Evidence Of Radiological Progression Research Articles

LGG-45. LOW DOSE CARBOPLATIN – ETOPOSIDE REGIMEN IN PEDIATRIC PATIENTS WITH LOW GRADE GLIOMA

Abstract INTRODUCTION Chemotherapy remains the cornerstone in case of incompletely resected pedatric Low Grade Glioma (pLGGs) and for recurrent tumors in unfavorable locations. Based on previous cisplatin etoposide regimen (INT Milan strategy), we tried to reduce toxicity and achieve a similar tumor control using a modified regimen composed of CBCDA-etoposide. METHODS From August 2012 to December 2023 we treated 79 pLGGS (45 F (57%), 34 M (43%)) with carboplatin (400 mg/m2 day 1) and etoposide (100 mg/2 day 1-3) at 4-6 weeks interval with 10 cycles in one year or until disease progression. Median age at diagnosis is 7 years. Seventeen patients were affected by neurofibromatosis type 1 (21.5%). 28 pLGGS affected visual pathway (35.4%). Treatment was delivered for clinical symptoms and/or radiological evidence of progression. RESULTS According to RAPNO criteria, on brain magentic resonance imaging (MRI) at the end of treatment 40 patients had stable disease (50.6%), 10 had partial response (12.7%), 7 had major response (8.9%), 5 had minor response (6.3%), 2 presented complete remission (2.5%), 13 patient had disease progression (16.5%). 2 patients are undergoing treatment (2.5%). Acute toxicity was unremarkable. During follow up (median time 59,5 months) 9 children (11,4%) developed audiological alterations but 2 of them also received radiotherapy. 14 patients presented hematological toxicity CTCAE grade 3 or 4 (17,7%). During follow up 30 patients developed a progressive disease (38%) and require further treatments and only one patients died because of progressive disease. Overall survival was 98,7% (78/79). CONCLUSIONS The combination of low doses CBCDA-etoposide seems equally effective with a lower hematological and audiological toxicity compared to other regimens.

New Guidelines for Idiopathic Pulmonary Fibrosis and Progressive Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal idiopathic interstitial pneumonia and is characterized by chronic progressive pulmonary fibrosis of indeterminate etiology. In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society published joint clinical practice guidelines for IPF. The guidelines require exclusion of known causes of interstitial lung disease and identification of a radiological and/or pathologic pattern of usual interstitial pneumonia (UIP). The diagnosis of IPF is a multidisciplinary process, involving pulmonologists, radiologists, pathologists and, if necessary, experts in other medical fields. The 2022 guidelines for IPF revisit and clarify the radiological and pathological features of UIP. In addition, recommendations regarding transbronchial lung cryobiopsy, antacid medication, and antireflux surgery are revised or established based on up-to-date evidence in the 2022 guidelines. The new guidelines also encompass the definition and treatment of progressive pulmonary fibrosis (PPF). PPF comprises diverse fibrotic interstitial lung diseases other than IPF, which progress despite standard treatment. The diagnosis of PPF is based on symptoms, physiologic evidence, and radiologic evidence of progression. The use of nintedanib was suggested for patients with PPF other than IPF who are unresponsive to standard treatment. This review introduces and discusses the recommendations for the diagnosis and treatment of IPF and PPF in the new international guidelines.

A phase 2 study of anlotinib in patients with metastatic pheochromocytoma/paraganglioma.

e15000 Background: Metastatic pheochromocytoma / paraganglioma (MPP) are rare while the prognosis was poor and the efficacy for current therapy was unsatisfactory. Anlotinib is a multikinase inhibitor targeting tumor angiogenesis and growth. Currently, there is no study evaluating the efficacy and safety of anlotinib in MPP pts. Methods: This is a prospective, single-arm phase 2 trial (NCT 04860700). Pts with histologically or radiologically confirmed MPP were enrolled. Main other inclusion criteria were 18-75 years old and ECOG PS 0-2. Anlotinib (8-12mg, QD) were given orally from d1 to d14 every 21 days until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included biochemical (catecholamine levels) response rate (BRR), progression-free survival (PFS) and safety. Results: 10 pts with MPP were enrolled and tumor response were evaluated in 6 patients. All these 6 patients had objective radiological evidence of progression within 6 months before enrollment. Tumor shrinkage was observed in 4 pts, 1 achieved partial response (PR) and 3 achieved stable disease (SD). The ORR was 16.7% (1/6). For 1 patient (p-1) with no measurable lesions, the pathological lymph nodes shrunk obviously and the rapid progression of bone metastatic lesion was well controlled. Among all 6 pts, catecholamine levels were obviously decreased in 4 pts, achieving a BRR of 67%. 1 patient who developed blindness at right eye caused by the progression of intracranial metastasis after chemotherapy had recovered the vision after anlotinib treatment. At the data cutoff date on February 1st, 2022, 1 patient terminated anlotinib since obvious elevation of catecholamine level and others were still in treatment with no radiographic disease progression. The median treatment duration was 7.5 cycles. The details of efficacy result were listed in table below. Overall, treatment of anlotinib blocked the rapid disease progression and achieved a durable disease control. The most common treatment-related adverse event (TRAE) was hypertension (5/6), which was well controlled, other TRAEs occurred in > 1 pts included grade 1 or 2 proteinuria (2/6) and palmar-plantar erythrodysesthesia syndrome (2/6). Conclusions: The preliminary results of this study indicated that anlotinib is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. Clinical trial information: NCT04860700. [Table: see text]

Oral metronomic chemotherapy after definitive chemoradiation in esophageal squamous cell carcinoma: a randomized clinical trial.

Improving outcomes in locally advanced esophageal/GEJ squamous cell cancer (SCC) is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC) following definitive chemoradiotherapy (CRT). This was a randomized open-label integrated phase II/III study in patients with SCC of esophagus/GEJ following definitive CRT who had no radiologic evidence of progression, and no endoscopically detected disease. Randomization was 1:1 to OMC (celecoxib 200mg twice daily and methotrexate 15mg/m2 weekly) for 12months or observation. The primary endpoint for the phase II portion was progression-free survival (PFS); secondary endpoints were overall survival (OS) and toxicity. P ≤ 0.2 for PFS was required to proceed to phase III. Between Jan 2016 and Dec 2019, we enrolled 151 patients for the phase II portion, 75 to OMC and 76 to observation. The tumor originated in the upper thoracic esophagus in 79% patients. Concurrent CRT consisted of median 63Gy in a median of 35 fractions; concurrent chemotherapy was weekly paclitaxel + carboplatin in 91%. OMC was started at a median of 2.6months (IQR 2.3-2.8) from CRT completion. Grade 3 or higher toxicities occurred in 18 patients (24%) in the OMC arm and 9 (12%) in the observation arm; P = 0.071. Median PFS was 25months (95% CI, 17-58) in the OMC arm and was not attained [NA] (95% CI, 25-NA) in the observation arm; HR, 1.51, 95% CI, 1-2; P = 0.073. Median OS was 36months (95% CI, 23-NA) in the OMC arm, and not attained (95% CI, NA-NA) in the observation arm; HR, 1.77; 95% CI, 1-2.9; P = 0.023. Oral metronomic methotrexate and celecoxib in patients who have not progressed radiologically and have no endoscopic evidence of disease following radical CRT for locally advanced esophageal/GEJ SCC does not improve outcomes and may lower survival. [Funded by the TMC-Research Administration Council (TRAC); CHROME study (CHemoRadiotherapy followed by Oral Metronomic therapy in Esophageal cancer); ctri.nic.in number: CTRI/2015/09/006204]. CTRI/2015/09/006204.

Pseudoprogression and cancer immunotherapy: A seven year retrospective study of rate, temporal course, and predictive markers in an Irish tertiary referral center.

2651 Background: Immunotherapy is a relatively new treatment strategy which has achieved unprecedented clinical efficacy in many advanced malignancies. However, the pattern of tumour response to immunotherapy is distinct from other therapies and poses major challenges to clinicians. One such challenge is pseudoprogression. The aim of this study was to assess the current management of patients on immunotherapy with radiological evidence of disease progression at first restaging imaging in an Irish cancer centre, and to determine the rate, time course, and predictive markers of pseudoprogression in those patients treated beyond progression (TBP). Methods: Patients treated with immunotherapy for metastatic malignancy in MMUH between March 2013 and September 2020 were retrospectively drawn. Inclusion required follow-up restaging imaging every 4-12 weeks for the duration of treatment. Patterns of response during immunotherapy were established from radiology reports and categorized as stable (SD), response (R), mixed disease (MD), or progressive disease (PD). Pseudoprogression was defined as progression/ mixed disease at first restaging compared to baseline followed by subsequent response/stable disease. Results: The cohort of 228 patients was comprised of 80 NSCLC, 74 melanoma, 25 RCC, 19 gynaecological, 14 gastrointestinal, 6 breast, 1 ESSCLC, and 9 other cancer patients. Median age was 61.16 (IQR 49.47-69.44). Therapeutic agents were anti-PD1 alone (176) or in combination with targeted therapy (6) or CTLA4 (13), CTLA4 alone (15), and anti-PD-L1 alone (13) or in combination with chemotherapy (5). At first restaging, the number (%) classified as SD, R, MD, and PD, respectively, was 29 (12.8), 62 (27.2), 16 (7), and 76 (33.3). Treatment was stopped prior to restaging in 44 (19.3) cases. Of the 92 patients with mixed/ progressive disease, 41 were TBP and 51 were not treated beyond progression (NTBP). Evidence of radiological progression and worsening performance status (PS) were the most common reasons given by clinicians for NTBP. Of those TBP, 20 had subsequent response/stable disease, occurring at a median of 105.50 (range 58.0-420) days after the initial restaging scan and giving an overall pseudoprogression rate of 8.8%. At one year, 100% of the pseudoprogression group was alive. The neutrophil-lymphocyte ratio (NLR) was significantly lower in the pseudoprogression group compared to those with true progression (p = 0.006). There was no significant difference in performance status between the two groups. Conclusions: Pseudoprogression on cancer immunotherapy is real but uncommon, with an overall incidence of 8.8%. It can occur any time up to 420 days after initial progression and indicates a high likelihood of > 1 year survival. A low NLR may be a useful predictor of pseudoprogression but a technological solution is likely needed.

Neoadjuvant chemotherapy and disease recurrence after curative-intent surgery in patients with pancreatic adenocarcinoma: A single-center retrospective review.

e18610 Background: Early stage pancreatic ductal adenocarcinoma (PDAC) account for up to 30% of newly diagnosed patients. Until recently, the mainstay of treatment remained curative-intent surgery followed by adjuvant chemotherapy. More recently, the incorporation of neoadjuvant therapy (NAT) has demonstrated clinical benefit. The two commonly used regimens are 5-Fluorouracil, Leucovorin, Oxaliplatin and Irinotecan (FOLFIRINOX), or Gemcitabine and nab-Paclitaxel. Limited data is available to differentiate outcomes between the 2 common NAT regimens. We conducted a retrospective review to assess the rates of disease recurrence and progression after neoadjuvant chemotherapy and to identify any associations that may predict early recurrence. Methods: A retrospective review was conducted of all patients diagnosed with PDAC from 2017-2019 at Allegheny General Hospital. Data analysis was completed using IBM SPSS v23. Disease recurrence or progression was assessed radiologically, and time to progression was calculated as time (months) since diagnosis to evidence of radiological progression. Results: Out of 171 patients reviewed, 56 were deemed resectable or borderline resectable and underwent curative-intent surgery and were included in the analysis. Median age was 68, and 12 (41%) were male. Majority of the patients were white (90%). 29 (52%) patients received neoadjuvant chemotherapy: 16 (55%) received FOLFIRINOX, 12 (41%) received Gemcitabine with nab-Paclitaxel, and 1 received another regimen. 9 patients out of 16 (56%) that received FOLFIRINOX progressed, and 5 out of 12 patients (42%) who received Gemcitabine with nab-Paclitaxel progressed. Patterns of progression in those that received FOLFIRINOX: 1 (11%) within 6 months, 4 (44%) between 6-12 months, and 4 (44%) after 12 months. Of those that received Gemcitabine with nab-Paclitaxel, 2 (40%) progressed within 6 months, 1 (20%) progressed between 6-12 months, and 2 (40%) progressed after 12 months. On multivariate analysis, no association was identified to predict progression. Conclusions: There was no significant difference in disease progression rates among patients that received neoadjuvant FOLFIRINOX versus Gemcitabine and nab-Paclitaxel (42% vs. 56%; p = 0.46). No predictive associations were identified in patients with disease recurrence. Study limitations include a low sample size and retrospective analysis. Further, larger scale studies are warranted to better assess the difference in rates of progression after neoadjuvant FOLFIRINOX versus Gemcitabine and nab-Paclitaxel.[Table: see text]

Abstract CT211: EF-19 - A post-approval registry study of TTFields for the treatment of recurrent glioblastoma (GBM)

Abstract Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In phase 3 studies leading to FDA approvals, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide, and achieved comparable survival outcome to best standard of care (BSC) when used as monotherapy in recurrent GBM. The aim of the EF-19 study was to confirm the efficacy of TTFields versus BSC for recurrent GBM in the post-approval real-life setting. Method: This non-inferiority, prospective, non-randomized, post approval registry trial enrolled 192 recurrent GBM patients (>21 years, KPS > 70). All patients were treated with TTFields (200 kHz, >18h/day). Eligibility criteria included histological diagnosis of GBM, past treatment with the Stupp protocol for the primary disease and radiological evidence of progression in the supratentorial region. The primary endpoint was overall survival (OS); secondary endpoints included OS in the per protocol (PP) population (>1 course of TTFields or BSC in each respective arm), time to treatment failure and incidence of adverse events. The TTFields patient registry data were compared to OS of all 117 recurrent GBM patients in the BSC group of the EF-11 pivotal trial (Stupp R., et al., EJC 2012). The sample size of 192 patients (10% loss to follow up) was determined based on non-inferiority log-rank test with a two-sided alpha level of 0.05 and a power of 80%, comparing time to event (i.e., death) between patients treated with TTFields and BSC. The analysis was based on true hazard ratio (HR) of 1.0 comparing TTFields to control with an upper one-sided 95% confidence bound of HR is not exceeding 1.375. Result: Median OS in patients treated with TTFields versus EF-11 BSC was 7.4 vs. 6.4 months, p=0.053; HR = 0.64 (95%CI 0.46-0.91, Cox-test P=0.012). In the PP population, the median OS with TTFields versus EF-11 BSC was 8.1 months vs. 6.5 months, respectively; p=0.045; HR 0.65. The results show a significant superiority HR of overall survival between the ITT groups, as superiority 95% confident interval upper limit of the HR was lower than the pre-defined threshold for non-inferiority for interval bound of 1.375. The overall incidence of adverse event was lower in the TTFields arm (67% vs. 95%) vs. EF-11 BSC arm. The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9)) compared to the BSC arm (1.6 months; 95% CI 1.1, 1.9); HR=0.53 (95% CI 0.41, 0.68, p<0.0001). Skin AE was the most frequently reported AEs in TTFields-treated patients; No unexpected adverse events were reported with TTFields. Conclusion: The EF-19 confirmed the effectiveness and safety of TTFields as monotherapy in recurrent GBM. Citation Format: Jay-Jiguang Zhu, Robert T. O'Donnell, Zvi Ram. EF-19 - A post-approval registry study of TTFields for the treatment of recurrent glioblastoma (GBM) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT211.

EF-19, a post-approval registry study of tumor treating fields (TTFields) in recurrent glioblastoma (rGBM).

e14536 Background: Tumor Treating Fields (TTFields) are an anti-mitotic non-invasive therapy of low intensity alternating electric fields delivered to the tumor via a portable medical device. In phase 3 studies that led to FDA approvals, TTFields plus maintenance temozolomide significantly extended survival in newly diagnosed GBM, and achieved comparable survival outcome to best standard of care (BSC) as monotherapy in recurrent GBM (rGBM). The EF-19 study aimed to confirm efficacy of TTFields vs BSC in rGBM in post-approval real-life setting. Methods: This non-inferiority, prospective, non-randomized, post approval registry trial enrolled 192 rGBM patients (>21 yrs, KPS > 70). Patients were treated with TTFields (200 kHz, > 18h/day). Eligibility criteria: histologic GBM, past treatment per Stupp protocol for primary disease and radiological evidence of progression in the supratentorial region. Primary endpoint was overall survival (OS); secondary endpoints were OS in the per protocol (PP) population ( > 1 course of TTFields or BSC in each respective arm), time to treatment failure and adverse events. The TTFields patient registry data were compared to OS of all 117 rGBM patients in the BSC group of the EF-11 trial (Stupp R, EJC 2012). The sample size of 192 patients (10% loss to follow up) was based on non-inferiority log-rank test with a two-sided alpha level of 0.05 and a power of 80%, comparing time to event (i.e., death) between patients treated with TTFields and BSC. The analysis was based on true hazard ratio (HR) of 1.0 comparing TTFields to control with an upper one-sided 95% confidence bound of HR not exceeding 1.375. Results: Median OS with TTFields versus EF-11 BSC was 7.4 vs. 6.4 months, p = 0.053; HR = 0.64 (95%CI 0.46-0.91, Cox-test P = 0.012). Median OS (PP population) with TTFields versus EF-11 BSC was 8.1 months vs. 6.5 months; p = 0.045; HR 0.65. The results showed a significant superiority in HR of OS between the 2 groups, as the 95% confident interval upper limit of the HR was lower than the pre-defined threshold for non-inferiority for interval bound of 1.375. The overall incidence of adverse event was lower with TTFields than EF-11 BSC (67% vs. 95%). The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9) versus BSC arm (1.6 months; 95% CI 1.1, 1.9); HR = 0.53 (95% CI 0.41, 0.68, p < 0.0001). Skin AE was the most frequently reported AEs in TTFields arm; no unexpected adverse events were reported with TTFields. Conclusions: The results of the EF-19 registry study confirm the effectiveness and safety of TTFields monotherapy in rGBM.

A retrospective case series on the usefulness of fractionated stereotactic radiotherapy for benign intracranial tumors

Abstract Introduction Conventional radiation therapy has been progressively replaced by fractionated stereotactic radiotherapy (FSRT) and single fraction radiosurgery for dealing with benign intracranial lesions. Purpose of our study is to investigate the safety and efficacy of FSRT in a series of patients with benign intracranial tumors. Methods 31 patients with benign intracranial lesions treated with FSRT between 2006 and 2014 were retrospectively reviewed. Indications for treatment included post-operative residual tumor growth or symptomatic exacerbation in patients in whom surgery was not indicated. A clinical and radiological outcome evaluation was performed. Univariate analysis was executed to identify predictors for post-treatment neurological function and radiological tumor control. Results Median age was 62 years (range 22–82). The lesions treated included 20 meningiomas, 2 vestibular schwannomas, 7 pituitary adenomas, 1 craniopharyngioma, 1 jugular-tympanic paraganglioma. Median clinical target volume was 14.59 cm3 (range 0.43–159.06) and median planning treatment volume was 18.16 cm3 (range 0.81–217.24). Median total dose was 45 Gy (range 25–54), and median daily fraction 4 Gy (range 1.8–9). At a median follow-up of 78 and 50 months, respectively clinical and neuroradiological, no tumor had larger dimensions, and only one lesion changed in a way other than size determining a concomitant clinical worsening. Other three patients deteriorated without evidence of radiological progression. Conversely, 12 patients improved clinically. No significant predictor for post-treatment neurological function or radiological tumor control was found. Conclusion FSRT may represent, when indicated, a safe and effective treatment modality for benign intracranial tumors, especially for large/irregular lesions.

Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT).

4090 Background: The efficacy of peptide-radiolabelled receptor targeted therapy (PRRT) in patients with well differentiated neuroendocrine tumours has been demonstrated in Phase II and Phase III studies. The recently completed phase IV NETTER-01 demonstrated disease stabilisation or partial response in approximately 80% of patients. However, more studies are needed to identify predictors of PRRT response. We sought to investigate the clinic-pathological characteristics in patients that had radiological progression or death within 12 months of completion of treatment with PRRT. Methods: We performed a retrospective analysis of all patients who had PRRT from 2011-2016. Patient with at least one year of follow-up data from the last treatment dose were included. Patients with evidence of radiological progression within one year of finishing treatment (Group 1) were compared to a similar group with disease stabilisation/response (Group 2)that were matched for age, grade, primary and distribution of metastases. The indication for PRRT was defined as either small volume progression ( < 20%) or progression by RECIST. Results: 307 patients underwent PRRT with Lu-177 or Y-90 DOTATATE during this period. 66 patients in Group 1 were compared to 64 patients in Group 2. There was a significant difference in median overall survival, Group 1 = 21 months compared to Group 2 = 35 months, (p < 0.002). A significantly higher proportion of patients in group 1 had more than 50% liver volume (p < 0.0001). Mean CgA was significantly higher in Group 1, 1250 pg/ml vs 608 pg/ml in Group 2 ( p < 0.03). 18 patients in Group 2 had small volume progression prior to treatment commencement compared to 6 in Group 1 (p < 0.003). Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be conisdered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.

Chromogranin A as a predictor of radiological disease progression in neuroendocrine tumours.

Chromogranin A (CgA) is the best established neuroendocrine biomarker. This study was aimed at investigating the prognostic value of CgA as a predictor of radiological disease progression in neuroendocrine tumour (NET) patients. Patients with metastatic NETs and evidence of radiological progression (RP) according to RECIST 1.1 were identified from a NET database. Plasma CgA levels were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). A total of 152 patients were evaluated including 91 midgut NETs and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. For all NETs, there was a positive trend in terms of increase of CgA values 6 months prior to RP compared to 12 months before RP. Subgroup analysis at first episode of RP showed that for PNETs there was evidence of a difference in the median CgA levels. CgA 6 months before RP was 100 pmol/L [interquartile 1 (Q1) =53 and Q3 =286.25 pmol/L) and 12 months before was 52 pmol/L (Q1 =36.25 and Q3 =128 pmol/L), W=52, P=0.48. This observation was not confirmed in midgut NETs, where median CgA 6 months before RP was 389.5 pmol/L (Q1 =131.5 and Q3 =791.5 pmol/L) and 12 months before was 319 pmol/L (Q1 =158 and Q3 =753 pmol/L), W=191, P=0.39]. Low grade tumours (G1) had a median CgA value at 6 months significantly higher than at 12 months [181 (Q1 =56.25, Q3 =624) vs. 149.5 (Q1 =44, Q3 =247.25) pmol/L, W=70, P=0.48]. CgA seems to have predictive value 6 months prior to RP for PNETs and G1 tumours. Further prospective analyses are needed to enable more definitive conclusions.

PTH-093 Chromogranin-a : Can It Predict Radiological Progression In Neuroendocrine Tumours?

IntroductionChromogranin A (CgA) is considered as the best general marker for the diagnosis and follow-up of neuroendocrine tumours (NETs) and is also of prognostic value. In literature, there are no...

Sa1935 Variation and Utility Ofchromogranin a Assays for Gastric Carcinoid Type 1

Introduction: Chromogranin A (CgA) is considered as the best and most sensitive general marker for the diagnosis and follow-up of neuroendocrine tumors (NETs) and is also of prognostic value. However, there are no available studies to date, which analysed the role of CgA as a predictor of radiological disease progression in all NETs. Aim: To investigate the prognostic value of CgA as a predictor of radiological disease progression in NET patients. Methods: Patients with metastatic NETs and evidence of Radiological Progression (RP) according to Radiological Evaluation Criteria In Solid Tumors (RECIST 1.1) were identified from our NETs database. Plasma CgA were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). In our laboratory, the reference value of CgA has been established as 20%). Results: 152 patients were evaluable including 91 midgut NETs (mNETs) and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. The majority of the patients (95.4%) had liver metastases, whereas bone and lung metastases were present in a smaller proportion of patients (27.6% and 9.9%, respectively). Median CgA for all NETs, 6 months before RP,

Changes in mutational status during third‐line treatment for metastatic colorectal cancer—Results of consecutive measurement of cell free DNA, KRAS and BRAF in the plasma

KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma at baseline and before each cycle was analyzed by an in-house qPCR. cfDNA and pKRAS levels decreased from baseline to cycle three and increased at time of progression (p = 0.008). The decrease was larger in responding patients than in non-responding (p < 0.05). Two patients with primary mutant disease had different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation appeared in plasma before radiological evidence of progression. Loss of mutations may explain observed benefit of treatment in primary mutant disease, whereas appearance of mutations during therapy may be responsible for acquired resistance in primary wt disease. Benefit from EGFR MoAbs may be influenced by the quantitative level of mutational alleles rather than by mutational status alone, and plasma levels of cfDNA, KRAS and BRAF could be used to monitor patients during treatment.

A single-arm, phase II, multicenter trial of sunitinib maleate (SU) in locally advanced or metastatic pheochromocytoma/paraganglioma (PC/PG): Interim results.

431 Background: Metastatic PC/PG is rare and may be sporadic or have a genetic basis. Treatment remains challenging in the absence of well-controlled randomized trials. Case reports suggest clinical activity of SU in this setting. We aim to prospectively evaluate radiological and biochemical response to SU, and assess its toxicity profile in PC/PG. Methods: This is an ongoing single-arm, phase II, multicenter, investigator-initiated clinical trial, enrolling patients (pts) with metastatic or unresectable locally advanced malignant PG or PC with ECOG PS 0-2, no previous treatment with tyrosine kinase inhibitors, and evidence of radiological progression or disease-related symptoms. All pts receive 50mg SU daily at standard dosing, following blood pressure stabilization, and are assessed for radiological and biochemical response (with urine metanephrines, catecholamines or serum chromogranin A) q12 weeks until disease progression, unacceptable toxicity or pts withdrawal. Futility was defined as no documented responses within the first 14 patients and would have led to trial cessation. Results: Since May 2009, 14 pts enrolled in 3 academic hospitals (Canada and the Netherlands). Interim results of 10 pts are presented (pts characteristics are tabulated). Two pts had symptoms related to hormonal-excess and both had clinical improvement on SU. All 10 pts had biochemical evidence of hormonal excess, of which 5 had biochemical response (50%). Best radiological responses achieved were partial response (3/10 pts; 30%, 1 unconfirmed), stable disease &gt; 3 months (6/10; 60%) and progressive disease (1/10; 10%). Adverse events were consistent with known side-effects of SU. Seven pts had toxicity-related dose reductions, contributing to treatment cessation in two. Conclusions: This trial surpassed the pre-specified futility stopping rule with the current documented responses on SU and with durable patient benefit seen. Updated data will be presented and discussed. Clinical trial information: NCT00843037. [Table: see text]

Gliomatosis Cerebri Type 1 with Extensive Involvement of the Spinal Cord and BRAF V600E Mutation

Gliomatosis cerebri (GC) is a rare neoplasm in which there is a diffuse cerebral infiltration by malignant glial cells with relative conservation of the underlying structures. A 67-year-old lady was admitted complaining of balance problems, troubled breathing, stuttered speech, decreased mobility, progressive ataxia and also some mild cognitive problems. MRI demonstrated ill defined T2 hyperintensity with mild mass effect mainly involving the brain stem and cerebellar hemispheres, with minor signal abnormalities extending supratentorially along the corticospinal tracts. The imaging appearances were static over a year. No biopsy was performed. The patient received palliative care and died 2 years after initial presentation. Macroscopic examination of the brain showed an extensive firm white-grey lesion predominantly in the cerebellar white matter, the brainstem, spreading to the full length of the spinal cord and invading the sensory ganglia. Histology revealed an extensively infiltrating diffuse glioma with small elongated fusiform nuclei. Diagnosis of GC type 1 was made. Molecular genetic tests revealed BRAF V600E mutation, while no IDH1 & IDH2 mutations were found. GC should be taken into account in the differential diagnoses mainly when there is rapid clinical deterioration without clear evidence of radiological progression. Extensive spinal cord infiltration has been reported only in 9% and BRAF V600E mutation was detected only in one case in GC previously. Future clinical trials should address whether BRAF V600E mutant brain tumour patients will benefit from BRAF V600E-directed targeted therapies.

A lower-dose, lower-toxicity cisplatin–etoposide regimen for childhood progressive low-grade glioma

After successfully using cisplatin (30 mg/m(2)/day) and etoposide (150 mg/m(2)/day) in ten three-day courses for progressive low-grade gliomas, a subsequent protocol reduced the daily doses of cisplatin (to 25 mg) and etoposide (to 100 mg), with the objective of achieving the same response and three-year PFS rates with lower neurotoxicity and myelotoxicity. We treated 37 patients (median age 6 years); 23 had optochiasmatic tumours and nine were metastatic cases. Diagnoses were clinical in 13 cases and histological in 24, and comprised: pilocytic astrocytoma (17), ganglioglioma (3), pilomyxoid astrocytoma (2), and fibrillary astrocytoma (2). Treatment was prompted by radiological evidence of progression and/or clinical deterioration a median 18 months after the first diagnosis. After initial MRI staging, neurological and clinical examinations were performed before each chemotherapy cycle, with MRI after the first three courses and every three months thereafter. After a median 48 months, a volume reduction was appreciable in 24 cases (65%) and response was maximum 12 months after starting treatment. The three-year EFS and OS rates were 65 and 97%, respectively. Clinical, neurological, or functional improvements were seen in 26/37 cases. No children had a WBC nadir below 2,000/mm(3). Audiological toxicity caused damage in 4/34 cases. The previous protocol had achieved volume reductions in 70% of cases, causing audiological damage (data updated) in 11/31 (P = 0.023), with three-year PFS and OS rates of 70 and 100%, respectively. Lower doses of cisplatin/etoposide are still effective in progressive low-grade glioma, with less acute and persistent morbidity.

Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC)

BackgroundHistone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). Patients and methodsA dose of 13 mg/m2 was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (Ho=0.10, Ha=0.30; α and β=0.10). ResultsThirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting ≥6 months, along with a confirmed prostate-specific antigen decline of ≥50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. ConclusionsAt the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.

Is There a Role for Circulating Tumor Cells in the Management of Breast Cancer?

Circulating tumor cells (CTC) can be identified and characterized in blood of patients with many solid tumors, particularly breast cancer. Between 10% and 30% of patients with stage I to III breast cancer and 50% to 70% of women with metastatic breast cancer have detectable CTCs. In both cases, presence and elevation of CTCs are associated with worse prognosis. In the metastatic setting, persistent CTC after 3 to 5 weeks of a new therapy seem to indicate lack of activity of that regimen, and an ongoing prospective randomized clinical trial is addressing the relative worth of changing to an alternative treatment rather than waiting for classic clinical and radiologic evidence of progression. Recent technical advances offer the promise of further genotyping and phenotyping for important tumor-associated genes and proteins.

Role of hypofractionated stereotactic radiotherapy in treatment of skull base meningiomas

The objective of this paper is to examine the efficacy and safety of hypofractionated stereotactic radiotherapy (SRT) in the treatment of skull base meningiomas. Thirty-eight patients were treated with a median prescribed dose of 37.5 Gy in 15 fractions to the 80% isodose. Median follow-up was 47 months. Ten males and 28 females of median age 55.5 years were followed. SRT was the primary treatment in 15 patients, adjuvant in 10 and given for recurrence in 14 patients. On clinical follow-up 27 patients are unchanged and in six their symptoms have resolved. One patient had symptomatic deterioration and four patients have developed new symptoms. No patients have radiological evidence of progression. Our data suggest that conventional hypofractionated radiotherapy schemes for benign CNS disease may be useful in conjunction with stereotactic techniques. Such schemes are attractive in terms of resource allocation and where tumour size or cranial nerve tolerance is of concern.