|Year : 2015 | Volume
| Issue : 3 | Page : 359-362
Everolimus plus octreotide long-acting repeatable in advanced neuroendocrine tumors in the routine tertiary cancer care setting: An Indian experience
R Tippeswamy1, S Patil2, CT Sateesh2, HP Shashidhara3, S Prabhudesai3, P Prashanth4, KM Haridas4
1 Consultant Medical Oncologist, Shankara Cancer Centre, Bengaluru, Karnataka, India
2 HCG Hospital, Singasandra, Bengaluru, Karnataka, India
3 Consultant, HCG Hospital, Singasandra, Bengaluru, Karnataka, India
4 Clinical Pharmacologist, Singasandra, Bengaluru, Karnataka, India
|Date of Web Publication||18-Feb-2016|
HCG Hospital, Singasandra, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Neuroendocrine tumors (NETs) are rare, heterogeneous, indolent tumors that are relatively insensitive to systemic chemotherapy. Therapeutic strategies for NETs broadly include somatostatin analogs, antiangiogenic therapy, and most recently, mammalian target of rapamycin inhibition. Combination therapy has shown promising antitumor activity and good tolerability in the randomized phase III trials. Aim: The aim was to evaluate the safety and efficacy of Everolimus plus Octreotide long-acting repeatable (LAR) in patients with advanced NETs in the routine tertiary cancer care setting in India in this postapproval, noninterventional trial. Patients And Methods: Patients presenting to selected centers between 2011 and 2013 with histologically confirmed low-, intermediate- or high-grade advanced NETs who may have had prior exposure to cytotoxic chemotherapy (≤2 lines) were treated with oral Everolimus (10 mg/day) plus intramuscular Octreotide LAR (30 mg once every 28 days) until disease progression or unacceptable toxicity was seen. Patients were evaluated every 3 months for a response to therapy as per Response Evaluation Criteria in Solid Tumors. Results: Everolimus plus Octreotide LAR was associated with a clinical benefit rate of 69% (best evaluable responses: Stable disease [SD] in 10 patients [63%], partial response in 1 patient [6%]). The average duration of therapy was 4.8 cycles, and 3 (17%) patients continued therapy for ≥12 cycles (all achieved SD). The therapy was found to be well-tolerated in all patients. Conclusions: Everolimus plus Octreotide LAR appears to be safe and efficacious in patients with advanced NETs who may have had prior exposure to chemotherapy – a finding consistent with recently conducted major trials.
Keywords: Everolimus, mammalian target of rapamycin inhibitor, neuroendocrine tumors, octreotide long-acting repeatable, pancreatic
|How to cite this article:|
Tippeswamy R, Patil S, Sateesh C T, Shashidhara H P, Prabhudesai S, Prashanth P, Haridas K M. Everolimus plus octreotide long-acting repeatable in advanced neuroendocrine tumors in the routine tertiary cancer care setting: An Indian experience. Indian J Cancer 2015;52:359-62
|How to cite this URL:|
Tippeswamy R, Patil S, Sateesh C T, Shashidhara H P, Prabhudesai S, Prashanth P, Haridas K M. Everolimus plus octreotide long-acting repeatable in advanced neuroendocrine tumors in the routine tertiary cancer care setting: An Indian experience. Indian J Cancer [serial online] 2015 [cited 2019 Jun 16];52:359-62. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/359/176709
| » Introduction|| |
The introduction and approval of molecular targeted therapy have considerably changed the cancer treatment protocols. This emerging treatment option, because of its target focused action, has promising results in improving the progression-free survival (PFS) and achieving a stable disease (SD) or a partial response (PR) in more number of patients. Their effect is enhanced with the addition of a somatostatin analog (SSA), in neuroendocrine tumors (NETs) as shown in previous studies.,,,,,, Here, we studied the effect of Everolimus with Octreotide long-acting repeatable (LAR) in NETs, an approved therapy for advanced, inoperable pancreatic neuroendocrine tumors (PNETs).
