Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :526
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (1,324 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 » Patients and Methods
 » Methods
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Tables

 Article Access Statistics
    Viewed1343    
    Printed30    
    Emailed0    
    PDF Downloaded239    
    Comments [Add]    

Recommend this journal

 


 
  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  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


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 Publication18-Feb-2016

Correspondence Address:
S Patil
HCG Hospital, Singasandra, Bengaluru, Karnataka
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.176709

Rights and Permissions

 » Abstract 

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 Aug 20];52:359-62. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/359/176709



 » Introduction Top


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.[1],[2],[3],[4],[5],[6],[7] 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.[8] 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).[9]

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.[10] 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.[11] 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.[12],[13] 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.[1],[2],[3],[4],[5]

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.[6] 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 Top


Patients

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.
Table 1: Demographic details

Click here to view


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.
Table 2: The site of primary tumor with frequency distribution

Click here to view
Table 3: Primary metastatic sites with frequency distribution

Click here to view



 » Methods Top


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 Top


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%]).
Table 4: Responses to Everolimus and octreotide (all lines)

Click here to view


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].
Table 5: Responses in 1st line treatment

Click here to view



 » Discussion Top


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.[14]

In a long prospective study with 156 patients with NETs, 64.3% of patients had metastases.[15] 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.[16] 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.[3] 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.[7] 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.[15] In another study, where the patients were treated with SSAs, SD achieved was 27.8% in pancreatic versus 81.8% in intestinal tumors.[13]

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.[1] 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).[15]


 » Conclusion Top


Although metastatic NETs are difficult to treat, new emerging therapies like peptide receptor radiotherapy,[17] 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.

 
 » References Top

1.
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514-23.  Back to cited text no. 1
    
2.
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-13.  Back to cited text no. 2
    
3.
Yao JC, Phan AT, Chang DZ, Mares JE, Rashid A, F. Meric-Bernstam. Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGNET). J Clin Oncol 2006: Vol 24, No 18S (June 20 Supplement), 4042. (Available from: http://meeting.ascopubs.org/cgi/content/abstract/24/18_suppl/4042).  Back to cited text no. 3
    
4.
Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: A phase II trial. J Clin Oncol 2010;28:69-76.  Back to cited text no. 4
    
5.
Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 2008;26:1316-23.  Back to cited text no. 5
    
6.
Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-14.  Back to cited text no. 6
    
7.
Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): A randomised, placebo-controlled, phase 3 study. Lancet 2011;378:2005-12.  Back to cited text no. 7
    
8.
Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011;30 Suppl 1:3-7.  Back to cited text no. 8
    
9.
Williams ED, Sandler M. The classification of carcinoid tum ours. Lancet 1963;1:238-9.  Back to cited text no. 9
    
10.
Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol 2005;19:753-81.  Back to cited text no. 10
    
11.
Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol 2010;16:2963-70.  Back to cited text no. 11
    
12.
Bajetta E, Procopio G, Catena L, Martinetti A, De Dosso S, Ricci S, et al. Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: A phase III study. Cancer 2006;107:2474-81.  Back to cited text no. 12
    
13.
Panzuto F, Di Fonzo M, Iannicelli E, Sciuto R, Maini CL, Capurso G, et al. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol 2006;17:461-6.  Back to cited text no. 13
    
14.
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-72.  Back to cited text no. 14
    
15.
Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, et al. Prognostic factors and survival in endocrine tumor patients: Comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 2005;12:1083-92.  Back to cited text no. 15
    
16.
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;27:4656-63.  Back to cited text no. 16
    
17.
Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H, Willinek W, Grünwald F, et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med 2014;55:183-90.  Back to cited text no. 17
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow