Neoadjuvant PRRT With Y-90-DOTATOC in pNET

GEP-NETs tend to be slow growing (although aggressive forms exist) and are often diagnosed when they have already metastasized, when a radical treatment is no longer possible.

Treatment of NETs is typically multidisciplinary and should be individualized according to tumor type, burden, and symptoms. Therapeutic tools include surgery, interventional radiology and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues [Modlin 2008]. Several clinical trials have indicated that PRRT with somatostatin analogues 90Y-DOTATOC, 177Lu-DOTATATE and 177Lu-DOTATOC, is an efficient tool in the management of NETs (30% objective responses with a great survival benefit) which compares favorably to classic chemotherapy results (up to 20% responses) [Kwekkeboom 2005].

Dosimetric studies demonstrated that these radiopeptides are able to deliver high radiation doses to somatostatin receptor sst2-expressing tumors and acceptable doses to normal organs [Cremonesi 2010]. Side effects, usually mild, may involve kidneys and bone marrow. Renal protection is used to minimize the risk of a late function decrease [Bodei 2003].

Pts are selected for PRRT based on molecular imaging with 111In-pentetreotide or, more recently, a 68Ga-SSA-PET, such as 68Ga-DOTATOC/DOTATATE/DOTANOC [Virgolini 2010], which have revolutionized the NET imaging, with an overall sensitivity of >90%, and specificity ranging from 92% to 98% [Ambrosini 2012].

PRRT is an innovative therapeutic approach for inoperable or metastasized, well/moderately differentiated GEP and bronchial NETs. PRRT in P-NETs has demonstrated efficacy in terms of objective response and impact on survival parameters. Since surgery is the only curative option for patients with GEP-NETs, it is proposed that neoadjuvant treatment will improve outcome by enabling disease regression that will enable surgical resection.

Identification of disease regression as assessed by a PCR-blood based analysis of circulating neuroendocrine tumor transcripts will provide objective and quantifiable molecular genomic early information that is additive to imaging criteria of regression. This will objectively establish PRRT treatment efficacy and thereby facilitate the identification and selection of individuals that would then benefit from surgical intervention.

The two most commonly used radiopeptides, 90Y-DOTATOC and 177Lu-DOTATATE, produce overall objective response rates of 15-35%. Particularly relevant is the outcome in terms of both progression-free and overall survivals, which compare favorably with biotherapies. PRRT is generally well tolerated with mild toxicity, if the necessary precautions, such as the co-administration of nephron-protective amino acids or the adjustment of the administered activity, are taken.

PRRT in P-NETs has demonstrated efficacy in terms of objective response and impact on survival parameters. Response rates are >35%, higher than in small intestine tumors. In particular, in 342 patients with P-NETs, out of the whole series of 1109 patients treated with 90Y-DOTATOC, 47% objective responses were reported by Imhof in 2011. In 2013, Sansovini reported 39% partial and complete responses using 177Lu-DOTATATE at full dosage, while 60.3% partial responses were reported by Ezziddin in 2014 using the same peptide. Reported progression free survival (PFS) rates are > 30 months.

An interesting new application for P-NETs is the neoadjuvant setting, which was suggested by sporadic case reports that described the successful surgical resection in patients with initially inoperable P-NETs treated with PRRT. However, this treatment modality has not been fully explored in dedicated studies.

Moreover, there are few experiences demonstrating the advantage of PRRT associated to surgery in a multidisciplinary setting [Bertani 2014, 2016].