Long‐Term Experience of Chemoradiotherapy Combined with Deep Regional Hyperthermia for Organ Preservation in High‐Risk Bladder Cancer (Ta, Tis, T1, T2)

2 weeks 6 days ago
AbstractBackground.The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high‐risk bladder cancer after transurethral resection of bladder tumor (TUR‐BT).Materials and methods.Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0–1 cM0 bladder cancer were treated with a multimodal treatment after TUR‐BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4–6 weeks after treatment with TUR‐BT.Results.Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05–5.12; p = .037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88–8.00; p = .092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50–0.99; p = .045). Five‐year OS from unadjusted Kaplan‐Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5‐year OS to 87% (HR, 0.32; 95% CI, 0.18–0.58; p = .0001). RCT + RHT compared with RCT showed a significantly better bladder‐preservation rate (HR, 0.13; 95% CI, 0.03–0.56; p = .006). Median follow‐up was 71 months. The median number of RHT sessions was five.Conclusion.The multimodal treatment consisted of a maximal TUR‐BT followed by RT; concomitant platinum‐based chemotherapy combined with RHT in patients with high‐grade bladder cancer improves local control, bladder‐preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy.Implications for Practice.Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle‐invasive bladder cancer in medically fit patients, despite many centers reporting excellent long‐term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder‐preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum‐based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1–2 bladder carcinomas improves local control, bladder‐preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.
Ricarda Merten, Oliver Ott, Marlen Haderlein, Simone Bertz, Arndt Hartmann, Bernd Wullich, Bastian Keck, Reinhard Kuhn, Claus Michael Rodel, Christian Weiss, Christine Gall, Wolfgang Uter, Rainer Fietkau

Comprehensive Clinical Trial Data Summation for BRAF‐MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

2 weeks 6 days ago
AbstractBackground.Immune checkpoint inhibitors, along with BRAF and MEK inhibitors, have dramatically changed the management of and outlook for patients with metastatic melanoma. Analyses of long‐term follow‐up data and subanalyses based on disease characteristics may inform clinical decision making.Methods.Reports of clinical trials in metastatic melanoma published between January 1, 2012, and August 30, 2018, were identified using PubMed (terms: melanoma AND [dabrafenib OR trametinib OR vemurafenib OR cobimetinib OR encorafenib OR ipilimumab OR nivolumab OR pembrolizumab]) and were systematically reviewed. Relevant congress proceedings were also assessed. Efficacy data from key phase III trials were analyzed and trends identified.Results.Substantial improvements in objective response rates, progression‐free survival, and overall survival were documented across 14 identified publications. Subgroup findings supported that patients with lower disease burden derive greater benefit than patients with more advanced disease, limiting the value of disease burden in the clinical decision‐making process. However, these agents consistently conferred benefits despite the presence of poor prognostic features. Several clinically relevant questions remain, including how best to sequence immune checkpoint inhibitors and combination targeted therapy.Conclusion.This research, coupled with ongoing investigations, including those on predictive biomarkers, suggests that the treatment decision‐making process is likely to become more nuanced.Implications for Practice.The management of melanoma has been rapidly advancing with new classes of agents, including immune checkpoint and BRAF inhibitors. With long‐term follow‐up, their impact on response rates and survival outcomes is well documented. Additional findings from subgroup analyses suggest that patients with lower disease burden derive greater benefit, yet both consistently confer benefit in patients with higher disease burden. Currently, there is a paucity of data to guide first‐line treatment selection between immunotherapy and BRAF‐targeted therapy in clinical practice or to estimate their impact when sequenced. Gaining these insights will facilitate a more nuanced management approach.
Jason J. Luke

HER2 Positivity Predicts Unresponsiveness to EGFR‐Targeted Treatment in Metastatic Colorectal Cancer

