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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

ABSTRACT: BACKGROUND:Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ?30% size decrease from baseline) are infrequent. METHODS:Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS:Data for 237 patients (85 placebo; 152 sunitinib (n=66.50?mg '4-weeks on/2-weeks off' schedule; n=86 '37.5?mg continuous daily dosing (CDD)')) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P<0.001). A PR was seen in 19 patients (13%) on sunitinib; the median change in the sum of the lesions (vs baseline) was -12.8% (range -100 to +36.4). Month 7 was the most informative time-point (AUC 0.78 (95% CI 0.66-0.9); odds ratio 1.05 (95% CI 1.01-1.08), P=0.002). Reduction of 10% (vs baseline) achieved the highest sensitivity (50%) and specificity (82%), amongst cut-offs tested. A 10% reduction in marker lesions was associated with improved PFS in the whole sunitinib population (HR 0.55 (95 CI 0.3-0.9); P=0.04); mostly in patients on sunitinib CDD (HR 0.33 (95% CI 0.2-0.7); P=0.005). A 10% reduction in marker lesions (P=0.034) and sunitinib treatment (P=0.012) independently impacted on PFS (multivariable analysis). CONCLUSIONS:A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design.

SUBMITTER: Lamarca A

PROVIDER: S-EPMC5785750 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

Lamarca Angela A Barriuso Jorge J Kulke Matthew M Borbath Ivan I Lenz Heinz-Josef HJ Raoul Jean Luc JL Meropol Neal J NJ Lombard-Bohas Catherine C Posey James J Faivre Sandrine S Raymond Eric E Valle Juan W JW

British journal of cancer 20171121 2

<h4>Background</h4>Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent.<h4>Methods</h4>Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The pr ...[more]

PMID: 29161241

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Project description:IntroductionRecent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens.Materials and methodsThis was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR).ResultsTreatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months.ConclusionAmong patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy.Implications for practiceHigh-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Dataset Information

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

Publications

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

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