Partial Biochemical Response Research Articles

Current and future opportunities for the management of primary biliary cholangitis

Primary biliary cholangitis (PBC) is a rare immune-mediated chronic cholestatic liver disease that can progress to liver fibrosis and, ultimately, cirrhosis if left untreated. Since the pathogenesis of PBC is not well understood, curative therapies have yet to be established. Ursodeoxycholic acid (UDCA), the standard of care treatment for PBC, has been proven to reduce disease progression and improve transplant-free survival. However, one third of patients have no response or partial biochemical response to UDCA and are at increased risk for disease progression. In such cases, second-line therapy with obeticholic acid (OCA) or peroxisomes proliferator-activated receptors (PPARs) should be considered in conjunction with UDCA. In this review article, we aim to provide an overview of the most recent data on PBC treatment in patients with inadequate response to UDCA, as well as novel therapies in the early stages of development.

Three Months PSA Response after PSMA-Guided Approach for Biochemical Relapse after Prostatectomy (PSICHE Trial).

Prostate bed salvage radiotherapy (SRT) is currently the main approach for early biochemical relapse (BR) after radical prostatectomy (RP). Nonetheless, 68Ga-PSMA-11 PET/CT implementation in this scenario prompted significant changes in patients' management. Our trial is aimed to prospectively assess the oncological outcomes after a pre-defined, 68Ga-PSMA-11 PET/CT based treatment strategy. In this analysis, we present early results focusing on three-months biochemical outcomes after treatment. Inclusion criteria were BR after RP (PSA ≥0.2 ng/ml; < 1 ng/ml) +/- postoperative SRT. All patients with PSA persistence after RP (PSA >0.2 ng/ml within 16 weeks from surgery) were excluded from the trial. After centralized 68Ga-PSMA PET/CT, a pre-defined treatment approach was proposed, consisting in Observation and re-staging at further PSA progression in case of negative 68Ga-PSMA PET/CT and previous postoperative RT, prostate bed SRT in case of negative imaging or positive imaging within prostate bed, Stereotactic body radiotherapy (SBRT) to all sites of disease in patients with pelvic nodal recurrence or oligometastatic disease (defined as (< 3 non-visceral metastatic lesions) or Androgen deprivation therapy +/- other systemic treatment indicated for hormone sensitive prostate cancer for widespread metastatic disease. PSA ≤0.2 ng/ml or ≤ 50% of baseline were defined as Complete or partial biochemical response (CBR or PBR), respectively. At present, 135 patients were enrolled within the protocol. Current analysis is focused on a cohort of patients with at least three months of follow up and excludes all patients who underwent only observation after re-staging due to previous prostate bed SRT (n = 42). In this subgroup, PBR or CBR were detected in 28 (66.7%) and 25 (59.5%) patients, respectively. PSA reduction if compared to baseline was detected in 34 patients, for an overall biochemical response rate of 80.9%. Biochemical progression after treatment was reported in 3 patients, who underwent a second 68Ga-PSMA PET/CT re-staging with detection of distant metastases. Promising results after a 68Ga-PSMA PET/CT targeted salvage treatment strategy were reported in terms of early biochemical response. This approach may allow to defer systemic treatment in this setting. Biochemical relapse free and progression free survival will be the objects of further analysis after longer follow-up.

Long-term Clinical Outcomes of Yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma: A 5-Year Institutional Experience

