Abstract
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, increases progression-free survival in patients with advanced neuroendocrine tumours. Patients with neuroendocrine tumours and symptomatic carcinoid have inferior health-related quality of life than those without symptoms. We aimed to evaluate the effect of everolimus on symptomatic control of neuroendocrine tumours. Fifteen patients with metastatic neuroendocrine disease pre-treated with depot octreotide received combination everolimus and octreotide (midgut = 8, pancreatic = 3, other = 4). Reasons for initiation of everolimus were progressive disease (PD) by response evaluation criteria in solid tumours (n = 5), worsening syndromic symptomology (n = 5), or both (n = 5). Symptomatic and objective response and toxicity were evaluated using standard criteria. 7/10 patients who were syndromic had improvements in symptomology, with a mean duration of symptom control 13.9 months (range 1–39). All 10 symptomatic patients had non pancreatic neuroendocrine (pNET) primaries, and with everolimus, 6/10 had reduced stool frequency, 3/7 had a reduction of asthenia, and 5/7 had reduced frequency and severity of flushing. Sixty percent of patients experienced any grade toxicities, including the following: 40 % grade 1/2 stomatitis, 7 % grade 3/4 stomatitis, 20 % grade 1/2 rash, 13 % diarrhoea, and one case of pneumonitis. In this cohort of 15 patients, we demonstrated that 70 % of non pNET individuals with common carcinoid syndrome symptoms resistant to depot octreotide had improvement in these symptoms on institution of everolimus, with meaningful durations of symptom control. Although this data is observational, to our knowledge, this represents the largest analysis of carcinoid syndrome control with combined everolimus and octreotide.
Keywords: Octreotide, Neuroendocrine Tumour, Everolimus, Symptom Control, Lanreotide
Introduction
The past two decades has seen an increase in the incidence and prevalence of malignant neuroendocrine tumours (NETs), with American data showing 1.09 cases per 100,000 in 1973, increasing to 5.25 per 100,000 in 2004 [1], the increase likely being secondary to improved diagnostic techniques and physician awareness. Carcinoid tumours and pancreatic neuroendocrine tumours (pNET) are commonly classified by site of primary origin: foregut (including lung and pancreas), midgut, and hindgut [2].
Having a neuroendocrine tumour has a negative impact on quality of life. Scandinavian and American data which non-specifically analysed patients either with “gastrointestinal” [3] or all cause primary NETs [4, 5] has shown an inferior health-related quality of life in patients with NETs, and this was more marked in patients with NETs plus carcinoid syndrome than those with NETs and no carcinoid syndrome due to the associated symptoms [5]. For patients with incurable disease, a somatostatin analogue can be beneficial, and in those with midgut tumours, octreotide increases progression-free survival (PFS) and controls symptoms such as diarrhoea and flushing in approximately 33 and 70 % of patients, respectively [6]. Two year results of a broader study using lanreotide in the midgut, hindgut, or pancreatic tumours show a significant PFS benefit in using a somatostatin analogue in the lanreotide group versus the placebo group [7], and this statistically significant benefit was predominantly driven by response in the midgut patients, and to a lesser extent those with pNET tumours.
Incremental PFS benefit has been found in the additional use of everolimus to octreotide for NET’s. RADIANT 1 and 3 trials, both of which exclusively included patients with pNETs, showed a PFS benefit to treatment with combination therapy everolimus octreotide versus everolimus alone [8], and everolimus versus placebo (with somatostatin analogue in approximately 40 % patients) [9]. RADIANT 2 investigated patient with well or moderately differentiated non-pancreatic NETs and again showed a PFS benefit using everolimus plus octreotide rather than octreotide alone [10].
However, whilst everolimus plus octreotide has proven beneficial for PFS in NET patients, these trials have not addressed symptom control in NET patients. In acknowledging the burden of symptomatic disease in metastatic NETs, we have evaluated our experience of the effectiveness of everolimus in NETs, focusing on its role in both disease and symptom control.
Materials and Methods
Appropriate institutional approval was obtained for this study.
