Cycles Of First-line Chemotherapy Research Articles

Unfavourable carcinoma of unknown primary (CUP) with gastrointestinal profile: A retrospective study.

e16374 Background: According to European Society of Medical Oncology (ESMO) guidelines, CUP are classified in favorable and unfavorable subsets. Favorable CUPs (20% of pts) have clinical aspects and either pathology highly suggestive for specific site of origin or with amenable metastases for localized treatment with curative intent; they are treated with site-specific chemotherapy (CT). All other CUPs (80%) are defined unfavorable and are treated with empiric CT regimens. There is no data about the best CT regimen for unfavourable CUPs with GI profile, i.e., those CUPs that do not meet the criteria of favourable colon-like CUP (CK7-/CK20+/CDX2+) but have a morphological/immunohistochemical profile suggestive for the digestive system. Methods: We conducted a single-center retrospective study to describe outcomes and prognostic factors of pts with unfavourable CUPs with GI profile, referred to our center from Jan 2000 to Aug 2023, who received at least one cycle of first-line CT. The definition of GI profile was: a) negativity for GATA-3, PAX-8 and TTF-1 and b) CK7+/CK20-/anyCDX2 or CK7-/CK20+/CDX2- or CK7-/CK20-/CDX2+, or c) presence of an abundant mucinous component and/or a signet ring cell component. The primary endpoint was the progression free survival (PFS) of first line chemotherapy for advanced disease. Results: 43 pts were included (characteristics in table). After a median follow-up of 43.9 months, 33 deaths were registered and the mOS was 12.6 months (95% CI, 8.7-16.5). Forty PFS events were registered and the mPFS was 6.1 months (95% CI, 3.5-8.9). At univariate analysis, male pts (p=0.034), peritoneal metastases (p=0.0282), residual tumor after surgery (p=0.002), suspected biliopancreatic origin (p=0.033), PS ECOG > 1 (p<0.001) and CDX2- status (p=0.025) were associated with shorter PFS. No CT regimen was superior in terms of PFS at both univariate (p=0.282) and multivariable analysis after adjusting for peritoneal metastases, suspected origin, gender and baseline ECOG PS. Conclusions: Although limited by the small sample size, this study showed that all CT regimens were comparable in terms of PFS among patients with unfavorable CUP with gastrointestinal profile. Keywords (3/10): cancer of unknown primary; peritoneal metastases; chemotherapy. [Table: see text]

The FJQR Has Synergistic Effect with Fluoropyrimidine in the Maintenance Treatment for HER-2 Negative Gastric Cancer.

Maintenance therapy aimed to strengthen the first-line chemotherapy and improve quality of life is needed for gastric cancer (GC). Currently, many clinical studies have confirmed the important role of fluoropyrimidine in the maintenance stage. Our team has created patented prescriptions "Fuzheng jiedu Quyu Method" recipe (FJQR), which was considered as an adjuvant therapeutic scheme (reduce toxicity and increase the efficacy of chemotherapy). This study aimed to evaluate the efficacy and safety of FJQR combined with fluoropyrimidine as a maintenance treatment in HER-2 negative GC patients. We performed the analysis of 129 patients with HER-2 negative GC who entered the maintenance stage in our hospital and Tianjin Cancer Hospital between January 2018 and December 2020. Out of the 129 eligible patients, 64 were categorized into the maintenance treatment group with FJQR+fluoropyrimidine, and 65 patients were assigned to the control group if they received fluoropyrimidine alone. Capecitabine was orally 1000mg/m2, Qd, half an hour after meals, and FGQR was 15g Bid after capecitabine. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), overall remission rate (ORR), quality of Life (QOL), TCM syndrome and safety. The mPFS in the treatment group was significantly prolonged compared with the control group (6.3 vs. 5.0 months, p = 0.03), while the mOS was not substantially improved (11.4 vs. 10.5 months, p = 0.38). Gastrointestinal symptoms and pain became better in the treatment group. The number of distant metastatic organs, first-line chemotherapy cycles, and lymph node metastasis were independent risk predictors for PFS. Blood stasis syndrome may be the protective factor. In terms of safety, treatment-related adverse events (AEs) in the treatment group were relatively lighter, and the incidence of grade III-IV AEs could be significantly reduced. FJQR and fluoropyrimidine have synergistic effects as maintenance treatment in HER-2 negative GC, with good efficacy and safety.

Avelumab or pembrolizumab: Which is the better subsequent treatment in patients with advanced urothelial carcinoma who did not show progression after 4 cycles of first line chemotherapy?