To examine the clinical outcomes of yttrium-90 (Y90) transarterial radioembolization (TARE) for primary hepatocellular carcinoma (HCC) through the evaluation of a 5-year institutional experience. This retrospective study evaluated 88 consecutive patients with primary HCC receiving Y90 TARE treatment at an academic medical center from 2017 to 2021. Disease distribution was bilobar in 60.2% of patients with an average lesion diameter of 5.0±3.4cm and Barcelona Clinic Liver Cancer stage B or C in 77% of the participants. Clinical outcomes were elucidated by examination of complications, liver function tests, biochemical response, and radiographic response. Objective response ratio (ORR) and progression-free survival (PFS) were also calculated. The mean administered Y90 radiation dose was 127.8±20.2Gy. No significant complications or LFT elevations occurred post-therapy. Of the 73.9% of patients with α-fetoprotein-producing tumors, 67.8% experienced a complete or partial biochemical response 1 month post-treatment. The ORR was 83.3% on 6-month imaging and PFS was 9.6±8.5 months. Functional outcomes (Eastern Cooperative Oncology Group) were maintained or improved in 79.6% and 76.1% of patients by 6 months and 1 year post-treatment, respectively. The mean survival was 14.7±12.1 months. At 6 months post-treatment, 77.3% of patients were downstaged to or maintained Milan criteria, which was sustained for 74.4% and 70.0% of patients 1 year and 2 years after treatment, respectively. Y90-TARE is a safe and effective therapy for primary HCC. Enduring outcomes further act as a realistic bridge to liver transplantation, with a majority of patients maintaining Milan criteria and preserving their functional status long term.

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Factors and cytokine signatures associated with the response to therapy in patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome: a real-world study.

Factors and cytokine signatures associated with the response to therapy in patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome: a real-world study.

Explorative analysis of a score predicting the therapy response of patients with metastatic, castration resistant prostate cancer undergoing radioligand therapy with 177Lu-labeled prostate-specific membrane antigen

ObjectiveUp to 60% of patients with metastatic, castration-resistant prostate cancer (mCRPC) treated with 177Lu prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) achieves a partial biochemical response with a decrease of > 50% in prostate-specific antigen (PSA) levels. The remaining fractions, however, do not respond to RLT. The aim of this explorative analysis was to identify pre-therapeutic factors for the prediction of response.Methods46 patients [age = 68 years (50–87)] with mCRPC who consecutively underwent RLT with 177Lu PSMA [median applied activity = 6 GBq (2.9–6.2)] were included and analysed retrospectively. The association of different clinical and laboratory factors and parameters from pre-therapeutic 68Ga PSMA positron emission tomography (PET) with the outcome of RLT was tested (Fisher’s test). Outcome was defined as PSA changes 8 weeks after second RLT [partial response (PR), PSA decrease > 50%; progressive disease (PD), PSA increase ≥ 25%; stable disease (SD), others]. Significant predictive factors were combined in a predictive score.Results30% showed a post-treatment PR (median 73% PSA decrease), 35% SD (median 17% PSA decrease) and 35% PD (median 42% PSA increase). Significant predictors for PD were alkaline phosphatase (ALP) > 135 U/l (p = 0.002), PSA > 200 ng/ml (p = 0.036), and maximum standardized uptake value (SUVmax) of the “hottest lesion” in pre-therapeutic PET < 45 (p = 0.005). The predictive score including PSA, ALP and SUVmax could separate 2 distinct groups of patients: ≤ 2 predictive factors (19% PD) and 3 predictive factors (90% PD).ConclusionThe presented predictive score allowed a pre-therapeutic estimate of the expected response to 2 cycles of RLT. As our study was retrospective, prospective trials are needed for validation.

Early biochemical response to parathyroidectomy for primary hyperparathyroidism and its predictive value for recurrent hypercalcemia and recurrent primary hyperparathyroidism

BackgroundThe traditional definition of cure after parathyroidectomy (PTX) for primary hyperparathyroidism is normocalcemia. Our hypothesis was that early postoperative levels of serum calcium and parathyroid hormone after PTX would have predictive value for later recurrence. MethodsWe performed a retrospective study of 1,146 patients with primary hyperparathyroidism who underwent PTX and had long-term biochemical follow-up. The first postoperative serum level of calcium and parathyroid hormone values were used to categorize patients into the following four early biochemical response groups: (1) complete response (normal calcium and normal parathyroid hormone), (2) partial response with hyperparathormonemia (normal calcium and increased parathyroid hormone), (3) partial response with hypercalcemia (increased calcium and normal parathyroid hormone), and (4) non-response (increases in both calcium and parathyroid hormone). Incidences of recurrent hypercalcemia and recurrent primary hyperparathyroidism >6 months after operation were then analyzed. ResultsThe overall rate of any elevated serum levels of calcium and any increase in serum levels of parathyroid hormone during >6-month follow-up was 9.8% (112 of 1146), with 6.6% (57 of 861) for group 1, 27% (35 of 129) for group 2, and 16% (20 of 127) for group 3 (P < .02). Partial biochemical responses with either increased serum calcium or increased parathyroid hormone levels were the strongest predictors of any episode of increased serum levels of calcium after 6 months and was associated with 2.7× to 4.3× the risk of recurrent primary hyperparathyroidism, respectively. ConclusionThis study demonstrates the importance of measuring parathyroid hormone in the early postoperative period to better predict later recurrent primary hyperparathyroidism.

11C-Choline PET/CT based Helical Tomotherapy as Treatment Approach for Bone Metastases in Recurrent Prostate Cancer Patients.

To evaluate the efficacy of 11C-choline PET/CT (CHO-PET/CT) based helical tomotherapy (HTT) as a therapeutic approach for bone metastases in recurrent prostate cancer (PCa) patients. This retrospective study includes 20 PCa patients (median age: 67; range: 51-80 years) presenting biochemical relapse after primary treatment who underwent CHO-PET/CT based HTT on positive bone metastases from December 2007 to June 2014. The effectiveness of HTT has been assessed with biochemical response at 3/6/12 months, biochemical relapse free survival (bRFS) and overall survival (OS) at 2 years. Toxicity has also been considered and assessed according to Common Terminology Criteria for Adverse Events (CTCAE). All patients presented a relapse at the time of CHO-PET/CT at bone level. In addition 15/20 (75%) also at lymph nodes (LNs) level (total lesions= 54). All patients underwent HTT on bone metastases and 19/20 concomitantly on prostatic bed and LNs. The median follow-up from CHO-PET/CT was 2 years (range: 1-7 years). At 3 months after the beginning of HTT treatment complete or partial biochemical response occurred in 79% of patients, at 6 months in 82% and at 12 months in 63% of patients. bRFS and OS at 2 years were 50% and 55% of patients, respectively. Patients presented mostly grade 1 or 2 toxicity according to CTCAE. The only grade 3 late toxicity has been observed in one patient. CHO-PET/CT based HTT is a suitable therapeutic approach in patients with recurrent PCa presenting bone metastases with a medium-low toxicity.

Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure?

The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center's Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric χ test was used to compare the initial and final treatment recommendations following choline PET/CT. Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n=6), radiation therapy (RT) (n=6), brachytherapy (n=2), RP+salvage prostate fossa RT (n=14), and RP+salvage prostate fossa/lymph node RT (n=6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans.PET/CT altered treatment approach in 18 of 33 (55%) patients (P=0.05). Sixteen of 27 patients (59%) treated previously with radiation were retreated with RT and delayed or eliminated androgen deprivation therapy: 1 received salvage brachytherapy, 10 received salvage pelvic lymph node or prostate fossa irradiation, 2 brachytherapy failures received salvage prostate and lymph nodes IMRT, and 3 with solitary bone metastasis were treated with radiosurgery. Eleven of 16 patients retreated responded to salvage therapy with a significant PSA response (<0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500±447 days. Two of 6 patients with no prior RT were referred for salvage prostatic fossa RT: 1 received dose escalation for disease identified in the prostate fossa and another had inclusion of "hot" pelvic lymph nodes in the treatment volume. These early results suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines may change management and improve care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning, and delaying or avoiding use of androgen deprivation therapy.

Total 18F-FDG PET/CT Metabolic Tumor Volume Is Associated With Postoperative Biochemical Response in Patients With Metastatic Pheochromocytomas and Paragangliomas.

The aim of this pilot study was to determine if metabolic tumor volume (MTV) and total lesion glycolysis (TLG) could serve as predictors of biochemical remission and pharmacotherapy-free interval in patients with metastatic pheochromocytomas (PCCs) and paragangliomas (PGLs). Patients with metastatic PCCs/PGLs have a high rate of biochemical recurrence, which can be associated with increased cardiovascular morbidity. Predictors of biochemical response are needed to guide and select patients who may benefit from therapy. Whole body MTV and TLG was calculated from preoperative 18F-FDG PET/CT scans and analyzed as marker of biochemical response and pharmacotherapy-free interval. Seventeen patients underwent a total of 19 procedures, with a median follow-up time of 26.4 months. Whole body MTV of patients with biochemical recurrence (n = 13, mean 73.8 mL) was higher than those who had a biochemical response (n = 6, mean 14.7 mL, P = 0.05). Patients with low MTV (<37.2 mL) had an improved durable partial biochemical response (P < 0.05), and a statistical trend for complete biochemical remission (P = 0.07) and pharmacotherapy-free interval (P = 0.06). In 8 patients with metastatic disease outside the abdomen, 4 patients had less than 35% of their disease burden outside the abdomen and these patients had a more durable partial biochemical response compared to patients with greater than 35% of their disease burden outside the abdomen (P < 0.05). Whole body MTV and TLG represents novel and valuable predictors of biochemical response for patients with metastatic PCCs and PGLs. A larger prospective study should be performed to validate these findings.

Response after Surgical Resection of Metastatic Pheochromocytoma and Paraganglioma: Can Postoperative Biochemical Remission Be Predicted?

Aggressive surgical resection with intent to cure and surgical debulking procedures are commonly recommended in patients with metastatic pheochromocytoma and paraganglioma. To date there are no data on operative outcomes of patients after surgical resection of metastatic pheochromocytoma and paraganglioma to determine if such an approach is appropriate and what factors may be associated with a favorable outcome. We performed a retrospective analysis of 30 patients with metastatic pheochromocytoma/paraganglioma who underwent surgical treatment. Clinical characteristics and genetic factors were analyzed as predictors of biochemical response to surgery. Thirty patients underwent a total of 42 operations, with a median follow-up time of 24 months (range 1 to 114 months). Complete disease resection (R0/R1) was achieved in 18 (42.9%) cases; 24 cases (57.1%) were debulking (R2) procedures without intent to cure. Complete biochemical remission was achieved in 10 (23.8%) cases and partial biochemical response was achieved in 23 (54.8%) cases. Patients with disease confined to the abdomen were more likely to achieve and maintain a biochemical response postoperatively than those with extra-abdominal disease (p = 0.0003). Debulking operations were significantly less likely to achieve or maintain biochemical palliation, with only 1 patient maintaining a biochemical response 12 months postoperatively (p < 0.0001). Patients were less likely to obtain pharmacologic independence after debulking (p = 0.0003), with only 2 (8.3%) not requiring pharmacotherapy 6 months after the intervention. Factors not associated with biochemical response to surgery include sex, family history, SDHB mutation status, systemic therapy, and preoperative biochemical profile. Depending on the extent of disease, patients with metastatic pheochromocytoma/paraganglioma can benefit from aggressive operative intervention and resection with intent to cure. Debulking procedures are unlikely to achieve clinically significant biochemical response, with any biochemical response achieved being very short-lived.

Low doses of ketoconazole and prednisone in patients with castration resistant prostate cancer (CRPC): A retrospective study on 73 patients.

e16099 Background: The management of rising PSA in metastatic CRPC remains controversial. In Italy, abiraterone and enzalutamide are not at all approved in this setting of patients (pts). Ketoconazole is an inhibitor of adrenal androgen synthesis that has shown anti-tumor activity by interfering with C-17,20-lyase and could be used as secondary hormonal manipulation. In this retrospective study we report our experience with low doses of ketoconazole and prednisone in the treatment for CRPC. Methods: From March 2007 to March 2012, 73 pts with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally 2 times daily, orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Overall, 40/73 (55%) pts had only bone metastases, 13/73 (18%) had nodal metastases, 20/73 (27%) both. Pts were monitored clinically and with serial PSA measurements every month. Partial biochemical response (PR) was defined as a &gt;50% fall in PSA from baseline. Progressive disease (PD) was defined by objective disease progression or PSA increase of &gt;50% above nadir or &gt;25% above baseline. The endpoints of the study were biochemical response (BR), progression free survival (PFS), overall survival (OS) and adverse events assessment. Results: Median age was 74 (70-78) years; median baseline PSA was 33.09 (1.18-1348.8) ng/ml; median duration of the treatment was 5.05 (0-56.8) months. Twenty out 73 pts (27%) showed a decrease in PSA &gt;50%, with a median duration of PSA response of 3.56 (1.17-33.58) months and 3 pts (4%) a PD. Fifty out 73 pts (68%) achieved a SD with an overall disease control (PR+SD) of 85%. PFS was 10 months for pts who achieved PR and 4 months for those with SD. Differences in PFS stratified according to site of metastases showed better prognosis in patients with only lymph nodes disease (p&lt;0.05). Treatment with Ketoconazole was well tolerated and grades 3-4 toxicities occurred in only 3% of patients. Conclusions: Low-dose ketoconazole is an effective and well-tolerated treatment in pts with CRPC and should be considered in the subset of pts with low tumor burden and a rising PSA level despite maximal androgen blockade.

Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma.

Choosing effective therapy for patients with malignant pheochromocytoma or paraganglioma (PPGL) is problematic and none of the options are curative. Although combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) is an established treatment option, only a limited number of case series have been reported in the literature. To determine the efficacy of CVD in patients treated at Tokyo Women's Medical University. Retrospective review of patients treated with CVD between 1989 and 2012 was conducted. Demographics, clinical presentation, imaging, and laboratory reports were reviewed and analyzed. Efficacy of CVD was ascertained from the biochemical and tumor responses. Twenty-three patients fulfilled study criteria and 6 of these were excluded due to inadequate follow-up or discontinuance by poor general condition or adverse effects. Thus, 17 cases were included in the study. The age and duration of the disease before initiation of CVD were 54.7 ± 12.0 years and 9.1 ± 8.1 years, respectively. The follow-up period after initiation of CVD ranged from 12 to 192 months (median, 60 months). Complete or partial biochemical and/or partial tumor response was achieved in 47.1 % (responders). No significant biochemical or tumor response was seen in 23.5 % and deterioration in biochemical and tumor outcomes was seen in 29.4 % (non-responders). No patient showed complete biochemical and tumor responses. In responders, these effects were documented within 4 months after initiation of CVD with a progression-free survival of 31 to 60 months (median, 40 months). Age at the first diagnosis with PPGL was younger (P < 0.05) and the lag time to eventual diagnosis of malignant disease was longer (P < 0.05) in responders than those in non-responders. The responders had improvements in hypertension and impaired glucose tolerance. Although CVD chemotherapy is not curative for patients with malignant PPGL, it does provide approximately half of the patients with biochemical, tumor, and hypertension benefits.

Neuroendocrine Hepatic Tumors: Summary of Patient Selection, Response and Toxicity of Radioembolization in 281 Patients

