Location in the large bowel influences the <Emphasis Type="Italic">APC</Emphasis> mutations observed in FAP adenomas

The right colon differs from the left, in embryological origin, luminal environment, and function. In both sporadic colorectal cancer and Familial Adenomatous Polyposis (FAP), polyp density and cancer susceptibility vary markedly by colonic site. Adenomas in FAP have a different mutational spectrum in small intestine versus colon. This study aimed to investigate whether colonic location also influences the APC mutation spectrum in FAP. 127 1–2 mm mildly dysplastic adenomas from 5 patients with a codon 1309 germline mutation, and 41 from 3 patients with mutations proximal to codon 1265, were analysed to assess the frequency of loss of heterozygosity (LOH). We chose polyps from different locations in the colon. Immunohistochemistry for beta-catenin, caspase-3 and Ki-67 was performed to assess Wnt pathway activation, apoptosis and proliferation. In polyps from patients with a 1309 mutation, the frequency of LOH showed a gradient from rectum (highest) to caecum/ascending colon (lowest), but this was not present in patients with proximal germline APC mutations. Crypt-by-crypt analysis confirmed the LOH findings from whole polyps. Beta-catenin and caspase-3 expression showed no significant variation by colonic region, but Ki-67 expression decreased from ascending colon to rectum in tumours and normal tissue. Colonic site alters the mutational spectrum of APC, and crypt cell proliferation. The higher frequency of LOH in rectal polyps from patients with codon 1309 mutations may help to explain their increased polyp burden at this site compared with patients who have other germline APC mutations.     

Randomized blinded clinical trial of intracoronary brachytherapy with 90Sr/Y beta-radiation for the prevention of restenosis after stent implantation in native coronary arteries in diabetic patients.

BACKGROUND: We report a double-blind, randomized clinical trial of intracoronary beta-radiation for prevention of restenosis after stent implantation in native coronary de novo lesions in diabetic patients. METHODS: After successful stent implantation in native coronary de novo lesions, 106 lesions in 89 diabetic patients were randomly allocated to treatment with beta-radiation with 18 Gy at 1 mm vessel depth (n = 53) or placebo treatment (n = 53). RESULTS: Angiographic analysis at 9 month follow-up revealed a late lumen loss of 0.7+/-0.9 mm in the radiotherapy group versus 1.2+/-0.8 mm in the control group at the injured segment (P = 0.006), 0.9+/-1.0 versus 1.3+/-0.7 mm at the radiated segment (P = 0.02), and 0.9+/-1.0 versus 1.3+/-0.7 mm at the target segment (P = 0.04) (defined as active source length plus 5mm on proximal and distal sites). Binary restenosis rates were significantly lower in the radiation group in all subsegments (injured segment: 10.9 versus 37.3%, P = 0.003; radiated segment: 21.7 versus 49.0%, P = 0.005; target segment: 23.9 versus 49.0%, P = 0.01). Target lesion revascularization for restenosis was required in nine lesions (17.6%) in the radiotherapy group versus 18 (34.0%) in the placebo group (P = 0.05). Late thrombosis occurred in four radiated patients (after premature discontinuation of antiplatelet therapy in all), resulting in a major adverse clinical event rate of 37.2% in the brachytherapy group versus 38.6% in the placebo group (P = ns). CONCLUSIONS: In diabetic patients with de novo coronary lesions, intracoronary radiation after stent implantation significantly reduced restenosis. However, this clinical benefit was reduced by the frequent occurrence of late thrombosis.     

Does a selective cyclooxygenase-2 inhibitor (tiracoxib) induce clinically sufficient suppression of adenomas in patients with familial adenomatous polyposis? A randomized double-blind placebo-controlled clinical trial

Background There have been few placebo-controlled randomized double-blind studies of the clinical effects of selective cyclooxygenase-2 (COX-2) inhibitors on the regression of colorectal tumors. This study was designed to examine the regressive effect of a selective COX-2 inhibitor, tiracoxib (JTE-522), on colorectal polyps in patients with familial adenomatous polyposis (FAP), and its safety. Methods Sixty-one patients with FAP diagnosed by Japanese criteria were assigned randomly to receive placebo or JTE-522, at either 150 mg or 200 mg, once daily orally for 26 weeks. Prior to and at the end of the medication period, endoscopy was performed. Adenomas located near an india-ink tattoo injected at the first colonoscopy were identified and measured. The response variables were the percent changes from the baseline in polyp numbers and in specified polyp diameters. Any adverse events that appeared in at least four persons were taken into consideration and compared between the JTE-522 treatment groups and the placebo group. Results No change in polyp number (median, 0) was observed in any of the three groups. There were no differences between the placebo group and the two treatment groups in the change in polyp size. JTE-522 was well tolerated. Conclusion Our findings, in keeping with other reports on COX-2 inhibitors, indicated that the inhibition of a COX-2 with a moderate dose of a selective COX-2 inhibitor did not induce clinically sufficient regression of adenomas in patients with FAP in a limited (6-month) medication period. Additional institutions and investigators participating in the study are listed in the Appendix.     

Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized,global, placebo-controlled study

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood–brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n?=?103), 200 mg veliparib BID (n?=?102), or placebo BID (n?=?102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.     

Genetic screening for colorectal cancer and intervention

There is a complex interaction between environmental/dietary factors and genetics underlying the pathogenesis of colon carcinogenesis. Little data exist concerning the impact of diet on the phenotypic expression of genetically linked colon cancer. As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes. Only 2 double-blinded, placebo-controlled trials have been published concerning the use of preventive strategies in patients with genetically inherited colorectal cancer syndromes, both in patients with FAP. One study evaluated the effects of vitamin C plus vitamin E with or without a high-dose wheat bran fiber supplement on the recurrence of rectal adenomas. Over a 48-month intervention period, only the wheat bran fiber intervention significantly reduced polyp growth. A second study reported that intervention with the NSAID sulindac for 9 months in young patients with FAP resulted in a significant reduction in both polyp number and size in the rectosigmoid colon. All of the large-scale (i.e., >500 randomized participants) phase III nutrient or chemopreventive agent intervention studies thus far have targeted participants with a history of non-familial, sporadic colorectal adenomas. Current clinical adenoma trials do not measure whether the regimen being tested can prevent genotoxic events occurring in early stages of abnormal cell development that contribute to the eventual formation of adenomas nor whether the agent(s) can inhibit events occurring during the progression of adenomas to carcinomas. Therefore, future clinical trial designs may have to consider (i) lengthening the clinical trial period before adenomas develop, (ii) testing at early patient ages and/or (iii) measuring the growth of adenomas as they progress to carcinomas. © 1996 Wiley-Liss, Inc.     

A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer

BackgroundFOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine.MethodsPatients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed.ResultsSix patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint.ConclusionsSOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell–mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.     

Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients.

BACKGROUND: Celecoxib was shown to regress colorectal adenomas in familial adenomatous polyposis (FAP) patients relative to placebo. To address the mechanism of polyp regression, we determined whether celecoxib can modulate cell proliferation, apoptosis, and prostaglandin E(2) (PGE(2)) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number. MATERIALS AND METHODS: Colorectal mucosal biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg twice daily) or placebo administration (6 months). Residual paraffin-embedded adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling indices and their ratios were calculated in superficials (s) and nonsuperficial (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences were calculated. PGE(2) levels were analyzed by mass spectroscopy (normal, n = 64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated with previously determined mean percentage reductions in colorectal polyp number. RESULTS: In adenomas, a reduction in the superficial proliferative activity i.e., Ki-67(s) labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AI(s))/nonsuperficial apoptotic index (AI(ns))] was found to correlate with reduced polyp counts in that higher apoptotic ratios correlated with better response to celecoxib (r = 0.71, P = 0.004). Furthermore, the AI(s)/Ki-67(s) ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AI(s) (r = 0.33, P = 0.053) and polyp regression was found. PGE(2) levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009; PGE(2), r = 0.50, P = 0.059) within individual patients. CONCLUSION: Suppression of cell proliferation and an increased apoptotic ratio, as well as the ratio of apoptosis to cell proliferation, accompany polyp regression in a chemoprevention trial in FAP patients. These findings suggest potential mechanisms for the efficacy of celecoxib and warrant further study of these biomarkers as intermediate endpoints in FAP patients.     

Growth of colorectal polyps: design of a prospective, randomized, placebo-controlled intervention study in patients with colorectal polyps.

