Role In Progression-free Survival Research Articles

Comparing the clinical efficacy and safety of second-line targeted therapy and immunotherapy in patients with mid- to advanced stages of hepatocellular carcinoma - A systematic review and meta-analysis of randomized clinical trials.

The aim of this study was to examine the efficacy and safety of second-line immunotherapy and targeted treatment in hepatocellular carcinoma (HCC). From January 2000 to January 2023, ProQuest, PubMed, Web of Science, Scopus, Embase, and the Cochrane Library databases were searched for randomized controlled trials (RCTs) using immunotherapy or targeted therapy as second-line therapy for mid-to-advanced stages of HCC. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) are all examples of measures of success. This analysis included twenty Randomized Clinical Trials (RCTs) from phases II and III. Collective data revealed better OS with immunotherapy (HR = 0.79; 95% CI: 0.67, 0.93 vs. 0.85; 95% CI: 0.78, 0.92), while the targeted therapy played a more effective role in PFS (0.67; 95% CI: 0.56, 0.81). Also, the second-line immunotherapy had a lower odds ratio of AEs of grades 3-5 than the targeted therapy did (OR = 1.75; 95% CI = 0.89, 3.46). Overall, it appears that targeted medication and immunotherapy as a second-line treatment strategy have generally improved substantially, as well as progression-free survival for patients with mid-to-advanced HCC. Although it is difficult to judge their efficiency, the occurrences of AEs were greater in targeted therapy compared to immunotherapy.

Identification and validation of PCSK9 as a prognostic and immune-related influencing factor in tumorigenesis: a pan-cancer analysis.

Proprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer. Using a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of PCSK9 and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma. Overall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients. PCSK9 could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers.

Gut Microbiome Is Associated With the Response to Chemoradiotherapy in Patients With Non-small Cell Lung Cancer

To explore the dynamic change of gut microbiota and its predictive role in progression-free survival (PFS) in non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). Forty-one patients with NSCLC in 2 phase 2 trials (NCT02573506 and NCT03006575) were analyzed. A total of 102 fecal samples were collected at 3 time points (T0, before CCRT; T1, 2 weeks after the initiation of CCRT; and T2, the end of CCRT). Gut microbiota composition and functionality were analyzed by 16S rRNA gene sequencing and shotgun metagenomics, respectively. Alpha diversity, taxonomic composition, and KEGG functional pathways were compared between patients in the long-PFS group (PFS ≥11.0 months) and short-PFS group (PFS <11.0 months). A random forest classifier was constructed to identify microbial signature related to PFS. Clinical and microbial factors potentially predictive of PFS were assessed in the univariate and multivariate Cox regression analysis. The abundance of Bacteroidota and Proteobacteria increased, while the abundance of Firmicutes decreased after CCRT. Shannon index (P=.006) and PD index (P=.022) were significantly higher in the long-PFS group than for those in the short-PFS group at T1. The PFS-prediction microbial signature at T1 included unclassified members of the Lanchospiraceae spp., such as NK4A136 and UCG-003 groups, Dorea sp., various strains from within the Eubacterium hallii and E. siraeum groups, and an unclassified member of the Muribaculaceae, which yielded an area under the ROC curve of 0.87. These discriminatory genera mostly belong to phylum Firmicutes/family Clostridia. Multivariate analysis indicated PD index (HR=8.036, P=.016) and the abundance of Dorea sp. at T1 (HR=4.186, P=.043) were independent predictors of PFS. The KEGG pathways at T1 overrepresented in the long-PFS group included fatty acid metabolism, fatty acid biosynthesis, and arginine biosynthesis. Those overrepresented in the short-PFS group included lipopolysaccharide biosynthesis, ascorbate and aldarate metabolism, and biosynthesis of vancomycin group antibiotics. Gut microbiota composition and functionality at 2 weeks after the initiation of CCRT were associated with PFS in NSCLC. Further research is needed to confirm these results.

Spectroscopic imaging of D-2-hydroxyglutarate and other metabolites in pre-surgical patients with IDH-mutant lower-grade gliomas

PurposePrognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of patients with grade 2 and 3 glioma using 2HG-specific in vivo MR spectroscopy, to determine their relationship with image-guided tissue pathology and predictive role in progression-free survival (PFS).MethodsForty-five patients received pre-operative MRIs that included 3-D spectroscopy optimized for 2HG detection. Spectral data were reconstructed and quantified to compare metabolite levels according to molecular pathology (IDH1R132H, 1p/19q, and p53); glioma grade; histological subtype; and T2 lesion versus normal-appearing white matter (NAWM) ROIs. Levels of 2HG were correlated with other metabolites and pathological parameters (cellularity, MIB-1) from image-guided tissue samples using Pearson’s correlation test. Metabolites predictive of PFS were evaluated with Cox proportional hazards models.ResultsQuantifiable levels of 2HG in 39/42 (93%) IDH+ and 1/3 (33%) IDH– patients indicated a 91.1% apparent detection accuracy. Myo-inositol/total choline (tCho) showed reduced values in astrocytic (1p/19q-wildtype), p53-mutant, and grade 3 (vs. 2) IDH-mutant gliomas (p < 0.05), all of which exhibited higher proportions of astrocytomas. Compared to NAWM, T2 lesions displayed elevated 2HG+ γ-aminobutyric acid (GABA)/total creatine (tCr) (p < 0.001); reduced glutamate/tCr (p < 0.001); increased myo-inositol/tCr (p < 0.001); and higher tCho/tCr (p < 0.001). Levels of 2HG at sampled tissue locations were significantly associated with tCho (R = 0.62; p = 0.002), total NAA (R = − 0.61; p = 0.002) and cellularity (R = 0.37; p = 0.04) but not MIB-1. Increasing levels of 2HG/tCr (p = 0.0007, HR 5.594) and thresholding (≥ 0.905, median value; p = 0.02) predicted adverse PFS.ConclusionIn vivo 2HG detection can reasonably be achieved on clinical scanners and increased levels may signal adverse PFS.

New Challenges in Evaluating Outcomes after Immunotherapy in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

In many recurrent and/or metastatic cancers, the advent of immunotherapy opens up new scenarios of treatment response, with new phenomena, such as pseudoprogression and hyperprogression. Because of this, different immune-related response criteria have been developed, and new therapeutic strategies adopted, such as treatment beyond progression. Moreover, the role of progression-free survival as a surrogate has been questioned, and new surrogate endpoint hypotheses have arisen. A proper understanding of radiological imaging, an assessment of the biological events triggered by therapy, and the clinical evolution of the lesions and of the patient performance status are all factors that should be considered to guide the oncologist’s treatment choice. The primary aim of this article is to discuss how all these concepts apply to recurrent/metastatic head and neck squamous cell carcinoma patients when treated with immunotherapy.

Diagnosis of first relapse and its impact on quality of life in patients with advanced ovarian cancer (AGO-OVAR 19/II).

e17609 Background: Maintenance or improvement of health-related quality of life (QoL) is one of the major goals for patients with advanced ovarian cancer (OC). QoL is influenced by symptoms of disease on the one and beneficial or adverse effects of surgical and systemic treatment on the other side. In addition, QoL is also an important patient centered endpoint in clinical trials to support primary endpoints such as progression-free survival (PFS). This analysis evaluates the impact of the diagnosis of first relapse on QoL. Methods: Patients with primary OC were included before start of treatment. QoL was assessed by the cancer-specific questionnaires EORTC QLQ‐C30 and QLQ‐OV28 and the generic EQ‐5D 3L at baseline and every 3 months thereafter, to describe the influence of treatment and course of disease on QoL. QoL data within 100 days before and after the first relapse were compared (part 2 of NCT02828618). QoL scales were analyzed by repeated measures regression. We report model-based pre- and post-recurrence means and p-values for the difference in means. Results: In total, 269 had a PFS event with a median PFS of 20.3 months. This analysis includes 186 patients; 122 with QoL assessment before and after relapse and 50 and 14 with assessment only before or after relapse. Median age was 62.5 years (range 31 – 90). The number of evaluable answers for each domain ranged between 166 and 172 before recurrence and 135 and 137 after recurrence. Global QoL decreased from 61.4 to 48.4 points (p &lt; 0.001) with the diagnosis of recurrence. The following scales showed a deterioration of at least 10 points: Social functioning (65.7- &gt; 52.6), fatigue (55.8 - &gt; 44.5), appetite loss (22.5 - &gt; 33.4), emotional functioning (65.2 - &gt; 54.9), role functioning (56.5 - &gt; 46.4); (all p &lt; 0.001). EQ-5D 3L visual analogue scale showed a deterioration from 66.4 to 55.0 (p &lt; 0.001). Conclusions: The event of first relapse is associated with a significant and clinically relevant deterioration of global QoL including several subscales. Therefore, prolongation of PFS preserves QoL, which supports the role of PFS as meaningful primary endpoint in ovarian cancer trials. Clinical trial information: NCT02828618.

Results of the surgical treatment of primary skin melanoma depending on the method of tumor excision and options for closing the surgical defect

The aim of the study was to analyze the results of the surgical treatment of patients with primary skin melanoma (SM) according to the location of the primary tumor, the type of incision, and the method of suturing the postoperative defect.&#x0D; Material and methods. Patients with primary SM, treated in 2013 (n = 337) were studied; these patients were randomized into two groups using the method of blind selection to the main (n = 182) comparisons (n = 155) (after removal of the tumor, simple linear wound closure was performed).&#x0D; Results. In patients with localized forms of SM, it was found necessary to perform a round incision when the tumor is localized on the trunk and an elliptical incision when localized on the extremities, followed by plastic replacement in all cases. In stage III patients with any tumor localization, the type of incision and suturing of the defect was not of fundamental importance.&#x0D; Discussion. It was revealed that patients with tumor on the trunk after rounded incision and plastic surgery had an advantage in progression-free survival (PFS) at all stages before an elliptical incision without plastic surgery during the entire observation period (123660 months) by 18.8%23%, 8%26.5% (p ˂ 0.050). Patients with localized forms of melanoma from stage 0 to IIc over the entire follow-up period of 123660 months had the greatest benefit in PFS from a round incision with plastic before conventional suturing without plastic surgery: from stage 0 to IIa by 22.0%31.8%32.0%, from stage IIb to IIc by 35.6%28.5%34.8%. In overall survival (OS), only patients with a rounded incision and plastic surgery in the initial stages of the disease stage 0 to IIa up to 36 and 60 months benefited by 24.4% and 29.3%, respectively. Compared with patients who underwent simple excision on the trunk, patients with stage IIbIIc with elliptical incisions and plasty had an advantage in PFS in the long term up to 3660 months of follow-up by 25.7% and in IDS with stages 0-IIa in the period 1236 months by 24.4%.&#x0D; With the localization of the primary tumor on the extremities, a statistical difference was revealed with the best indicators in patients with an elliptical incision and plastic surgery in the OS compared to patients with a rounded incision and plastic surgery in the period of 3660 months by 18.6% and 26.7%, respectively, as well as over patients with a conventional incision without plastic surgery in PFS as a whole in the subgroup at periods up to 36 and 60 months by 26.4% and 29.4% with a tendency to improve this indicator in the long term, as well as better SOS in the long term in these patients with a difference in OS of 19.3% (3660 months of observation).&#x0D; Conclusion. In patients with localized stages (0IIc), with the localization of the primary SM on the trunk, it is necessary to perform a round excision followed by plasty of the defect with displaced tissues; in addition, it is advisable to have an elliptical incision along the axial line for the limbs, followed by plasty of the defect. In patients with stage III, the shape of the incision and the method of suturing do not play a significant role in PFS and OS.

Prognostic Factors Associated With Progression for Advanced-Stage/G1 and G2 Small-Bowel Neuroendocrine Tumors After Multimodal Therapy: Experience From a Tertiary Referral Center.

Neuroendocrine tumors represent approximately 40% of primary small bowel malignancies. However, factors predictive of progression after multimodal surgical therapy have not been well described. We evaluated the characteristics of small bowel neuroendocrine tumor patients associated with progression after multimodal surgical resection. A retrospective chart review identified 99 stage III and stage IV small bowel neuroendocrine tumor patients at Mount Sinai diagnosed and treated with surgery between 2005 and 2019. Progression-free survival (PFS) was defined as time from surgery until progression in surveillance radiologic imaging. Kaplan-Meier method was used to calculate PFS. Cox proportional hazard models were used to study the prognostic factors for PFS. Of 99 patients, 48 had tumor progression during the follow-up period. Median PFS was 5.7 years (95% confidence interval [CI], 3.73-8.66) for the entire cohort. Prognostic factors for PFS were age at diagnosis (hazard ratio [HR], 1.04; 95% CI, 1.01-1.07), perineural invasion (HR, 2.19; 95% CI, 1.13-4.23), and elevated preoperative chromogranin level (HR, 2.31; 95% CI, 1.01-5.27). Age at diagnosis, perineural invasion, and elevated preoperative chromogranin level may play a prognostic role in PFS.

