Progressive Metastatic Neuroendocrine Tumors Research Articles

Safety and Efficacy of 177 Lu-DOTATATE in Neuroendocrine Tumor Patients With Extensive Bone Disease.

The aim of this study was to assess the efficacy and safety of 177 Lu-DOTATATE in patients with neuroendocrine tumors (NETs) and extensive bone metastases, that is, more than 50% of the skeleton involved. A single-center retrospective analysis was performed in 30 patients (13 women and 17 men, mean age, 60 years; range, 35-77 years) undergoing 177 Lu-DOTATATE therapy. Patients had progressive metastatic NETs with extensive skeletal metastases (>50% skeletal involvement seen on baseline 68 Ga-DOTATATE PET/CT). The average administered activity was 7.308 (SD, 0.02) GBq per cycle with average treatment interval of 15 weeks. Survival analyses (progression-free survival [PFS], overall survival), radiological response assessment, toxicity assessment, and health-related quality of life (QoL) was performed. Overall, 26 patients completed 4 cycles, and 4 patients had less than 4 cycles of 177 Lu-DOTATATE. One patient (3%) did not complete treatment because of hematological toxicity. The estimated median PFS and median overall survival were calculated at 27 and 35 months, respectively. End-of-treatment radiological assessment showed partial response in 5 patients (17%), stable disease in 20 patients (66%), and radiological progressive disease in 3 patients (10%). Clinical progression was seen in a further 2 patients (7%).The incidence of grade 3/4 bone marrow toxicity was 10%. No patient had grade 3/4 peptide receptor radionuclide therapy-related nephrotoxicity. There was overall improvement in global QoL score (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Gastrointestinal NET-21) ( P = 0.019). 177 Lu-DOTATATE seems to have satisfactory therapeutic outcome in patients with advanced metastatic NET with extensive bone disease, with reasonable PFS and significant improvement in the global health-related QoL. The bone marrow toxicity was within the accepted range. Increasing the interval between cycles does not seem to reduce efficacy and may reduce toxicity, ensuring the bone marrow has sufficient time to recover between cycles.

FOLFOX-bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of sevencycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5months (95% CI: 9.8-21.2) and was shorter in patients age > 60 years (HR 2.56, 95% CI: 1.16-5.64), p= .020) and >1 previous systemic treatment line (HR 4.15, 95% CI: 1.96-8.78), p< .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI: 1.13-24.35), p= .034) and G3 NET (OR 5.39, 95% CI: 1.23-23.52), p= .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

Salvage 177Lu-dotatate therapy in patients with progressive metastatic neuroendocrine tumors.

e16212 Background: 177Lu-dotatate (LuPRRT) is effective in selected patients with metastatic neuroendocrine tumours (NETs). Most of these patients will subsequently have progressive disease with limited treatment options available. We analyzed the outcomes and toxicities of salvage LuPRRT in this study. Methods: This is a retrospective cohort study. Patients who had salvage LuPRRT at Royal Brisbane and Women’s Hospital (RBWH) from November 2016 to January 2021 were identified and included in this study. We manually reviewed the hospital electronic medical records and radiology databases to review patient characteristics, outcomes, and toxicities from salvage LuPRRT. Results: Of the 37 patients included, 37.8% (14/37) had small bowel primary, 27.0% (10/37) had pancreatic primary and 10.8% (4/37) had pulmonary primary. 83.8% (31/37) received 4 cycles of initial LuPRRT (I-PRRT) with a median dose of 32.0 GBq. The median duration of response to I-PRRT was 31 months. These patients had salvage LuPRRT (R-PRRT) on progression with 83.8% (31/37) received 2 cycles with a median cumulative 177LuTate dose of 48.0 GBq. Partial response, stable disease and progressive disease were observed in 10.8% (4/37), 40.5% (15/37) and 27.0% (10/37) of patients respectively. Median duration of response with R-PRRT was 8 months. 2.7% (1/37) developed Grade 3 anaemia and 2.7% (1/37) developed Grade 3 thrombocytopenia with R-PRRT. 8.1% (3/37) developed nephrotoxicity Grade 1 nephrotoxicity. 21.6% (8/37) of patients had re-retreatment with further LuPRRT (RR-PRRT) on progression. The median retreatment cycles were 2 and the median cumulative 177LuTate dose received was 58.8 GBq. Partial response, stable disease and progressive disease were seen in 25% (2/8), 12.5% (1/8) and 62.5% (5/8) of patients respectively. Median duration of response with RR-PRRT was 4 months. There were no reported Grade 3 haematologic toxicities with RR-PRRT. 1 patient developed Grade 1 nephrotoxicity with RR-PRRT. At time of data analysis in April 2021, 27% (10/37) had ongoing response while 73% (27/37) had progressed. Conclusions: Salvage LuPRRT is an effective and safe treatment option for selected patients with progressive metastatic NETs.