633 Background: In platinum eligible patients with advanced urothelial carcinoma (UC), there are two treatment options if they did not show progression after 4 cycles of first line chemotherapy. One is switching to avelumab maintenance therapy and the other is pembrolizumab after the disease progression on first line chemotherapy. However, there is no data witch treatment strategy demonstrate better survival. This study aimed to compare the efficacy between avelumab and pembrolizumab after first line chemotherapy without disease progression. Methods: We retrospectively reviewed patients with advanced UC who received avelumab or pembrolizumab as subsequent therapy following first line platinum-based chemotherapy between March 2018 and Jun 2023. In patients who receive pembrolizumab, only patients who did not show progression after 4 cycles of first line chemotherapy were included in the study cohort. The oncological outcomes were compared between the patients who received avelumab and pembrolizumab. Results: Thirty-three and 100 patients received avelumab and pembrolizumab during study periods, respectively. Among 100 patients who received pembrolizumab, 14 patients did not show progression during 4 cycles of first line chemotherapy. Median 4 and 6 cycles of first line chemotherapy were performed in patient treated with avelumab and pembrolizumab, respectively. All patients treated with pembrolizumab showed disease progression after 1st line chemotherapy. With the median follow-up of 16.7 months, progression was observed in 19 (57%) and 12(86%) patients in avelumab and pembrolizumab group, respectively. Among the patients with progression, all patients had treated with avelumab received subsequent treatment mainly enfortumab vedotin. However, only 2 patients (17%) had treated with pembrolizumab received subsequent treatment and the other patients were not candidate of additional treatment due to poor PS or cachexia. Although median progression free survival from starting first line chemotherapy was shorter in patients with avelumab compared to pembrolizumab (9.7 vs. 19.9 months, P=0.06), median OS was longer in patients with avelumab (40.9 vs. 24.9 months, P=0.34). Conclusions: In patients who did not show progression after 4 cycles of first line chemotherapy, avelumab maintenance therapy might be a better treatment option with longer overall survival compared to pembrolizumab.

The Relative Dose Intensity Changes during Cycles of Standard Regimens in Patients with Diffuse Large B-Cell Lymphoma.

No studies have focused on the trajectory of the average relative dose intensity (ARDI) during cycles of first-line chemotherapy for patients with diffuse large B-cell lymphoma. To evaluate the impact of attenuating ARDI during cycles on overall survival, we conducted a multi-centre, longitudinal, observational retrospective study. A total of 307 analysable patients were enrolled. Multivariate Cox hazards modelling with restricted cubic spline models revealed prognostic benefits of higher ARDI up to, but not after, cycle 6. According to group-based trajectory modelling, patients were classified into five groups depending on the pattern of ARDI changes. Among these, two groups in which ARDI had fallen significantly to less than 50% by cycles 4-6 displayed significantly poorer prognosis, despite increased ARDI in the second half of the treatment period (log-rank p = 0.02). The Geriatric Nutritional Risk Index offered significant prediction of unfavourable ARDI changes (odds ratio 2.540, 95% confidence interval 1.020-6.310; p = 0.044). Up to cycle 6, maintenance of ARDI in all cycles (but particularly in the early cycles) is important for prognosis. Malnutrition is a significant factor that lets patients trace patterns of ARDI changes during cycles of chemotherapy associated with untoward prognosis.

Prognostic Value of FDG PET/CT in Patients with Nodal Peripheral T-Cell Lymphoma.

This study evaluated the prognostic significance of FDG PET/CT in patients with nodal peripheral T-cell lymphoma (PTCL). We retrospectively reviewed patients with histologically confirmed nodal PTCL who underwent FDG PET/CT at baseline, after three cycles of first-line chemotherapy (interim), and at the end of therapy. Response was assessed visually using the Deauville 5-point scale (D5PS); scores of 1, 2, and 3 were considered PET-negative, and scores of 4 and 5 were considered PET-positive. The associations between FDG PET/CT findings and survival were assessed using Cox regression analysis. A total of 79 patients (44 males and 35 females; median age 56 years) were included in this study. In response assessment, 17 (22%) had an interim PET-positive result and 10 (13%) had an end-of-therapy PET-positive result. During a median follow-up of 50 months, 37 patients (47%) presented with disease progression and 30 patients (38%) died. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 57% and 64%, respectively. An interim PET-positive result was the only significant indicator of PFS. Higher International Prognostic Index and end-of-therapy PET-positive result were significant independent prognostic factors of OS. Interim and end-of-therapy FDG PET/CT responses based on D5PS are meaningful in predicting the outcomes of patients with nodal PTCL.

Disparate Outcomes, Biologic and Therapeutic Differences in Pediatric versus Adult Patients with Ewing Sarcoma

Introduction: Ewing sarcoma (ES) is a small blue round cell sarcoma affecting a wide age spectrum. Clinical advances predominately stem from pediatric research consortia clinical trials. In most series, adults have poorer outcomes when compared to children. The aim of this study was to perform a detailed evaluation of factors potentially accounting for this difference. Methods: A single institution retrospective chart review was conducted on patients with ES diagnosed from 2005 to 2015, identified using a free-text search engine with the keywords “Ewing sarcoma” as well as a corresponding pathologic database. Data were analyzed based on age, pediatric (age <18) and adult (age >18 years), using a multivariate analysis model. Results: Eighty-eight ES patients (34 pediatric, 54 adult) were identified with a median age of 13 (range 3–18) and 31 (range 19–70) in their respective cohorts. Five-year overall survival (OS) was higher in pediatric patients (73.5% vs. 48.1%, p = 0.0213). By stage, 5-year OS in pediatric versus adult patients was 65% versus 20% (p = 0.0530) in metastatic (n = 32) and 68.1% versus 58.8% (p = 0.278) in localized (n = 56) patients. Lung-only metastases were present in 83% of metastatic pediatric patients versus 35% of adult metastatic patients. Pediatric patients received more cycles of first-line chemotherapy (13.8 vs. 11.4, p = 0.001), independent of stage. More cycles of chemotherapy correlated with improved OS (HR: 0.864, CI: 0.773–0.967) and progression-free survival (HR: 0.897, CI: 0.808–0.996). Conclusions: Outcome differences were most notable in patients with metastatic disease, although not statistically significant. Our series found differences in presentation between pediatric and adult populations with adult patients receiving fewer cycles of chemotherapy. This may suggest that both variations in underlying disease biology and potentially differences in treatment may account for outcome disparities.

Clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas.

We examined the clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas (NECs) to offer additional guidance for the clinical treatment of small-cell lung cancer (SCLC), which is a type of advanced intrapulmonary NEC (IPNECs). The clinical data and survival of 123 patients with advanced IPNECs and extrapulmonary NECs (EPNECs) were obtained. We retrospectively examined the corresponding clinical diagnosis and treatment and investigated the significant factors influencing the survival prognosis of patients with NECs. There were 90 cases of IPNECs (including 81 cases of SCLC), and 33 cases of EPNECs. The median overall survival (OS) of IPNECs was significantly longer than that of the EPNECs in the gastrointestinal tract and in the other regions (P < 0.05). The median OS of patients with other IPNECs was longer than that of patients with SCLC (P > 0.05). Multivariate analysis demonstrated that age, liver metastasis, number of cycles of first-line chemotherapy, and chest radiotherapy were risk factors influencing OS in patients with NECs (P < 0.05). The survival of IPNECs was significantly longer than that of EPNECs in the gastrointestinal tract and other regions. Nevertheless, patients with advanced NECs who were older and had liver metastases had a poorer prognosis. Multidisciplinary treatments including multicycle chemotherapy and a combination of chemotherapy and radiotherapy should function significantly in extending the survival of NECs.

Prognostic factors in refractory metastatic colorectal cancer patients treated with Trifluridine/Tipiracil

PurposeThe systemic treatment options for metastatic colorectal cancer (mCRC) are unsatisfactory, and the disease recurs despite the use of numerous medications and their combinations. Trifluridine/Tipiracil is a relatively new drug used in refractory mCRC. Little is known about its real-world effectiveness and prognostic and predictive factors. Therefore, this study aimed to develop a prognostic model for refractory mCRC treated with Trifluridine/Tipiracil.MethodsWe retrospectively evaluated the data from 163 patients who had received Trifluridine/Tipiracil as a third or fourth line of treatment for refractory mCRC.ResultsAfter starting Trifluridine/Tipiracil, 21.5% of patients survived one year, and the median overall survival after Trifluridine/Tipiracil initiation was 251 days (SD: 17.855; 95%CI: 216–286). Median progression-free survival after Trifluridine/Tipiracil initiation was 56 days (SD: 4.826; 95%CI 47–65). Moreover, the median overall survival from diagnosis was 1333 days (SD: 82.84; 95%CI: 1170–1495). In forward stepwise multivariate Cox regression analysis, initial radical treatment (HR = 0.552, 95% CI 0.372–0.819, p < 0.003), the number of cycles of first-line chemotherapy (HR = 0.978, 95% CI 0.961–0.995, p < 0.011), the number of cycles of second-line chemotherapy (HR = 0.955, 95% CI 0.931–0.98, p < 0.011), BRAF mutation (HR = 3.016, 95% CI = 1.207–7.537, p = 0.018), and hypertension (HR = 0.64, 95% CI = 0.44–0.931, p = 0.02) were all associated with survival after Trifluridine/Tipiracil initiation. Our model and model-based nomogram displayed an AUC of 0.623 for one-year survival estimation in the testing cohort. The C-index for the prediction nomogram was 0.632.ConclusionWe have developed a prognostic model for refractory mCRC treated with Trifluridine/Tipiracil based on five variables. Moreover, we reported a nomogram which could be used by oncologists in clinic visits on a daily basis.Graphical abstract

Low diffusion capacity predicts poor prognosis in extensive stage small cell lung cancer: a single-center analysis of 10 years

BackgroundPoor pulmonary function and chronic obstructive pulmonary disease (COPD) are associated with poorer overall survival (OS) in non-small-cell lung cancer (NSCLC) patients. Few studies have investigated the association between pulmonary function and OS in small-cell lung cancer (SCLC) patients. We compared the clinical characteristics of extensive disease SCLC (ED-SCLC) with or without moderately impaired diffusion capacity for carbon monoxide (DLco) and investigated the factors associated with survival in ED-SCLC patients.MethodsThis retrospective single-center study was performed between January 2011 and December 2020. Of the 307 SCLC patients who received cancer therapy during the study, 142 with ED-SCLC were analyzed. The patients were divided into DLco < 60% group and DLco ≥ 60% groups. OS and predictors of poor OS were analyzed.ResultsThe median OS of the 142 ED-SCLC patients was 9.3 months and the median age was 68 years. In total, 129 (90.8%) patients had a history of smoking, and 60 (42.3%) had COPD. Thirty-five (24.6%) patients were assigned to the DLco < 60% group. Multivariate analysis revealed that DLco < 60% (odds ratio [OR], 1.609; 95% confidence interval [CI], 1.062–2.437; P = 0.025), number of metastases (OR, 1.488; 95% CI, 1.262–1.756; P < 0.001), and < 4 cycles of first-line chemotherapy (OR, 3.793; 95% CI, 2.530–5.686; P < 0.001) were associated with poor OS. Forty (28.2%) patients received < 4 cycles of first-line chemotherapy; the most common reason for this was death (n = 22, 55%) from grade 4 febrile neutropenia (n = 15), infection (n = 5), or massive hemoptysis (n = 2). The DLco < 60% group had a shorter median OS than the DLco ≥ 60% group (10.6 ± 0.8 vs. 4.9 ± 0.9 months, P = 0.003).ConclusionsIn this study, approximately one quarter of the ED-SCLC patients had DLco < 60%. Low DLco (but not forced expiratory volume in 1 s or forced vital capacity), a large number of metastases, and < 4 cycles of first-line chemotherapy were independent risk factors for poor survival outcomes in patients with ED-SCLC.

GNRI Sustainability during One Cycle of First-Line Chemotherapy as a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma

Introduction: This study evaluated the prognostic value of a sustained high Geriatric Nutritional Risk Index (GNRI) during first-line chemotherapy for patients with metastatic urothelial carcinoma (mUC). Methods: Between January 2018 and February 2022, 123 patients received platinum-based chemotherapy at Nagoya City University Hospital and affiliated institutions. Of these, 118 eligible patients who showed an Eastern Cooperative Oncology Group performance status (ECOG-PS) between 0 and 2 were retrospectively examined. Based on body mass index and serum albumin levels, GNRI was calculated immediately before and after the first primary chemotherapy cycle. Patients were divided into two groups based on GNRI: GNRI sustained ≥92 in sustainable (n = 63) and GNRI <92 in unsustainable (n = 55) groups, respectively. Clinical outcomes were compared. Results: No significant differences were noted between the two groups for age, gender, cycle of first-line treatment, and type of series of sequential treatments after failure of first-line therapy. Median overall survival from the start of first-line chemotherapy was 30.2 months (95% confidence interval [CI]: 20.9–NA) for sustainable and 12.6 months (95% CI: 9.0–21.2) for unsustainable groups, respectively (p < 0.05). Multivariate analysis identified ECOG-PS:2 and fatigue, an adverse event, as independent predictors of unsustainable GNRI transition (95% CI: 1.29–90.6, odds ratio [OR]: 10.8; 95% CI: 1.06–26.9, OR: 5.34, respectively). Conclusion: : Sustaining a high level of GNRI was an important prognostic indicator in patients with mUC receiving first-line chemotherapy. Appropriate intervention for controlling adverse events, including fatigue, may enhance physical strength during cancer treatment.

Limited predictive impact of tumor size dynamics on further tumor shrinkage after 4 cycles of first-line chemotherapy in patients with advanced urothelial carcinoma.

To investigate the correlation between tumor size changes during the initial 4 cycles of first-line chemotherapy and tumor shrinkage following 2 additional cycles of chemotherapy in patients with advanced urothelial carcinoma (aUC) who experienced disease control after initial chemotherapy. We retrospectively reviewed 128 patients with aUC who received first-line chemotherapy. We analyzed 51 patients with disease control (stable disease or better) at the end of the fourth cycle. Of these, 47 patients received 1 to 2 additional cycles of chemotherapy, whereas the remaining patients underwent observation. For patients who received additional chemotherapy, the change in tumor size after additional chemotherapy (cycles 5-6) was defined as "no shrinkage" (tumor growth), "minor shrinkage" (no tumor growth or ≤10% reduction in tumor size), or "shrinkage" (>10% reduction in tumor size). Then, we investigated the relationship between the rate of tumor size change during the initial 4 cycles and that after additional chemotherapy. Of the patients who received additional chemotherapy, the change in tumor size was categorized as no shrinkage in 21 patients (44.7%), minor shrinkage in 18 patients (38.3%), and shrinkage in 8 patients (17%). Regarding predictors of tumor shrinkage after additional chemotherapy, the rate of tumor size change between the cycles 3 and 4 (area under the receiver operating characteristics curve = 0.642) was correlated with the trend of the tumor shrinkage (P = 0.009) and the likelihood of beneficial tumor shrinkage after additional chemotherapy (minor shrinkage + shrinkage; P = 0.02). However, the change in tumor size between cycles 1 and 2, cycles 1 and 4, or cycles 3 and 4 was not satisfactorily predictive of further tumor shrinkage because of substantial overlaps of the tumor size changes. Only a small subset of patients would have substantial tumor shrinkage by additional cycles after successful induction of 4 cycle chemotherapy. Tumor size dynamics during the initial 4 cycles of chemotherapy displayed limited ability to predict the subset of patients with further tumor shrinkage after additional chemotherapy. Therefore, it might be better to consider switch maintenance immunotherapy for patients who experience disease control after the fourth cycle of first-line chemotherapy.

Comparison of follow-up treatment regimens for colorectal cancer liver metastases without objective response to neoadjuvant chemotherapy: direct surgery or surgery after second-line chemotherapy

Objective: To compare the effect of direct surgery or surgery after second-line chemotherapy for colorectal cancer patients with liver metastases who did not achieve objective remission after neoadjuvant chemotherapy. Methods: A retrospective case cohort study was used. The clinical and pathological data of 107 patients with colorectal cancer liver metastases who did not achieve objective response to neoadjuvant chemotherapy at Department of Hepatobiliary Surgery,Cancer Hospital,Chinese Academy of Medical Sciences from December 2008 to December 2016 were retrospectively collected. There were 71 males and 36 females, median age was 57 years (range: 28 to 79 years). According to the different treatment regimens after neoadjuvant chemotherapy,107 cases were divided into a direct surgery group (direct group,n=65) and an operation after receiving second-line chemotherapy group (second-line group,n=42). The propensity score matching(PSM) of the Logistic regression model was used to match the bilobar distribution of liver metastases and the number of first-line chemotherapy cycles in the two groups of patients. The caliper value was set to 0.10 and the matching ratio was 1∶2. T test, Mann-Whitney U test, χ2 test or Fisher's exat test was used to analyzed the data between the tuo groups, respectively. Survival analysis design was used to investigate the difference in prognosis between the two groups of patients. Results: The follow-up time(M(IQR)) was 56.3(34.3) months (range: 2.1 to 95.0 months),and all patients were followed up. After PSM,there were 28 cases in the direct group and 42 cases in the second-line group, there were no significant differences in whether R0 resection was feasible,blood loss,blood transfusion,postoperative complications and postoperative hospital stay between the two groups (all P>0.05). The 1,3,and 5-year progression-free survival(PFS) rates of the direct group were 40.0%,16.5%,and 11.0%,and the 1,3,and 5-year overall survival(OS) rates were 98.5%,61.2%,and 41.4%,respectively, the second-line group 1,3,5 years PFS rates were 35.7%,14.3%,14.3%,1,3,5-year OS rate were 95.2%,55.1%,44.4%,respectively. The median PFS time of the direct group and the second-line group was 8.5 months and 7.5 months,respectively,and the difference was not statistically significant (P=0.826). The median OS time of the direct group and the second-line group were 33.8 months and 46.9 months,respectively. The difference was not statistically significant(P=0.646).The median PFS time of the direct group and second-line chemotherapy complete remission and partial remission group(CR/PR group) was 10.2 months and 9.1 months,respectively,and the difference was not statistically significant(P=0.669). The median OS time of the direct group and the second-line CR/PR group was 51.0 months and 46.9 months,respectively,and the difference was not statistically significant(P=0.427). The results of survival analysis suggested that major liver resection was an independent prognosis factor for PFS (HR=1.809,95%CI: 1.067 to 3.067,P=0.028) and OS(HR=2.751,95%CI: 1.317 to 5.747,P=0.007). Second-line chemotherapy was not an independent prognostic factor for PFS (HR=0.945, 95%CI:0.570 to 1.567,P=0.828) and OS (HR=0.866,95%CI: 0.468 to 1.602,P=0.646). Conclusions: There is no significant difference in the short-term outcome and long-term prognosis between direct surgery patients and second-line chemotherapy followed by surgery. Second-line chemotherapy is not an independent prognostic factor for colorectal cancer liver metastases patients who fail to achieve objective response after neoadjuvant chemotherapy.

Complete resection after pembrolizumab treatment followed by salvage surgery in stage IVB endometrial cancer: A case report.

IntroductionThere is little evidence regarding the treatment of stage IVB endometrial cancer. Therefore, chemotherapy is more likely to be chosen as the initial and first-line treatment. Pembrolizumab is a new treatment choice for unresectable endometrial cancer after first-line chemotherapy failure.Presentation of caseHerein, we report the case of a 56-year-old patient diagnosed with stage IVB endometrial cancer. After eight cycles of first-line chemotherapy, computed tomography (CT) revealed relapse with re-enlargement of the para-aortic lymph nodes. Since the primary tumour had high microsatellite instability, we switched to pembrolizumab treatment. Pembrolizumab was effective but could not be continued due to adverse events after 10 cycles. Positron emission tomography-CT revealed active cancer in the uterus and para-aortic lymph nodes.DiscussionSince pembrolizumab treatment had to be discontinued, we performed salvage surgery, which achieved complete tumour removal, and the patient has had no evidence of disease for 16 months.ConclusionThis is the first case of complete surgical resection after administering pembrolizumab as a second-line treatment for advanced endometrial cancer.

IJU this issue

This issue of International Journal of Urology contains 11 Original Articles, two Urological Notes, two Letters to the Editor, two Author’s reply, and three Editorial Comments. Partial nephrectomy for totally endophytic renal tumor is a surgical challenge and even if under robotic assistance, off-clamp partial nephrectomy is considered a risky procedure. Tuderti et al. (Rome, Italy) reported 56 consecutive patients with totally endophytic renal masses treated with off-clamp robotic partial nephrectomy (RAPN) in their institution. Preoperative super-selective delivery of a lipiodol-indocyanine green mixture into arterial branches feeding the renal mass provides a quick guide to identify tumor location without intraoperative ultrasound. Furthermore, it gives us a straight access to surgical area with minimal opening of Gerota’s capsule. Trifecta achievement was 91% in their patients with low operative complication rates. As Pandolfo et al. (Viriginia, USA) described in the Editorial Comment, the Editor also thinks that this procedure sacrifices visibility due to increased bleeding during the procedure. Moreover, it needs an extra step (preoperative super-selective delivery of a lipiodol-indocyanine green mixture) before surgery, which makes the procedure more complicated. With the technical advancement and accumulation of experience, the debate “on-clamp versus off-clamp” RAPN for completely endophytic renal masses will be settled in the near future. Gleason pattern 5 has been considered an independent unfavorable prognostic factor in localized and advanced prostate cancer. Morozumi et al. (Miyagi, Japan) retrospectively conducted multicenter analysis of outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) with a Gleason score (GS) ≥8. They revealed that in high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival (OS), while both Gleason pattern 5 and primary Gleason pattern 5 were not significant predictive factors after multivariate analysis. On the contrary, in the low-volume (LV) metastatic groups, only Gleason pattern 5 was an independent unfavorable predictive factor for OS after the analysis. Although there are several limitations, such as a lack of central pathology, they concluded that only in LV mHSPC patients with GS ≥8, primary Gleason pattern 5 should be considered as an unfavorable factor for the treatment strategy. As a homeostatic system, bladder storage function keeps the micturition interval constant by increasing bladder capacity during the diuretic phase, which is known as vesical adaptation response to diuresis (VARD). Matsuoka et al. (Fukushima, Japan) analyzed 94 male patients older than 65 years with lower urinary tract symptoms (LUTS). They found that 48 patients (51%) had VARD but in 46 patients (49%), VARD was lacking. Interestingly, absence of VARD was significantly associated with overactive bladder and benign prostate enlargement after adjusting for confounders. Although there are several limitations in their study, understanding of the pathophysiology underlying VARD might contribute a novel strategy for the treatment of bladder storage dysfunction in patients with LUTS. Immune checkpoint inhibitors (ICIs) therapy has become a key therapy against advanced urothelial carcinoma (UC), but there are no definitive data available for the association of the oncological outcome to first-line chemotherapy to subsequent ICIs therapy. Ozaki et al. (Hirosaki, Japan) reported their retrospective analysis of 218 patients with advanced UC who received systematic, platinum-based first-line chemotherapy. Focusing upon OS between patients treated with or without second-line ICIs therapy who had no progressive disease (PD) within four or few cycles of first-line chemotherapy (the non-PD ≤4 group), there was significant difference in the median survival (63 vs 26 months). On the contrary, in patients who had PD within four or few cycles of first-line chemotherapy (the PD ≤4 group), there was no significant difference in OS whether they were treated with ICI or not. These results suggest that the favorable response to the first-line chemotherapy was significantly associated with longer survival in patients with subsequent ICIs therapy than those without. Although we do not know the precise mechanisms of the results of the article, Miyake (Nara, Japan) commented in this issue that platinum derivatives could induce immunogenic cell death, which might enhance the antitumor activity of dendritic cells and T cells, which results in modulation of the expression of immune checkpoint molecules. Moreover, we still do not have the answer to how many first-line chemotherapy cycles will be appropriate before ICIs therapy. Consideration of introduction of antibody-drug conjugate, enfortumab vedotin for advanced UC treatment, we should accumulate more data about appropriate timing of changing armaments against this difficult disease. Unfortunately, the limited space restricts me to introduce the other excellent articles in this issue. I hope that the articles in this issue will help you in daily clinical practice. None declared.

Bevacizumab in combination with pemetrexed and platinum for elderly patients with advanced non-squamous non-small-cell lung cancer: a retrospective analysis

Bevacizumab, an anti-VEGF monoclonal antibody, has significantly improved the clinical outcomes of patients with advanced non-squamous NSCLC (ns-NSCLC). However, the safety and efficacy of bevacizumab for elderly patients with advanced NSCLC require further investigation. Thus, 59 patients were included in the present retrospective study, 22 patients in the bevacizumab plus pemetrexed and platinum (B + PP) group, and 37 patients in the pemetrexed and platinum (PP) group. For the entire cohort of patients, the median OS was 33.3 months, and the 1-year and 2-year overall survival rates were 88.5% and 67.8%, respectively. The median OS and 1-year and 2-year OS rates were 20.5 months, 70.3% and 0%, respectively, in the B + PP group and 33.4 months, 97.0% and 89.4%, respectively, in the PP group (P < 0.001). The incidence of grade ⩾ 3 adverse events was higher in the B + PP group than in the PP group (27.3% vs. 10.8%, respectively; P = 0.204). Univariate and multivariate analyses suggested that the receipt of ⩾ 5 cycles of first-line chemotherapy was an independent favorable prognostic factor for OS, whereas the addition of bevacizumab was an unfavorable prognostic factor. With increased toxicities, the addition of bevacizumab to PP does not improve the overall survival of elderly patients with advanced ns-NSCLC.

A phase 1 first-in-human study of XL092 administered alone or in combination with immune checkpoint inhibitors (ICIs) in patients (pts) with inoperable locally advanced or metastatic solid tumors: Description of genitourinary (GU) expansion cohorts.

TPS401 Background: XL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases MET, VEGFR2, and TAM kinases (AXL, MER), which are important in tumor growth, neovascularization, and immune modulation of the tumor microenvironment. XL092 as a single-agent and in combination with an anti-PD-1 antibody showed antitumor activity in xenograft tumor models (Hsu et al. 2020). This first-in-human study is evaluating safety, pharmacokinetics (PK), and preliminary antitumor activity of XL092 with or without (w/wo) ICIs in pts with advanced solid tumors. Presented here are the trial design and details of GU cohorts. Methods: In this phase 1, multicenter, open-label, dose-escalation and expansion study (NCT03845166), pts will receive escalating doses of XL092 w/wo atezolizumab (ATEZO) 1200 mg Q3W or avelumab (AVE) 800 mg Q2W. The dose-escalation stage is enrolling pts with inoperable locally advanced or metastatic solid tumors using a 3+3 (single-agent) or rolling 6 (combination) design; the primary objective is to determine maximum tolerated dose and/or recommended dose of XL092 for further evaluation when administered w/wo ICIs; secondary objective is to evaluate plasma PK of XL092 and its metabolites alone and in combination with ICIs. Primary objectives for the expansion stage are to evaluate preliminary efficacy of XL092 w/wo ICIs by estimating objective response rate (ORR) by investigator (Inv) per RECIST 1.1 and for specific cohorts by estimating the % of pts with PFS at 6 months by Inv per RECIST 1.1; secondary objective is safety of XL092 w/wo ICIs via monitoring nonserious and serious adverse events (AEs) including immune related AEs and AEs of special interest. For GU cohorts in expansion stage, single-agent XL092 will be tested in: (i) previously treated advanced clear cell (cc) renal cell carcinoma (RCC; progression on 1-3 prior systemic regimens w/wo a sarcomatoid component); (ii) previously treated advanced non-cc RCC (progression on 1-3 prior systemic regimens); (iii) metastatic castration resistant prostate cancer (mCRPC; prior treatment with ≥1 novel hormonal therapy and taxane-based chemotherapy, ≤4 prior systemic regimens). XL092 + ATEZO will be tested in non-cc RCC and mCRPC cohorts. Pts with advanced urothelial carcinoma will be enrolled in 3 cohorts: (i) pts with ongoing CR/PR/SD after 4-6 cycles of first-line chemotherapy (gemcitabine + cisplatin and/or gemcitabine + carboplatin) will receive XL092 + AVE; (ii) pts with progression on/after prior ICI therapy (≤2 prior systemic therapies) will be randomized 1:1 to XL092 + AVE or single-agent XL092; (iii) pts with progression on/after first-line platinum-based chemotherapy will receive XL092 + AVE. The study is currently enrolling pts. Clinical trial information: NCT03845166.

Impact of the objective response to and number of cycles of platinum-based first-line chemotherapy for metastatic urothelial carcinoma on overall survival of patients treated with pembrolizumab.

To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab. This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis. Overall, 391 patients received standard first-line chemotherapy and pembrolizumab as a second-line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first-line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy. Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum-based first-line chemotherapy.

Higher neutrophil-to-lymphocyte ratio after the first cycle of the first-line chemotherapy is associated with poor cancer specific survival of upper urinary tract carcinoma patients.

BackgroundInflammatory cytokines and immature myeloid derived suppressor cells (MDSCs), which increase during cancer progression, could lead to a neutrophil increase and lymphocyte reduction. Thus, the neutrophil-lymphocyte ratio (NLR) was used to predict survival of patients suffering from urological cancers including upper urinary tract carcinoma. We further determined whether the NLR during the first cycle of first-line chemotherapy could predict cancer specific survival.MethodsWe recruited patients with locally advanced or metastatic upper urinary tract urothelial carcinoma (UTUC) who received chemotherapy between January 2014 and July 2019. We investigated the impact of various clinical variables, including age, sex, performance status, and estimated creatinine clearance (CCr), and NLR before and after the first cycle of the first-line chemotherapy on prognosis.ResultsA total of 41 patients were included in our study. Cancer specific survival of the patients with lower NLR was significantly better than that of the patients with higher NLR measured after the first cycle of the first-line chemotherapy (log-rank test P=0.005, median 29.2 vs. 11.9 months, respectively). Cox proportional regression analysis showed that higher NLR after the first cycle of the first-line chemotherapy was a significant predictor of cancer specific survival.ConclusionsThe NLR after the first cycle of the first-line chemotherapy could be an indication for patients with locally advanced or metastatic UTUC to maintain their first-line chemotherapy treatment.