One hundred and sixteen patients were included, during 18 months, in a double-blind placebo-controlled intervention study, with calcium, vitamins A, C, E and selenium (in a cocktail) or placebo against growth of colonic polyps. Patients were randomized within three arms, according to diameter of the largest polyp, < 5 mm, 5-9 mm or > 9 mm. Polyps > 9 mm were resected, the others were left to be measured annually before resection after 3 years. The protocol (performed in all of the patients) included registration of demographic data, family and personal history, measurement of polyps, collection of blood specimens, stools and biopsy samples. Registration of nutritional status, diet history and 5-day prospective food consumption, was performed in 108 patients. The patient compliance was registered every third month by the hospital pharmacist, with concomitant delivery of new boxes of capsules. Additionally, stool collections were performed from all of the patients for the measurement of faecal calcium, bile salts and fat. Inclusion rate of 37, 41 and 38 patients in each of the three 6-month periods was uniform. The group with the largest polyps measuring 5-9 mm comprised 44% of the material. The sex ratio corresponded to that in overall referrals for colonoscopy. The age relationship of size and multiplicity of polyps and the distribution of polyps in the large bowel corresponded to previous experience in polyp-bearing individuals of the same age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lapatinib activity in premalignant lesions and HER-2-positive cancer of the breast in a randomized, placebo-controlled presurgical trial

Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2-positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models. Ki-67 labeling index (LI) has prognostic and predictive value and can be used to screen drugs' therapeutic and preventive potential in a clinical model of short-term presurgical therapy of breast cancer. We conducted a randomized, placebo-controlled trial of lapatinib (1500 mg/d) administered orally for three weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary endpoint, Ki-67 LI) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (DIN, which comprises ductal carcinoma in situ and atypical ductal hyperplasia), and distant ductal hyperplasia without atypia (DH). Ki-67 LI increased progressively in association with disease stage, increasing in the placebo arm, for example, by medians of 3% in DH to 20% in DIN to 30% in invasive cancer. Ki-67 LI in cancer tissue decreased by a mean (±SD) of 9.3% (±34.2) in the lapatinib arm and increased by 15.1% (±30.9) in the placebo arm (P = 0.008). Compared with placebo, lapatinib reduced Ki-67 significantly more in ER-negative tumors (by 34.8%; P = 0.01) but not significantly more in ER-positive tumors (by 12.3%; P = 0.2) and reduced Ki-67 more (nonsignificantly) in cytosol PTEN-overexpressing tumors (P = 0.057). The prevalence of DIN in post-treatment surgical specimens of both arms was similar (70%-76%), with a median Ki-67 of 15% (range, 5%-35%) on lapatinib versus 20% (5%-60%) on placebo (P = 0.067). The prevalence of DH also was similar in both arms (>90%), with a median Ki-67 of 1% (1%-7%) on lapatinib versus 3% (1%-5%) on placebo (P = 0.006). Other results of lapatinib versus placebo, respectively, were as follows: Median tumor diameter at surgery of 18 mm (11 mm-57 mm) versus 24 mm (10 mm-37 mm; P = 0.009); partial response of 13.6% versus 3.7%, stable disease of 59.1% versus 40.7%, and progression of 27.3% versus 55.6% (P-trend = 0.035). In conclusion, short-term lapatinib decreased cell proliferation in DIN, DH, and invasive HER-2-positive (especially ER-negative) breast cancer, thus providing the rationale for further clinical development of lapatinib for breast cancer prevention in high-risk patients, including those with HER-2-positive DIN.     

Colorectal cancer prevention: is an ounce of prevention worth a pound of cure?

Colorectal cancer (CRC) is among the most common human malignancies and remains a leading cause of cancer-related morbidity and mortality. Colorectal carcinogenesis is a multistep process characterized by molecular and cellular alterations that result in an identifiable precursor lesion, ie, the adenomatous polyp. The transition from normal mucosa to adenoma and its subsequent progression to carcinoma are protracted events that offer opportunities for preventive interventions. Suppression or reversal of the carcinogenic process in the colorectum with nonpharmacologic or pharmacologic agents, ie, chemoprevention, is an area of considerable research interest and activity. Interest in this field derives from multiple epidemiologic studies showing that regular and continued use of nonsteroidal anti-inflammatory drugs (NSAIDs), predominantly aspirin, is associated with significant reductions in both colorectal adenoma and carcinoma incidence. NSAIDs were first shown to be effective in patients with familial adenomatous polyposis (FAP). Subsequent randomized trials in FAP demonstrated that sulindac and the selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, can significantly regress existing adenomas, and resulted in Food and Drug Administration (FDA) approval of celecoxib for adjunctive management of these patients. Based on the aforementioned data, aspirin and coxibs have been or are currently being evaluated for the prevention of sporadic adenoma recurrence in high-risk patient populations. Evidence indicates that aspirin can reduce adenoma recurrence rates in patients with prior colorectal neoplasia; however, questions remain, including the optimal dosage, timing of initiation and duration of treatment, and clinical benefit versus potential harm to patients. These same issues apply to the nonpharmacologic agents such as calcium, folic acid, and selenium given as dietary supplements. Apart from aspirin, calcium carbonate is the only other agent that has been shown to modestly reduce sporadic adenoma recurrence rates in a randomized trial. Folate and selenium are being actively studied based on provocative preclinical data. In addition to demonstrating efficacy, chemopreventive agents must also be safe for long-term use, be well accepted by patients, and be cost-effective. In this review, the current status of CRC chemoprevention will be discussed, including the available evidence for selected pharmacologic and nonpharmacologic agents, particularly among high-risk populations.     

