Case Of Pseudoprogression Research Articles

Efficacy of immunotherapy in advanced gastric cancer: preliminary results of a multicenter observational study

Background: Due to the low efficacy of PD-L1 antibodies in second and subsequent lines of metastatic gastric cancer (mGC), the optimal treatment strategy of such patients and appropriate choice of predictive biomarkers remain challenging. The aim of our study is to assess the efficacy of immune checkpoint inhibitors monotherapy in patients with mGC in routine clinical practice, especially in heavily-pretreated patients. Materials and methods: We retrospectively analyzed data of patients treated in five oncology centers in Moscow between 2018 and 2023, who received nivolumab or pembrolizumab for advanced gastric cancer. Primary end-point of our study was 6-months PFS. Secondary end-points were overall survival (OS), objective respons e rate (ORR), and disease control rate (DCR). Toxicity was assessed using CTC AE v5.0 scale. Results: 122 patients with mGC who received immune checkpoint inhibitors were included between 1 January 2018 and 28 February 2023. 6-months PFS rate was 31,6 %. The median OS was 7 months (95 % CI: 2–20), the median PFS was 3 months (95 % CI: 1,5–9,5). A statistically significant difference in OS was detected in patients with MSI compared to MSS (25 months vs 6 months; 95 % CI: 0,21–0,86; HR: 0,43). A trend towards higher PFS was observed as well (10 months in MSI vs 3 months in MSS; 95 % CI:0,26–1,01; HR: 0,51). No statistical significance in PFS and OS according to PD-L1 CPS was found among patients with MSS. ORR and DCR were 36,6 % and 10,6 %, respectively. No cases of pseudoprogression or fatal immune-related AEs were observed. Conclusion: Our real-world data is consistent with published literature and the results from clinical trials. Further studies are needed to determine prognostic factors and to establish prognostic model of patients receiving ICIs for optimal treatment strategy of mGC.

BIOM-20. IDENTIFICATION OF BLOOD BIOMARKERS FOR DIFFERENTIATING PSEUDOPROGRESSION FROM RECURRENCE IN GLIOBLASTOMA

Abstract After the initial treatment of glioblastoma, we occasionally encounter difficulty in distinguishing between pseudoprogression and recurrence. Observation without obtaining a pathological diagnosis is a common strategy in clinical practice. If the differentiation can be achieved easily, and reliably, early treatment can be introduced appropriately, leading to the benefits of early glioblastoma treatment. In this study, we attempted to identify blood biomarkers that help distinguish between recurrence and pseudoprogression. Blood samples were collected in 25 cases of primary glioblastoma, IDH wild type, at three time points: before treatment, after standard treatment: operation and temozolomide chemotherapy with concomitant radiation therapy, and when an enhancing lesion was recognized (21 cases of recurrence, 4 cases of pseudoprogression). Gelsolin (GSN), Apolipoprotein A-IV, Osteopontin, SERPINA3, ITIH2/4 Ceruloplasmin, LRG1, Collagen-1A2, which we previously extracted as diagnostic markers, using the comprehensive proteomics SWATH method, in blood samples of healthy volunteers and patients with glioblastoma (PLoS One. 2018, J Proteome Res. 2020), were analyzed. Absolute quantitative values of candidate molecules in the blood were obtained using a commercially available enzyme-linked immunoassay. Among the candidate molecules, GSN was significantly lower in pseudoprogression than in recurrence (p = 0.0032), and ROC analysis showed sensitivity of 95%, specificity of 100%, and an AUC = 0.98, which makes GSN a useful molecule to consider as a differential marker. We previously reported that GSN, actin binding protein, and inflammation markers are downregulated in glioblastoma (Cancer Sci. 2020). In summary, GSN was extracted as a candidate blood biomarker for the diagnosis of pseudoprogression. We are planning to validate the research with nationwide multi-institutional studies.

Toripalimab combined with nab-paclitaxel/gemcitabine as first-line treatment for advanced pancreatic adenocarcinoma: Updated results of a phase Ib/II clinical study.

e16244 Background: Much controversy remains regarding the immune-checkpoint-inhibitor plus Nab-paclitaxel/gemcitabine (AG) as the treatment in advanced pancreatic ductal adenocarcinoma (aPDAC). We assess safety and efficacy of toripalimab plus AG in aPDAC, this was the updated results of the study. Methods: This was a phase Ib/II clinical study of toripalimab plus AG as first-line treatment for aPDAC. Toripalimab (240mg, Q3W), combined with AG (nab-paclitaxel 125 mg/m2, d1, d8 plus gemcitabine 1000 mg/m2, d1, d8) were administrated until the disease progresses/unacceptable toxicity or receiving toripalimab maintenance treatment. The primary endpoints were safety and OS; the secondary endpoints were ORR, DCR and PFS. Predictive biomarkers including gene mutations based on next-generation sequencing and PD-L1 expression were assessed. Results: Until January 2022, 55 chemotherapy-naïve aPDAC evaluable patients (beyond 90% patients with metastatic lesions) to safety and response, ECOG PS≤2 were enrolled. The ORR was 29.1%, the DCR was 90.9%, including 15 patients with PR and 1 patient with CR, 34 patients with SD respectively. 33 patients were alive and 16 patients were still ongoing study. Median PFS was 5.0 months (95% CI: 4.033-5.967), the 6-month PFS rate was 56.4%; median OS was 10.0 months (95% CI: 6.321-13.679), the 1-year OS rate was 69.1%. 2 cases of pseudoprogression were observed. The most frequent treatment related adverse events (TRAE) were anemia (90.1%, G3/4: 9.1%), hypoproteinemia (73%, G3/4: 5.5%), AST elevation (61.0%, G3/4: 3.6%), ALT elevation (60%, G3/4: 5.5%), hypothyroidism (51%, G3/4: 0%), leukocytopenia (45.4%, G3/4: 5.5%), neutropenia (44%, G3/4: 9.1%), nausea (44%, G3/4: 3.6%), rash (38.1%, G3/4: 0%). And 23 patients (41.8%) experienced grade 3/4 TRAE. In the biomarker analysis, all 55 patients were MMR-proficient status; 37 patients were evaluated for PD-L1 expression, PD-L1 positive cases (PD-L1 TPS > 1% and/or CPS > 2, n = 12, 6 patients achieved PR) compared with PD-L1 negative cases (n = 25) presented higher ORR (50% vs 16%). 44 patients were investigated for NGS in 55 evaluable patients, KRAS mutation (86.4%) was the most frequently mutated genes (KRAS G12D = 20 patients, KRAS G12V = 13 patients, KRAS G12R = 4 patients, KRAS G12C = 1 patients), and germline BRCA2 mutation was observed in one patient. The correlation between gene mutation and efficacy and prognosis is under analyzed. Conclusions: The updated results of this phase Ib/II study has met our preset primary endpoint with 69.1% in 1-year OS rate, provided promising evidence that toripalimab in combination with AG has a manageable safety profile and expected antitumor activity. The correlation between biomarkers with clinical efficacy are under investigation. The results supported ongoing combined treatment in aPDAC patients. Clinical trial information: ChiCTR2000032293.

Toripalimab with nab-paclitaxel/gemcitabine as first-line treatment for advanced pancreatic adenocarcinoma: Updated results of a single-arm, open-label, phase Ib/II clinical study.

e16213 Background: Currently nab-paclitaxel/gemcitabine (AG) is the standard first-line treatment for advanced pancreatic ductal adenocarcinoma (aPDAC), which is still needed to improve. The phase Ib/II study aiming to evaluate safety and efficacy of AG plus toripalimab, an anti-PD-1 monoclonal antibody, showed well tolerability and encouraging efficacy in aPDAC patients (preliminary data presented at 2020 ASCO). Here, we updated new results of this study. Methods: This was a single-arm, open-label, phase Ib/II clinical trial of AG with toripalimab as first-line treatment for aPDAC. Patients received toripalimab (240mg, Q3W), combined with AG (nab-paclitaxel 125 mg/m2, d1, d8 plus gemcitabine 1000 mg/m2, d1, d8) until the disease progresses/unacceptable toxicity or receiving toripalimab maintenance treatment. The primary objectives were safety and OS; the secondary objectives were ORR, DCR and PFS. Predictive biomarkers including MMR protein and PD-L1 expression, the tumor mutation burden (TMB) based on next-generation sequencing, genomic alteration signatures and the number of TILs were evaluated. Results: At data cutoff (Feb 3, 2021), 20 chemotherapy naïve aPDAC patients (female: 65.0%, median age: 55.5 years) with ECOG PS ≤ 2 were enrolled. Of the 17 evaluable patients, the ORR was 35.3%, the DCR was 82.4%, including 5 patients with PR and 1 patient with CR, respectively. 12 patients were alive and the study treatments for 9 patients were still ongoing. Median PFS was 5.0 months (95% CI：4.216-5.784), the 6-month PFS rate was 60%; median OS was 14.0 months (95% CI：9.445-18.555), the 1-year OS rate was 80%. 2 cases of pseudoprogression were observed. The most frequent treatment related adverse events were ALT elevation (35.0%), leukocytopenia (30.0%) metabolic disorder (25.0%) and hypothyroidism (25.0%). 4 patients (20.0%) experienced grade 3/4 TRAE (including myocardial enzyme elevation, neutropenia, vomiting and nausea). In the biomarker analysis, all patients were MMR-proficient status; 14 patients were evaluated for PD-L1 expression compared with PD-L1 negative cases (n = 5), PD-L1 positive cases (n = 9) did not show higher RR or longer PFS, responses were observed in both groups. 10 patients were investigated for NGS, 2 patients with TMB > 10 Muts/Mb, the most frequently mutated genes were KRAS (90%), TP53 (90%) and ARID1A (20%). Conclusions: The updated results of this phase Ib/II study provided preliminary evidence that toripalimab in combination with AG has a manageable safety profile consistent with known safety profile for each agent alone and demonstrates signals of clinical activity. The correlation between biomarkers with clinical efficacy are under investigation. The results supported ongoing combined treatment in aPDAC patients. Clinical trial information: ChiCTR2000032293.

Pretreatment ADC predicts tumor control after Gamma Knife radiosurgery in solid vestibular schwannomas.

Radiosurgery is a well-established treatment for vestibular schwannomas (VSs), but it is often difficult to identify which tumors will respond to treatment. We sought to determine whether pretreatment or posttreatment tumor apparent diffusion coefficient (ADC) values could predict tumor control in patients undergoing Gamma Knife radiosurgery (GKRS) and whether these values could differentiate between cases of pseudoprogression and cases of true progression in the early posttreatment period. We retrospectively identified patients who underwent GKRS for solid VSs between June 2008 and November 2016 and who had a minimum follow-up of 36 months. Pretreatment and posttreatment minimum, mean, and maximum ADC values were measured for the whole tumor volume and were compared between patients with tumor control and those with tumor progression. In patients with early posttreatment tumor enlargement, ADC values were compared between patients with pseudoprogression and those with true progression. Of the 44 study patients, 34 (77.3%) demonstrated tumor control at final follow-up. Patients with tumor control had higher pretreatment minimum (1.35 vs 1.09; p = 0.008), mean (1.80 vs 1.45; p = 0.004), and maximum (2.41 vs 1.91; p = 0.011) ADC values than patients with tumor progression. ADC values did not differ between patients with pseudoprogression and those with true progression at early posttreatment follow-up. ADC values may be helpful in predicting response to GKRS in patients with solid VSs but cannot predict which tumors will undergo pseudoprogression. Patients with higher pretreatment ADC values may be more likely to demonstrate posttreatment tumor control.

BIOM-49. SERUM microRNA IS A PROGNOSTIC AND POST-OPERATIVE MONITORING BIOMARKER IN GLIOMA

Abstract Although magnetic resonance imaging (MRI) provides accurate anatomical and spatial details regarding gliomas, it is not reliable at predicting biological behaviour and is confounded by problems such as pseudo-progression. A circulating biomarker has potential to improve predictions of glioma outcomes and identify tumor progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA (miRNA) serum biomarker for longitudinal monitoring of glioma patients as well as identify miRNAs that are predictive of survival outcomes. To investigate this a prospectively collected cohort of 91 gliomas and 17 healthy controls underwent pre- and post-operative serum miRNA profiling using the next-generation sequencing platform Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow-up samples and compared to tumor volume based on MRI. A lasso-regression model was used to identify candidate miRNAs from pre-operative serum that were associated with both progression-free and overall survival. We identified a 9-gene miRNA signature that could distinguish between glioma and healthy controls with 99.8% accuracy. From this signature, we identified two miRNAs that demonstrated dynamic changes which correlated closely with tumor volume in both LGG and GBM. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. Additionally, altered expressions of 6 miRNAs were found to be associated with overall and progression-free survival and were incorporated in a predictive model with already known survival factors. In conclusion, we have identified a highly accurate 9-miRNA signature associated with glioma serum and observed specific miRNAs that both correlated with tumor volume over long-term follow up and were predictive of survival. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

Serum microRNA is a biomarker for post-operative monitoring in glioma.

A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients. A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging. A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

A Case of Pseudoprogression in Oropharyngeal Cancer with Nivolumab

A Case of Pseudoprogression in Oropharyngeal Cancer with Nivolumab

Pseudoprogression presenting as intestinal perforation in non-small cell lung cancer treated with anti-PD-1: A case report.

Pseudoprogression is not frequently observed in patients with non-small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. We report on a case of pseudoprogression, which was presented as intestinal perforation after pembrolizumab immunotherapy for NSCLC. A-54-year-old man with stage IV NSCLC received pembrolizumab therapy. The patient was admitted to our hospital because of acute abdominal pain and the computed tomography scan revealed diffuse wall thickening of the small bowel with free intraperitoneal air. Intestinal perforation was suspected and surgical resection was performed. Histological evaluation of the resected specimen showed infiltrated lymphocytes positive for CD3, CD8 with necrotic tumor cells, suggestive of an immune reaction. Although intestinal perforation after treatment with immune checkpoint inhibitors is rare, it can be an unusual presentation of pseudoprogression and clinicians should be aware of this possibility.

Response assessment in non-small cell lung cancer immunotherapy: initial experiences in utilizing FDG PET/CT and the PD-1 blocker nivolumab

Most Non-Small-Cell lung cancer (NSCLC) patients need systemic treatment. Immunotherapy is now current standard in first- and second-line treatment. In all pivotal studies, staging was performed using conventional computer tomography (CT) scans. PET/CT-based treatment monitoring is on the contrary recommended in NSCLC guidelines. This investigation aims at describing the benefits, challenges and possible pitfalls of using PET/CT-based monitoring for lung cancer during immunotherapy. We analyzed 11 NSCLC patients treated with nivolumab at a German tertiary care lung cancer center between 2015 and 2016. All patients received at least two follow-up PET-CTs. Evaluation of response was based on both Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST) criteria. In 7 out of 11 cases, the RECIST and PERCIST results concurred, but two patients with initial stable disease regarding RECIST were reclassified as progressive metabolic disease based on PERCIST criteria. Additionally we identified one case of pseudoprogression using PERCIST criteria in contrast to stable disease using RECIST criteria and one case showing an early and durable response to nivolumab treatment using RECIST, despite a highly hypermetabolic mediastinal lymph node metastasis. The findings indicate that the PERCIST-based evaluation could identify progressive disease earlier. Early identification of nonresponders could lead to prevention of overtreatment and to an early switch to a more effective therapy.

A Case of Pseudoprogression in Lung Adenocarcinoma Treated with Nivolumab

A Case of Pseudoprogression in Lung Adenocarcinoma Treated with Nivolumab

Histological and Immunohistological Features of Reccurences in Patients with High Grade Diffuse Astrocytic Tumors

The objective: to study recurrences of high grade diffuse astrocytic tumors and to attempt to create some recommendations for their following treatment.Materials and methods. 25 relapsed cases were investigated. 15 of them were early recurrences and 10 were late recurrences. The primary tumor specimens from patients with early recurrences were additionally examined to value tumor transformation. Case histories of patients were studied retrospectively. The histological investigation and immunohistochemistry were performed. Immunohistochemical analysis included expression of 12 markers: GFAP, Anti-IDH1R132H, vimentin, EGFR, Ki-67, MMP-9, VEGF,CD34, CD3,CD4, CD8, CD68. Mutation IDH1105GGTSNP was detected through molecular analysis. Statistical analysis was used to value quantitative and qualitative data. Tumor transformation in paired samples was valued with the McNemar test.Results. The one case of pseudoprogression was found among all studied recurrences. Post-treatment effects were more common in early recurrences rather than for late recurrences. In early relapsed tumors, a significant increase of CD8-cell infiltration was observed (McNemar test p-value=0,01343; p <0,05). The index of vascularisation was significantly higher in early recurrences (Mann-Whitney U test, р exect=0,016, р<0,05). There was a strong direct correlation between the index of vascularisation and the percentage of tumor cells expressed MMP-9 (rs=0,893, р<0,05). The mutation IDH1105GGTSNP related to cases of late recurrences (Mann-Whitney U test; p=0,043 p<0,05).Conclusion. It is important to distinguish pseudoprogression from true progression because it leads to a different treatment strategy. The knowledge of proliferative, vascular and invasive features of the relapsed tumor, the study of their immune response will make possible to create and to put into practice the effective personalized treatment for patients with high grade astrocytomas.

Phase I study of hypofractionated intensity modulated radiation therapy with concurrent and adjuvant temozolomide in patients with glioblastoma multiforme

PurposeTo determine the safety and efficacy of hypofractionated intensity modulated radiation therapy (Hypo-IMRT) using helical tomotherapy (HT) with concurrent low dose temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma multiforme (GBM).Methods and materialsAdult patients with GBM and KPS > 70 were prospectively enrolled between 2005 and 2007 in this phase I study. The Fibonacci dose escalation protocol was implemented to establish a safe radiation fractionation regimen. The protocol defined radiation therapy (RT) dose level I as 54.4 Gy in 20 fractions over 4 weeks and dose level II as 60 Gy in 22 fractions over 4.5 weeks. Concurrent TMZ followed by adjuvant TMZ was given according to the Stupp regimen. The primary endpoints were feasibility and safety of Hypo-IMRT with concurrent TMZ. Secondary endpoints included progression free survival (PFS), pattern of failure, overall survival (OS) and incidence of pseudoprogression. The latter was defined as clinical or radiological suggestion of tumour progression within three months of radiation completion followed by spontaneous recovery of the patient.ResultsA total of 25 patients were prospectively enrolled with a median follow-up of 12.4 months. The median age at diagnosis was 53 years. Based on recursive partitioning analysis (RPA) criteria, 16%, 52% and 32% of the patients were RPA class III, class IV and class V, respectively. All patients completed concurrent RT and TMZ, and 19 patients (76.0%) received adjuvant TMZ. The median OS was 15.67 months (95% CI 11.56 - 20.04) and the median PFS was 6.7 months (95% CI 4.0 – 14.0). The median time between surgery and start of RT was 44 days (range of 28 to 77 days). Delaying radiation therapy by more than 6 weeks after surgery was an independent prognostic factor associated with a worse OS (4.0 vs. 16.1 months, P = 0.027). All recurrences occurred within 2 cm of the original gross tumour volume (GTV). No cases of pseudoprogression were identified in our cohort of patients. Three patients tolerated dose level I with no dose limiting toxicity and hence the remainder of the patients were treated with dose level II according to the dose escalation protocol. Grade 3–4 hematological toxicity was limited to two patients and one patient developed Grade 4 Pneumocystis jiroveci pneumonia.ConclusionHypo-IMRT using HT given with concurrent TMZ is feasible and safe. The median OS and PFS are comparable to those observed with conventional fractionation. Hypofractionated radiation therapy offers the advantage of a shorter treatment period which is imperative in this group of patients with limited life expectancy.

Pseudoprogression after radiotherapy with concurrent temozolomide for high-grade glioma: clinical observations and working recommendations

Background Treatment of newly diagnosed GBM with postoperative RT and concomitant TMZ followed by 6 months of TMZ maintenance therapy has been shown to significantly improve overall survival compared with RT alone. Standard clinical assessments of these patients include Gd-MRI as well as neurologic evaluation. Frequently, patients exhibit immediate post-RT changes in enhancement on Gd-MRI that mimic tumor progression (ie, pseudoprogression or radiation-induced imaging changes). With the introduction of concomitant RT plus TMZ for treatment of malignant glioma, there appears to be an increasing incidence of pseudoprogression. Case Description In our experience, pseudoprogression after concomitant RT plus TMZ is typically not observed at first imaging immediately after completion of the therapy; but delayed focal enhancement mimicking tumor progression frequently occurs during the 6 months of maintenance therapy with TMZ. Pseudoprogression may reflect the radiosensitizing effect of TMZ during concomitant therapy, and retaining patients on treatment allows them to have enhanced survival and preserved quality of life. We observed 3 cases of pseudoprogression among 54 consecutive patients who were treated with this regimen. These patients developed pseudoprogression within 2 to 6 months after completion of concomitant RT plus TMZ, but all 3 patients completed maintenance chemotherapy and remained progression free for at least 15 months after diagnosis. Conclusion Functional imaging may improve the noninvasive diagnosis of pseudoprogression, but randomized prospective studies are needed to evaluate the real impact of pseudoprogression and validate neuroradiological techniques able to make a reliable distinction between tumor recurrence and pseudoprogression.