The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy

As immunotherapy has gained increasing interest as a new foundation for cancer therapy,some atypical response patterns,such as pseudoprogression and hyperprogression,have garnered the attention of physicians.Pseudoprogression is a phenomenon in which an initial increase in tumor size is observed or new lesions appear,followed by a decrease in tumor burden;this phenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing to the false judgment of progression.Accurately recognizing pseudoprogression is also a challenge for physicians.Because of the extensive attention on pseudoprogression,significant progress has been made.Some new criteria for immunotherapy,such as irRC,iRECIST and imRECIST,were proposed to accurately evaluate the response to immunotherapy.Many new detection indexes,such as ctDNA and IL-8,have also been used to identify pseudoprogression.In this review,the definition,evaluation criteria,mechanism,monitoring,management and prognosis of pseudoprogression are summarized,and diagnostic and treatment processes for patients with progression but with a suspicion of pseudoprogression are proposed;these processes could be helpful for physicians in clinical practice and enhances the understanding of pseudoprogression.

Diagnostic accuracy of dynamic contrast-enhanced magnetic resonance imaging for distinguishing pseudoprogression from glioma recurrence:a meta-analysis

Background:It is crucial to differentiate accurately glioma recurrence and pseudoprogression which have entirely different prognosis and require different treatment strategies.This study aimed to assess the diagnostic accuracy of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)as a tool for distinguishing glioma recurrence and pseudoprogression.Methods:According to particular criteria of inclusion and exclusion,related studies up to May 1,2019,were thoroughly searched from several databases including PubMed,Embase,Cochrane Library,and Chinese biomedical databases.The quality assessment of diagnostic accuracy studies was applied to evaluate the quality of the included studies.By using the"mada"package in R,the heterogeneity,overall sensitivity,specificity,and diagnostic odds ratio were calculated.Moreover,funnel plots were used to visualize and estimate the publication bias in this study.The area under the summary receiver operating characteristic(SROC)curve was computed to display the diagnostic efficiency of DCE-MRI.Results:In the present meta-analysis,a total of 11 studies covering 616 patients were included.The results showed that the pooled sensitivity,specificity,and diagnostic odds ratio were 0.792(95%confidence interval[CI]0.707-0.857),0.779(95%CI 0.715-0.832),and 16.219(97.5%CI 9.123-28.833),respectively.The value of the area under the SROC curve was 0.846.In addition,the SROC curve showed high sensitivities(>0.6)and low false positive rates(<0.5)from most of the included studies,which suggest that the results of our study were reliable.Furthermore,the funnel plot suggested the existence of publication bias.Conclusions:While the DCE-MRI is not the perfect diagnostic tool for distinguishing glioma recurrence and pseudoprogression,it was capable of improving diagnostic accuracy.Hence,further investigations combining DCE-MRI with other imaging modalities are required to establish an efficient diagnostic method for glioma patients.

Challenges of evaluating immunotherapy efficacy in solid tumors

Immunotherapy is one of the most promising treatments for multiple tumor types.The significant clinical benefits and durable responses of immunotherapy have led to the emergence of various immune-related clinical response patterns that extend beyond those achieved with cytotoxic agents.Various studies investigated the efficacy of immunotherapy,including the effect on tumor size,long-term survival benefits,and the ability to overcome the particularly challenging survival curves tailing phenomenon.The current immune-related methods guidelines,such as immune-related Response Criteria(irRC),immune-related Response Evaluation Criteria in Solid Tumors(irRECIST),immune Response Evaluation Criteria in Solid Tumors(iRECIST),and immune-modified Response Evaluation Criteria in Solid Tumors(imRECIST),could be well-adapted to identify the heterogeneity of responses that appear in patients receiving immunotherapy,such as pseudoprogression(PsPD)and hyperprogressive disease(HPD),and to some extent to overcome the limitation of evaluating the efficacy of immunotherapy on tumor size by imaging.Additionally,a second type of evaluation method was proposed based on survival,which includes milestone analysis and restricted mean survival time.Currently,milestone analysis is a complementary tool to summarize and interpret trial results along with more conventional measures of survival and other less established metrics.A golden standard evaluation method to distinguish the efficacy of immunotherapy may improve the process of imaging and aid survival-based efficacy evaluation in patients with solid tumors.

Immune response evaluation criteria in solid tumors for assessment of atypical responses after immunotherapy

In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.

Pseudo-or real progression? An ovarian cancer patient under nivolumab:A case report

BACKGROUND Checkpoint-Inhibition has revolutionized the treatment for several entities such as melanoma and renal cell carcinoma.The first encouraging experience in ovarian cancer was reported for nivolumab,a fully humanized anti-programmed death-1 antibody.Pseudoprogression is a new phenomenon associated with these novel immuno-oncologic agents.It can be explained by infiltrating leucocytes and edema that result in a temporary increase in tumor size and delayed subsequent shrinkage due to tumor cell destruction.CASE SUMMARY We report on a 47-year old patient with platinum-resistant ovarian cancer that was treated off-label with nivolumab 3mg/kg iv d1q14d.She first experienced classic pseudoprogression with inguinal lymph node swelling after cycle two and subsequent shrinkage.After 6 cycles she presented with rectal bleeding and progressive disease was diagnosed due to new tumor infiltration into the rectum.CONCLUSION Clinicians should be aware of pseudoprogression,its underlying mechanisms and strategies to discriminate pseudo-from real progression in ovarian cancer.

Magnetic resonance imaging appearance and changes on intracavitary Gliadel wafer placement:A pilot study

AIM:To investigate changes on magnetic resonance imaging(MRI) which occur with intracavitary Gliadel wafer placement in patients with glioblastoma multiforme(GBM).METHODS:This retrospective Health Insurance Portability and Accountability Act-compliant study was approved by the institutional review board,with a waiver of informed consent.A total of eight patients aged 29-67 years with GBM underwent Gliadel wafer placement.T2-weighted/FLAIR images and post-contrast T1-weighted images both before and after wafer placement were retrospectively reviewed in consensus to determine changes in the following parameters:appearance of the pericavitary tissue,pattern of tumor recurrence or progression and appearance of the Gliade lwafer itself.RESULTS:Five out of the eight patients had a progressive increase in enhancement and pericavitary T2/FLAIR hyperintensity within the first 2 mo and a subsequent decrease in these MRI findings.None ofthese patients had tumor recurrence within the first6 mo.Three out of the eight patients demonstrated aprogressive increase in enhancement and pericavitary T2 hyperintensity,which continued after the first 6 mo,and were subsequently diagnosed with true tumor progression.There was no increase in distant/nonlocal tumor recurrence.The Gliadel wafer appearance changed over time.CONCLUSION:Pseudoprogression is common after intracavitary Gliadel wafer placement and thus care should be taken before diagnosing tumor progression or recurrence within the first 2 mo.

Issues to Consider in Designing Immunotherapy Clinical Trials for Glioblastoma Management

Glioblastoma (GBM) is the most common primary brain malignancy in adults and has a poor prognosis despite standard of care treatment. The mainstay of GBM treatment has relied on maximum surgical resection and chemotherapy and radiation. Cancer immunotherapy has made great strides since the advent of anti-PD-1, anti-CTLA-4, and other immune checkpoint inhibitors. With the advancement of novel therapeutics, more clinical trials for patients have opened as well. An important future direction of clinical trials is the ability to identify appropriate patients to optimize treatment response and minimize toxicities. This review describes considerations in designing future GBM clinical trials in not only immunotherapy but also with other promising treatments. We will discuss factors, such as pseudoprogression, genetic and circulating biomarkers, and the commensal microbiome of patients in the setting of clinical trial design.

Diagnostic pitfalls in malignant gliomas： the analysis of misdiagnosis and current recommendations

The malignant glioma is characterized by intrinsic aggressiveness and carries a dismal prognosis. Thecurrent standard treatment regimen for patients with malignant gliomas, specifically glioblastoma, is a combined therapy comprised of surgical resection followed by adjunctive radiation and chemotherapy. Yet, even with this new multimodality treatment, glioblastoma （GBM） recurs after a median time of 7 months following diagnosis, requiring a second-line treatment. But the clinical decisions are always difficult.