Add-on anti-vascularendothelial growth factor agents with the second-line chemotherapy in metastatic colorectal cancer: A meta-analysis of randomized trials.

e15059 Background: Whether the survival benefits of anti-VEGF agents in second-line treatment for metastatic colorectal cancer (mCRC) are confounded by clinical factors is unclear. Methods: We searched literatures from PubMed, Embase, Cochrane Library, and conference abstracts through February 2017. Results: Seven randomised controlled trials with total 4931 patients comparing add-on anti-VEGF agents and second-line chemotherapy with chemotherapy alone were included with extracted outcomes from published reports. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Anti-VEGF agents improved PFS and OS (PFS: hazard ratio [HR], 0·78; 95% CI, 0·69–0·88; OS: HR, 0·86; 95% CI, 0·78–0·95) without significant subgroup differences in age(&lt; 65 or ≥65 years, p = 0·815), gender (p = 0·322), ECOG performance status (0 or ≥1, p = 0·514), number of metastases (1 or &gt; 1, p = 0·903), metastasis to the liver only (yes or no, p = 0·713), second-line chemotherapy regimen (oxaliplatin- or irinotecan-based, p = 0·509), and the previous use of bevacizumab (yes or no, p = 0·185). The funnel plots showed symmetrical patterns and the result of Egger’s test was insignificant (PFS, p = 0·220; OS, p = 0·361), indicating no apparent publication bias. Conclusions: For second-line treatment in mCRC, anti-VEGF agents play an important role in PFS and OS in all subgroups of patients.

Surgical Resection and Adjuvant Radiation Therapy in the Treatment of Skull Base Chordomas

Chordomas are rare tumors of notochordal origin that are known to be locally aggressive and are often treated with surgical resection followed by adjuvant radiation therapy (RT). The accepted standard of treatment for chordomas of the mobile spine, which includes en-bloc resection with wide margins, cannot be easily applied to the chordomas of the skull base because of their proximity to critical neurovascular structures. We describe our experience with the role of surgery and adjuvant RT in the treatment of chordomas over 16 years. We performed a retrospective chart review on patients with diagnoses of clival chordoma between the years 2000 and 2015 at Northwestern Memorial Hospital. We reviewed presenting symptoms, tumor location and size, extent of resection, complications, recurrence, adjuvant treatment, and follow-up duration. A total of 20 patients underwent 32 surgeries. Of the 20 initial surgeries, 80% underwent gross total resection, and 20% had subtotal resection. The mean follow-up time was 60.75 months. Mean tumor volume was 23.07 cm3. Most common presenting signs and symptoms were headaches (70%), cranial nerve palsies (45%), and diplopia (55%). Diplopia was defined as complaints of double vision without any objective evidence of a cranial nerve palsy. Median time to progression was 57 months, and median overall survival was 136 months. Initial tumorvolume and the need for a second dose of RT eitheras sole or as adjuvant treatment of a recurrence hada statistically significant effect on progression-free survival (P= 0.009, 0.009). None of the factors studied had a statistically significant effect on overall survival. The treatment of chordomas remain challenging and requires multimodal treatment strategies spanning different specialties. Initial tumor size and need for second dose of RT for recurrence appear to play a significant role in progression-free survival. Adjuvant RT after gross total resection may play a role in improved progression-free and overall survival in patients with clival chordomas.

Evaluation of incidence, significance, and prognostic role of circulating tumor microemboli and transforming growth factor-β receptor I in head and neck cancer.

Circulating tumor microemboli (CTM) are clusters of circulating tumor cells (CTCs), involved in metastasis, as also transforming growth factor-β (TGF-β). The purpose of this study was to verify their role in progression-free survival (PFS). Blood from patients with locally advanced head and neck squamous cell carcinoma (HNSCC; n = 53) was analyzed in 2 moments. TGF-β receptor I (TGF-βRI) expression was evaluated by immunocytochemistry. Comparing CTM1 (baseline) with CTM2 (first follow-up), patients with CTM1-positive disease who became CTM2-negative were classified as favorable (PFS 20 months). Patients with unfavorable evolution (CTM1-negative/CTM2-positive), had PFS of 17.5 months. Patients always CTM-negative showed PFS of 22.4 months, those always positive, 4.7 months (P < .001). The TGF-βRI expression in the first follow-up correlated with poor PFS (12 × 26 months; P = .007), being an independent prognostic factor (hazard ratio [HR] = 6.088; P = .033). CTM1/2, TGF-βRI expression, and unfavorable CTM kinetics may represent poor prognosis in locally advanced HNSCC.