Neuroendocrine tumors can be broadly classified into carcinoid tumors and PNETs. They form an important group of neoplasms because of their mimicking of the functions of their parent cells and the relative unresponsiveness to systemic chemotherapy. NET are rare, with the estimated incidence of 2.5–5/100,000 people/year and prevalence of 35/100,000 people/year. There are limited data available on epidemiology and patterns of these tumors in India.
Although these can arise from any site in the body, most commonly, they arise from embryonal neural crest cells, found abundantly in the gastrointestinal tract and bronchopulmonary system. In 1963, Williams and Sandler had classified carcinoid tumors on the basis of their embryological origin – foregut (bronchial, stomach, duodenal), midgut (jejunal, ileal, cecal, appendiceal), and hindgut (distal colon and rectal).
While these tumors grow and spread relatively slowly, they may present a unique clinical picture like diarrhea and flushing, because of production of serotonin and other vasoactive substances.
Pancreatic neuroendocrine tumors, which arise from the islets of Langerhans, are a rare subset, with an annual incidence of approximately 1/100,000. These can release several active hormones including insulin, gastrin, glucagon, and vasoactive intestinal peptide.
These tumors are optimally treated with surgery, chemotherapy, and SSAs. There has been a major evolution in the medical treatment options available for NETs. Drugs initially developed for palliating the functional symptoms, have now shown to be effective in curbing the progress of the tumors. This positive effect was seen in Octreotide LAR and lanreotide, which can significantly delay tumor progression among patients with metastatic midgut NETs and other NETs, regardless of their functional status., These SSAs bind to the five somatostatin receptor subtypes (sst1-5) on secretory endocrine cells, inhibiting hormonal secretions in functioning NETs.
In addition, targeted agents have yielded results positive enough in phase II and phase III studies, for them to be utilized in clinical practice.,,,,
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which is involved in the growth and proliferation of cells and their response to hypoxic stress. When the kinase activity of mTOR is activated, the synthesis of cell cycle proteins and hypoxia are increased. It was approved by US FDA in May 2011 for the treatment of patients with progressive PNET that is unresectable, locally advanced, or metastatic.
The aim of this noninterventional study was to evaluate the efficacy and safety of Everolimus plus Octreotide LAR in 16 patients with advanced NETs in the routine tertiary cancer care setting in India.
| » Patients and Methods|| |
The demographic details of the patients enrolled into the study are as shown in [Table 1]. Of a total of 18 patients diagnosed with NET, 16 patients (mean age, 52 years; range, 34–74 years) were administered Everolimus plus Octreotide either as first second or third line of treatment.
The primary tumor site and sites of metastases are in as detailed in [Table 2] and [Table 3]. Fifteen (83%) had metastatic disease, and 10 (56%), 5 (27%) had low-, and high-grade tumors, respectively. The most common sites of the primary tumor was the pancreas (n = 7, 39%) and the most common site of metastases was liver (n = 10, 56%), respectively.
| » Methods|| |
Patients presenting to the related tertiary care centers between 2011 and 2013 with histologically confirmed low-, intermediate- or high-grade advanced NETs who may have had prior exposure to cytotoxic chemotherapy (≤2 lines) were treated with Everolimus (10 mg/d PO) plus Octreotide LAR (30 mg IM once every 28 days) until disease progression or unacceptable toxicity were seen. Patients were evaluated every 3 months for a response to therapy as per Response Evaluation Criteria in Solid Tumors.
| » Results|| |
As evident in [Table 4], Everolimus plus Octreotide LAR was associated with a clinical benefit rate of 69% (best evaluable responses: SD in 10 patients [63%], PR in 1 patient [6%]).
The average duration of therapy was 4.8 cycles, and 3 (17%) patients continued therapy for ≥12 cycles (all achieved SD). All patients tolerated the therapy well. Toxicities were limited and consistent with previous reports. These include pneumonitis, stomatitis, rash, and fatigue.