Debulking neuroendocrine hepatic metastases is commonplace as both symptoms and disease are better controlled. The challenge in clinical decision making includes patient selection, timing and procedure. Extirpation, radiofrequency ablation, hepatic artery chemoembolization, bland embolization and radioembolization are techniques widely available in the U.S. For patients undergoing intrahepatic therapies, procedure selection is based not only on disease bulk but also on disease location. From 8 published studies, the outcomes of 281 patients who underwent radioembolization were reviewed. Symptomatic improvement occurs within 3 months in approximately half the patients. Partial biochemical responses (>50% reduction from baseline) using chromogranin A occur in two thirds of subjects as 2 centers have observed. Disease control (complete + partial + stable responses) is reported in 50-100% of patients. The median time to progression is 11.1 months in one report. Six centers report a median survival ranging from 14 to 70 months. One, 2 and 3 year survival ranges from 2 reports are 86-100%, 57-58% and 47-57%, respectively As more choices become available in controlling neuroendocrine disease, optimally combining debulking procedures such as radioembolization with systemic therapy is challenging. Using infusional 5-FU with radioembolization can be done safely but added benefit remains uncertain. Prior hepatic artery chemoembolization may not be a contraindication to radioembolization. Future trials are needed to guide the practitioner in using radiation sensitizers with radioembolization.

An Open-Label, Phase II Study Evaluating the Safety and Efficacy of PTK787/ZK222584 in Patients With Metastatic Neuroendocrine Tumors That Have Evidence of Progressive Disease or an Increase in Disease Related Syndrome Symptoms

Background: Vatalanib inhibits endothelial growth factor receptor (VEGFR) by binding to the intracellular kinase domain of all 3 VEGFRs. Neuroendocrine tumors (NETs) express VEGF receptors. Inhibiting VEGF with bevacizumab, sorafenib, and sunitinib reduced time to progression or tumor size in some NET patients (pts). To determine vatalanib's tolerability and efficacy in NET pts, a trial was performed. Methods: Eligibility criteria included NET pts with biopsy-proven metastatic disease and rising biomarkers on somatostatin analog therapy. Eligible pts had measurable lesions, a KPS > 60%, and normal hematologic, renal, and hepatic functions. A stable octreotide LAR dose, not exceeding 30 mg monthly, was required. Initial total daily dosing of vatalanib was 1,250 mg. Biochemical responses within a 90 day interval were the primary response criteria. Secondary endpoints included radiographic/scintigraphic scan changes and safety. Results: Twenty-four pts (12 males) were enrolled between 5/20/05 to 5/28/09. The median age (range) was 60.4 (25-74). Eighteen pts were evaluable for efficacy and safety. Four pts continue on therapy. One pt withdrew consent; 2 pts died of disease prior to first cycle initiation; 1 pt was allergic to vatalanib. Six pts required a 10-28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase, G2 proteinuria, G2 headache, and G3 nausea/vomiting. Resumption of vatalanib at 1,000 mg daily was well tolerated in 2 pts and 750 mg in another. One pt developed carcinoid crisis with fever, flushing, and rising 5HIAA. Grade 1 nausea occurred in 15 pts with antiemetics required for 4 pts. A partial (> 50% decrease) biochemical response occurred in 4 pts. The observed radiographic and scintigraphic responses in 16 pts have shown progressive disease in 6 and stable/minimal response in 10 pts. Accrual continues. Conclusions: Vatalanib is well tolerated in most pts and results in a 24% biochemical partial response rate in NET pts with rising biochemical markers on somatostatin analog therapy.

Dosimetry-guided high-activity 131I therapy in patients with advanced differentiated thyroid carcinoma: initial experience

