We searched PubMed and the Cochrane Library databases and five conferences: American Society of Clinical Oncology (ASCO) annual meeting and ASCO Gastrointestinal Cancers Symposium, Endocrine Society (ENDO), European Neuroendocrine Tumor Society (ENETS), European Society for Medical Oncology (ESMO), and North American Neuroendocrine Tumor Society (NANETS). In supplementing our search, we also reviewed reference lists of records included for data abstraction and asked for article nominations from physician experts that were part of a NET treatment consensus panel[2].

We searched PubMed using the keywords and Medical Subject Headings terms: “neuroendocrine tumors”, “carcinoid tumor”, and “carcinoma, neuroendocrine”, and “octreotide”. Our search was limited to human subjects and studies published from 1998 to present. The search year limit of “1998” was imposed based on octreotide acetate LAR (Sandostatin LAR) original approval date (http://www.accessdata.fda.gov/). In addition to the terms used in the PubMed search, the Cochrane Library was also searched using word combinations of “octreotide” and limited to Cochrane Reviews and Protocols. Conference abstracts were searched using an expanded version of search terms listed above: neuroendocrine tumor, neuroendocrine tumour(s), neuroendocrine carcinoma(s), carcinoid tumor(s), carcinoid tumour(s), carcinoid syndrome, octreotide, and sandostatin. The conference search was limited to studies in human subjects and published in 2000 or later.

Identified articles were screened in three phases, article title and abstract review, first full article review, and second full article review, and conference abstracts in one phase. Articles were advanced to the next phase of screening only if they met the screening criteria or if it was unclear if they met the screening criteria in the prior screening phase. The first and second screening phases were done by a single reviewer and the third by two reviewers. In the first phase, titles and abstracts of identified studies were screened for data in human subjects on the drug (octreotide-LAR) and condition (neuroendocrine tumors) of interest. If an article that passed this screening phase was not in English, it was translated and moved to phase two (first full article review). In phase two, studies were screened for use of octreotide acetate LAR at doses > 30 mg/4 wk. In phase three, an article was excluded if an outcome of interest (efficacy, safety, and/or expert clinical opinion) was not reported or if the article was a case report, since case reports present data on too few patients to be able to draw any generalizable conclusions. Conference abstracts were screened by a single reviewer in one phase. Studies that passed the screening were abstracted. All screening and abstraction of the identified studies was done using specialized software[5].

The outcomes of interest included reports of efficacy/effectiveness and safety surrounding the use of octreotide-LAR at doses higher than 30 mg or administered at a frequency greater than 4 wk. We also reviewed expert clinical opinion statements surrounding the use of above-label use of octreotide-LAR. Measures of efficacy included symptom burden, disease markers, tumor response, time to progression of disease, requirements for additional intervention, and survival. Measures of safety included frequency of various adverse effects.

The weighted Kappa inter-rater reliability was calculated between the two reviewers at the screening phase using an independently-screened sample of articles, considering that a Kappa value ranging from 0.81 to 0.99 is interpreted to indicate “almost perfect agreement”[6]. After determining that the inter-rater reliability was high (i.e., > 0.81)[6], the remaining articles were divided between the two reviewers. Data were also first independently extracted from a sample of accepted articles by the two reviewers, and any resultant inconsistencies were discussed. The remaining articles were then split up between the two reviewers to finalize data extraction. Further accuracy of data abstraction was assured by ongoing consultation between the reviewers and the research team, such that ambiguities were resolved via consensus. The Oxford’s Centre for Evidence-based Medicine Levels of Evidence (OCEBM) was used to assign a quality of evidence grade of 1 to 5 to each included study, with 1 indicated a study with the strongest scientific basis for support of conclusions and 5 the weakest (e.g., expert opinion)[7].

The PubMed and the Cochrane Library databases searches, conducted on 12/9/12, yielded 705 articles: 692 were identified in PubMed, 13 in the Cochrane Library database, and 3 more provided by experts (Figure 1). A search of conferences resulted in 116 abstracts identified from the ASCO meetings (87 from 2000-2012 annual meetings; 29 from 2004-2013 Gastrointestinal Cancers Symposiums), 83 from 2000- 2012 ENDO meetings, 92 from 2004, 2006, 2009- 2012 ENETS meetings, 29 from 2000 and 2002-2012 ESMO meetings, and 54 from 2008-2012 NANETS meetings. An update to the search was conducted in June 2013 to identify articles in the ASCO 2013 meeting, which resulted in 4 more abstracts. A total of 708 articles and 378 conference abstracts were screened.

