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Summary: Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58–5.68) and 7.0 (95% CI 3.82–10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184). [ABSTRACT FROM AUTHOR]

Background: Definitive concurrent chemoradiation (cCRT) is offered to only 3% of Russian patients with stage III NSCLC. To determine the patterns of care and barriers to cCRT utilization in Russia, we conducted a survey of practicing radiation oncologists (ROs). Methods: Electronic IRB-approved survey containing 15 questions was distributed to Russian ROs. Fisher's exact test or Cochran-Armitage test of trend was used to assess the associations between clinical experience, practice type, and patterns of care. Results: We analyzed 58 questionnaires completed by ROs—16 respondents from tertiary referral hospitals, and 42 from community or private centers. A total of 88% of respondents formulate treatment recommendations in multi-disciplinary tumor boards. For unresectable stage III NSCLC, the most common recommendation is sequential CRT (50%), followed by concurrent CRT (40%), with an observed higher utilization of cCRT in tertiary centers (9/16, 56% vs 14/42, 33%). Of the respondents, 31% do not offer cCRT to their pts. Among reasons for avoiding cCRT are (1) poor performance of pts (76%); (2) high toxicity of therapy (55%); (3) lack of consensus among tumor board members (33%); and (4) preference for sequential CRT (31%). Only 3% do not irradiate elective LNs. Eighty-six percent of respondents counsel their NSCLC pts regarding smoking cessation. Conclusions: Despite level 1 evidence, cCRT is rarely used in Russia for pts with locally advanced NSCLC, and preference for sequential therapy and concerns over high toxicity are the most common barriers. Education of Russian ROs may increase cCRT utilization, leading to improved survival, notably in the era of maintenance immunotherapy. [ABSTRACT FROM AUTHOR]

Trimodality bladder preservation (BP) is an accepted alternative to radical cystectomy for patients with muscle invasive bladder cancer (MIBC). The global utilization of BP is variable, and practice patterns have not been previously studied in Russia. We sought to elucidate the contemporary BP practice patterns in Russia and determine the impact of the BP workshop on attitudes of Russian radiation oncologists (ROs) towards BP. The workshop was focused on patient workup, selection for BP, chemotherapy choices, radiation therapy (RT) contouring and planning, patient counseling. A total of 77 pre- and 32 matched post-workshop IRB-approved surveys, based on the workshop content, were analyzed using descriptive statistics to determine baseline clinical experience and patterns of care. The impact was judged by changes in participants' responses. A total of 56% of respondents had experience with delivering bladder-directed RT, and 60% of those treated both operable and inoperable MIBC patients. Only 10% felt uncomfortable offering an operable patient BP modality. Prior to the workshop, almost half of respondents estimated universal poor bladder (44%) and erectile functions (47%) after BP. The workshop resulted in dramatic change in participants' attitudes towards long-term urinary (Stuart-Maxwell test, p < 0.01) and sexual (exact McNemar test, p < 0.01) side effects. Prior to the workshop, only 47% of respondents routinely discussed smoking cessation (SC) with their patients, whereas after workshop, 88% agreed that SC discussion is mandatory (exact McNemar test, p = 0.04). BP for MIBC is commonly used in Russia. Our workshop resulted in dramatically improved understanding of long-term BP toxicities and inspired Russian ROs to incorporate SC counseling into routine clinical management. [ABSTRACT FROM AUTHOR]

The goal of the CLOVER study was to perform a pairwise comparison of four tests based on the same patient population with non-small cell lung cancer (NSCLC): three validated PDL1 immunohistochemistry (IHC) assays (Ventana SP142, Ventana SP263, Dako 22C3) and one PCR test. Four hundred seventy-three NSCLC samples were obtained from a biobank and were stained using PDL1 IHC assays. Four trained pathologists independently evaluated the percentage of tumor cells (TC) and immune cells (IC) that stained positive at any intensity. PDL1 transcripts were quantified in 437 patients by a standard Taqman RT-PCR assay using SDHA as a reference gene. A concordance analysis was performed to assess (1) the correlation of TC and IC between different assays and (2) the predictive properties of one test for another. "High" RNA expression was detected in 187 of 437 (43%) patients. The percentage of PDL1-positive cells (≥1%) was higher among the IC than the TC in all IHC three assays. The Pearson correlation coefficients (PCC) for TC were 0.71, 0.87, and 0.75 between 22C3/SP142, 22C3/SP263, and SP263/SP142, respectively. The PCC for IC were 0.45, 0.61, and 0.68 for the same pairs. A low correlation was observed between the PCR test and each of the three IHC assays; however, if a patient tested low/negative by PCR, then they were likely to test negative by any single IHC test with a high probability (92–99%). Among patients who tested positive by PCR, only 9–45% tested positive by IHC assays. There was excellent positive and negative agreement (>91%) between 22C3 and SP263 staining using the recommended individual cutoffs for first-line treatment. PCR RNA expression analysis is not equivalent to IHC. However, this method may have some potential for the identification of PDL1-negative tumors. 22C3 could be considered as a substitute for SP263 in first-line treatment. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) is an effective treatment modality for hepatocellular carcinoma (HCC), but globally, it is underutilized. In Russia, practice patterns with regard to liver-directed radiation are unknown. Under the auspices of Russian Society of Clinical Oncology (RUSSCO), our team conducted an IRB-approved contouring workshop for Russian radiation oncologists. Pre- and post-workshop surveys were analyzed to determine baseline clinical experience and patterns of care for liver-directed RT among Russian providers. The effect of the contouring workshop on participants' knowledge was tested using mixed effects model. Forty pre-workshop and 24 post-workshop questionnaires were analyzable with a 100% response rate. Sixty percent of respondents had never evaluated a patient with HCC and only 8% (3 out of 40) reported treating an HCC patient with liver-directed RT. Nonetheless, 73% of respondents were comfortable offering liver-directed RT prior to the workshop. After the workshop, 85% of respondents felt comfortable treating a patient with HCC with liver-directed RT and 50% were comfortable recommending stereotactic body radiation therapy (SBRT). Measures of knowledge pertaining to evaluation of HCC patients and selection for appropriate liver-directed therapies were dramatically improved after the workshop. Liver-directed RT is not commonly used in Russia in the management of patients with HCC, and few centers are equipped for motion management. Our contouring workshop resulted in dramatically improved understanding of the evaluation and management of HCC patients. We recommend starting with a more protracted fractionated RT and building experience through attendance of additional educational activities, participation in multidisciplinary liver tumor boards, and prospective analysis of treatment toxicity and outcomes. [ABSTRACT FROM AUTHOR]

In this collaborative study by the Russian Society of Clinical Oncology and the Russian Society of Pathology, we assessed the concordance among three validated, commercially available PD-L1 immunohistochemistry assays for patients with urothelial cancer. Tumors from 100 urothelial cancer patients were stained with the antibody clones 22C3 (Agilent), SP142 (Ventana Medical Systems), and SP263 (Ventana Medical Systems), which are used in clinical trials of second-line therapy with checkpoint inhibitors. Four trained pathologists independently evaluated the percentages of tumor cells (TC) and tumor-infiltrating immune cells (IC) that were stained at any intensity by each of the antibodies. The test-specific cutoffs for the proportions of stained cells in a positive sample were pre-specified as TC + IC ≥ 10% or TC ≥ 10% for 22C3, IC ≥ 5% for SP142, and TC ≥ 25% or IC ≥ 25% for SP263. Three hundred immunohistochemistry slides were scored. The percentages of PD-L1 staining in the three assays without using any cutoff were higher in the IC than in the TC (55% versus 24% for 22C3, 45% versus 8% for SP142, and 72% versus 27% for SP263, respectively). The Pearson correlation coefficients for anti-PD-L1 staining in the IC were 0.5, 0.69, and 0.85 with 22C3/SP142, 22C3/SP263, and SP142/SP263, respectively. The Pearson correlation coefficients for PD-L1 staining in the TC were 0.93, 0.99, and 0.91 for the same pairs. Among the patients who were negative for PD-L1 staining by one test, 91-100% were also negative by the other tests. Among the patients who were positive by one test, 43-100% were also positive by the other tests. Our data indicate that repeated testing can be avoided as a patient with urothelial cancer who is classified as negative for PD-L1 expression by one of the three single tests using the corresponding cutoff rule is highly likely (91-100%) to be classified as negative by either of the other tests. [ABSTRACT FROM AUTHOR]