In patients with advanced differentiated thyroid carcinoma (DTC), therapy with the highest safe (131)I activity is desirable to maximize the tumour radiation dose yet avoid severe myelotoxicity. Recently, the European Association of Nuclear Medicine (EANM) published a standard operational procedure (SOP) for pre-therapeutic dosimetry in DTC patients incorporating a safety threshold of a 2 Gy absorbed dose to the blood as a surrogate for the red marrow. We sought to evaluate the safety and effectiveness in everyday tertiary referral centre practice of treating advanced DTC with high (131)I activities chosen primarily based on the results of dosimetry following this SOP. We retrospectively assessed toxicity as well as biochemical and scintigraphic response in our first ten patients receiving such therapy for advanced DTC. The 10 patients received a total of 13 dosimetrically guided treatments with a median administered activity of 14.0 GBq (range: 7.0-21.4 GBq) (131)I. After 6 of 13 treatments in 6 of 10 patients, short-term side effects of (131)I therapy, namely nausea, vomiting or sialadenitis, were observed. Leukocyte and platelet counts dropped significantly in the weeks after (131)I treatment, but returned to pre-treatment levels by 3 months post-therapy. Serum thyroglobulin levels decreased after 12 of 13 treatments (median reduction: 58%) in 9 of 10 patients. In our initial patient cohort, high-activity (131)I therapy for advanced DTC based on pre-therapeutic blood dosimetry following the EANM SOP was safe and well tolerated. Such treatment almost always produced a partial biochemical tumour response.

Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions

Background: Insulin resistance plays an important role in the pathogenesis of NAFLD. Pharmacological treatment of patients with NAFLD is still evolving. Insulin sensitizing drugs like metformin may be effective in these patients. Twenty five adult patients with NAFLD who did not achieve normalization of alanine transaminases (ALT) after 6 months of lifestyle interventions and UDCA were treated with metformin 500mg tid for 6 months. Insulin resistance was determined by HOMA-IR. Liver function tests were done monthly and patients were defined having no response, partial response or complete biochemical response depending on the change in ALT. Results were compared with 25 patients with NAFLD from the same cohort treated only with lifestyle interventions (disease controls). Results: Thirteen (52%) patients had class III (n = 5) or class IV (n = 8) disease amounting to histological NASH. Of these 13 patients none had severe inflammation and none had stage 4 fibrosis (cirrhosis). All 25 patients with NAFLD had insulin resistance in comparison to healthy controls. In comparison to disease controls (127.5 ± 41.8 vs. 118 ± 21.6 p = NS), all patients treated with metformin had partial biochemical response (mean ALT 122.2 ± 26.8 vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them achieved complete normalization of ALT. Conclusions: Metformin is effective to achieve biochemical response in patients with NAFLD who do not respond to lifestyle interventions and UDCA.

An open-label phase II clinical trial of PTK787 in patients with progressive neuroendocrine cancer

14127 Background: PTK787 is an orally active angiogenesis inhibitor blocking all known vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptor (PDGFR)-tyrosine kinases . The majority of metastatic neuroendocrine malignancies express VEGF and PDGF receptors. Since both growth factors have been implicated in tumor-induced angiogenesis, PTK787 offers a novel approach for inhibiting tumor growth. Methods: In a phase II trial, we investigated the safety and antitumor activity of PTK787 in patients who had biopsy-proven metastatic neuroendocrine cancer, such as carcinoid, and had shown evidence of progression on somatostatin analog therapy. Eligible patients had measurable lesions other than bone, a Karnofsky performance status &gt; 60% and normal hematologic, renal and hepatic functions. Patients on octreotide therapy were required to be on a stable dose not exceeding 30 mg monthly of the LAR formulation. Initial dosing of PTK787 was 1,250 mg daily. Results: Eight patients (5 males) were enrolled between 5/20/05 to 9/09/06. Median age was 61 years (range, 48 to 65). There was 1 withdrawal of consent. The median time on study was 6.2 ± 2.1 mos with 1 patient continuing on treatment as of January 2007. Three patients required a 10–28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase and Grade2 proteinuria. Resumption of PTK787 at 1,000 mg daily was well tolerated in 1 patient. One patient developed carcinoid crises with fever, flushing, rising 5-HIAA accompanied by Grade 2 proteinuria. A partial (&gt;50% decrease in 5-HIAA) biochemical response was observed in 25% of the patients. The observed radiographic (CT scans) and scintigraphic (OctreoScan) responses in 6 patients has been stable disease at 3 and 6 mos. Recruitment to this trial continues. Conclusions: PTK787 results in a 25% biochemical partial response rate in neuroendocrine tumor patients with progressive disease following somatostatin analog therapy. Alternative dosing schedules are planned to improve tolerability. [Table: see text]