Patients
All patients suffering from NETs who were managed at our regional neuroendocrine unit and commenced on everolimus between April 2009 and September 2011 were considered for inclusion in this retrospective analysis, and were followed up until progression, death, or September 2014. All patients received pre-treatment depot octreotide, at a dose of 20 mg IM given every 4 weeks, but if this did not adequately control symptoms, the dose was titrated up to 30 mg IM given every 3 or 4 weeks and any other supportive medication necessary to try and help with symptoms. Patient demographics were evaluated and patients were clinically reviewed, examined, and assessed with routine blood tests on a monthly basis or more frequently if indicated.
Changes in symptoms were reported and documented in patient’s notes in the form of standard clinic letters during at least monthly clinical consultations. Not every clinic letter documented symptom severity, but changes in symptoms (flushing, diarrhoea, asthenia, pain, performance status, toxicities) were recorded. We devised a pro forma which enabled us to document and quantify a retrospective analysis of patients’ notes. Some physicians scored toxicities using the National Cancer Institute’s common terminology criteria for adverse events (CTCAE) version 3.0 scoring system in their standard letters, in which case we included these scores in our trial documentation, but others simply described the symptoms, in which case we retrospectively applied symptom/toxicity scores using CTCAE version 3.0.
As per our standard practice, triglyceride levels were taken at baseline and repeated every 8 weeks. Computed tomography (CT) scans were taken at baseline prior to treatment and repeated at least once every 3 months. Imaging was assessed using response evaluation criteria in solid tumours (RECIST). For the purpose of sub-classification, patients were classed as PD at baseline if they had radiological proof of PD on CT imaging within 2 months of commencing everolimus. Blood and imaging results were all recorded electronically at the time of testing, and results were freely available at the time of analysis.
Therapy
Everolimus (RAD001) was given at a starting dose of 10 mg as an oral once-a-day tablet. Dose reduction to 5 mg was made if clinically required.
All patients were pre-treated with Sandostatin LAR (octreotide acetate) at a variable dose pre treatment. Octreotide was continued concomitantly for the duration of treatment with everolimus.
Results
Included in the analysis were 15 patients: nine female, six male. Median age was 56.5 years (range 38–80 years). More than 70 % of patients had PS 0–1 and only one patient had PS = 3 (Table 1). Eight patients had tumours originating in the midgut, three had pNETs and four were ‘other’ (three lung and one disseminated disease of unknown primary). Prior to everolimus, five patients had previously received radionuclide therapy and one had required bronchial arterial chemo-embolisation for severe haemoptysis. Eight patients had previously had chemotherapy: all three pNET patients had received combination 5-flurouracil/ cisplatin/ streptozocin (FCiST) treatment; all 3 lung patients had been pre-treated (one with FCiST, the second with FCiST and then doxorubicin/cyclophosphamide/etoposide, and the third with gemcitabine/carboplatin followed by carboplatin/etoposide); of the two midgut previously treated chemotherapy patients, one had carboplatin/etoposide followed by gemcitabine/carboplatin and the second had FCiST followed by ECX (epirubicin/cyclophosphamide/capecitabine). The majority of patients (10/15) were commenced on everolimus for symptom control, and of these, five additionally had PD by RECIST criteria. One third of patients were commenced on everolimus for radiologically progressive disease without symptoms, and all patients with pancreatic NETs fell into this group. All patients started on everolimus for PD alone had a Ki67 ≥10 %, and all those commenced on treatment for symptoms alone had a Ki67 <5 %.
Table 1.
Clinico-pathological characteristics of 15 patients with metastatic neuroendocrine disease treated with Everolimus
| Patient characteristics (n = 15) | |||
|---|---|---|---|
| Number of patients | % | ||
| Age (years) | 36–45 | 3 | 20.0 |
| 46–55 | 4 | 26.7 | |
| 56–65 | 3 | 20.0 | |
| 66–75 | 4 | 26.7 | |
| 76–85 | 1 | 6.7 | |
| Gender | Male | 6 | 40.0 |
| Female | 9 | 60.0 | |
| Primary site | Midgut | 8 | 53.3 |
| PNET | 3 | 20.0 | |
| Other | 4 | 26.7 | |
| Ki67 | <1 % | 3 | 20.0 |
| 1–<10 % | 4 | 26.7 | |
| 10–20 % | 4 | 26.7 | |
| >20–<75 % | 0 | 0 | |
| >75 % | 2 | 13.3 | |
| ND | 2 | 13.3 | |
| Primary in situ | Yes | 9 | 60.0 |
| No | 6 | 40.0 | |
| Prior treatment | Octreotide (Sandostatin LAR) | 15 | 100.0 |
| Interferon alpha | 5 | 33.3 | |
| MIBG | 1 | 6.7 | |
| Yttrium DOTATOC octreotide | 4 | 26.7 | |
| Chemotherapy | 8 | 53.3 | |
| Chemo-embilisation | 1 | 6.7 | |
| Surgical debulking | 6 | 40.0 | |
| Indication for everolimus | (i) Progressive disease (PD) | 5 | 33.3 |
| (ii) Syndromic (S) | 5 | 33.3 | |
| Both i and ii (PD and S) | 5 | 33.3 | |
| ECOG performance status (PS) | 0 | 2 | 13.3 |
| 1 | 9 | 60.0 | |
| 2 | 3 | 20.0 | |
| 3 | 1 | 6.7 | |
ND no data, MIBG meta-iodobenzylguanidine
All patients were pre-treated with a somatostatin analogue prior to commencing everolimus. With the exception of two individuals, all patients with any form of symptomatic disease were on octreotide LAR at a dose of at least 30 mg IM every 4 weeks: one patient was also on a continuous IV infusion of octreotide, and had no benefit with 0.5 months of everolimus; and two symptomatic patients were on 20 mg octreotide and commenced everolimus within 2 months of starting octreotide. The two patients on lower dose octreotide had good symptomatic benefit with everolimus, so octreotide dose was not up-titrated. Only one non-symptomatic patient was on the higher dose of octreotide (30 mg), and on this dose, he was adequately symptom controlled.
In terms of radiological disease control, the majority of patients (4/5) put on everolimus due to PD without symptoms had pancreatic primaries and had rapidly progressive disease, with a mean time to progression of 1.2 months. The one exception to rapidly progressive disease was a 51-year-old male, ECOG performance status (PS) of 1 with a high proliferation fraction (Ki-67 20 %) metastatic pNET who was commenced on everolimus for PD alone and had stable disease for 10 months (Tables 2 and 3).
Table 2.
Objective response to everolimus by RECIST criteria by indication for treatment
| Response to everolimus (RECIST criteria) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Indication for everolimus and site of primary | Complete/partial response | Stable disease | Progressive disease or death | ||||||
| No. of patients (%) | Duration of response | No. of patients (%) | Duration of response | No. of patients (%) | Duration of response | ||||
| Mean no. of months | Range (months) | Mean no. of months | Range (months) | Mean no. of months | Range (months) | ||||
| PD (n = 5: PNET x3, 1x midgut, 1x foregut) | 0 (0) | – | – | 1 (20) | 10 | – | 4 (80) | 1.2 | 0.8–2 |
| S (n = 5:a 3x midgut, 1x foregut, 1x unknown) | 1 (20) | 39b | – | 2 (40) | 13.5 | 8–19 | 1 (20) | 2 | – |
| PD and S (n = 5: 4x midgut, 1x foregut) | 0 (0) | – | – | 4 (80) | 12 | 4–24 | 1 (20) | 1 | – |
| Total (n = 15)a | 1 (7) | 39b | – | 7 (47) | 12.1 | 4–24 | 6 (40) | 1.3 | 0.8–2 |
aOne patient not included in analysis, everolimus commenced just for symptom control and stopped after 0.5 months due to no effect, and repeat imaging not immediately done
bIndicates that at the time of analysis, one patient remains on everolimus with ongoing disease response by RECIST criteria
Table 3.