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Figure 1 Record search and screening flow chart. ¹Phase I: Title and abstract screen of all identified records through database search; screens for records that contain: octreotide LAR, neuroendocrine tumors, and human subjects. ²Duplicates include duplicate abstracts presented at different conferences and data reported in full-length articles included in this review. ³Phase II: Full-text screen of those records that passed phase I; screens for records containing use of octreotide LAR of doses greater than 30 mg/4 wk. ⁴Phase III: Full-text screen of those records that passed phase II; screen for records containing safety and effectiveness outcomes, and exclude records that are case reports. ⁵Two of the 10 included articles reported data on the same patients, hence only the most recent study (Woltering 2006) was retained in this review. American Society of Clinical Oncology (ASCO), Endocrine Society (ENDO), European Neuroendocrine Tumor Society (ENETS), European Society for Medical Oncology (ESMO), and North American Neuroendocrine Tumor Society (NANETS).

In the first phase of screening, 848 of 1086 records were excluded from further screening (Figure 1). Twenty articles were translated before phase two (2 from Spanish, 6 from Italian, 4 from Japanese, 1 from French, 6 from Hungarian, and 1 from Danish). In phase two, 205 of 230 full-length articles were excluded due to lack of data on the use of octreotide acetate LAR at doses > 30 mg/mo. In the final phase, 15 of 33 additional articles (10 did not discuss outcomes of interest and 5 were case reports) were excluded. Bibliographies of the 10 accepted full-length articles were screened for additional studies of interest but no additional studies were identified. Eight of the 378 identified abstracts passed the screening and were abstracted. The weighted kappa for the two reviewers was 0.94[6]. During abstraction, it was determined that 2 of the 10 included articles reported data on the same patients, hence only the most relevant and recent of the two studies (Woltering 2006), which reported data on outcomes of interest, was retained in this review.

The review consisted of 17 studies, including 8 conference abstracts and 9 articles (Table 1). Four were clinical studies, one was a report of a modified Delphi process[2], one was a systematic review[21], two were non-systematic reviews[8,9] and one was a letter to the editor[10]. Seven conference abstracts reported on clinical studies and one a randomized phase III trial. Eight studies were performed in the United States, two in Italy, one in both the United States and Europe, and the location for the remaining 6 was not reported. Ten studies considered efficacy, 8 addressed safety, and eight provided expert clinical opinion. OCEBM grades ranged from 2b to 5, with 9 studies out of 17 scoring 4 or 5.

The efficacy of high dose octreotide-LAR was reported in 10 studies, of which 4 were full-length articles[11-20] (Table 2). Doses studied ranged from a minimum of either 40 mg per month or 30 mg per 3 wk up to a maximum of 120 mg per month. The studies describe over 260 subjects who received increased doses of octreotide-LAR (the exact number cannot be stated with certainty, as some studies did not report the number of patients treated with above-label doses and grouped them with other patients).

Chadha et al[12] retrospectively studied high dose octreotide-LAR used to treat 30 patients with GEP-NETs. Compared to 24 subjects receiving conventional dose octreotide-LAR therapy, there was a trend (P = 0.12) toward increased time before further treatment intervention was required in this group but no effect on survival (P = 0.48). Ferolla[14] was the only prospective trial of high dose octreotide-LAR, examining the effect of 30 mg every 3 wk on tumor progression, serum markers and symptoms. The comparator group was historical and consisted of the same subjects receiving octreotide-LAR 30 mg/mo. Control of symptoms was seen with increased dose of octreotide-LAR, with 40% noting normalization and 60% noting control of symptoms (flushing, diarrhea, and bronchospasm). The time to tumor progression and the time to biochemical progression (increase in serum CGA, serum gastrin and/or urinary 5-HIAA) were both significantly delayed (P < 0.01). The study reported that “weakness and well-being improved in all patients” but a specific tool for measuring quality of life was not described. One of the larger studies[11] reported physician practice patterns in medical management of 392 patients with NETs. Data were reported by doses delivered rather than by patients treated, so it was not possible to compare this study to the other studies of efficacy that used more standard methodology. Tumor responses to doses of octreotide-LAR 20 and 30 mg were similar to those at doses of 40 and 60 mg. Woltering[20] examined whether CgA levels correlated with octreotide-LAR dose and symptoms in 40 patients with carcinoid syndrome, and determined that CgA levels were similar for those receiving octreotide-LAR 20 mg, 30 mg or 60 mg/mo.