Purpose: Patients with metastatic nonseminomatous germ cell tumors (mNSGCT) and a high tumor burden or a poor performance status at initial diagnosis are at risk from potentially life-threatening early complications during or after the first chemotherapy cycle. The outcomes with dose-reduced first cycle of chemotherapy in this population of patients are not well established.Methods: We performed a retrospective analysis of patients with mNSGCT and International Germ Cell Cancer Collaborative Group (IGCCCG) poor risk features. All patients received cisplatin and etoposide-based combinations as first-line treatment. Ultra high tumor marker levels were defined as α-fetoprotein ≥ 100,000 ng/ml or human chorionic gonadotropin ≥ 200,000 mIU/ml. Before 2005, the first treatment cycle was administered at a full dose in our center. After 2005, we used an abbreviated course of cisplatin and etoposide (EP) for the first cycle, followed by subsequent full-dose administration.Results: From 1987 to 2012, 265 patients with poor risk features according to IGCCCG received first-line chemotherapy. Among them, 63 out of 265 (24%) patients had ultra high tumor marker levels and/or ECOG performance status of 3-4. Dose reduction of the first chemotherapy cycle was associated with a significant decrease of life-threatening complications from 76 to 44% (p = 0.01), but not with the overall survival (HR 0.99, 95% CI 0.44-2.26).Conclusions: Dose reduction of the first EP cycle by 40-60% in the subgroup of poor risk patients with ultra high tumor marker levels and/or ECOG performance status 3-4 is associated with significantly lowered acute complication rates but not with overall survival. [ABSTRACT FROM AUTHOR]

Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of SKOV3 cancer cells. Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 31 days after tumor inoculation. Number of tumor vessels and Ki-67 index were calculated. Results SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the ovarian cancer cells in untreated control group ( P = 0.001). Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37 μmol/L. Treatment with alofanib in combination with paclitaxel/carboplatin resulted in tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated significant effect (inhibiting growth by 80 % and by 53 % in comparison with vehicle and chemotherapy group alone, respectively ( P < 0.001). Alofanib decreased number of vessels in tumor (−49 %; P < 0.0001) and number of Ki-67-positive SKOV3 cells (−42 %, P < 0.05 ). There were tumor necrosis and cell degeneration in alofanib group. Conclusions We suggest that FGFR2 inhibition has potent effects on ovarian cancer growth in preclinical studies. [ABSTRACT FROM AUTHOR]

Radiation oncologists in Russia face a number of unique professional difficulties including lack of standardized training and continuing medical education. To combat this, under the auspices of the Russian Society of Clinical Oncology (RUSSCO), our group has developed a series of ongoing in-person interactive contouring workshops that are held during the major Russian oncology conferences in Moscow, Russia. Since November 2016 during each workshop, we utilized a web-based open-access interactive three-dimensional contouring atlas as part of our didactics. We sought to determine the impact of this resource on radiation oncology practice in Russia. We distributed an IRB-approved web-based survey to 172 practicing radiation oncologists in Russia. We inquired about practice demographics, RUSSCO contouring workshop attendance, and the clinical use of open-access English language interactive contouring atlas (eContour). The survey remained open for 2 months until November 2017. Eighty radiation oncologists completed the survey with a 46.5% response rate. Mean number of years in practice was 13.7. Sixty respondents (75%) attended at least one RUSSCO contouring workshop. Of those who were aware of eContour, 76% were introduced during a RUSSCO contouring workshop, and 81% continue to use it in their daily practice. The greatest obstacles to using the program were language barrier (51%) and internet access (38%). Nearly 90% reported their contouring practices changed since they started using the program, particularly for delineation of clinical target volumes (57%) and/or organs at risk (46%). More than 97% found the clinical pearls/links to cooperative group protocols in the software helpful in their daily practice. The majority used the contouring program several times per month (43%) or several times per week (41%). Face-to-face contouring instruction in combination with open-access web-based interactive contouring resource had a meaningful impact on perceived quality of radiation oncology contours among Russian practitioners and has the potential to have applications worldwide. [ABSTRACT FROM AUTHOR]

It is known that tumor cells have the ability to penetrate into the bloodstream. The identification of such circulating tumor cells (CTC) determines the prognosis in several tumors, including colon cancer. Tumor DNA (ctDNA), which is only a part of the total circulating DNA obtained from the blood of cancer patients, is also further separated from plasma. This separation of the neoplastic derivatives of the primary tumor and metastases (CTC, ctDNA, RNA, proteome) in plasma is called 'liquid biopsy.' CTC increasingly represents the pool of tumor cells that can initiate the growth of metastatic lesions, while the ctDNA provides the information about the whole tumor mass. Traditional tissue biopsy gives information based only on one small section of the primary tumor or metastasis, often retrieved before the start of treatment; however, liquid biopsy provides real-time information about the molecular disorders for the whole tumor mass and allows us to estimate the dynamics of the evolutionary tumor changes, the heterogeneity of the disease, and the effect of chemotherapy. With the possibility of obtaining multiple blood samples for analysis during the therapy, in contrast to traditional biopsy, it also allows us to evaluate the mechanisms of resistance to treatment, which in the future will perhaps lead to modification of the treatment in accordance with the detected molecular defects in tumors. Thus, this would facilitate implementing the principles of personalized therapy. In this literature review, we concentrate on liquid biopsy in patients with colon cancer. [ABSTRACT FROM AUTHOR]

Purpose: The aim of our study was to identify factors which influence survival in patients with disseminated seminoma in the good prognostic group according to IGCCCG, as well as to evaluate the impact of treatment intensification in patients with negative prognostic factors. Methods: We analyzed the database of the patients with metastatic seminoma who had received treatment at our department from 1986 to 2005. Inclusion criteria were as follows: morphologically verified seminoma; favorable prognosis according to IGCCCG; modern chemotherapy regimen (EP ± bleomycin); AFP level <15 IU/ml; and HCG level <300 mIU/ml. The primary endpoint was overall survival (OS). Results: With median follow-up 83 months, 5-year OS rate was 91 % in 206 patients. Only three negative prognostic factors were associated with OS: retroperitoneal lymph nodes >5 cm ( p < 0.01), pulmonary metastases ( p < 0.01) and LDH level ≥2.25×ULN ( p = 0.01). In view of the obtained data, we have changed our treatment approach since 2005. In case of any negative prognostic factors, we administered an intensified CT regimen-4BEP or 3BEP + 1EP. Prospective phase of the study included 34 patients with unfavorable prognosis. We observed an increase of 5-year OS rate in the intensified CT group in comparison with the standard CT group in patients with unfavorable prognostic from 85 to 100 %. Conclusion: Administration of 4 cycles of induction CT (4BEP or 3BEP + 1EP) in patients with metastatic seminoma who have LDH level ≥2.25 ULN, and/or retroperitoneal lymph nodes >5 cm and/or pulmonary metastases results in decreased disease progression rate and significant gain in OS. [ABSTRACT FROM AUTHOR]

A role of maintenance chemotherapy (mCT) in patients (pts) with metastatic colorectal cancer (mCRC) is still controversial. The purpose of this retrospective study was to investigate the toxicity and efficacy of mCT in pts with mCRC. There were 97/291 (33 %) pts with mCRC completed 18-20 weeks of first-line CT from 2007 to 2013 in our center. Then, pts who had no disease progression were non-randomly allocated to mCT with capecitabine ± bevacizumab ( n = 35) or surveillance ( n = 62). PFS was used as a primary endpoint and was calculated from the date of completion of first-line CT. Multivariate Cox stepwise regression analysis was performed to determine independent prognostic factors. Median follow-up time was 15 (range 5-60) months. Median PFS and OS were higher in pts with mCT: 7 versus 3 months (HR 0.5, 95 %CI 0.28-0.82, p = 0.007) and 29 vs 16 months (HR 0.6, 95 %CI 0.3-1.1, 0.04-Gehan-Breslow-Wilcoxon test). Following independent negative prognostic factors was significant on multivariate analysis: CEA level >2.5 ng/ml before start of first-line CT ( p = 0.02), liver metastases ( p = 0.03) and number of metastatic zones >2 ( p = 0.008). MCT had an independent positive impact on PFS (HR 0.5, p = 0.003). MCT prolonged PFS in pts with at least one negative prognostic factors (7 vs. 3 months, p = 0.001, HR 0.38, 95 % CI 0.22-0.68). The mCT was most beneficial in pts with negative prognostic factors: CEA level >2.5 ng/ml before start of first-line CT and/or liver metastases and/or number of metastatic zones >2. [ABSTRACT FROM AUTHOR]