Objective response to everolimus by RECIST criteria by site of primary
| Response to everolimus (RECIST criteria) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Site of primary NET | Complete/partial response | Stable disease | Progressive disease or death | ||||||
| No. of patients (%) | Duration of response | No. of patients (%) | Duration of response | No. of patients (%) | Duration of response | ||||
| Mean no. of months | Range (months) | Mean no. of months | Range (months) | Mean no. of months | Range (months) | ||||
| Foregut (excl pancreas) (n = 3) | – | – | – | 1 (33) | 24 | – | 2 (67) | 1.5 | 1–2 |
| Pancreas (n = 3) | – | – | – | 1 (33) | 10 | – | 2 (67) | 0.9 | 0.8–1 |
| Midguta (n = 8) | – | – | – | 5 (63) | 10.2 | 4–19 | 2 (25) | 1 | – |
| Unknown (n = 1) | 1 (100) | 39 | – | – | – | – | – | – | |
| Total (n = 15)a | 1 (7) | 39b | – | 7 (47) | 12.1 | 4–24 | 6 (40) | 1.3 | 0.8–2 |
aOne patient not included in analysis, everolimus commenced just for symptom control and stopped after 0.5 months due to no effect, and repeat imaging not immediately done
bIndicates that at the time of analysis, one patient remains on everolimus with ongoing disease response by RECIST criteria
Patients (7/10) who were symptomatic had improvements in symptoms with an improvement duration range of 1 month to not reached (patient remains symptom controlled at 39 months), and with a current mean of 13.9 months (Table 4). The majority of symptomatic patients (7/10) had midgut primaries, and everolimus was particularly effective at controlling flushing and diarrhoea (Table 4). All patients with symptom-controlled disease for ≥2 months had a Ki67 ≤5 %. Of the four patients started on everolimus with a baseline PS or 2 or 3, two died within 2 months of commencing treatment due to PD, and of the other two (both commenced on everolimus for symptoms and not PD), one stopped treatment after 2 weeks as there was no symptomatic benefit, and the other had an improvement in symptoms for 8 months. With the exception of one patient (lung primary) commenced on everolimus for radiologically stable but symptomatic disease, who did get symptomatic benefit for 2/12 before radiological PD, and all other patients who symptomatically responded to everolimus also had either radiologically stable or responsive disease for the duration of their symptom control. The one patient who had radiological response by RECIST criteria (unknown primary with multi-focal bi-lobar liver metastasis at presentation and Ki67 <5 %), had the longest duration of symptom control (39 months and remains on treatment).
Table 4.
Type and duration of symptom control
| Diarrhoea (n = 10) | Flushing (n = 7) | Asthenia (n = 7) | ||||
|---|---|---|---|---|---|---|
| Site of primary and total no. of symptomatic pts | No. of symptom controlled pts/total no. of symptomatic patient in that group | Mean no. of months of symptom control (range) | No. of symptom controlled pts/total no. of symptomatic patient in that group | Mean no. of months of symptom control (range) | No. of symptom controlled pts/total no. of symptomatic patient in that group | Mean no. of months of symptom control (range) |
| Foregus (excl pancreas) (n = 2) | 2/2 | 11 (2–20) | 1/1 | 2 | 1/2 | 2 |
| Pancreas (n = 0) | N/A | N/A | N/A | N/A | N/A | N/A |
| Midguta (n = 7) | 3/7 | 9.3 (1–19) | 3/5 | 10.3 (4–19) | 2/6 | 13.5 (8–19) |
| Unknown (n = 1) | 1/1 | 39b | 1/1 | 39b | 0/0 | N/A |
| Total no. of symptom controlled patients (%) | 6/10 | 15.5 (1–39b) | 5/7 | 14.4 (2–39b) | 3/7 | 9.7 (2–19) |
bIndicates that at the time of analysis, one patient remains on everolimus with ongoing symptomatic response
Of the patients, 60 % experienced any grade toxicities; 40 % grade 1/2 stomatitis; 7 % grade 3/4 stomatitis; 20 % grade 1/2 rash; 13 % diarrhoea; and one case of pneumonitis (Table 5). In terms of grade 3 toxicities, one patient had grade 3 pneumonitis and stomatitis which resulted in him stopping everolimus after 1/12. His grade 3 toxicities were thought to have been exacerbated by concurrent use of diltiazem, a moderate CYP3A4 inhibitor. A dose reduction was offered to 6/15 patients (40 %) on everolimus. The indication for dose reduction was stomatitis in two patients, stomatitis and diarrhoea in two patients, skin rash with pruritis and diarrhoea in one patient, and significant peripheral oedema in one patient. All six patients had received a dose reduction by 4 weeks on everolimus.