Six conference abstracts reported efficacy of high dose octreotide-LAR[13,15-19]. Costa[13] analyzed characteristics and clinical outcomes in patients with progressive metastatic NETs treated with octreotide-LAR. The authors noted that “after evidence of objective progressive disease in liver, a second response with disease stabilization was achieved with octreotide dosage increase from 30 mg to 40 mg every 4 wk” in two subjects that received high dose octreotide-LAR. Koumarianou[15] studied efficacy of octreotide-LAR (30 mg/3 wk) combination therapy in 13 subjects with NETs. There was no comparator group. Disease remained stable in 25% (3/12) and 75% showed over > 50% reduction in tumor size. The median progression free survival in evaluable patients was 24.6 wk. Markovich[16] studied the efficacy of long acting octreotide (including octreotide-LAR, Octreotide-Depot and Octreotide-LONG) 30-40 mg/mo in heavily pretreated patients with disseminated NETs. Subjects (n = 29) initially received long-acting octreotide 20 mg/mo and the dose was escalated to 30 mg/mo (n = 18) or 40 mg/mo (n = 13). The reason for dose escalation was disease progression in 19 and lack of symptom control in 12. Those receiving long-acting octreotide alone (n = 14) did not have a response. However, tumor growth was controlled in 25 subjects (80.7%). Median time to progression in the total group was 18 mo. The report did not indicate what percentage of subjects specifically received octreotide-LAR vs other forms of long acting octreotide. Valle et al[17] determined patient acceptability and control of carcinoid-related symptoms in 8 patients receiving octreotide-LAR, two of which started on high dose. Three subjects required dose escalation to high dose octreotide-LAR to control symptoms. Valle et al[17] reported “patients who required continued dose-escalation of Sandostatin LAR showed evidence of increased urinary 5-HIAA suggesting increased disease activity.” Weber et al[18] determined the frequency of “above-label” octreotide-LAR dosing and outcomes. Of 337 subjects treated with octreotide-LAR for metastatic NETs at a single tertiary care institution, 99 (27%) received high dose. The indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression (33 patients), and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, flushing improved in 56% and diarrhea improved in 62%. Finally, a randomized phase III clinical trial by Wolin et al[19] showed that treatment with octreotide-LAR to 40 mg/4 wk led to better control of diarrhea and flushing at 6 mo after starting treatment. Progression free survival was 6.8 mo. The comparator arm in this trial was a novel long-acting somatostatin analog (pasireotide-LAR 60 mg/4 wk), which showed a longer progression free survival (11.8 mo).

Considering these studies together, there is a trend supporting the use of octreotide-LAR at above-label doses to control symptoms and tumor progression.

The safety of high dose octreotide-LAR was reported in 8 studies[11,12,14-17,19,21] (Table 3). There was no increased toxicity compared to conventional dose therapy reported in 3 of the studies that examined safety[12,17,21]. Wolin et al[19] compared octreotide-LAR treatment arm to patients using pasireotide-LAR, and showed the two arms have a similar safety profile (diarrhea: 7% vs 9%; abdominal pain: 9% vs 2%) except for the higher frequency of hyperglycemia (0% vs 11%) in the pasireotide group, and 4 (7%) and 7 (13%) patients that discontinued due to adverse events. Overall, our review shows that adverse events were not well described. This may be because octreotide-LAR has a favorable safety profile and that modest increases in the dose may not lead to significant increases in toxicity, or because the studies were too small to identify rare events.

Expert clinical opinions were reported in 8 articles[2,8-10,12,13,22,23] (Table 4). Both Oberg et al[9] and Strosberg et al[2] supported the idea of increasing octreotide-LAR dose up to 60 mg/mo for control of symptoms. Chadha et al[12], Colao et al[8], and Costa et al[13] further suggested that increased doses of octreotide-LAR may be effective for tumor progression. Strosberg et al[22] reported above-label dosing of octreotide-LAR is common in NCCN institutions, and the primary indication is refractory carcinoid syndrome. Yao et al[10] cautioned that until there are appropriate studies (i.e., randomized controlled trials) completed, escalating doses of octreotide-LAR should be done only for control of symptoms. Xu et al[23] reported that a substantial number of patients in this study required doses greater than the FDA approved dose of 30 mg/mo. Overall, our review indicated that clinical experts support dose escalation of octreotide-LAR.