Of the 11 patients who received Everolimus plus Octreotide as 1st line of treatment, 7 patients (64%) had an SD, 1 (9%) had a PR as shown in [Table 5].
| » Discussion|| |
Medical treatment plays a vital role where surgery is not practicable or when surgery has failed to completely remove the disease. Although the surgery still remains the first choice of treatment, medical intervention for NETs sometimes becomes necessary, as many patients present with metastases at diagnosis.
In a long prospective study with 156 patients with NETs, 64.3% of patients had metastases. In the present study, 83% patients had metastases on diagnosis.
One of the findings of importance in this study was that Everolimus along with Octreotide produced promising results in NETs, consistent with previous large studies discussed below, with majority of patients achieving an SD in 2 years of follow-up.
Somatostatin analogs, even when used alone, are capable enough of producing inhibition of tumor progression in well-differentiated metastatic NETs, with or without functional symptoms. This was established in 2009 by the PROMID study, which was a randomized, double-blind, placebo-controlled, phase III trial. Octreotide LAR achieved an SD in 66.7% of patients, as compared to 37.2% of patients in the placebo group. Response was better in cases where the primary tumor was resected. Median time to tumor progression in the Octreotide LAR and placebo groups was 14.3 and 6 months, respectively.
Octreotide LAR, when used along with an mTOR inhibitor like Everolimus, has shown to further increase the efficacy in terms of inhibition of tumor progression of NETs. RADIANT-1 was a phase II study which assessed the clinical activity of Everolimus plus Octreotide in patients with metastatic PNETs who experienced progression on or after chemotherapy, in 2010. SD was achieved in 80% patients and PR in 4.4% patients. The median PFS for patients on combination therapy was 16.7 months.
To follow-up and confirm these positive results of combination therapy, RADIANT-2 was performed in 2011. It was a randomized, double-blind, placebo-controlled, phase III study comparing oral Everolimus with placebo, both in conjunction with intramuscular Octreotide LAR. It involved 429 patients. Median PFS was consistent with RADIANT 1 and PROMID studies – 16.4 months in the Everolimus plus Octreotide LAR group and 11.3 months in the placebo plus Octreotide LAR group.
The primary origin of NETs as seen in this study was again consistent with previous studies – the pancreas being the main site of origin. This is important, as tumors arising from the pancreas are especially resistant to medical therapy and have a poor prognosis. In a study aimed at assessing the prognostic factors involving 185 patients showed majority of NETs – 42.9% had pancreas as a primary site of origin, which was one of the factors significantly associated with a negative outcome. In another study, where the patients were treated with SSAs, SD achieved was 27.8% in pancreatic versus 81.8% in intestinal tumors.
RADIANT-1, which primarily involved patients with PNETs, showed promising results with Everolimus plus octreotide, as discussed earlier. These findings were confirmed with RADIANT-2 accentuated by the RADIANT-3 trial, which was the largest phase III, randomized, double-blind clinical trial to date in patients with advanced PNETs. In line with these trials, our study showed that 85.7% patients with pancreas as the primary site of tumor origin achieved SD and 14.2% patients achieved PR. None of them died during the 2 years of follow-up.
Apart from pancreas as the primary tumor site, other factors which are directly associated with poor prognosis are age >50 years, primary tumor size >3 cm, Ki67 (assessment of tumor proliferation) on tumor cells >2%, degree of differentiation (poorly differentiated tumors), and presence of metastases at time of diagnosis (hepatic and distant extra-hepatic).
| » Conclusion|| |
Although metastatic NETs are difficult to treat, new emerging therapies like peptide receptor radiotherapy, targeted molecular therapy, and modern surgical techniques have shown to improve the overall outcome. Therapeutic options, especially SSAs in combination with targeted molecular therapy have provided a high level evidence as antiproliferative agents in metastatic well-differentiated midgut NETs and PNETs. Our study results yet again support this finding of antiproliferative effect of combination therapy (Everolimus plus Octreotide LAR). However, because of varied treatment options available, it is imperative to choose the best possible line of treatment and its timing, in each individual case. Further high-quality trials and individual experiences will help develop new treatment algorithms and enhance the current ones.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]