Table 5.
Illustrating the prevalence and grade of toxicity with everolimus prior to any dose reduction
| Symptom | No. of patients with toxicity from everolimus (%) | |
|---|---|---|
| Toxicity grade 3 or 4 | All grade toxicity | |
| Stomatitis | 1 (6.7) | 7 (46.7) |
| Rash | 0 (0) | 3 (20.0) |
| Diarrhoea | 1 (6.7) | 2 (13.3) |
| Pneumonitis | 1 (6.7) | 1 (6.7) |
| Hypertriglyceridaemia | 0 (0) | 2 (13.3) |
| Overall toxicity rate | 3 (20) | 9 (60.0) |
Discussion
In this cohort of 15 patients, we have demonstrated that approximately 70 % of patients with common carcinoid syndrome had improvement in some or all symptoms on initiation of everolimus, with meaningful durations of symptom control. Patients with midgut tumours were the most symptomatic group, and for these patients, and those with lung or “unknown” primary, everolimus appears to be particularly effective at reducing flushing, a response that was seen in 60 % (3/5) of symptomatic midgut patients, and in both patients with flushing from either a lung or “unknown” primary. Good symptomatic response to everolimus in a midgut primary tumour has been previously documented in a single case report [11], but to our knowledge, this is the first case series to investigate and demonstrate meaningful symptom control in non pNET patients with everolimus-treated cacinoid syndrome. None of our patients with pNETs had symptoms, therefore we are unable to comment on symptom control with everolimus in this patient group. Correlation of duration of symptom control and baseline performance status shows that those with PS 0–1 have more durable symptom control as do patients with a Ki-67 ≤5 % in comparison to those with a higher PS, or Ki-67.
Our results for objective radiological response to everolimus in all patient categories (Tables 2 and 3) show lower mean response rates than would have been expected from the RADIANT studies, but in reality, our results are not directly comparable: our results reflect the practice of an unselected group of patients with an inferior spectrum PS than the RADIANT study participants (where more than 90 % of patients had a performance status of 0–1) [8–10]; and for the purpose of our analysis, all patients categorised in the “progressive disease” subcategory had radiological PD within 2 months of commencing treatment, rather than 12 months as per the RADIANT studies, as we felt this more accurately reflected local practice. Whilst our range of toxicities was not as great as that seen in larger trials, we did see a similar frequency of side effects, the most common being stomatitis and rash [9, 10].
There are a number of limitations of this research, including the retrospective collection of data from patient notes rather than questionnaires, and the small number of patients. Previous research documents that in up to 15 % of documentation, physicians can underestimate symptom severity, in comparison to when patients self-rate their symptoms [12], and physicians are not as reliable as questionnaires at picking up adverse effects and toxicities from treatment [13]. However, as we were analysing symptom change with intervention, any bias in symptom reporting would systematically be altered in all patients at all times (pre and post treatment). A further potential limitation was that octreotide dose was not standardised. For reasons previously explained, two of the symptomatic patients who benefitted from everolimus treatment were on 20 mg octreotide LAR given every 4 weeks rather than the standard PROMID dose of 30 mg [6].
Despite the limitations, this has been a worthwhile research which suggests the beneficial use of everolimus for durable symptom control, particularly in patients with midgut tumours, a Ki67 ≤5 %, and a good performance status. Through this work, we have highlighted and identified a number of additional issues, such as whether, if given to patients in the setting of radiologically stable, but symptomatic disease, everolimus increases patients’ overall survival or PFS as well as controlling symptoms. Although these tumours are rare, and data therefore challenging to collect, large, multicentre, blinded, prospective randomized trials with integrated patient self-reporting questionnaires would clearly be helpful. However, at present, we feel that the routine use of everolimus for symptom control of non pNET patients should be considered, and represents a potentially worthwhile treatment option for patients whose quality of life may well be otherwise impaired by debilitating symptoms.
Acknowledgments
Conflict of Interest
The authors declare that they have no competing interests.
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