Circulating tumor cells as predictive marker in panitumumab after progression of cetuximab in Japanese patients with KRAS wild-type metastatic colorectal cancer.

440 Background: Panitumumab has a high affinity for epidermal growth factor receptor. Its utility as a salvage therapy is unknown in cetuximab-resistant colorectal cancer. We assessed the prognostic and predictive role of circulating tumor cells (CTC) in KRAS wild-type metastatic colorectal cancer (mCRC) patients treated with panitumumab after progression of cetuximab. Methods: Panitumumab (6 mg/kg, every 2 weeks) was administered as a salvage therapy to cetuximab-resistant mCRC. CTCs of whole blood at baseline were isolated and enumerated using immunomagnetics. Results: Nineteen patients were enrolled in this prospective study between July 2010 and March 2011. Five patients had stable disease (SD) with a response rate of 0%. Four patients reached long SD, which was defined as continuous SD of more than 120 days. All of the four patients had &lt;2 CTC. &lt;2 CTC showed an independent predictive role for progression-free survival (PFS) at multivariate analysis (HR; 7.275, p=0.013). Patients with &gt;2 CTC had shorter median PFS than those with &lt;2 CTC (1.8 and 3.6 months, p=0.008). There was no statistical significance in median OS between patients with &lt;2 CTC and those with &gt;2 CTC (3.2 and 6.7 months, p=0.164). Conclusions: Panitumumab may be effective for patients with &lt;2 CTC, KRAS-wild-type mCRC after progression of cetuximab.

Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: analysis of 36 randomized trials

Progression-free survival (PFS) and time to progression (TTP) have been reported to correlate with overall survival (OS) in several types of cancers. To our knowledge, however, their use in the evaluation of new agents for AGC has not been investigated. We evaluated the potential of PFS and TTP to act as surrogates of OS in clinical trial settings. Randomized trials of systemic chemotherapy for advanced gastric cancer were identified by comprehensive electronic and manual search. Correlations between PFS/TTP and OS were evaluated. Thirty-six trials with a total of 83 treatment arms and 10,484 patients were selected for analysis. The nonparametric Spearman rank correlation coefficient (ρ) between median PFS/TTP and OS was 0.70 (95% CI, 0.59 to 0.82) and the correlation coefficient between hazard ratios in PFS/TTP and OS was 0.80 (95% CI, 0.68 to 0.92). Correlation tended to be higher in trials reporting PFS (ρ = 0.85; 0.72-0.97) than in those reporting TTP (ρ = 0.60; 0.24-0.97), trials in Non-Asian countries (ρ = 0.80; 0.61-0.99) than Asia (ρ = 0.67; 0.39-0.94), trials in patients with measurable lesions only (ρ = 0.91; 0.77-1.00) than in those including non-measurable lesions (ρ = 0.71; 0.50-0.93), albeit that none of these differences was significant. Our results indicate that improvements in PFS/TTP in advanced gastric cancer strongly correlate with improvements in OS. Further research is needed to clarify the surrogacy of PFS/TTP for OS or the role of PFS as the true end point in future randomized clinical trials of chemotherapy for AGC.

Significance of erb-B2 immunoreactivity in cervical cancer

C-erbB2 is over-expressed or amplified in many carcinomas. We assessed the relationship between erb-B2 immunoreactivity, and its predictive role in progression-free survival and treatment outcome in patients with cervical carcinoma. Sections from 65 cervical carcinoma were immunostained with antibody to p185 erbB2. Immunoreactive ErbB2 was found in 25 patients (38%) [+ 15 pts. (23%); ++ 10 pts. (15%)]. There were no correlation with age, performance status, grading and histology. Erb-B2 immunoreactivity significantly correlated with stage of the disease. Positive immunoreactivity was found in 63%, 44%, 14% and 0% of stage I, II, III and IV carcinomas, (p = 0.0045). Progression-free survival was longer in erb-B2 positive patients without reaching significance. No correlation was found between erbB2 and response to radiotherapy or chemotherapy. In conclusion, a significant proportion of stage I and II cervical cancer express erb-B2 compared to more advanced stages. Expression of the oncogene does not appear to be related to prognosis or treatment outcome.