CHANGES IN THE MGMT GENE EXPRESSION IN PATIENTS WITH PRIMARY GLIOBLASTOMA AFTER RELAPSE. INFLUENCE OF CLINICAL CHARACTERISTICS AND MGMT EXPRESSION ON SURVIVAL OF PATIENTS

Background . Over the past 10–15 years, there has been a clearer understanding of the processes occurring in cells of the primary glioblastoma. However, the change in MGMT gene expression and its role after disease relapse remain understudied. Purpose : to study changes in MGMT gene expression in case of recurrent primary glioblastoma after the standard therapy; to determine influence of clinical factors and MGMt gene expression on relapse-free survival of patients. Materials and Methods . We carried out a prospective analysis of clinical and molecular genetic characteristics of 21 patients aged from 28 to 63 with primary glioblastoma before and after recurrence. Relative mRna expression of MGMT gene and mutations in IDH1/IDH2 genes were determined in surgical biopsies using PCR techniques. after the first surgery, all patients received radiation therapy (60 Gy) and chemotherapy with adjuvant temozolomide (2–18 cycles). the second-line chemotherapy was performed in 17 (80.9 %) patients, and 8 patients received (47 %, 8/17) temozolomide. Results. the relationship between the progression-free survival (PFs) and mRna expression of MGMT gene (73.5 vs 33 weeks, p=0.013) and objective response to therapy (88 vs 36 weeks, p=0.046) was found. The number of cycles of first-line chemotherapy with temozolomide influenced the duration of the first PFs (65 weeks vs 21.5 weeks, p=0,07). the first PFs was not affected by patients’ age (p=0.64), sex (p=0.17), Karnofsky performance scale index (p=0.43), extent of brain damage (p=0.41) and extent of the resection (p=0.27). after onset of relapse, mRna expression of MGMT gene remained the same, being 66.7 % (14/21). The increased expression was observed in 23.8 % (5/21) of cases, and decreased gene expression was observed in 9.5 % (2/21) of cases. the second PFs was affected by the extent of tumor resection, although there were no statistically significant differences (p=0.52). the effect of mRna expression of MGMT gene on the median second PFs was not revealed (p=0.39). no objective response to therapy was found in patients with a low mRna expression of MGMT gene. Conclusion . Recurrent glioblastoma becomes more resistant to further therapy. With the development of tumor recurrence, the predictive value of MGMT gene is lost and the role of the extent of cytoreductive surgery increases.

Exploring Older Women's Attitudes to and Experience of Treatment for Advanced Ovarian Cancer: A Qualitative Phenomenological Study.

Simple SummaryOlder women with ovarian cancer often receive less anti-cancer treatment than younger women despite evidence showing they may benefit from similar levels of treatment. Little is known, however, about older women’s preferences toward chemotherapy and treatment experience. We aimed to understand the lived experience of older women with ovarian cancer undergoing chemotherapy though interviews and focus groups. Participants expressed a strong desire to undergo full treatment to improve survival for themselves and for their families. Women did not see their age as a reason to have less intensive treatment. Despite feeling overwhelmed with information and daily tasks due to fatigue, participants did not want cancer to interfere with their daily lives. Women felt distressed by logistical issues with transportation and communication between healthcare providers; however, they still felt positive about their care experience and desire for treatment. Older women may benefit from additional help to support effective communication around treatment preferences.Older women with ovarian cancer more often receive less intensive treatment and early discontinuation compared to younger women. There is little understanding of older women’s treatment experience and whether this contributes to declining intensive treatment. We aimed to explore the lived experience of older patients with advanced ovarian cancer undergoing chemotherapy, their treatment preferences and treatment burden. We conducted a phenomenological qualitative study with 15 women who had completed at least three cycles of first-line chemotherapy for advanced epithelial ovarian cancer, aged 65 years or older at the first cycle, at one tertiary cancer centre. We conducted interviews and focus groups and analysed the transcripts using inductive thematic analysis. Women reported a strong preference for active treatment despite treatment burden and toxicities. Participants undertook treatment to lengthen their lives for themselves and their families. Participants did not see age as a barrier to treatment. Patients expressed determination not to let cancer interfere with daily life. Women felt overwhelmed with information and struggled with daily tasks due to fatigue. Logistical issues, such as transportation and ineffective communication between healthcare providers, caused substantial distress. Despite these logistical burdens and toxicities, participants were positive about their care experience and desire for anticancer treatment. Older women may benefit from additional support to facilitate effective communication during the early stages of treatment.