肾移植患者术后肿瘤发病特点及预后

背景与目的由于肾移植患者长期应用免疫抑制剂,与普通人群相比更易发生肿瘤。本研究中我们主要分析肾移植患者术后发生肿瘤的临床特点和预后,并评价根治性手术(radicalsurgery,RS)对其预后的影响。方法对本院1987年11月～2004年5月行肾移植手术的2160例患者进行回顾性分析,分析肾移植术后肿瘤的发生时间、肿瘤类型及生存时间等,总结肾移植术后肿瘤的发病特点。按是否行RS将肿瘤患者分为两组,对比研究RS对其预后的影响。结果2160例肾移植手术的患者中33例术后发生肿瘤,以消化系统肿瘤为主(33.3%)。10例行RS治疗(RS组)的患者中位生存时间为41.5个月;23例未行RS治疗(非RS组)者中位生存时间为6.0个月。两组20个月生存率分别为70.0%和13.0%。结论肾移植患者比普通人群更易发生肿瘤,肿瘤类型与普通人群所患不同,以肝癌、皮肤癌、淋巴瘤、甲状腺癌等为主。早期发现、早期治疗,尤其是病情允许行根治性手术者,近期疗效较好,远期效果有待进一步观察。     

A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients.

PURPOSE: The aim of this study was to examine the effect of a specific cyclooxygenase-2 inhibitor, rofecoxib, on rectal polyps in familial adenomatous polyposis patients. EXPERIMENTAL DESIGN: This was a randomized, double-blind, placebo-controlled study of the efficacy and safety of rofecoxib in the rectum. Initially, 21 patients were assigned randomly in a 1:1 ratio to receive either 25 mg rofecoxib once a day or a placebo p.o. for 9 months. Patients underwent endoscopy at the beginning of the study and then every 3 months thereafter. We reviewed the videotapes to measure the number and size of polyps in the same area throughout the study period in each individual patient. RESULTS: The polyp number, measured as the percentage of change from the baseline values, was significantly decreased in the rofecoxib group at 3, 6, and 9 months. At 9 months, the polyp number in the rofecoxib group decreased by 6.8% from the baseline values, whereas that in the placebo group increased by 3.1%. The 9.9% difference between the rofecoxib and placebo groups was statistically significant (P = 0.004). At 9 months, the rofecoxib group showed a significant reduction from the baseline in polyp size as compared with the placebo group (-16.2% versus 1.5%; P < 0.001). There was no statistically significant increase in the incidence of any adverse events in treatment with rofecoxib compared with placebo (P = 0.922). CONCLUSIONS: In this study, once-daily treatment with 25 mg rofecoxib, a cyclooxygenase 2-specific inhibitor, significantly decreased the number and size of rectal polyps in familial adenomatous polyposis patients.     

Chemoprevention in Lynch syndrome

CAPP1 tested aspirin 600 mg/day and/or resistant starch 30 g/day in 200 adolescent FAP carriers. Aspirin treatment resulted in a non-significant reduction in polyp number and a significant reduction in polyp size among patients treated with aspirin for more than 1 year. CAPP2 RCT used the same interventions in 937 Lynch syndrome patients, the first RCT to have cancer prevention as the primary endpoint. Aspirin did not reduce the risk of colorectal neoplasia in a mean treatment period of 29 months but double blind post intervention follow-up has revealed 48 participants developed 53 CRCs. Per protocol analysis showed 63 % fewer colon cancers with aspirin (p = 0.008) apparent from 4 years, with a similar effect on other LS cancers. Resistant starch was not beneficial at long term followup. CAPP3 will involve a double blind dose non-inferiority trial comparing 100, 300 or 600 mg daily in 3,000 gene carriers. We can now recommend aspirin in people at high risk of colorectal cancer.     

Randomized,phase II,placebo-controlled trial of onartuzumab and/or bevacizumab in combination with weekly paclitaxel in patients with metastatic triple-negative breast cancer

BackgroundIncreased hepatocyte growth factor/MET signaling is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer (TNBC). We evaluated the benefit of adding onartuzumab, a monoclonal anti-MET antibody, to paclitaxel with/without bevacizumab in patients with TNBC.Patients and methodsWomen with metastatic TNBC were randomized to receive onartuzumab plus placebo plus weekly paclitaxel (OP; n = 60) or onartuzumab plus bevacizumab plus paclitaxel (OBP; n = 63) or placebo plus bevacizumab plus paclitaxel (BP; n = 62). The primary end point was progression-free survival (PFS); additional end points included overall survival (OS), objective response rate (ORR), and safety. This trial was hypothesis generating and did not have power to detect minimum clinically meaningful differences between treatment arms.ResultsThere was no improvement in PFS with the addition of onartuzumab to BP [hazard ratio (HR), 1.08; 95% confidence interval (CI) 0.69–1.70]; the risk of a PFS event was higher with OP than with BP (HR, 1.74; 95% CI 1.13-2.68). Most patients had MET-negative tumors (88%); PAM50 subtype analysis showed basal-like tumors in 68% of samples. ORR was higher in the bevacizumab arms (OBP: 42.2%; 95% CI 28.6-57.1; BP: 54.7%; 95% CI 41.0-68.4) compared with OP (27.5%; 95% CI 15.9-40.6). Median OS was shorter with OBP (HR, 1.36; 95% CI 0.75-2.46) and OP (HR, 1.92; 95% CI 1.03-3.59), than with BP. Peripheral edema was more frequent in the onartuzumab arms (OBP, 51.8%; OP, 58.6%) versus BP (17.7%).ConclusionThis study did not show a clinical benefit of the addition of onartuzumab to paclitaxel with/without bevacizumab in patients with predominantly MET-negative TNBC.ClinicalTrials.govNCT01186991.     

Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m² every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m² (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.     

Brief Report: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage SCLC Treated First Line With Atezolizumab Plus Carboplatin and Etoposide

IntroductionIn the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.MethodsPatients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase.ResultsA similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43–0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49–0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event.ConclusionsThese data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.     

A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer

Significant morbidity and expense result from frequent recurrences of nonmuscle-invasive bladder cancer (NMIBC) after standard treatment, and carcinoma in situ (Tis) is a poor prognostic factor. Predicated on observational and preclinical data strongly supporting cyclooxygenase-2 (COX-2) in the pathogenesis, and the activity of COX-2 inhibitors, in bladder cancer, we conducted a randomized, double-blind, placebo-controlled trial to determine whether celecoxib could reduce the time-to-recurrence (TTR) in NMIBC patients at high risk for recurrence. A total of 146 patients were randomized to celecoxib (200 mg) or placebo orally twice daily for at least 12 months. The average treatment duration was 1.25 years. Primary intent-to-treat analysis revealed celecoxib did not statistically significantly prolong TTR compared with placebo (P = 0.17, log rank) with a median follow-up of 2.49 years. The recurrence-free rate at 12 months with celecoxib was 88% (95% CI: 0.81-0.96) versus 78% (95% CI: 0.69-0.89) with placebo. After controlling for covariates with Cox regression analysis, recurrence rates did not differ between the two study arms (HR = 0.69; 95% CI: 0.37-1.29). However, celecoxib had a marginally significant effect on reducing metachronous recurrences (vs. placebo) with HR of 0.56 (95% CI: 0.3-1.06; P = 0.075). Celecoxib was well tolerated, with similar adverse events and quality-of-life in both arms. Our clinical trial results do not show a clinical benefit for celecoxib in preventing NMIBC recurrence but further investigation of COX-2 inhibitors in this setting is warranted.     

Borealis-1: a randomized,first-line,placebo-controlled,phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer

BackgroundFive-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%–15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients.Patients and methodsThis placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N=62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N=61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS.ResultsOS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms.ConclusionsEven though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.     

Ondansetron plus dexamethasone is superior to ondansetron alone in the prevention of emesis in chemotherapy-naive and previously treated patients

BACKGROUND: This prospective, randomized, double-blind study assessed whetherthe addition of dexamethasone to ondansetron leads to improvedcontrol of chemotherapy - induced emesis, both in patients undergoingtheir first course of highly emetogenic chemotherapy and inchemotherapypretreated patients refractory to standard anti-emetics. PATIENTS AND METHODS: Patients were randomized to receive either 20 mg dexamethasoneas an intravenous infusion or placebo plus ondansetron 8 mg15 minutes prior to and 4 and 8 hours after the administrationof chemotherapy. According to the randomisation code patientsreceived from day 2 to day 5 either ondansetron 8 mg p.o. +placebo p.o., three times daily, or ondansetron 8 mg p.o. +dexamethasone 4 mg p.o., three times daily. Patients undergoingmultiple-day treatment received intravenous study treatmenton the days of chemotherapy and thereafter oral treatment asoutlined above. RESULTS: A total of 215 patients were entered into the study. Of these,207 were evaluable (111 previously-untreated and 96 previously-treatedpatients). In the chemotherapynaive patients the combinationof ondansetron plus dexamethasone was significantly superiorto ondansetron plus placebo in protecting the patients completelyfrom emesis (retching and vomiting) (81% versus 64%, p –0.04). The mean number of vomiting episodes was significantlylower in the ondansetron-plus-dexamethasone-treated patientsthan in those receiving ondansetron plus placebo (0.8 versus2.1, p – 0.03). In this group of patients there was significantlysuperior protection from emesis on the second day (pvalue –0.04), and a trend towards a better protection on the thirdand fourth days. On each day the active combination offeredbetter protection from nausea with an approximately 20% differencein favor of ondansetron plus dexamethasone. In the group ofestablished vomiters the combination of ondansetron plus dexamethansonewas superior to ondansetron plus placebo in protecting the patientsfrom acute emesis, with 70% versus 48% of the patients beingcompletely protected (p = 0.03). The mean number of vomitingepisodes was significantly lower in the ondansetron-plusdexamethasone-treated-patientsthan in those receiving ondansetron plus placebo (0.9 versus2.1, p = 0.02). In the ondansetron-plus-dexamethasone arm 55%of the patients had complete protection from nausea, retchingand vomiting compared to 35% in the ondansetron-plus-placebo-treatedgroup (p = 0.05). Overall 22% of the patients (20% in the ondansetronplus-placeboand 25% in the ondansetron-plus-dexamethasone arm) experiencedat least one, usually mild, adverse event. More patients inthe ondansetron-plus-dexamethasone arm complained of epigastricpain or burning (8/101 versus 4/112, p-value = 0.16). The differencein patients reporting constipation (6/101 versus 0/112) washighly significant at a p-value of 0.008. CONCLUSIONS: The combination of dexamethasone plus ondansetron is more effectivein protecting chemotherapynaive patients undergoing their firstcourse of highly emetogenic chemotherapy with cisplatin andchemotherapy-pretreated patients refractory to standard antiemeticsfrom chemotherapy-induced nausea and vomiting compared to ondansetronplus placebo. nausea, vomiting, chemotherapy, ondansetron, dexamethasone, delayed emesis     

Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917

The threat of prostate cancer and the significant and often negative impact of its treatment underscore the importance of prevention. High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a potential premalignant lesion marking an increased risk of prostate cancer and substantial evidence suggests that men with HGPIN are in need of prostate cancer prevention. In vitro, in vivo, epidemiologic, and clinical trial evidence that selenium supplementation protects against prostate cancer motivated the study we report here: a double-blind, randomized, placebo-controlled trial of selenium 200 (μg/d) as selenomethionine in men with HGPIN. The primary endpoint was progression of HGPIN to prostate cancer over a 3-year period. This National Cancer Institute Intergroup trial was coordinated by the Southwest Oncology Group (SWOG). Of 619 enrolled patients, 423 randomized men with HGPIN (212 selenium and 211 placebo) were eligible (by central pathology review) and included in the primary analysis. Three-year cancer rates were 36.6% (placebo) versus 35.6% (selenium; P = 0.73, adjusted). The majority of patients who developed cancer on trial (70.8%, selenium and 75.5%, placebo) had a Gleason score of 6 or less than 6; there were no differences in Gleason scores between the two arms. Subset analyses included the finding of a nonsignificantly reduced prostate cancer risk (relative risk = 0.82; 95% CI: 0.40-1.69) in selenium versus placebo patients in the lowest quartile of baseline plasma selenium level (<106 ng/mL). Overall, and in all other subsets defined by baseline blood selenium levels, selenium supplementation had no effect on prostate cancer risk. The 36% prostate cancer rate in men with HGPIN indicates the association of this lesion with an elevated prostate cancer risk. Future study in this setting should focus on selenium-deficient populations and selenium pharmacogenetics.