Pseudoprogression in Immunotherapy and Identification of Clinical-Biologic Predictive Factors: A Retrospective Pan-Tumor Cohort Study

Pseudoprogression in Immunotherapy and Identification of Clinical-Biologic Predictive Factors: A Retrospective Pan-Tumor Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pseudoprogression in Immunotherapy and Identification of Clinical-Biologic Predictive Factors: A Retrospective Pan-Tumor Cohort Study Amélie TOULET, Frédéric BIGOT, Valérie SEEGERS-THEPOT, Sylvère GUILLEMOIS, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7765256/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 15 You are reading this latest preprint version Abstract Background Immune Checkpoint inhibitors (ICI) have emerged as one of the leading cancer therapies. Inflammatory mechanism induced by ICI can lead to increased tumor lesions that could be wrongly misinterpreted as progressive disease (PD). Currently, there are no imaging modalities that can differentiate true progression from pseudoprogression (PP). Although the iRECIST criteria have been developed to characterize these atypia, they appear to be inadequate in practice. The aim of this study is to determine whether this concept of PP exists and whether there are clinical or biological criteria that can be used to distinguish PP and true progression (PD). Methods We conducted a retrospective study in patients (pts) treated with ICI for metastatic cancer at Institut de Cancérologie de l’Ouest, and for whom PP was raised. Data were collected at initiation of ICI (t0), at evocation of PP (t1) and at subsequent evaluation (t2), treatment outcome and adverse events. Primary endpoint was to determine the percentage of pts with confirmed PP at t2. Secondary endpoints were to determine clinical or biological criteria associated to PP. Results 123 pts were included, 59% were men, most commonly with lung (38%), kidney (24%) or bladder (11%) cancer, and mainly treated in 2nd line with anti-PD1 (85%). We identified 56 confirmed PP (45%), with a median time of 79 days (28–227) between the first ICI infusion and evoked PP. ECOG score 0 and no weight loss were statistically associated with confirmed PP, respectively p < 0.0001 and p = 0.031. There was no association between PP and cancer type, metastatic site or type of ICI. For biological variable, only LDH was significantly different between the 2 groups (p = 0.003). More specifically, a 10% variation or more in LDH level was in favor of PD (OR = 0.72 with p = 0.005). Conclusions PP on ICI are real events and should be considered, regardless of tumor location, in pts in good general condition with stable LDH levels. Furthermore, with the development of artificial intelligence, some new imaging techniques could be developed to distinguish PP and PD. Some studies focusing on the circulating tumor DNA are also an interesting perspective. Immune checkpoint inhibitor pseudoprogression LDH ECOG metastatic cancer predictive factors Figures Figure 1 Figure 2 Figure 3 Introduction Since the end of the twentieth century, immunotherapy has gradually become one of the most important cancer therapies, significantly improving the clinical outcomes and survival of patients, initially those with metastatic disease 1 – 3 . Indeed, in-depth analysis of this pathology has highlighted the involvement of not only cancer cells, but also the tumor microenvironment, which, via numerous vectors, enables cancer cells to evade the immune system 4 . One of the major discoveries that led to the advent of immunotherapy was immune checkpoints. The main target molecules with therapeutic impact are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand programmed death-ligand 1 (PD-L1). These co-inhibiting molecules regulate the immune system through negative feedback preventing it from running out of control. One of the mechanisms explaining the ability of tumors to avoid the immune system is the overexpression of these molecules 5 . Atypical responses have been observed since the advent of these new treatments. One of these is the pseudoprogression (PP). First mentioned with the use of IPILIMUMAB (anti-CTLA4) in melanoma in 2007, this could be explained by stimulation of the patient's immune system leading to tumor site lymphocyte infiltration 6 – 8 . Pseudoprogression is a controversial phenomenon, defined as an objective response following initial progression with the same treatment, with an incidence ranging from 0 to 15%, depending on the series and primary cancer site, most often described in the follow-up of melanoma 9 , 10 . As a result, during follow-up imaging examinations, target lesions may appear to have increased in size because of lymphocyte infiltration and inflammatory mechanisms, rather than disease progression (PD). Currently, there are no imaging modalities that can differentiate true progression from PP. At present, the iconographic evaluation of tumor response is based on the Response Evaluation Criteria in Solid Tumors (RECIST) 11 . A new classification named iRECIST was established in 2017 to consider paradoxical evolutions linked to immunotherapy 12 . This classification has given rise to the notion of unconfirmed progressive disease (iUPD), which requires confirmation by follow-up imaging 4 to 8 weeks later. However, these criteria cannot be used to differentiate between PD and PP which leads us to adopt an attitude of close monitoring, with the risk of continuing ineffective treatment, thus losing the patient's chance of success 13 . This study aimed to determine whether this concept of PP exists and whether there are clinical and/or biological criteria that can be used to distinguish between PP and PD. Methods We conducted a retrospective, monocentric, cohort study of patients treated at the Institut de Cancérologie de l’Ouest (ICO). Patients included had to have metastatic cancer, regardless of the primary location or the histological type, treated with Immune Checkpoint Inhibitors (ICI) with the hypothesis of PP raised during follow-up. This study was conducted with the authorization of the CNIL (the French Data Protection Agency) and was approved by an independent local ethics review board from Angers University Hospital, registered under number 2022 − 157. This study adhered to the Declaration of Helsinki. All surviving patients were informed and we obtained their written consent. To identify relevant cases, we searched our database for the keywords “immunotherapy” and “pseudoprogression”. For cohort homogeneity, we excluded, among others, patients with localized cancer, those receiving combined treatments with chemotherapy or targeted therapy, those with interruption of ICI before CT re-evaluation (death or toxicity) and those with incomplete files. We collected data on patients’ clinical characteristics, treatment outcome, and safety with all grade treatment-related adverse events (TRAEs) using the Common Terminology Criteria for Adverse Events (version 4.0). We collected biological values, such as hemoglobin level, neutrophil count, albumin, calcemia and lactate dehydrogenase (LDH) levels. All these data were examined at baseline, corresponding to the initiation of the ICI (t0), at the evocation of PP (t1) and at the final evaluation, which confirmed or not PP (t2). PP could be evoked by the clinician or by an evaluation tomography (CT) scan report at t1. The confirmed PP was validated using the CT scan report at t2 if the disease was considered stable or shrinking. The primary endpoint was the percentage of patients with a confirmed PP at t2. The secondary endpoint was to determine the clinical or biological criteria associated with PP. A flow chart was produced to identify the number of patients for whom PP was evoked during ICI treatment, and those who had iconography confirming or refuting the diagnosis of PP. Descriptive statistics were used to summarize the patient and treatment characteristics. Clinical and disease characteristics are presented as medians and ranges for continuous variables and as numbers and percentages for categorical variables. Non-parametric statistical tests were used, considering the cohort size to compare the characteristics of patients with true PP and those with true progression under immunotherapy. We used Kaplan-Meier estimation to summarize the Overall Survival (OS), defined as the time from evocation of PP (t1) until the time of death or last follow-up for censored patients. To quantify the association between candidate variables (collected at t0 and t1) and the probability of progression, we used a logistic regression model and estimated the Odds Ratio (OR) and 95% confidence interval. An OR value greater than 1 indicates an association with true progression, whereas an OR value lower than 1 indicates an association with PP. We built a multivariable regression model to estimate the adjusted ORs. Candidate variables were those whose p-values were lower than 0.3 from the univariable logistic regression model (except for cerebral progression where the number of events was too low). We performed an automatic, step-by-step multivariable model selection procedure based on the AIC to identify the final multivariable model. To explore the true progression predictive value of LDH (and relative LDH evolution between t0 and t1), we built a receiver operating curve (ROC) and estimated the area under the curve (AUC) 14 . We interpreted the discriminative ability as follows: AUC ≤ 0.5 corresponds to no discriminative ability; 0.5 < AUC < 0.7 corresponds to poor ability, 0.7 ≤ AUC 0.9 corresponds to good ability. We used the Youden index to identify the LDH threshold that minimizes the false positive rate (1- Specificity) and maximizes the true positive rate (Sensibility). No imputation of the missing data was performed. Statistical analysis was performed using R software (version 4.3.1) 15 , pROC 16 , ROCR 17 and crosstable 18 packages. Results From September 2013 to June 2022, we identified 311 patients with cancer treated with ICI in our database, for whom PP was raised. After excluding patients with localized cancer most of the time, treated by combined ICI with another treatment (chemotherapy or targeted therapy), interruption of ICI before CT re-evaluation (death or toxicity) incomplete file or in whom the clinician did not accept the hypothesis of PP, we enrolled 123 patients with metastatic cancer. Of these 123 patients, 56 had confirmed PP (46%) and 67 had confirmed PD (54%) (Fig. 1 ). Characteristics at ICI treatment initiation (t0) In this cohort, 59% of the patients were male. The median age at diagnosis was 62 years (13–81). At ICI initiation, the median age was 65 years (14–85), and the median weight was 72 Kg (37–123). The primary sites were mainly lung (38%), kidney (24%) and bladder (11%) cancers. In addition, 7% of cases are skin cancers, 2% are digestive cancers, 4% are gynecologic cancers, 11% are ORL cancers, 2% are breast cancers and 1% are central nervous system cancers (metastatic uveal melanoma). Different histological types were included, with 38% adenocarcinoma, 17% squamous cell carcinoma, 22% clear cell renal carcinoma, 2% undifferentiated carcinoma, 12% urothelial carcinoma, 1% high-grade salivary carcinoma, 2% infiltrative ductal carcinoma and 6% melanoma. Every patient had metastatic cancer with a median of two metastatic sites (1–8). In the overall cohort, there was 23% of bone metastases, 25% of liver metastases, 57% of lymph nodes metastases, 61% of lung metastases, 16% of brain metastases, 3% of skin metastases and 13% of adrenal metastases at the beginning of immunotherapy. The characteristics were well balanced with no significant differences in sex, age at diagnosis or at the initiation of ICI treatment, location of primitive, histological type or metastatic sites between patients with PP and those with PD (Table 1 ) and between baseline biological characteristics (Table S1). ICI treatment was most often a second-line treatment (1–8) in both groups, with no significant difference. Patients were treated with anti-PD1 alone (84%), anti-PDL1 alone (9%), a combination of both (1%), or a combination of anti-PD1 and anti-CTLA4 (6%). No significant differences were observed between the PP and PD groups according to the type of immunotherapy used (Table 1 ). In terms of general condition, there were significantly more Eastern Cooperative Oncology Group (ECOG) 0 patients in the PP group at the start of immunotherapy, 55% than in the PD group (32%), more ECOG 1 patients in the PD group (59%) than in the PP group (38%), and similar ECOG 2 in the PP group (7%) and in the PD group (9%). None of the patients had an ECOG score of 3 or 4 (p = 0.05) (Table 1 ). Table 1 Baseline characteristics and immune checkpoint inhibitor treatment. Baseline characteristics Overall cohort N = 123 Pseudo-progression N = 56 (46%) Progression disease N = 67 (54%) Gender Male 73 (59%) 31 (55%) 42 (63%) Female 50 (41%) 25 (45%) 25 (37%) Age at diagnostic median (range) 62 (13–81) 64 (13–81) 60 (33–77) Location of primitive Skin 9 (7%) 5 (8%) 4 (6%) Digestive 3 (2%) 2 (4%) 1 (2%) Gynecologic 5 (4%) 1 (2%) 4 (6%) ORL 13 (11%) 8 (14%) 5 (8%) Lung 47 (38%) 20 (36%) 27 (40%) Kidney 30 (24%) 16 (29%) 14 (21%) Breast 2 (2%) - 2 (3%) Central Nervous System 1 (1%) - 1 (2%) Bladder 13 (11%) 4 (7%) 9 (13%) Histological type Adénocarcinoma 47 (38%) 19 (34%) 28 (42%) Squamous cell carcinoma 21 (17%) 11 (20%) 10 (15%) Undifferentiated carcinoma 2 (2%) 1 (2%) 1 (2%) High grade salivary carcinoma 1 (1%) 1 (2%) - Urothelial carcinoma 15 (12%) 6 (11%) 9 (13%) Infiltrating ductal carcinoma 2 (2%) - 2 (3%) clear cell renal carcinoma 27 (22%) 14 (25%) 13 (19%) melanoma 8 (6%) 4 (7%) 4 (6%) Age at first perfusion of ICI median (range) 65 (14–85) 66.5 (14–82) 64 (38–85) Weight at first perfusion of ICI median (range) 72 (37–123) 73 (40–123) 70.5 (37–108) Na n = 5 n = 4 n = 1 Type of ICI Anti-PD1 104 (84%) 48 (86%) 56 (84%) Anti-PD1 + Anti-PDL1 1 (1%) - 1 (1%) Anti-PDL1 11 (9%) 5 (9%) 6 (9%) Anti-PD1 + Anti-CTLA4 7 (6%) 3 (5%) 4 (6%) Line of ICI use median (range) 2 (1–8) 2 (1–5) 2 (1–8) Number of metastatic sites median (range) 2 (1–8) 2 (1–6) 2 (1–8) Metastatic sites Bone 28 (23%) 10 (18%) 18 (27%) Liver 31 (25%) 12 (21%) 19 (28%) Lymph nodes 70 (57%) 28 (50%) 42 (63%) Lung 75 (61%) 34 (61%) 41 (61%) Brain 20 (16%) 7 (13%) 13 (19%) Skin 4 (3%) 2 (4%) 2 (3%) Adrenal 16 (13%) 7 (13%) 9 (13%) ECOG* 0 51 (43%) 30 (55%) 21 (32%) 1 59 (49%) 21 (38%) 38 (59%) 2 10 (8%) 4 (7%) 6 (9%) Abbreviations: ICI, immune checkpoints inhibitors; ECOG, Eastern Cooperative Oncology Group; PD1, programmed cell death 1; PDL1, programmed death-ligand 1; CTLA4, cytotoxic T-lymphocyte-associated antigen 4. P values were obtained using the two-sided Mann-Whitney test (*p<0.05). Characteristics at time of PP evocation (t1) All evaluation scans reported an aspect of progression. Some radiologists raised the diagnosis of PP in their reports, recommending a new, closer scan 4 to 8 weeks later, but most of the time, the oncologist made the diagnosis and decided to continue ICI with a re-evaluation scan at a median time of 66 days (6 to 204), depending on the practitioner (Table S2). Suspicion of PP was raised with a median time of 79 days (28 - 927), after ICI treatment initiation, most of the time during the first scan evaluation. We confirmed PP early, at 28 days, but also later, at 227 days (Table 2). Table 2: Characteristics of the patient population at the evocation of pseudoprogression (t1) and toxicity of immune checkpoint inhibitor treatment. Characteristics at t1 Overall cohort N = 123 Pseudo-progression N = 56 (46%) Progression disease N = 67 (54%) ECOG 0 40 (33%) 20 (36%) 20 (30%) 1 74 (61%) 32 (57%) 42 (64%) 2 8 (6%) 4 (7%) 4 (6%) Age median (range) 65 (14-85) 66.5 (14-82) 64 (38-85) Time between first ICI perfusion and PP evocation median (range) 79 (28-927) 79 (28-227) 78 (28-927) Weight median (range) 72 (38-120) 72 (39-120) 71.5 (38-112) Na n=5 n=2 n=3 Weight variation median (range) 0 (-14.9-16.4) 0 (-11.3-11.1) 0 (-14.9-16.4) Na n=7 n=4 n=3 Albumin median (range) 40 (23.2-47) 40 (31-46.2) 39 (23.2-47) Na n=50 n=26 n=24 Albumin variation median (range) -2.1 (-27.1-42.3) -1.8 (-13.2-42.3) -2.3 (-27.1-22.7) Na n=63 n=33 n=30 Hemoglobin median (range) 12.9 (7.4-16.1) 13 (8.9-15.3) 12.4 (7.4-16.1) Na n=16 n=7 n=9 Hemoglobin variation median (range) 0 (-36.3-47.3) 2.1 (-35.9-21.2) -1.1 (-36.3-47.3) Na n=24 n=11 n=13 Neutrophils median (range) 4460 (1620-19090) 4390 (1730-12410) 4529.5 (1620-19090) Na n=20 n=9 n=11 Neutrophils variation* median (range) 11.4 (-57.6-208.9) 3 (-57.6-134.8) 20.3 (-39.4-208.9) Na n=27 n=12 n=15 LDH ** median (range) 201 (95-3223) 189 (95-480) 232.5 (148-3223) Na n=45 n=18 n=27 LDH variation** median (range) -0.6 (-61.4-258.2) -4.2 (-61.4-40.8) 8.5 (-32.8-258.2) Na n=48 n=20 n=28 Calcemia median (range) 2.4 (2.1-2.8) 2.4 (2.1-2.6) 2.4 (2.1-2.8) Na n=49 n=24 n=25 Calcemia variation median (range) 0 (-14.5-11.6) 0.5 (-14.5-6.8) 0 (-12.7-11.6) Na n=62 n=31 n=31 Progression on scan report 123 (100%) 56 (100%) 67 (100%) Metastatic site in progression Bone 13 (11%) 4 (7%) 9 (13%) Liver 29 (24%) 12 (21%) 17 (25%) Lymph node 61 (50%) 23 (41%) 38 (57%) Lung 63 (51%) 29 (52%) 34 (51%) Brain 4 (3%) 3 (5%) 1 (2%) Skin 4 (3%) 2 (4%) 2 (3%) Adrenal 5 (4%) 2 (4%) 3 (5%) Toxicity of ICI* At least one 39 (32%) 23 (41%) 16 (24%) No one 83 (68%) 33 (59%) 50 (75%) Grade 1/2 35 (29%) 19 (34%) 16 (24%) Grade 3/4 7 (6%) 5 (9%) 2 (3%) Abbreviations: ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoints inhibitors; PP, pseudoprogression; LDH, lactate dehydrogenase; Na, unknown P values were obtained using the two-sided Mann-Whitney test (*p<0.05 ; **p<0.01). Patients with PP had a significantly better overall survival (median 39.7 months, 95%CI: 26.8 to NA) than patients who had real cancer progression (median 12 months; 95%CI 10.4 to 19.8; p<0.001) (figure 2). Clinically, we found no significant difference between PP and PD with respect to ECOG performance status at t1. There were as many ECOG 0 patients, 36% in the PP group and 30% in the PD group, 57% were ECOG 1 in the PP group and 64% in the PD group, and similar ECOG 2 in the PP group (7%) and PD group (6%). None of the patients had an ECOG score of 3 or 4 in the 2 groups (Table 2). There was no significant difference in weight at t1 in either group, or weight variation between t0 and t1 with stable weight in 79.3% of the patients (+/-5%) (Table 2). We did not observe differences in the metastatic sites where PP was evoked between PP and PD patients (Table 2). Biologically, we found no significant difference values between PP and PD patients, nor relative variation from t0 to t1, for albumin (figure 3a), hemoglobin (figure 3b) and calcemia (figure 3d). We did not find a difference in neutrophil counts at t1 (figure 3c), but the relative variation in neutrophil counts between t0 and t1 was significantly greater in the PD group than in the PP group (p=0.04) (Table 2 and figure 3). LDH levels were clinically and statistically higher in the PD group at t1 (median 232.5U/L) than in the PP group (median 189U/L, p=0.003). We also showed that from t0 to t1, LDH increased in PD (median elevation of 8.5U/L) while LDH decreased in PP group (median reduction of 4.2U/L, p=0.002) (Table 2 and figure 3e). Predictive parameters for PP at t1 First, we performed a univariate analysis. The risk of PD was increased in patients having ECOG 1 than in patients having ECOG 0 at t0 (OR: 2.59, 95%CI: 1.20 to 5.59, p=0.02), in patients having higher LDH at t1 (for 100 U/L of increase LDH, the OR was 1.90, 95%CI: 1.07 to 3.37, p=0.03), and in patients with a 10% or greater increase in LDH between t0 and t1 (OR: 1.39, 95%CI: 1.14 to 1.78, p<0.005). The risk of PD decreased in patients who experience at least one immunotherapy-related toxicity (OR: 0.46, 95%CI: 0011 to 0.99, p=0.049) (Table S3). In multivariable analysis (Table 3), a 100 U/L increased in LDH level was significantly associated with PD (OR=7, 95%CI: 2.3 to 36.7, p=0.004) as well as bone metastatic site progression (p=0.041) and ECOG performance status at t0 (p=0.03) while type of immunotherapy (PD1 alone vs other), time between t0 to t1 and neutrophils count at t1 were not significantly associated with PD. Table 3: Final multivariable logistic regression model Characteristic OR (95% CI) 1 p-value Type of ICI Anti-PD1 alone 1 Anti-PDL1 or combination 5.76 (0.73 to 69.5) 0.12 ECOG at t0 0 1 1 5.88 (0.98 to 53.5) 0.074 2 44.2 (1.76 to 2,497) 0.033 Time from t0 to t1: 1 month increase 2.07 (1.16 to 5.44) 0.073 Neutrophils count: 1000 units increase 1.59 (1.05 to 2.80) 0.066 LDH at t1: 100 units increase 7.07 (2.30 to 36.7) 0.004 Bone site metastatic progression vs other site 14.6 (1.40 to 289) 0.041 1 OR = Odds Ratio, CI = Confidence Interval Abbreviations: ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoints inhibitors; LDH, lactate dehydrogenase; vs, versus This observation led us to focus on the evolutionary kinetics of LDH. Indeed, exploratory, we studied a threshold beyond which the PP cannot be considered. According to LDH level, we established that the best threshold was a value of 148 U/L with an AUC=0.7 (0.56-0.8) (figure S1, black curve). The sensitivity was of 72.5%, specificity of 65.8%, positive predictive value of 69% and negative predictive value of 44.7%. According to the variation in LDH levels between t0 and t1, an increase in LDH over 32.8% would favor progression, not PP (figure S1, red curve). Characteristics at time of PP or PD confirmation (t2) Clinically, ECOG was significantly better in PP patients than in PD patients (93% vs 59% had ECOG 0 or ECOG1, p<1.10 -4 ) and more patients had weight loss in the PD group than in the PP group (p=0.001) (Table S2). Biologically, at t2, we found higher hemoglobin levels in the PP group than in the PD group (median 13.2 vs 12.1 g/dL, p= 0.014) and lower LDH levels in the PP group than in the PD group (190 vs 254 UI/L, p<0.0001). We did not observe differences in albumin, neutrophil count, or calcemia at t2. Between t1 and t2, we found that relative albumin increased in the PP group (median increase = +2.5%) compared to the PD group (median decrease -0.7%, p=0.0125), and a higher relative hemoglobin increase in the PP group (median increase +1.6%) compared to the PD group (median decrease -1.5%, p=0.0195). We did not find statistical differences between t1 and t2 in terms of neutrophil count variation, calcemia variation, or LDH variation (Table S2 and figure 3). Adverse events and immunotherapy We tracked the toxicity through the final radiological assessment. There were more patients with at least one side effect of ICI in the PP group (41%) than in the PD group (24%) (p=0.05) (Table 2). Most of the time there were side effects such as dysthyroidism, diarrhea or skin disorders. However, the difference in severity was not statistically significant. These were mainly grade 1 or 2 toxicities, 34% in the PP group and 24% in the PD group. Two patients in the PD group and five in the PP group experienced grade 3 or 4 toxicity (Table 2). In the PP group, when confirmed, 53 patients continued ICI treatment. Immunotherapy was interrupted in 3 patients because of toxicity. ICI was continued in the other 2 patients because of doubts regarding the imputability of the treatment. In the PD group, 44% of patients who progressed received new chemotherapy, 14% received targeted therapy, 18% stopped every treatment. Two patients continued immunotherapy because the progression was unclear and minimal, eight patients continued immunotherapy and underwent irradiation at a progressive metastatic site if the disease was otherwise controlled. Discussion To our knowledge, this is the largest retrospective cohort of patients with metastatic cancers treated with ICI for whom PP was suspected, regardless of location. Pseudoprogression must be induced during ICI treatment. We demonstrated that this concept was not rare, with 46% of PP confirmed. This percentage is higher than that in other cohorts reported in the literature, which ranges from 0.6 to 15% 7,19 . However, we studied the percentage of proven PP compared with evoked PP and not the percentage of PP in all patients undergoing ICI therapy in our institution. It is important to note that PP can occur regardless of cancer localization, although PP seems to be more common in lung and kidney cancers, as reported in the literature 20,21 . Interestingly, this phenomenon of PP can be observed regardless of ICI type. The aim of our study was to confirm or refute the existence of this concept and thus guide our decisions, that is to continue immunotherapy if it is justified or, on the contrary, to stop it and rapidly change treatment if progression is certain. It is also important to consider this phenomenon in the design of many therapeutic trials evaluating immunotherapy 22 . The median time between the start of ICI and evocation of PP was 79 days, mostly at the first evaluation scan. We observed a difference in the maximal range between the two groups (927 vs 227 days in the PD and PP groups, respectively) which is in line with the literature 23 . Indeed, most of the cases of PP described occurred relatively soon after the initiation of immunotherapy; however PP can also be induced at a later stage 19,24 . Moreover, we showed that patients with PP had significantly better OS than with PD. This result is consistent with the literature data 19 and the pathophysiology of PP, wich is an atypical response to treatment. In addition, in a systematic review by Chen et al , of PP in non-small cell lung cancer, they looked at biopsies of suspected PP sites and found that increased lesion size may be induced by inflammatory changes. The infiltrating inflammatory cells are mainly composed of CD4+ and CD8+ T cells and macrophages 20 . Our secondary objective was to identify clinico-biological factors that could help in the decision-making process, without waiting for controlled imaging. We found that there were significantly more patients with an ECOG performance status of 0 in the PP confirmed group than in the PD group. This result is similar to the subgroup analysis of the phase 3 CheckMate 025 study, which evaluated patients with advanced renal cell carcinoma treated with nivolumab and who had RECIST progression on their scan but a clinical benefit. Immunotherapy was continued for at least 4 weeks, before re-evaluation by CT scan. Among the 153 patients who continued receiving nivolumab, 13% had at least 30% reduction in tumor burden. Those patients had a significantly better general condition with a Karnofsky Performance Status >= 90% in 80% of them vs 71% in the PD group 21 . Indeed, this notion of maintaining good general condition during PP has been described in the literature 25,26 . However, deterioration of the general condition was reported when the patient progressed 27 . Additionally, some studies have suggested a correlation between the occurrence of side effects and possible PP 28 . We also showed that there were significantly more immunotherapy-related adverse events in the PP group, but we did not find a difference in severity or association that could be considered predictive of efficacy. LDH levels and variations were significantly different between the two groups. With an OR of 0.72, we found a strong association between an LDH elevation of more than 10% and the risk of PD, rather than PP. This biological variable is particularly interesting because it was reported in previous studies 29,30 . Our study had several limitations. First, its retrospective design may have led to potential selection bias. Unfortunately, there is a lack of data concerning calcemia, albumin, neutrophils and LDH levels, which may lead to a lack of statistical power. We thought that the albumin level which is often correlated with general condition, would be significantly higher in the PP group, but there was no difference. Similarly, it is well known that elevated calcemia is a sign of cancer progression, but there was no difference between the PP and PD groups. Furthermore, in some cases, the use of biomarkers such as carcino-embryonic cntigen (CEA) can be helpfull 31 . In our study, we did not report them because of a lack of data and many different histological types and primary locations, with no clearly established biomarkers. Otherwise, the AUC of the LDH ROC curves is under 0.8, which confers unsatisfactory predictive properties of progression. It would be interesting to monitor LDH levels in patients undergoing ICI, to assess whether, in a larger cohort, the predictive value of LDH would be confirmed. However, this finding was consistent with that reported by Basler et al . Indeed, the blood prediction model (LDH+S100) achieved a similar AUC of 0.71, but a model combining LDH and S100 protein associated with radiomic assessment of lesions (describing shape, intensity, and texture) was the best predictive model of PP with an AUC of 0.82, in 112 patients with metastatic melanoma treated with ICI 30 . Currently, the most promising technique for understanding the heterogeneity of responses to ICI is the use of radiomics 32,33 . Radiomics is a technique used for extracting large volumes of imaging data. It involves extracting several parameters from a single raw image, such as the geometry and shape, histogram analysis and texture. These parameters can be pooled in a statistical model to predict the treatment response. Barabino et al. included 33 patients under ICI with non-small cell lung cancer. They studied many radiomic features at baseline and re-evaluation scan. They found that an increase in heterogeneity in energy, contrast and graey level non-uniformity favors PD 34 . Finally, circular tumoral DNA seems to be an interesting perspective too 35 . Guibert et al . showed an important decrease in KRAS mutated ctDNA in two patients who experienced a PP under ICI for lung adenocarcinoma compared to the KRAS ctDNA level of one patient with PD 36 . Similarly, Lee et al. demonstrated that, in patients followed up for melanoma treated with ICI, that an undetectable level of ctDNA at baseline or a more than 10-fold decrease over the first 12 weeks could predict PP with a sensitivity of 90% (95% CI, 68%-99%) and a specificity of 100% (95% CI, 60%-100%) 37 . In conclusion, PP in patients treated with ICI is a real event and should be considered regardless of tumor location, especially if a good general condition is maintained with stable LDH levels. It is essential to confirm these data in a prospective, independent validation cohort to establish a predictive score. Furthermore, with the development of artificial intelligence, new imaging techniques can be used to distinguish PP from PD in larger clinical trials. Declarations Acknowledgement section We are grateful to all our co-authors and patients for their contribution to this study. Author contributions statement: Study concepts : M.de Vries-Brilland, A.Toulet, R.Delva Study design: M.de Vries-Brilland, A.Toulet, V.Seegers-Thepot Data acquisition: A.Toulet Quality control of data and algorithms: A.Toulet, M.de Vries-Brilland Data analysis and interpretation: A.Toulet, V.Seegers-Thepot, M.de Vries-Brilland Statistical analysis: V.Seegers-Thepot Manuscript preparation: A.Toulet, M.de Vries-Brilland Manuscript editing: A.Toulet, M.de Vries-Brilland, R.Delva, F.Bigot, S.Guillemois, D.Vansteene, V.Seegers-Thepot Manuscript review: A.Toulet, M.de Vries-Brilland, R.Delva, F.Bigot, S.Guillemois, D.Vansteene, V.Seegers-Thepot All authors have read and approve the final version of the manuscript. Ethical considerations This study was conducted with the authorization of the CNIL (the French Data Protection Agency) and was approved by an independent local ethics review board from Angers University Hospital, registered under number 2022-157. This study adhered to the Declaration of Helsinki. Consent to participate All surviving patients were informed and we obtained their written consent. Consent for publication Not applicable Declaration of conflicting interest Amélie TOULET : The author declare no potential conflicts of interest. Fréderic BIGOT : • Advisory role for : Astrazeneca, BMS, Sanofi, MSD • Travel grants for : MSD Valérie SEEGERS-THEPOT : The author declare no potential conflicts of interest. Sylvère GUILLEMOIS : • Advisory role for : SANOFI Damien VANSTEENE : • Advisory rôle for : Pfizer, Astellas Rémy DELVA : The author declare no potential conflicts of interest. Manon DE VRIES-BRILLAND : • Advisory role for : AAA, BMS, Ipsen • Travel grants for : Ipsen, Pfizer, BMS • Research grants for : Ipsen Funding statement: We had no funding for this study. Data availability: Our clinical data will be made available on request, subject to justification of the project. For obtaining the data, please contact our corresponding author, Doctor Manon DE VRIES BRILLAND. References Hodi et al Improved Survival with Ipilimumab in patients with metastatic melanoma Motzer RJ et al (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373:1803–1813 Balar AV et al (2017) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18:1483–1492 Wu T, Dai Y (2017) Tumor microenvironment and therapeutic response. Cancer Lett 387:61–68 Hanahan D (2022) Hallmarks of Cancer: New Dimensions. Cancer Discov 12:31–46 Di Giacomo AM et al (2009) Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother 58:1297–1306 Chiou VL, Burotto M (2015) Pseudoprogression and Immune-Related Response in Solid Tumors. J Clin Oncol 33:3541–3543 Somarouthu B et al (2018) Immune-related tumour response assessment criteria: a comprehensive review. Br J Radiol 91:20170457 Wolchok JD et al (2009) Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 15:7412–7420 Frelaut M, Du Rusquec P, De Moura A, Le Tourneau C, Borcoman E (2020) Pseudoprogression and Hyperprogression as New Forms of Response to Immunotherapy. BioDrugs 34:463–476 Eisenhauer EA et al (2009) New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247 Seymour L et al (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18:e143–e152 Persigehl T, Poeppel TD, Sedlaczek O (2017) Radiologische Responsebeurteilung moderner Immuntherapien mithilfe von iRECIST. Radiol 57:826–833 Hosmer DW, Lemeshow S (2000) Applied Logistic Regression. Wiley. 10.1002/0471722146 R Core Team (2023) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna Robin X et al (2011) pROC: an open-source package for R and S + to analyze and compare ROC curves. BMC Bioinformatics 12:77 Sing T, Sander O, Beerenwinkel N, Lengauer T (2005) ROCR: visualizing classifier performance in R. Bioinformatics 21:3940–3941 Chaltiel D (2021) crosstable: Crosstables for Descriptive Analyses. https://doi.org/10.32614/CRAN.package.crosstable . 0.7.0 Hodi FS et al (2016) Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol 34:1510–1517 Chen M-Y, Zeng Y-C (2022) Pseudoprogression in lung cancer patients treated with immunotherapy. Crit Rev Oncol Hematol 169:103531 Escudier B et al (2017) Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025. Eur Urol 72:368–376 Wagner MJ et al (2018) Response to PD1 inhibition in conventional chondrosarcoma. J Immunother Cancer 6:94 Wolchok JD et al (2009) Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 15:7412–7420 Nishino M et al (2017) Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. Clin Cancer Res 23:4671–4679 Wang Q, Gao J, Wu X (2018) Pseudoprogression and hyperprogression after checkpoint blockade. Int Immunopharmacol 58:125–135 Chae YK, Wang S, Nimeiri H, Kalyan A, Giles FJ (2017) Pseudoprogression in microsatellite instability-high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review. Oncotarget 8:57889–57897 Champiat S et al (2018) Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol 15:748–762 Li H et al (2020) Early Onset Immune-Related Adverse Event to Identify Pseudo-Progression in a Patient With Ovarian Cancer Treated With Nivolumab: A Case Report and Review of the Literature. Front Med 7:366 Kim JY et al (2019) Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis. Cancers 11:1699 Basler L et al (2020) Tumor Volume, and Blood Biomarkers for Early Prediction of Pseudoprogression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibition. Clin Cancer Res 26:4414–4425Radiomics Tanizaki J et al (2016) Report of two cases of pseudoprogression in patients with non–small cell lung cancer treated with nivolumab—including histological analysis of one case after tumor regression. Lung Cancer 102:44–48 Ding H et al (2021) Radiomics in Oncology: A 10-Year Bibliometric Analysis. Front Oncol 11:689802 Sun R et al (2018) A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study. Lancet Oncol 19:1180–1191 Barabino E et al (2022) Exploring Response to Immunotherapy in Non-Small Cell Lung Cancer Using Delta-Radiomics. Cancers 14:350 Kato S et al (2022) Serial changes in liquid biopsy-derived variant allele frequency predict immune checkpoint inhibitor responsiveness in the pan-cancer setting. OncoImmunology 11:2052410 Guibert N et al (2017) Monitoring of KRAS -mutated ctDNA to discriminate pseudo-progression from true progression during anti-PD-1 treatment of lung adenocarcinoma. Oncotarget 8:38056–38060 Lee JH et al (2018) Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti–Programmed Cell Death 1 Antibodies. JAMA Oncol 4:717 Additional Declarations Competing interest reported. Amélie TOULET : The author declare no potential conflicts of interest. Fréderic BIGOT : • Advisory role for : Astrazeneca, BMS, Sanofi, MSD • Travel grants for : MSD Valérie SEEGERS-THEPOT : The author declare no potential conflicts of interest. Sylvère GUILLEMOIS : • Advisory role for : SANOFI Damien VANSTEENE : • Advisory rôle for : Pfizer, Astellas Rémy DELVA : The author declare no potential conflicts of interest. Manon DE VRIES-BRILLAND : • Advisory role for : AAA, BMS, Ipsen • Travel grants for : Ipsen, Pfizer, BMS, Novartis • Research grants for : Ipsen Supplementary Files PPITSupplementaltablesv2.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 26 Nov, 2025 Reviews received at journal 25 Nov, 2025 Reviews received at journal 22 Nov, 2025 Reviews received at journal 21 Nov, 2025 Reviewers agreed at journal 19 Nov, 2025 Reviewers agreed at journal 18 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers invited by journal 06 Oct, 2025 Editor assigned by journal 03 Oct, 2025 Submission checks completed at journal 03 Oct, 2025 First submitted to journal 02 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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12:25:34","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":165471,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7765256/v1/9c81ac4eb25eb3ae1e7f87cc.html"},{"id":93775833,"identity":"e0750c83-2b85-462e-8c0a-1be2a8680420","added_by":"auto","created_at":"2025-10-17 12:33:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75669,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart\u003c/p\u003e","description":"","filename":"floatimage118.png","url":"https://assets-eu.researchsquare.com/files/rs-7765256/v1/dc3fe7b2592ca0d2f3fa4dca.png"},{"id":93774656,"identity":"34676ab8-196b-4527-874e-40007939ec26","added_by":"auto","created_at":"2025-10-17 12:25:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":39387,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves overall survival (OS) between pseudo progression (PP) group (blue curve) and progression disease (PD) group (red curve). The median OS was estimated to 40 months in PP group versus 12 months in PD group (p\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7765256/v1/c5aaf54ac531a423e972df70.png"},{"id":93774662,"identity":"78760a92-6694-42a5-8c62-bf119414ef43","added_by":"auto","created_at":"2025-10-17 12:25:34","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":545292,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots representing level and variation of albumin (a), hemoglobin (b), neutrophils (c), calcium (d) and LDH (e) at the initiation of the ICI (t0), at the evocation of PP (t1) and at the final evaluation which confirmed or not PP (t2) in pseudo progression (PP) group and progression disease (PD) group\u003cem\u003e. P values were obtained using the two-sided Mann-Whitney test (*p\u0026lt;0.05 ; **p\u0026lt;0.01 ; ***p\u0026lt;0.001).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7765256/v1/aee451ceca3118fe0771c467.jpeg"},{"id":93777503,"identity":"0b8f7788-787c-4a7e-9211-fe0f6ce5fc00","added_by":"auto","created_at":"2025-10-17 12:41:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1871651,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7765256/v1/cee03e27-d30a-4c04-88b6-f07adfe0f56a.pdf"},{"id":93774657,"identity":"1a3b68aa-e391-4cb3-b5d5-49c870d2d268","added_by":"auto","created_at":"2025-10-17 12:25:34","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":29733,"visible":true,"origin":"","legend":"","description":"","filename":"PPITSupplementaltablesv2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7765256/v1/c6d794812ca72148faf10200.docx"}],"financialInterests":"Competing interest reported. Amélie TOULET : The author declare no potential conflicts of interest. \nFréderic BIGOT : \n• Advisory role for : Astrazeneca, BMS, Sanofi, MSD \n• Travel grants for : MSD \nValérie SEEGERS-THEPOT : The author declare no potential conflicts of interest. \nSylvère GUILLEMOIS : \n• Advisory role for : SANOFI \nDamien VANSTEENE : \n• Advisory rôle for : Pfizer, Astellas \nRémy DELVA : The author declare no potential conflicts of interest. \nManon DE VRIES-BRILLAND : \n• Advisory role for : AAA, BMS, Ipsen \n• Travel grants for : Ipsen, Pfizer, BMS, Novartis \n• Research grants for : Ipsen","formattedTitle":"Pseudoprogression in Immunotherapy and Identification of Clinical-Biologic Predictive Factors: A Retrospective Pan-Tumor Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince the end of the twentieth century, immunotherapy has gradually become one of the most important cancer therapies, significantly improving the clinical outcomes and survival of patients, initially those with metastatic disease\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Indeed, in-depth analysis of this pathology has highlighted the involvement of not only cancer cells, but also the tumor microenvironment, which, via numerous vectors, enables cancer cells to evade the immune system\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOne of the major discoveries that led to the advent of immunotherapy was immune checkpoints. The main target molecules with therapeutic impact are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand programmed death-ligand 1 (PD-L1). These co-inhibiting molecules regulate the immune system through negative feedback preventing it from running out of control. One of the mechanisms explaining the ability of tumors to avoid the immune system is the overexpression of these molecules\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAtypical responses have been observed since the advent of these new treatments. One of these is the pseudoprogression (PP). First mentioned with the use of IPILIMUMAB (anti-CTLA4) in melanoma in 2007, this could be explained by stimulation of the patient's immune system leading to tumor site lymphocyte infiltration\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Pseudoprogression is a controversial phenomenon, defined as an objective response following initial progression with the same treatment, with an incidence ranging from 0 to 15%, depending on the series and primary cancer site, most often described in the follow-up of melanoma\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAs a result, during follow-up imaging examinations, target lesions may appear to have increased in size because of lymphocyte infiltration and inflammatory mechanisms, rather than disease progression (PD). Currently, there are no imaging modalities that can differentiate true progression from PP. At present, the iconographic evaluation of tumor response is based on the Response Evaluation Criteria in Solid Tumors (RECIST)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. A new classification named iRECIST was established in 2017 to consider paradoxical evolutions linked to immunotherapy\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This classification has given rise to the notion of unconfirmed progressive disease (iUPD), which requires confirmation by follow-up imaging 4 to 8 weeks later. However, these criteria cannot be used to differentiate between PD and PP which leads us to adopt an attitude of close monitoring, with the risk of continuing ineffective treatment, thus losing the patient's chance of success\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis study aimed to determine whether this concept of PP exists and whether there are clinical and/or biological criteria that can be used to distinguish between PP and PD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a retrospective, monocentric, cohort study of patients treated at the Institut de Canc\u0026eacute;rologie de l\u0026rsquo;Ouest (ICO). Patients included had to have metastatic cancer, regardless of the primary location or the histological type, treated with Immune Checkpoint Inhibitors (ICI) with the hypothesis of PP raised during follow-up. This study was conducted with the authorization of the CNIL (the French Data Protection Agency) and was approved by an independent local ethics review board from Angers University Hospital, registered under number 2022\u0026thinsp;\u0026minus;\u0026thinsp;157. This study adhered to the Declaration of Helsinki. All surviving patients were informed and we obtained their written consent.\u003c/p\u003e\u003cp\u003eTo identify relevant cases, we searched our database for the keywords \u0026ldquo;immunotherapy\u0026rdquo; and \u0026ldquo;pseudoprogression\u0026rdquo;. For cohort homogeneity, we excluded, among others, patients with localized cancer, those receiving combined treatments with chemotherapy or targeted therapy, those with interruption of ICI before CT re-evaluation (death or toxicity) and those with incomplete files.\u003c/p\u003e\u003cp\u003eWe collected data on patients\u0026rsquo; clinical characteristics, treatment outcome, and safety with all grade treatment-related adverse events (TRAEs) using the Common Terminology Criteria for Adverse Events (version 4.0). We collected biological values, such as hemoglobin level, neutrophil count, albumin, calcemia and lactate dehydrogenase (LDH) levels. All these data were examined at baseline, corresponding to the initiation of the ICI (t0), at the evocation of PP (t1) and at the final evaluation, which confirmed or not PP (t2).\u003c/p\u003e\u003cp\u003ePP could be evoked by the clinician or by an evaluation tomography (CT) scan report at t1. The confirmed PP was validated using the CT scan report at t2 if the disease was considered stable or shrinking.\u003c/p\u003e\u003cp\u003eThe primary endpoint was the percentage of patients with a confirmed PP at t2. The secondary endpoint was to determine the clinical or biological criteria associated with PP.\u003c/p\u003e\u003cp\u003eA flow chart was produced to identify the number of patients for whom PP was evoked during ICI treatment, and those who had iconography confirming or refuting the diagnosis of PP.\u003c/p\u003e\u003cp\u003eDescriptive statistics were used to summarize the patient and treatment characteristics. Clinical and disease characteristics are presented as medians and ranges for continuous variables and as numbers and percentages for categorical variables. Non-parametric statistical tests were used, considering the cohort size to compare the characteristics of patients with true PP and those with true progression under immunotherapy.\u003c/p\u003e\u003cp\u003eWe used Kaplan-Meier estimation to summarize the Overall Survival (OS), defined as the time from evocation of PP (t1) until the time of death or last follow-up for censored patients.\u003c/p\u003e\u003cp\u003eTo quantify the association between candidate variables (collected at t0 and t1) and the probability of progression, we used a logistic regression model and estimated the Odds Ratio (OR) and 95% confidence interval.\u003c/p\u003e\u003cp\u003eAn OR value greater than 1 indicates an association with true progression, whereas an OR value lower than 1 indicates an association with PP. We built a multivariable regression model to estimate the adjusted ORs. Candidate variables were those whose p-values were lower than 0.3 from the univariable logistic regression model (except for cerebral progression where the number of events was too low). We performed an automatic, step-by-step multivariable model selection procedure based on the AIC to identify the final multivariable model.\u003c/p\u003e\u003cp\u003eTo explore the true progression predictive value of LDH (and relative LDH evolution between t0 and t1), we built a receiver operating curve (ROC) and estimated the area under the curve (AUC)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. We interpreted the discriminative ability as follows: AUC\u0026thinsp;\u0026le;\u0026thinsp;0.5 corresponds to no discriminative ability; 0.5\u0026thinsp;\u0026lt;\u0026thinsp;AUC\u0026thinsp;\u0026lt;\u0026thinsp;0.7 corresponds to poor ability, 0.7\u0026thinsp;\u0026le;\u0026thinsp;AUC\u0026thinsp;\u0026lt;\u0026thinsp;0.8 corresponds to acceptable ability; AUC\u0026thinsp;\u0026gt;\u0026thinsp;0.9 corresponds to good ability. We used the Youden index to identify the LDH threshold that minimizes the false positive rate (1- Specificity) and maximizes the true positive rate (Sensibility).\u003c/p\u003e\u003cp\u003eNo imputation of the missing data was performed.\u003c/p\u003e\u003cp\u003eStatistical analysis was performed using R software (version 4.3.1)\u003csup\u003e15\u003c/sup\u003e, pROC\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, ROCR\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e and crosstable\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e packages.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom September 2013 to June 2022, we identified 311 patients with cancer treated with ICI in our database, for whom PP was raised. After excluding patients with localized cancer most of the time, treated by combined ICI with another treatment (chemotherapy or targeted therapy), interruption of ICI before CT re-evaluation (death or toxicity) incomplete file or in whom the clinician did not accept the hypothesis of PP, we enrolled 123 patients with metastatic cancer. Of these 123 patients, 56 had confirmed PP (46%) and 67 had confirmed PD (54%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eCharacteristics at ICI treatment initiation (t0)\u003c/h3\u003e\n\u003cp\u003eIn this cohort, 59% of the patients were male. The median age at diagnosis was 62 years (13\u0026ndash;81). At ICI initiation, the median age was 65 years (14\u0026ndash;85), and the median weight was 72 Kg (37\u0026ndash;123). The primary sites were mainly lung (38%), kidney (24%) and bladder (11%) cancers. In addition, 7% of cases are skin cancers, 2% are digestive cancers, 4% are gynecologic cancers, 11% are ORL cancers, 2% are breast cancers and 1% are central nervous system cancers (metastatic uveal melanoma). Different histological types were included, with 38% adenocarcinoma, 17% squamous cell carcinoma, 22% clear cell renal carcinoma, 2% undifferentiated carcinoma, 12% urothelial carcinoma, 1% high-grade salivary carcinoma, 2% infiltrative ductal carcinoma and 6% melanoma. Every patient had metastatic cancer with a median of two metastatic sites (1\u0026ndash;8). In the overall cohort, there was 23% of bone metastases, 25% of liver metastases, 57% of lymph nodes metastases, 61% of lung metastases, 16% of brain metastases, 3% of skin metastases and 13% of adrenal metastases at the beginning of immunotherapy. The characteristics were well balanced with no significant differences in sex, age at diagnosis or at the initiation of ICI treatment, location of primitive, histological type or metastatic sites between patients with PP and those with PD (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and between baseline biological characteristics (Table S1).\u003c/p\u003e\u003cp\u003eICI treatment was most often a second-line treatment (1\u0026ndash;8) in both groups, with no significant difference. Patients were treated with anti-PD1 alone (84%), anti-PDL1 alone (9%), a combination of both (1%), or a combination of anti-PD1 and anti-CTLA4 (6%). No significant differences were observed between the PP and PD groups according to the type of immunotherapy used (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn terms of general condition, there were significantly more Eastern Cooperative Oncology Group (ECOG) 0 patients in the PP group at the start of immunotherapy, 55% than in the PD group (32%), more ECOG 1 patients in the PD group (59%) than in the PP group (38%), and similar ECOG 2 in the PP group (7%) and in the PD group (9%). None of the patients had an ECOG score of 3 or 4 (p\u0026thinsp;=\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics and immune checkpoint inhibitor treatment.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline characteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOverall cohort\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;123\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePseudo-progression\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;56 (46%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProgression disease\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;67 (54%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e73 (59%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 (55%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42 (63%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50 (41%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25 (45%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e25 (37%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at diagnostic\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62 (13\u0026ndash;81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64 (13\u0026ndash;81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e60 (33\u0026ndash;77)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLocation of primitive\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSkin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDigestive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGynecologic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eORL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (11%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (14%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e47 (38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 (36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27 (40%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKidney\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14 (21%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCentral Nervous System\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBladder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (11%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 (13%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHistological type\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAd\u0026eacute;nocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e47 (38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19 (34%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28 (42%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (17%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (15%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUndifferentiated carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh grade salivary carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUrothelial carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (12%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (11%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 (13%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfiltrating ductal carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eclear cell renal carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (22%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (19%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emelanoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at first perfusion of ICI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65 (14\u0026ndash;85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e66.5 (14\u0026ndash;82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e64 (38\u0026ndash;85)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWeight at first perfusion of ICI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72 (37\u0026ndash;123)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e73 (40\u0026ndash;123)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e70.5 (37\u0026ndash;108)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eType of ICI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnti-PD1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104 (84%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e48 (86%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e56 (84%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnti-PD1\u0026thinsp;+\u0026thinsp;Anti-PDL1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnti-PDL1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnti-PD1\u0026thinsp;+\u0026thinsp;Anti-CTLA4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLine of ICI use\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1\u0026ndash;5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (1\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of metastatic sites\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1\u0026ndash;6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (1\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMetastatic sites\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (23%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (18%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e18 (27%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLiver\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (21%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e19 (28%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70 (57%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42 (63%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75 (61%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34 (61%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41 (61%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (16%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (19%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSkin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdrenal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 (13%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eECOG*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51 (43%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (55%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21 (32%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59 (49%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21 (38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e38 (59%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eAbbreviations: ICI, immune checkpoints inhibitors; ECOG, Eastern Cooperative Oncology Group; PD1, programmed cell death 1; PDL1, programmed death-ligand 1; CTLA4, cytotoxic T-lymphocyte-associated antigen 4.\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003cem\u003eP values were obtained using the two-sided Mann-Whitney test (*p\u0026lt;0.05).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics at time of PP evocation (t1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll evaluation scans reported an aspect of progression. Some radiologists raised the diagnosis of PP in their reports, recommending a new, closer scan 4 to 8 weeks later, but most of the time, the oncologist made the diagnosis and decided to continue ICI with a re-evaluation scan at a median time of 66 days (6 to 204), depending on the practitioner (Table S2). Suspicion of PP was raised with a median time of 79 days (28 - 927), after ICI treatment initiation, most of the time during the first scan evaluation. We confirmed PP early, at 28 days, but also later, at 227 days (Table 2).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2:\u003c/strong\u003e Characteristics of the patient population at the evocation of pseudoprogression (t1) and toxicity of immune checkpoint inhibitor treatment.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"651\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics at t1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN = 123\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePseudo-progression\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN = 56 (46%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProgression disease\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN = 67 (54%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e40 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e20 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e20 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e74 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e32 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e42 (64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e8 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e65 (14-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e66.5 (14-82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e64 (38-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime between first ICI perfusion and PP evocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e79 (28-927)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e79 (28-227)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e78 (28-927)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e72 (38-120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e72 (39-120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e71.5 (38-112)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Weight variation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0 (-14.9-16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0 (-11.3-11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0 (-14.9-16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlbumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e40 (23.2-47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e40 (31-46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e39 (23.2-47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Albumin variation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e-2.1 (-27.1-42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e-1.8 (-13.2-42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e-2.3 (-27.1-22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHemoglobin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e12.9 (7.4-16.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e13 (8.9-15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e12.4 (7.4-16.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Hemoglobin variation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0 (-36.3-47.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2.1 (-35.9-21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e-1.1 (-36.3-47.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeutrophils\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4460 (1620-19090)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4390 (1730-12410)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4529.5 (1620-19090)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Neutrophils variation*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e11.4 (-57.6-208.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e3 (-57.6-134.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e20.3 (-39.4-208.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDH **\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e201 (95-3223)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e189 (95-480)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e232.5 (148-3223)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;LDH variation**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e-0.6 (-61.4-258.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e-4.2 (-61.4-40.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e8.5 (-32.8-258.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCalcemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2.4 (2.1-2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2.4 (2.1-2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2.4 (2.1-2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Calcemia variation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0 (-14.5-11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0.5 (-14.5-6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e0 (-12.7-11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003en=31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProgression on scan report\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e123 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e56 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e67 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic site in progression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e13 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e9 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e29 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e12 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e17 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eLymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e61 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e23 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e38 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e63 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e29 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e34 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eBrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e3 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eSkin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e4 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eAdrenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e5 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e3 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 26.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eToxicity of ICI*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eAt least one\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e39 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e23 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e16 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 26.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eNo one\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e83 (68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e33 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e50 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eGrade 1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e35 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e19 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e16 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.1538%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6154%;\"\u003e\n \u003cp\u003eGrade 3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e7 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e5 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.3846%;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0.153846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 26.1538%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 14.6154%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 17.3846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 17.3846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 17.3846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 6.92308%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoints inhibitors; PP, pseudoprogression; LDH,\u003c/em\u003e \u003cem\u003elactate dehydrogenase; Na, unknown\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eP values were obtained using the two-sided Mann-Whitney test (*p\u0026lt;0.05 ; **p\u0026lt;0.01).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients with PP had a significantly better overall survival (median 39.7 months, 95%CI: 26.8 to NA) than patients who had real cancer progression (median 12 months; 95%CI 10.4 to 19.8; p\u0026lt;0.001) (figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinically, we found no significant difference between PP and PD with respect to ECOG performance status at t1. There were as many ECOG 0 patients, 36% in the PP group and 30% in the PD group, 57% were ECOG 1 in the PP group and 64% in the PD group, and similar ECOG 2 in the PP group (7%) and PD group (6%). None of the patients had an ECOG score of 3 or 4 in the 2 groups (Table 2). There was no significant difference in weight at t1 in either group, or weight variation between t0 and t1 with stable weight in 79.3% of the patients (+/-5%) (Table 2). We did not observe differences in the metastatic sites where PP was evoked between PP and PD patients (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBiologically, we found no significant difference values between PP and PD patients, nor relative variation from t0 to t1, for albumin (figure 3a), hemoglobin (figure 3b) and calcemia (figure 3d). We did not find a difference in neutrophil counts at t1 (figure 3c), but the relative variation in neutrophil counts between t0 and t1 was significantly greater in the PD group than in the PP group (p=0.04) (Table 2 and figure 3). LDH levels were clinically and statistically higher in the PD group at t1 (median 232.5U/L) than in the PP group (median 189U/L, p=0.003). We also showed that from t0 to t1, LDH increased in PD (median elevation of 8.5U/L) while LDH decreased in PP group (median reduction of 4.2U/L, p=0.002) (Table 2 and figure 3e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePredictive parameters for PP at t1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, we performed a univariate analysis. The risk of PD was increased in patients having ECOG 1 than in patients having ECOG 0 at t0 (OR: 2.59, 95%CI: 1.20 to 5.59, p=0.02), in patients having higher LDH at t1 (for 100 U/L of increase LDH, the OR was 1.90, 95%CI: 1.07 to 3.37, p=0.03), and in patients with a 10% or greater increase in LDH between t0 and t1 (OR: 1.39, 95%CI: 1.14 to 1.78, p\u0026lt;0.005). The risk of PD decreased in patients who experience at least one immunotherapy-related toxicity (OR: 0.46, 95%CI: 0011 to 0.99, p=0.049) (Table S3).\u003c/p\u003e\n\u003cp\u003eIn multivariable analysis (Table 3), a 100 U/L increased in LDH level was significantly associated with PD (OR=7, 95%CI: 2.3 to 36.7, p=0.004) as well as bone metastatic site progression (p=0.041) and ECOG performance status at t0 (p=0.03) while type of immunotherapy (PD1 alone vs other), time between t0 to t1 and neutrophils count at t1 were not significantly associated with PD.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 3:\u003c/strong\u003e Final multivariable logistic regression model\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"474\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e \u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eType of ICI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Anti-PD1 alone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Anti-PDL1 or combination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.76 (0.73 to 69.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eECOG at t0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.88 (0.98 to 53.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.2 (1.76 to 2,497)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTime from t0 to t1: 1 month increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.07 (1.16 to 5.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeutrophils count: 1000 units increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.59 (1.05 to 2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLDH at t1: 100 units increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.07 (2.30 to 36.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBone site metastatic progression vs other site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.6 (1.40 to 289)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e OR = Odds Ratio, CI = Confidence Interval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoints inhibitors; LDH,\u003c/em\u003e \u003cem\u003elactate dehydrogenase; vs, versus\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis observation led us to focus on the evolutionary kinetics of LDH. Indeed, exploratory, we studied a threshold beyond which the PP cannot be considered. According to LDH level, we established that the best threshold was a value of 148 U/L with an AUC=0.7 (0.56-0.8) (figure S1, black curve). The sensitivity was of 72.5%, specificity of 65.8%, positive predictive value of 69% and negative predictive value of 44.7%. According to the variation in LDH levels between t0 and t1, an increase in LDH over 32.8% would favor progression, not PP (figure S1, red curve).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics at time of PP or PD confirmation (t2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinically, ECOG was significantly better in PP patients than in PD patients (93% vs 59% had ECOG 0 or ECOG1, p\u0026lt;1.10\u003csup\u003e-4\u003c/sup\u003e) and more patients had weight loss in the PD group than in the PP group (p=0.001) (Table S2).\u003c/p\u003e\n\u003cp\u003eBiologically, at t2, we found higher hemoglobin levels in the PP group than in the PD group (median 13.2 vs 12.1 g/dL, p= 0.014) and lower LDH levels in the PP group than in the PD group (190 vs 254 UI/L, p\u0026lt;0.0001). \u0026nbsp;We did not observe differences in albumin, neutrophil count, or calcemia at t2. Between t1 and t2, we found that relative albumin increased in the PP group (median increase = +2.5%) compared to the PD group (median decrease -0.7%, p=0.0125), and a higher relative hemoglobin increase in the PP group (median increase +1.6%) compared to the PD group (median decrease -1.5%, p=0.0195). We did not find statistical differences between t1 and t2 in terms of neutrophil count variation, calcemia variation, or LDH variation (Table S2 and figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events and immunotherapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe tracked the toxicity through the final radiological assessment. There were more patients with at least one side effect of ICI in the PP group (41%) than in the PD group (24%) (p=0.05) (Table 2). Most of the time there were side effects such as dysthyroidism, diarrhea or skin disorders. However, the difference in severity was not statistically significant. These were mainly grade 1 or 2 toxicities, 34% in the PP group and 24% in the PD group. Two patients in the PD group and five in the PP group experienced grade 3 or 4 toxicity (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the PP group, when confirmed, 53 patients continued ICI treatment. Immunotherapy was interrupted in 3 patients because of toxicity. ICI was continued in the other 2 patients because of doubts regarding the imputability of the treatment. In the PD group, 44% of patients who progressed received new chemotherapy, 14% received targeted therapy, 18% stopped every treatment. Two patients continued immunotherapy because the progression was unclear and minimal, eight patients continued immunotherapy and underwent irradiation at a progressive metastatic site if the disease was otherwise controlled.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the largest retrospective cohort of patients with metastatic cancers treated with ICI for whom PP was suspected, regardless of location. Pseudoprogression must be induced during ICI treatment. We demonstrated that this concept was not rare, with 46% of PP confirmed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis percentage is higher than that in other cohorts reported in the literature, which ranges from 0.6 to 15%\u003csup\u003e7,19\u003c/sup\u003e. However, we studied the percentage of proven PP compared with evoked PP and not the percentage of PP in all patients undergoing ICI therapy in our institution. It is important to note that PP can occur regardless of cancer localization, although PP seems to be more common in lung and kidney cancers, as reported in the literature\u003csup\u003e20,21\u003c/sup\u003e. Interestingly, this phenomenon of PP can be observed regardless of ICI type. The aim of our study was to confirm or refute the existence of this concept and thus guide our decisions, that is to continue immunotherapy if it is justified or, on the contrary, to stop it and rapidly change treatment if progression is certain. It is also important to consider this phenomenon in the design of many therapeutic trials evaluating immunotherapy\u003csup\u003e22\u003c/sup\u003e. The median time between the start of ICI and evocation of PP was 79 days, mostly at the first evaluation scan. We observed a difference in the maximal range between the two groups (927 vs 227 days in the PD and PP groups, respectively) which is in line with the literature\u003csup\u003e23\u003c/sup\u003e. Indeed, most of the cases of PP described occurred relatively soon after the initiation of immunotherapy; however PP can also be induced at a later stage\u003csup\u003e19,24\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMoreover, we showed that patients with PP had significantly better OS than with PD. This result is consistent with the literature data\u003csup\u003e19\u003c/sup\u003e and the pathophysiology of PP, wich is an atypical response to treatment. In addition, in a systematic review by \u003cem\u003eChen et al\u003c/em\u003e, of PP in non-small cell lung cancer, they looked at biopsies of suspected PP sites and found that increased lesion size may be induced by inflammatory changes. The infiltrating inflammatory cells are mainly composed of CD4+ and CD8+ T cells and macrophages\u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur secondary objective was to identify clinico-biological factors that could help in the decision-making process, without waiting for controlled imaging.\u003c/p\u003e\n\u003cp\u003eWe found that there were significantly more patients with an ECOG performance status of 0 in the PP confirmed group than in the PD group. This result is similar to the subgroup analysis of the phase 3 CheckMate 025 study, which evaluated patients with advanced renal cell carcinoma treated with nivolumab and who had RECIST progression on their scan but a clinical benefit. Immunotherapy was continued for at least 4 weeks, before re-evaluation by CT scan. Among the 153 patients who continued receiving nivolumab, 13% had at least 30% reduction in tumor burden. Those patients had a significantly better general condition with a Karnofsky Performance Status \u0026gt;= 90% in 80% of them vs 71% in the PD group\u003csup\u003e21\u003c/sup\u003e. Indeed, this notion of maintaining good general condition during PP has been described in the literature\u003csup\u003e25,26\u003c/sup\u003e. However, deterioration of the general condition was reported when the patient progressed\u003csup\u003e27\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAdditionally, some studies have suggested a correlation between the occurrence of side effects and possible PP\u003csup\u003e28\u003c/sup\u003e. We also showed that there were significantly more immunotherapy-related adverse events in the PP group, but we did not find a difference in severity or association that could be considered predictive of efficacy.\u003c/p\u003e\n\u003cp\u003eLDH levels and variations were significantly different between the two groups. With an OR of 0.72, we found a strong association between an LDH elevation of more than 10% and the risk of PD, rather than PP. This biological variable is particularly interesting because it was reported in previous studies\u003csup\u003e29,30\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur study had several limitations. First, its retrospective design may have led to potential selection bias. Unfortunately, there is a lack of data concerning calcemia, albumin, neutrophils and LDH levels, which may lead to a lack of statistical power. We thought that the albumin level which is often correlated with general condition, would be significantly higher in the PP group, but there was no difference. Similarly, it is well known that elevated calcemia is a sign of cancer progression, but there was no difference between the PP and PD groups. Furthermore, in some cases, the use of biomarkers such as\u0026nbsp;carcino-embryonic cntigen (CEA) can be helpfull\u003csup\u003e31\u003c/sup\u003e. In our study, we did not report them because of a lack of data and many different histological types and primary locations, with no clearly established biomarkers. Otherwise, the AUC of the LDH ROC curves is under 0.8, which confers unsatisfactory predictive properties of progression. It would be interesting to monitor LDH levels in patients undergoing ICI, to assess whether, in a larger cohort, the predictive value of LDH would be confirmed. However, this finding was consistent with that reported by \u003cem\u003eBasler et al\u003c/em\u003e. Indeed, the blood prediction model (LDH+S100) achieved a similar AUC of 0.71, but a model combining LDH and S100 protein associated with radiomic assessment of lesions (describing shape, intensity, and texture) was the best predictive model of PP with an AUC of 0.82, in 112 patients with metastatic melanoma treated with ICI\u003csup\u003e30\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCurrently, the most promising technique for understanding the heterogeneity of responses to ICI is the use of radiomics\u003csup\u003e32,33\u003c/sup\u003e. Radiomics is a technique used for extracting large volumes of imaging data. It involves extracting several parameters from a single raw image, such as the geometry and shape, histogram analysis and texture. These parameters can be pooled in a statistical model to predict the treatment response. \u003cem\u003eBarabino et al.\u003c/em\u003e included 33 patients under ICI with non-small cell lung cancer. They studied many radiomic features at baseline and re-evaluation scan. They found that an increase in heterogeneity in energy, contrast and graey level non-uniformity favors PD\u003csup\u003e34\u003c/sup\u003e. Finally, circular tumoral DNA seems to be an interesting perspective too\u003csup\u003e35\u003c/sup\u003e. \u003cem\u003eGuibert et al\u003c/em\u003e. showed an important decrease in KRAS mutated ctDNA in two patients who experienced a PP under ICI for lung adenocarcinoma compared to the KRAS ctDNA level of one patient with PD\u003csup\u003e36\u003c/sup\u003e. Similarly, \u003cem\u003eLee et al.\u003c/em\u003e demonstrated that, in patients followed up for melanoma treated with ICI, that an undetectable level of ctDNA at baseline or a more than 10-fold decrease over the first 12 weeks could predict PP with a sensitivity of 90% (95% CI, 68%-99%) and a specificity of 100% (95% CI, 60%-100%)\u003csup\u003e37\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn conclusion, PP in patients treated with ICI is a real event and should be considered regardless of tumor location, especially if a good general condition is maintained with stable LDH levels. It is essential to confirm these data in a prospective, independent validation cohort to establish a predictive score. Furthermore, with the development of artificial intelligence, new imaging techniques can be used to distinguish PP from PD in larger clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement section\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to all our co-authors and patients for their contribution to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concepts : M.de Vries-Brilland, A.Toulet, R.Delva\u003cbr\u003e\u0026nbsp;Study design: M.de Vries-Brilland, A.Toulet, V.Seegers-Thepot\u003cbr\u003e\u0026nbsp;Data acquisition: A.Toulet\u003cbr\u003e\u0026nbsp;Quality control of data and algorithms: A.Toulet, M.de Vries-Brilland\u003cbr\u003e\u0026nbsp;Data analysis and interpretation: A.Toulet, V.Seegers-Thepot, M.de Vries-Brilland\u003cbr\u003e\u0026nbsp;Statistical analysis: V.Seegers-Thepot\u003cbr\u003e\u0026nbsp;Manuscript preparation: A.Toulet, M.de Vries-Brilland\u003cbr\u003e\u0026nbsp;Manuscript editing: A.Toulet, M.de Vries-Brilland, R.Delva, F.Bigot, S.Guillemois, D.Vansteene, V.Seegers-Thepot\u003cbr\u003e\u0026nbsp;Manuscript review: A.Toulet, M.de Vries-Brilland, R.Delva, F.Bigot, S.Guillemois, D.Vansteene, V.Seegers-Thepot\u003c/p\u003e\n\u003cp\u003eAll authors have read and approve the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted with the authorization of the CNIL (the French Data Protection Agency) and was approved by an independent local ethics review board from Angers University Hospital, registered under number 2022-157. \u0026nbsp;This study adhered to the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll surviving patients were informed and we obtained their written consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of conflicting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAm\u0026eacute;lie TOULET : The author declare no potential conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFr\u0026eacute;deric BIGOT :\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Advisory role for : Astrazeneca, BMS, Sanofi, MSD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Travel grants for : MSD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVal\u0026eacute;rie SEEGERS-THEPOT : The author declare no potential conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSylv\u0026egrave;re GUILLEMOIS :\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Advisory role for : SANOFI\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDamien VANSTEENE :\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Advisory r\u0026ocirc;le for : Pfizer, Astellas\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eR\u0026eacute;my DELVA : The author declare no potential conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eManon DE VRIES-BRILLAND : \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Advisory role for : AAA, BMS, Ipsen\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Travel grants for : Ipsen, Pfizer, BMS\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Research grants for : Ipsen\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe had no funding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur clinical data will be made available on request, subject to justification of the project. For obtaining the data, please contact our corresponding author, Doctor Manon DE VRIES BRILLAND.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHodi et al Improved Survival with Ipilimumab in patients with metastatic melanoma\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMotzer RJ et al (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373:1803\u0026ndash;1813\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBalar AV et al (2017) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18:1483\u0026ndash;1492\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu T, Dai Y (2017) Tumor microenvironment and therapeutic response. 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JAMA Oncol 4:717\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Immune checkpoint inhibitor, pseudoprogression, LDH, ECOG, metastatic cancer, predictive factors","lastPublishedDoi":"10.21203/rs.3.rs-7765256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7765256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eImmune Checkpoint inhibitors (ICI) have emerged as one of the leading cancer therapies. Inflammatory mechanism induced by ICI can lead to increased tumor lesions that could be wrongly misinterpreted as progressive disease (PD). Currently, there are no imaging modalities that can differentiate true progression from pseudoprogression (PP). Although the iRECIST criteria have been developed to characterize these atypia, they appear to be inadequate in practice. The aim of this study is to determine whether this concept of PP exists and whether there are clinical or biological criteria that can be used to distinguish PP and true progression (PD).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective study in patients (pts) treated with ICI for metastatic cancer at Institut de Canc\u0026eacute;rologie de l\u0026rsquo;Ouest, and for whom PP was raised. Data were collected at initiation of ICI (t0), at evocation of PP (t1) and at subsequent evaluation (t2), treatment outcome and adverse events. Primary endpoint was to determine the percentage of pts with confirmed PP at t2. Secondary endpoints were to determine clinical or biological criteria associated to PP.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e123 pts were included, 59% were men, most commonly with lung (38%), kidney (24%) or bladder (11%) cancer, and mainly treated in 2nd line with anti-PD1 (85%). We identified 56 confirmed PP (45%), with a median time of 79 days (28\u0026ndash;227) between the first ICI infusion and evoked PP. ECOG score 0 and no weight loss were statistically associated with confirmed PP, respectively p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 and p\u0026thinsp;=\u0026thinsp;0.031. There was no association between PP and cancer type, metastatic site or type of ICI. For biological variable, only LDH was significantly different between the 2 groups (p\u0026thinsp;=\u0026thinsp;0.003). More specifically, a 10% variation or more in LDH level was in favor of PD (OR\u0026thinsp;=\u0026thinsp;0.72 with p\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePP on ICI are real events and should be considered, regardless of tumor location, in pts in good general condition with stable LDH levels. Furthermore, with the development of artificial intelligence, some new imaging techniques could be developed to distinguish PP and PD. Some studies focusing on the circulating tumor DNA are also an interesting perspective.\u003c/p\u003e","manuscriptTitle":"Pseudoprogression in Immunotherapy and Identification of Clinical-Biologic Predictive Factors: A Retrospective Pan-Tumor Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 12:25:29","doi":"10.21203/rs.3.rs-7765256/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-26T09:29:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-26T01:43:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-22T10:27:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T13:56:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29128492862552692511729643153703012867","date":"2025-11-19T11:13:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"107279343846567798580267985589416208747","date":"2025-11-18T07:16:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326238231396397427244545518799057893559","date":"2025-11-18T03:36:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"205419892746314634314346979766855137032","date":"2025-11-17T15:27:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"112704814095231823317231057028433355264","date":"2025-11-17T11:40:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"71063442699422619952221243296222134863","date":"2025-11-17T10:15:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93331208537663459043144965670800354943","date":"2025-11-17T10:05:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-06T07:50:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-03T13:56:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-03T13:55:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2025-10-02T09:20:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dbbd4277-a5b1-4727-a126-cb3acca25d9e","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2025-11-26T09:38:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 12:25:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7765256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7765256","identity":"rs-7765256","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}