Repeated [131I]Metaiodobenzylguanidine Therapy in Two Patients with Malignant Pheochromocytoma

Approximately 10% of pheochromocytomas are malignant with a 5-yr survival rate of less than 40%. Promising results have been published on single high-dosage [131I]metaiodobenzylguanidine ([131I]MIBG) treatment for malignant pheochromocytoma. We present our experience with multiple intermediate-dosage [131I]MIBG therapy instead of single high-dosage therapy. The study took place at University Medical Centers and included two patients (one male, 36 yr of age, and one female, 43 yr of age) with widely spread metastatic pheochromocytoma and bad prognosis because of liver and lung metastases. Instead of a single high dosage, these two patients were treated with multiple intermediate dosages of [131I]MIBG. The first patient received 37 GBq (1 Ci) [131I]MIBG in five sessions [7400 MBq (200 mCi) each; interval range, 2-11 months]; the second patient received 66.6 GBq (1.8 Ci) [131I]MIBG in 12 sessions [5550 MBq (150 mCi) each; interval range, 2-14 months]. We measured efficacy, toxicity, and survival. Both patients had a complete symptomatic response and a partial tumor volume response. The first patient had a partial biochemical response, the second a complete biochemical response. In both cases, toxicity has been confined to nausea during treatment. Hematological toxicity was minimal, and both patients stayed euthyroid. The survival (so far) of these patients was 5 yr (clinical case 1) and 16 yr (clinical case 2) after initial diagnosis. Repeated intermediate-dosage [131I]MIBG treatment appears to be a reliable and well-tolerated radionuclide therapy and might be a useful adjunct in patients with malignant pheochromocytoma, providing longstanding palliation and prolonged survival.

A Phase I/II trial of weekly gemcitabine with celecoxib and thalidomide for patients with advanced pancreatic cancer

4241 Gemcitabine-based combination regimens have been utilized in the treatment of advanced disease with minimal effect on survival. VEGF and COX-2 overexpression in pancreatic tumor tissue suggest that an anti-angiogenic agent such as thalidomide and a COX-2 inhibitor such as celecoxib may improve response. Addition of celecoxib (C) to thalidomide (T) and gemcitabine (G) was therefore evaluated in a Phase I/II trial. Methods: Twelve patients with unresectable, locally-advanced or metastatic adenocarcinoma of pancreas were enrolled in Phase I/II trial of weekly G(1,000mg/m2) on days 1 and 8 every 21 days. Patients received C 400mg PO BID and T 200mg PO QHS and titrating to 300mg PO QHS if tolerated after one week. C and T were started 2 weeks prior to the first dose of G and continued throughout the treatment. To assess possible response from C and T alone, tumor markers CEA and CA19–9 were followed prior to initiation of G and throughout the course of therapy. Patients were followed closely for major toxicities including neutropenia, renal failure, gastrointestinal hemorrhage, thrombotic events, thrombocytopenia, peripheral neuropathy, somnolence, and rash. Therapy was held or discontinued if significant toxicities developed or if disease had progressed upon clinical or radiographic evaluation. Results: Twelve patients were enrolled. Mean age was 57 years (range 45 to 72) with ECOG status 0,1, or 2 at initiation. Mean number of cycles received was 2.3. Five patients were noted to have a partial biochemical response to C and T alone as evidenced by a decrease in CA19–9 levels. No radiographic responses were noted, although several patients had improvement in metastatic disease or stable disease. Mean survival of patients from time of diagnosis was 10 months. Toxicities included 3 patients with a skin rash and 1 patient with pulmonary embolism. Conclusions: The partial biochemical CA19–9 response of advanced pancreatic cancer to oral C and T alone or in combination with G in a significant fraction of patients suggests anti-tumor activity. Measureable radiographic responses from the combination of G, C and T appear to be no better than single agent G, but the regimen was well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene