Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.
Conclusions: This is the first multi-center study in Mexico. Which reflects the clinical characteristics of the NET_GET. The results differ in their epidemiology from that reported in other countries. However, the clinical and therapeutic results are very similar.
Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496
Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348
Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930
Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.
Conclusions: In this poor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.
Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients.
Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patient medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.
Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be considered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.
Conclusions: To the best of our knowledge, this is the first population-based study to examine potentially relevant pre-existing symptoms, resource utilization and healthcare costs before NET diagnosis. NET patients were more likely to have certain conditions and incurred higher resource utilizations and costs in the year preceding diagnosis of NET.
Conclusions: This population-based study showed that elderly NET pts have significantly different prevalence of co-morbidities compared to non-cancer controls. The impact of these conditions on survival and therapeutic decisions is being evaluated.
Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary. | 2017 ASCO Annual Meeting Abstracts
Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).
Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.
Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( > 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.
Check out my blog post on Gradingwhich has incorporated latest thinking in revised grade 3 classification
Seung Tae Kim
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists 68Ga-OPS202 and 177Lu-OPS201.
Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of 68Ga-OPS202/177Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737
Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.
Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.
I recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.
In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.
OncLive: Please highlight some of the main points from your presentation.
Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.
Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.
OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?
Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.
The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.
The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.
OncLive: Are we getting better at diagnosing and managing the treatment of NETs?
Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.
We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.
And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.
OncLive: With sequencing, what are the main questions that we’re still trying to answer?
Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.
For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.
OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?
Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.
OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?
Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.
See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf
Thanks for reading
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Please note a new syringe for Lanreotide will be available in 2019, at least in Ireland and UK which have confirmed dates (UK is end of June rollout begins). However, Ipsen are committed to roll it out to the rest of Europe, US, Canada, Australia and New Zealand by end of 2019 (details to follow) following necessary regulatory approvals.
Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside.
The new pre-filled syringe for Somatuline® Autogel® was the result of several studies, involving patients, their caregivers, nurses and other healthcare professionals, to inform and test enhancements to the existing pre-filled syringe. Notable new features are modified ergonomics and handling, a needle shield removal system, an injection process with plunger support and heightened ease of use. The automatic, built-in safety system, which helps to prevent needle stick injury by locking in place following the administration, has not been changed.
Please note that the medicine is still the same and the formulation and storage conditions have not changed.
The picture below is the new injection inside its protective case.
My Lanreotide Experience
When I was discharged from hospital following major surgery in Nov 2010, I knew I would shortly be commencing long-term monthly ‘somatostatin analogue’ treatment and had assumed Octreotide (Sandostatin LAR) would be the drug of choice. However, my Oncologist prescribed Lanreotide (known in the UK as Somatuline Autogel and elsewhere as Somatuline Depot). Technically this is a hormone therapy (it’s not chemo).
Somatostatin Analogues (Octreotide/Lanreotide) are mainstay treatments for many Neuroendocrine Cancer patients and their introduction is a very significant factor in the improvement of both prognostic outcomes and quality of life. Both drugs are designed to control Carcinoid Syndrome (but can be used selectively in other NET syndromes) and both have anti-tumour effects. Check out my Lanreotide vs Octreotide comparison blog.
Although I didn’t relish the thought of any injection in the ‘rear end’ every 28 days for the rest of my life, I admit to being slightly relieved with his choice. I had been reading about patient experiences with the alternative, mainly the needle length and the occasional problems mixing the drug prior to injection. Although Lanreotide has a similar gauge (thickness), the needle is a good bit shorter and is deep subcutaneous rather than Octreotide LAR’s intramuscular (IM) route. No mixing is required as Lanreotide comes prefilled.
If you’re interested in the science, please be aware that a somatostatin analogue is a synthetic (manufactured) version of a naturally occurring hormone which inhibits the peptides and amines that can be dangerously hypersecreted by certain neuroendocrine tumours.
Following an Octreotide Scan, various areas lit up confirming the output from previous CT scans. It also confirmed new ‘hotspots’ for further investigation. This specialist scan confirmed I probably had working receptors to receive something known as a Somatostatin Analogue to help with combatting the effects of Carcinoid Syndrome (please note that not having working receptors does not mean there is no benefit of receiving somatostatin analogues). I was therefore prescribed daily Octreotide (self-injecting) whilst I was waiting for my first major ‘debulking’ surgery, This treatment did eventually lessen the main effect of the carcinoid syndrome, facial flushing. It wasn’t until after my first surgery that the facial flushing was dramatically reduced. I commenced Lanreotide on 9 Dec 2010 and I haven’t had a facial flush since. It’s worth adding that my Chromogranin A (CgA) blood test (correlated to tumour mass) did not return to normal until after a liver resection 3 months later. My 5HIAA urine test results (mainly correlated to serotonin levels) returned to normal prior to liver surgery in Apr 2011 indicating the Lanreotide was doing its job! Somatostatin Analogue side effects are to be expected and most people seem to have different and/or greater or lesser effects than others. The daily Octreotide did not bother me too much other than some discolouring of the stomach at the injection sites (i.e. black and blue!) ….I’m more observant nowadays, so it’s possible I may not have recorded this experience properly.
If you read the UK patient leafletwhich comes with each injection, you can see a list of potential side effects as long as your arm. Neuroendocrine Cancer comes with many signs, syndromes, symptoms and suspicions, so I always advise caution and some analysis when assigning reasons for problems encountered. For North America, the equivalent instructions can be found here (Somatuline Depot). I don’t know precisely why (……. I do have my suspicions), but I’m always very sceptical about the criteria used to compile the list of side effects for any medicine. In my own mind, I’m fairly certain that people have existing symptoms or new symptoms as a result of coincidental treatment that are erroneously labelled under drugs during trials.
You can also self-inject Lanreotide but I’m not ready for that yet! If you do self inject, please note it the site is “the upper outer part of your thigh”. Check out the Ipsen leaflet here.
I think the injection site is very important and getting this wrong will worsen the side effects. For the Healthcare Professional or trained family member administration, the site should be the superior external quadrant but not of the whole ‘butt’, it means of the left or right buttock that is being used on an alternative basis. If nurses think the whole ‘butt’, they might be tempted to stick it quite close to the ‘intergluteal cleft’ – not advisable!
Although the patient leaflets are very clear on how to administer the drug, once the location is established, I always discuss the following with the Nurse before I receive the ‘dart’:
1. The injection should have been removed from the fridge at least 30 minutes before treatment. However, please note Ipsen clarified in 2019 that the product can be put back in the fridge in the original packaging for later use, provided it has been stored for no longer than 24 hours at below 40 deg C (104 deg F) and the number of ‘temperature excursions’ does not exceed three. If you are taking the drug somewhere to be administered or were waiting on a home visit, this might help with scheduling issues.
2. Don’t pinch the skin, stretch it.
3. Put the needle in fast at 90 degrees, inject the drug slow – 20 seconds is recommended. As the drug is viscous, in any case, there is normally some resistance to a fast release.
4. Do not rub or massage the area after as this action can interfere with the formulation of the drug. This is clearly stated on the drug information leaflet, i.e. ” Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding. Do not rub or massage the injection site after administration”.
My experience with side effects. People have different experiences with side effects and just because a particular side effect is mentioned, does not mean to say that everyone will be troubled – many patients experience little or none. For me, over 7 years, I think I can attribute the following to Lanreotide:
itching but only on the legs below the knees centred on the ankles – and nearly always the right leg. Occasionally, the injection site will itch but only for a day or two. I have a tub of emollient cream (almond oil) on standby which seems to calm it down. Note …… a little bit of me thinks there could be a connection with vitamin/mineral deficiency and perhaps a coincidental occurrence and this problem seems much less of an issue over 7 years later. EDIT- could have been Hypothyroidism – click here.
minor pain at the injection site but this only lasts for an hour or two and I believe this to be associated with the administration of the injection, i.e. if the injection is done properly, I don’t really have this problem except for a second or two as it enters. Once, I had pain for 10 days. In my own experience, the best and least painful injections are those done by trained personnel who are confident.
small lumps form at the injection site which is alternating superior external quadrant of the each buttock. You may occasionally hear these being called ‘granulomas‘ or ‘injection site granulomas’. The issue of ‘injection site granulomas’ seems to figure in both Lanreotide and Octreotide. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues. I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade. I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site. I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans. This is not a new problem and has been highlighted for the last 10 years in academic papers. This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here
fatigue normally within 24-48 hours of the injection but this is not consistent. Not even sure it can be classed as proper fatigue but it’s a ‘you need to sit down and fall asleep‘ feeling! When this occurs, it normally only lasts for 1 day before the normal energy levels return. Again, like the itching, this appears to be less of an issue today.
malabsorption. although the side effects of gastro-intestinal (GI) surgery and gallbladder removal can cause malabsorption issues leading to steatorrhea (basically the inability to digest fat properly); somatostatin analogues can cause or exacerbate existing steatorrhea, as they inhibit the production of digestive/pancreatic enzymes which aid fat digestion. Most months, I notice a marked but short-term increase in this problem normally within 48-72 hours of the injection.
elevated blood glucose. This is a new issue in 2018 but has been brewing for a year or two. The patient information leaflet for Lanreotide (and for Octreotide) clearly states that this is a potential side effect and also asks those who are already diabetic, to consult their doctor about monitoring doses of diabetic medicine. I’m working with my doctors to keep my blood glucose down to avoid becoming diabetic. Please read this article covering the connections between NETs and Diabetes
A few years ago, there was some ‘talk’ that somatostatin analogues were also able to stunt or reverse the growth of certain neuroendocrine tumours. Has this been the case for me? Possibly. I’ve had regular CT scans every 3-6 months and since two bouts of major surgery in 2010/2011, I’ve also had 3 x Octreoscans over the same period. I did once spend a day analysing 5 years of scan results looking for variations in size and concluded that there was a stable trend and potentially a fading of one or two of my largest liver tumours. I was reminded these two types of scans were not really precise enough to detect small millimetre increases or decreases and as there were other factors at play, there was little commitment to make this declaration. However, I did note in the summary of theCLARINETstudy, Lanreotide was associated with prolonged progression-free survival among patients with advanced, grade 1 or 2 (Ki-67 <10%) enteropancreatic, somatostatin receptor–positive neuroendocrine tumours with prior stable disease, irrespective of the hepatic tumour volume. In terms of its anti-proliferative effects, aninterim report from the CLARINET extension studysuggested longer-term Lanreotide treatment is well tolerated with ‘anti-tumour’ effects in patients with progressive disease. The final CLARINET open label extension studyreport additionally provided evidence for long-term PFS benefits of Lanreotide Autogel 120 mg in patients with indolent pancreatic and intestinal NETs.
There’s currently a trial ongoing in relation to Lanreotide and Lung NETs – read by clicking here.
I have my ups and downs and I do feel quite well most of the time. Most people tell me I look quite well too – lucky they can’t see my insides! Over the last 7 years, I’ve made some fairly significant adjustments to cope with my condition and maintain a reasonable quality of life – my monthly injection of Lanreotide is no doubt playing a big part.
Finally, please spend 5 minutes watching this fascinating video from Ipsen. It explains in easy terms how Lanreotide works. It also has a useful summary of the side effects at the end. Click here to watch the video.
I’ve just been enrolled onto a new service called HomeZone whereby the injection is now administered at my home via an Ipsen provided and funded nurse. Read here to see if you can also take advantage of this service.
In July 2018, I received my 100th injection of Somatuline Autogel (Lanreotide). I was very grateful to still be here so I thought it was worth a celebratory cake – injection themed!