The strength of this review lies in its comprehensive search, review, and synthesis of global literature on above the FDA-approved label dosage and frequency of administration of octreotide-LAR in patients with NETs. This study also has limitations. The data on symptom improvement are limited by lack of quantitative measurements of symptom severity and absence of formal quality of life analysis. Nine of the 17 included studies were retrospective, and retrospective studies may be subject to recall and reporting biases. The only prospective trial reporting efficacy data in a full-length article[14] used historical controls, which may limit estimation of effects. Wolin et al[19] reported on a randomized clinical trial of pasireotide-LAR (comparator arm) vs octreotide-LAR 40 mg/28 d. However, this trial did not assess other doses of octreotide-LAR. The studies included in this review varied in design, patient population, octreotide-LAR regimens, and definitions of outcomes, and the data were reported in several ways across the reviewed studies. Thus, the heterogeneity of these data made it difficult to compare directly between studies and prevented us from conducting a meta-analysis. OCEBM grades ranged from 2b to 5, with 9 studies out of 17 scoring 4 or 5, indicating a relatively low quality of evidence (grade C)[7]. Of the 10 studies that reported data on efficacy and of the 8 that reported data on safety, 5 and 4 were small (< 100 patients) retrospective studies, respectively. Finally, in this study, we were unable to assess separately the effects of octreotide-LAR co-therapy vs monotherapy on safety and efficacy outcomes given the limited data for co-therapy in this review.

Future research efforts should focus on establishing efficacy and safety of prescribing octreotide-LAR at doses higher than the FDA-approved 30 mg/mo for management of neuroendocrine tumors using generalizable randomized controlled trial study designs. Studies comparing the safety of octreotide-LAR in patients treated with doses < 30 mg/mo vs those treated with above-label regimens of octreotide-LAR are also warranted.

In conclusion, this systematic literature review suggests that above-label doses of octreotide-LAR are being used frequently for the management of NETs in clinical practice and excess toxicity has not been observed in the reviewed studies. In most articles reviewed, above-label octreotide-LAR appears to be prescribed in patients with disease progression or uncontrolled symptoms while on standard dose therapy. Expert clinical opinion, as reported in this review, supports escalation of SSAs for patients with refractory hormonal symptoms. However, given limited published information on this topic, the safety and efficacy of above-label doses and/or frequency of octreotide-LAR in treatment of NETs warrants further evaluation.

Gastrointestinal neuroendocrine tumors (NETs) are rare and generally slow-growing neoplasms that secrete various peptides and neuroamines, some of which cause clinical symptoms. These tumors may be classified in multiple ways but are often divided into carcinoid tumors and pancreatic neuroendocrine tumors. First-line systemic therapy for NETs often consists of somatostatin analogs (SSAs) such as octreotide acetate or lanreotide.

The maximum Food And Drug Administration-approved dosage and administration of octreotide long-acting repeatable (LAR), indicated for severe diarrhea/flushing episodes associated with metastatic carcinoid tumors and VIPomas, is 30 mg every 4 wk. However, in clinical practice, octreotide-LAR is sometimes prescribed at above-label doses but evidence for this practice has not been systematically assessed.

This systematic literature review suggests that above-label doses of octreotide-LAR are being used frequently for the management of NETs in clinical practice and excess toxicity was not observed in the reviewed studies. In most articles reviewed, above-label octreotide-LAR appears to be prescribed in patients with disease progression or uncontrolled symptoms while on standard dose therapy. Expert clinical opinion, as reported in this review, supports escalation of SSAs for patients with refractory hormonal symptoms. However, given limited published information on this topic, the safety and efficacy of above-label doses and/or frequency of octreotide-LAR in treatment of NETs warrants further evaluation.

The strength of this study lies in its comprehensive search, review, and synthesis of global literature on above the FDA-approved label dosage and frequency of administration of octreotide-LAR in patients with NETs. Thus, the findings summarized in this review may inform clinicians who manage patients with NETs and motivate future research in this field.

This is an informative, well conducted and documented review about a focused topic on the use of above-label doses of octreotide-LAR in patients with NETs.