The association between lesion tracer uptake on 68Ga-DOTATATE PET with morphological response to 177Lu-DOTATATE therapy in patients with progressive metastatic neuroendocrine tumors.

To determine in a group of patients with progressive metastatic neuroendocrine tumors (PM-NETs) treated with 177Lu-DOTATATE whether a correlation exists between somatostatin receptor (SSTR)-2 expression in various tumors on baseline 68Ga-DOTATATE PET and their response to therapy. A secondary aim was to determine whether an association exists between tumor product of diameter (POD) and PET-derived Krenning score. Patients treated PM-NETs who had SSTR-2 overexpression (SSTR-RADS 5) on screening 68Ga-DOTATATE PET and CT at baseline and 3 months after therapy completion were included. Marker lesions on baseline CT were reassessed on CT after therapy using adapted Southwest Oncology Group solid tumor evaluation criteria. For each lesion, bidimensional diameter on CT and SSTR expression on PET (SSTR-RADS uptake score & PET-derived Krenning score) were recorded. Logistic regression models fitted through generalized estimating equations were used to assess for an association between SSTR expression and response to therapy, or lesion's POD. Forty-one patients with SSTR-RADS 5 PM-NETs treated with 177Lu-DOTATATE were included. There were 135 marker lesions (mean 3.2 lesions/patient) with Krenning score of 4 (n = 74), 3 (n = 44) or 2 (n = 17). There was no association found between SSTR-2 expression, as determined by SSTR-RADS uptake score or PET-derived Krenning score, and POD or response to therapy. In patients with SSTR-RADS 5 PM-NETs treated with 177Lu-DOTATATE, there was similar response to therapy for all lesions with PET-generated Krenning score ≥2. No correlation was found between lesion's POD and level of tracer uptake.

568P FOLFOX-bevacizumab chemotherapy in patients with progressive metastatic neuroendocrine tumors

Well-differentiated neuroendocrine tumors (NETs) are relatively rare, highly vascularized neoplasms. Antiangiogenic drugs have shown efficacy in patients with advanced NETs, although the efficacy of FOLFOX-bevacizumab has been scarcely described in this setting. Hence, we aimed to report its efficacy and tolerance in patients with metastatic NETs.

Clinical application of 18F-FDG PET/CT in&#x0D; oncology: Rare gastrointestinal malignant tumors&#x0D; (literature review)

Relevance: PET/CT is now becoming an integral part of cancer management protocols. 18F-fluorodeoxyglucose (18F-FDG)&#x0D; is the most common radiopharmaceutical for PET. However, the 18F-FDG PET/CT sensitivity and specificity vary widely in tumors of different histological structures and cell atypia degrees.&#x0D; The role of PET/CT in complex diagnostics of lymphomas is known. However, the specific use of this method in gastrointestinal neoplasms, especially at the initial stage of examination and in differential diagnostics, is not clearly defined since&#x0D; lymphomas account for only 1-5% of GI tumors.&#x0D; Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the diffuse neuroendocrine system&#x0D; enterochromaffin cells. NETs account for 0.5% of all neoplasms but become more common recently due to the advances in diagnostics. However, the significant achievements in the study of biological and molecular mechanisms of NETs’ behavior have&#x0D; not yet resulted in a common algorithm for their diagnostics and treatment.&#x0D; The purpose of this study was to review the experience of using 18F-FDG PET/CT in diagnostics of lymphomas and gastrointestinal neuroendocrine tumors as rare tumors to improve the criteria for the rational use of the 18F-FDG PET/CT method in&#x0D; their diagnostics and monitoring.&#x0D; Results: The use of 18F-FDG PET/CT is advisable at any stage of non-Hodgkin lymphomas, which are most common in the&#x0D; gastrointestinal tract, and for differential diagnostics, primary staging, and treatment efficiency monitoring in gastrointestinal&#x0D; lymphomas. 18F-FDG PET CT is also most valuable in aggressive non-Hodgkin lymphomas.&#x0D; Despite the importance of functional imaging in NETs, 18F-FDG PET/CT plays a supporting role in monitoring gastrointestinal NETs. 18F-FDG PET/CT is known to be efficient in prognosing the outcome of radionuclide therapy with peptide receptors&#x0D; in low-grade and progressive metastatic NETs.&#x0D; Conclusion: In lymphomas, 18F-FDG PET/CT is useful for primary staging, assessing early response to treatment, and&#x0D; re-staging. 18F-FDG PET/CT has a diagnostic value in undifferentiated gastrointestinal NETs, while its usefulness in well-differentiated gastrointestinal NETs is limited.

Quantifying Renal And Tumor Doses with Individualized Dosimetry In 177Lu DOTATATE Therapy – What Difference Does It Make?

The 177Lu DOTATATE (Lu) therapy can potentially improve progression free and overall survival in patients (pts) with progressive metastatic neuroendocrine tumors. We hypothesized that individualized dosimetry is effective in enabling normal tissue adapted prescription of Lu. A multi-institution prospective single arm study of Lu (4 cycles) with individualized dosimetry, in pts with 68Ga DOTATATE positive, progressive metastatic disease is ongoing in Ontario (NCT02743741). Dosimetry calculations are based on quantitative SPECT/CT images acquired at 4, 24, and 72 hours post Lu therapy. A 2cm spherical region of interest (ROI) is placed over normal kidneys and a vertebral body to estimate renal and bone marrow (BM) absorbed dose after each cycle. All pts received 7.4GBq for cycle (C) 1 (with modifications based on creatinine clearance and hematology for all cycles). Subsequent injected activities were varied based on renal absorbed dose (tolerance dose of 23Gy). Dose escalation was permitted to a max. of 11.1GBq/cycle. To quantify tumor absorbed dose, a ROI was placed over representative (highest SUV uptake) intra and extrahepatic areas. In addition, the liver was segmented and a threshold of >41%Max SUV was used to auto-segment liver tumors. To explore if tumor dose changed during treatment, we calculated the actual and normalized (using 7.4GBq) absorbed dose change. Between August 2016 and December 2018, 100 pts were accrued from the four consortium sites, 62 pts have completed the therapeutic phase, 53 pts have received all four cycles and were the basis of the current analysis. Using 29.6GBq (±10%) as the conventional total dose (when no Individualized dosimetry is used), 36 (68%) pts had dose escalation (>32.56GBq), 9 (17%) pts no change, and 8 (15%) pts had dose de-escalation (<26.64GBqi). The median (med) total renal dose absorbed was 18 (SD4, range 7 – 24) Gy. Only 1 pt received renal dose above tolerance. The med BM dose was 0.79 (SD1.3; range 0.15– 9.69) Gy. In 4 pts, the BM dose was >2Gy, attributable to multiple bone metastases and difficulty identifying a tumor free ROI. Using the threshold method, the med % liver containing tumor was 5% (SD 5; range 1-31%). The med liver tumor dose was 69 (SD 48; range 12 – 227) Gy. The med uninvolved liver dose was 10 (SD 8, range 5-33) Gy. Using the ROI method, the med liver tumor dose was 93Gy (SD64; range 20-291) Gy. The C1 med liver tumor dose was 21 (SD19 range: 4 – 112) Gy. In contrast, the C4 dose was 16 (SD 16; range 2 – 67) Gy. The normalized med difference was -4 (SD 15; range -45 to 38) Gy. Individualized dosimetry allowed dose escalation in 68% and de-escalation in 15% of pts while maintaining the renal dose within tolerance. Dose absorbed by tumor (ROI method) showed a >10-fold variation across patients. Longer follow-up is required to understand the impact of individualized dosimetry on outcomes.

SVEGFR2 and circulating tumor cells to predict for the efficacy of pazopanib in neuroendocrine tumors (NETs): PAZONET subgroup analysis.

4140 Background: The PAZONET trial (Grande et al, ESMO 2012) performed by the GETNE group analyzed the efficacy and safety of the use of pazopanib (800 mg/qd) in patients (pts) with progressive metastatic NETs that had been previously treated with other novel targeted agents. Here we report on the relationship between clinical outcome and circulating and tumor-related biomarkers. Methods: Kaplan-Meier analysis was used to correlate progression-free survival (PFS) with: blood circulating markers at baseline and after 12 weeks of treatment (VEGF-A and sVEGFR2 circulating plasma, Circulating Tumor Cells (CTC) and Circulating Endothelial Cells (CEC)), tumor functional status, Ki67, concomitant somatostatin analogues (SSA), chromogranin A (CgA) and primary tumor location. Results: 44 pts were enrolled, 42 were evaluable for response. sVEGFR2 decreased after 12 weeks of treatment (median decrease 20%, p&lt;0.0001) and the duration of treatment with pazopanib was associated with a decrease in sVEGFR2 (p=0.0046). Pts with a decrease in sVEGFR2 of &gt;20% and &lt;=20% had a median progression-free survival (mPFS) of 12.6 and 9.1 months (mo) respectively (p=0.067). Pts with and without CTC at baseline had a mPFS of 5.8 and 9.1 mo respectively (p=0.12). VEGFA and CEC were not found to predict PFS. mPFS in the intention to treat population was 10.0 mo (95% CI 4.3-15.6). Significant differences in mPFS were found in concomitant SSA treatment (11.9 mo [10.6-13.2]) vs. pazopanib alone (4.8 mo [3.0-6.6]) (p=0.007); decrease of CgA (3.4 mo [0.0-6.8]) vs no decrease (11.2 mo [8.4-14.1]) (p=0.024) and pancreatic (12.8 mo [11.0-14.6]) vs gastrointestinal (10.0 mo [4.9-15.1]) vs other primary tumors (3.4 mo [0.0-7.0]). No differences in mPFS were seen in functioning (10.0 mo) and non-functioning tumors (9.3 mo) and Ki67 status (&lt; 2% 10.0 mo, 3-10% 10.8 mo or &gt;10% 4.1 mo). Conclusions: sVEGFR2 and baseline CTC are promising predictive biomarkers for pazopanib in NETs. The updated results confirm the efficacy of pazopanib as a sequencing treatment of pts with progressive NETs, particularly in those with pancreatic primary tumors. The combination of pazopanib and SSA seems to be synergistic. Clinical trial information: NCT01280201.

1157O - Pazonet: A Phase II Trial of Pazopanib as a Sequencing Treatment in Progressive Metastatic Neuroendocrine Tumors (NETS) Patients (PTS), On Behalf of The Spanish Task Force for Nets (GETNE)

ABSTRACT Background Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT with demonstrated clinical activity in NETs. The aims of our study were to assess efficacy, safety and potential predictive biomarkers of pazopanib in pts with NETs who may have received previous antiangiogenic or mTOR inhibitor treatment. Methods All pts had pancreatic or extra-pancreatic metastatic NET disease documented as progressive. Pazopanib 800 mg was given daily until disease progression (DP) or unacceptable toxicity. Primary endpoint was Clinical Benefit Rate (CBR) at 6 months (m) defined as Complete Response (CR) plus Partial Response (PR) plus Stable Disease (SD) by RECIST-V-1.0. Optimal two-stage Simon design was utilized with H1 and H0 set at 70 % and 50 % respectively, Kaplan-Meier estimates were used for the analysis of time-to-event variables: 95% CI. Results 41 evaluable pts for response per protocol. 53.7% males, mean age 59.2 ± 10.3 years. At 6 months, 3 pts had PR (7.36%), 32 SD (78.0%), and 6 DP (14.6%), thus the CBR was 85.4%. Global median PFS 48,3 (13.9-82.7) weeks (w). By subgroups, CBR at 6 m and median PFS were 100% and 25.7 w in pts with no previous targeted therapy (9 pts), 88.9% and 48.3 w in pts with previous mTOR inhibitors (9 pts), 83.3% and 50.3 w in pts with previous antiangiogenics (16 pts) and 71.4% and 20.6 w in pts with previous antiangiogenics and mTOR inhibitors (7 pts) respectively. The sum of the longest diameter of target lesions had a decrease > 10% in 32.5 % of pts (37.5% without previous biological treatment, 22.2 % with previous mTOR inhibitor, 31.3% with prior multitarget inhibitor, and 42.9% with previous multitarget and mTOR, p = 0.506). Most frequent toxicities at of any grade were: asthenia (75%), diarrhoea (63%), nausea (42%). Translational studies on angiogenesis and inmunohistochemistry biomarkers and CTCs are ongoing. Conclusions Pazopanib 800 mg daily has promising activity in advanced NET regardless of previous treatment with other targeted therapies. This trial suggests the role that treatment sequencing with novel targeted agents may have in NETs. Disclosure All authors have declared no conflicts of interest.

PAZONET: Results of a phase II trial of pazopanib as a sequencing treatment in progressive metastatic neuroendocrine tumors (NETs) patients (pts), on behalf of the Spanish task force for NETs (GETNE)—NCT01280201.

4119 Background: Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT that has demonstrated clinical activity in NETs. The aims of our study were to assess efficacy, safety and potential predictive biomarkers of pazopanib in pts with NETs who had previously failed to at least one antiangiogenic or mTOR inhibitor treatment. Methods: Pts presented locally-advanced or metastatic gastrointestinal or pancreatic NET disease documented as progressive. Pazopanib 800 mg was given daily until disease progression (DP) or unacceptable toxicity. Primary endpoint was Clinical Benefit Rate (CBR) defined as Complete Response plus Partial Response (PR) plus Stable Disease (SD) at 6 months by RECIST-V-1.0. Optimal two-stage Simon design was utilized with H1 and H0 set at 70 % and 50 % respectively, Kaplan-Meier estimates waere used for the analysis of time-to-event variables: 95% CI. Results: 33 pts were evaluable for response per protocol. 54.5% males, mean age 60.7±10.3 years. At 6 months, 2 pts had PR (6%), 26 SD (79%), and 5 DP (15%), thus the CBR was 85%. By subgroups, CBR was 100% in pts with no previous targeted therapy (7 pts), 89% in pts with previous mTOR inhibitors (9 pts), 83% in pts with previous antiangiogenics (12 pts), and 60% in pts with previous antiangiogenics and mTOR inhibitors (5 pts). The sum of the longest diameter of target lesions had a decrease over 10% in 22% of pts (29% without previous biological treatment, 22% mTOR without prior multitarget, 18% prior multitarget without mTor, and 20% with previous multitarget and mTOR. Median PFS was only reached in the subgroup of pts (26 pts) with previously treated with antiangiogenics and mTOR inhibitors (20.6 weeks, 95% CI, 10.4-30.8). Most frequent toxicities, any grade: asthenia (75%), diarrhoea (63%), nausea (42%). Translational studies on angiogenesis and inmunohistochemistry biomarkers and CTCs are ongoing. Conclusions: Pazopanib at 800 mg daily has promising activity in advanced NET regardless of previous treatment with other targeted therapies. This trial may introduce the concept of treatment sequencing with novel targeted agents in NETs.

Hepatic artery radioembolization (HARE) in the management of progressive metastatic neuroendocrine tumors (NETs): A survival and biochemical response analysis in geriatric (G) and young (Y) populations.

e19727 Background: HARE with Y-90 SIR-Spheres is a treatment (Rx) option for NET patients (pts); however, survival statistics, biochemical responses (BR) and factors influencing outcomes are lackin...

A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study

4043 Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104. No significant financial relationships to disclose.

Preliminary results of a phase II trial of gefitinib in progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study

4083 Background: Metastatic NET (including islet cell carcinoma (ICC) and carcinoid tumors) are progressive in nature despite their indolent behavior. Systemic treatment options are limited. Immunohistochemichal (IHC) data suggest these tumors frequently express the epidermal growth factor receptor (EGFR). This suggests that EGFR mediated signaling may contribute to the growth of NET. Gefitinib is a small-molecule inhibitor of the EGFR tyrosine kinase domain. Methods: We evaluated 6 month progression-free survival (PFS) in two separate cohorts (ie, carcinoid and ICC) and using two separate Phase II trial designs. PFS rates at 6 months of 30% (carcinoid) and 10% (ICC) were considered promising. Importantly, objective radiologic progression by RECIST criteria was required for study entry. Other eligibility criteria included: ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior or concurrent octreotide and prior interferon were allowed. Results: 37 patients (pts) were enrolled: (22 carcinoid, ...

Effective treatment of neuroendocrine tumors With temozolomide and capecitabine

4216 Background: Low grade neuroendocrine tumors (NET), which are differentiated and metastatic, have a poor response to chemotherapy (<10%). This group (7000 cases per year in the U.S.) includes carcinoid tumors, pancreatic endocrine tumors (PETs), catecholamine-secreting tumors (e.g. pheochromocytomas), medullary carcinoma of the thyroid and excludes small cell cancers of the lung and GI tract. In our lab, we have found that capecitabine (5-FDUR), an oral pro-drug for 5-FU, and temozolomide are synergistic for induction of apoptosis in 2 human NET cell lines when given in a specific sequence and schedule. Our hypothesis is that the DNA damage induced by capecitabine, by incorporation of 5-FdUTP into DNA and reducing thymidine pools by inhibition of thymidylate synthase via 5-FdUMP, synergistically potentiates the effect of temozolomide on O6-alkylguanyl alkyl-transferase (O6-AGAT). Methods: We have treated ten patients with progressive metastatic NET who had failed chemotherapy and/or octreotide. Treatm...