3 weeks 1 day ago
AbstractBackground.HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti‐epidermal growth factor receptor (EGFR) treatment.Subjects and Methods.Patients with KRAS exon 2 wild‐type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2‐negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti‐EGFR treatment.Results.From August 2012 to April 2018, a total of 100 HER2‐positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild‐type screened patients (6.7%). HER2‐positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15–3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10–2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22–1.11; p = .088). HER2‐positive patients who received treatment with anti‐EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression‐free survival, 5.7 months vs. 7 months, p = .087).Conclusion.Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2‐amplified metastatic CRC are less likely to respond to anti‐EGFR therapy.Implications for Practice.Patients with HER2‐amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti‐epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression‐free survival in response to previous anti‐EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2‐targeted double blockade independently of previous anti‐EGFR treatment.
Andrea Sartore-Bianchi, Alessio Amatu, Luca Porcu, Silvia Ghezzi, Sara Lonardi, Francesco Leone, Francesca Bergamo, Elisabetta Fenocchio, Erika Martinelli, Beatrice Borelli, Federica Tosi, Patrizia Racca, Emanuele Valtorta, Emanuela Bonoldi, Cosimo…

A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN

3 weeks 4 days ago
AbstractLessons Learned. This is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline PTEN gene.Single‐agent sirolimus, a mTOR inhibitor, suppressed mTOR signaling in surrogate human tissues without significant toxicity.Background.Cowden syndrome is characterized by inactivating germline PTEN mutations, which can lead to activation of the PI3K‐Akt‐mTOR pathway.Methods.Adult subjects with germline PTEN mutation who met international diagnostic criteria for Cowden syndrome and who had Eastern Cooperative Oncology Group (ECOG) performance status 0–2 and adequate organ function were enrolled. Subjects were treated with a 56‐day course of daily oral sirolimus. In addition to symptom assessment and physical examination, dermatologic, endoscopic, neurologic (cerebellar), and radiographic assessments were conducted. Inhibition of the mTOR pathway in benign skin and gastrointestinal (GI) lesion was assessed by immunohistochemistry.Results.A total of 18 patients and 16 families were enrolled. PTEN mutations were located at exons 1–8. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at 1 month. Immunohistochemistry (IHC) analysis in skin and GI benign lesions showed a decrease in the ratio of phosphorylated (p)S6 to total S6 in response to sirolimus. Ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline (p = .0026, p = .0391, respectively). A 56‐day course of sirolimus was well tolerated.Conclusion.A 56‐day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling.
Takefumi Komiya, Gideon M. Blumenthal, Roopa DeChowdhury, Susan Fioravanti, Marc S. Ballas, John Morris, Thomas J. Hornyak, Stephen Wank, Stephen M. Hewitt, Betsy Morrow, Regan M. Memmott, Arun Rajan, Phillip A. Dennis

Pathological Response to Neoadjuvant Chemotherapy and the Molecular Classification of Locally Advanced Breast Cancer in a Latin American Cohort

3 weeks 5 days ago
AbstractBackground.The majority of patients with breast cancer in Colombia are admitted into oncological centers at locally advanced stages of the disease (53.9%). The aim of this study was to describe the pathological response obtained with neoadjuvant chemotherapy (NACT) according to the molecular classification of breast cancer in patients with locally advanced tumors treated within the National Cancer Institute (NCI) Functional Breast Cancer Unit (FBCU) in Bogotá, Colombia.Materials and Methods.This was an observational, descriptive, historical cohort study of patients with locally advanced breast cancer treated within the NCI FBCU.Results.We included 414 patients who received NACT and surgical management. Most patients had luminal B HER2‐negative tumors (n = 134, 32.4%). The overall rate of pathological complete response (pCR) ypT0/ypN0 was 15.2% (n = 63). Tumors that presented the highest rate of pCR were pure HER2, at 40.5% (n = 15; odds ratio [OR], 6.7); however, with a follow‐up of 60 months, only the triple negative tumors presented a statistically significant difference for event‐free survival (EFS; median recurrence time, 18 months; range, 1–46) and overall survival (OS; median follow‐up, 31 months; range 10–57). The molecular subtype that most recurrences presented was luminal B HER2 negative, at 38.3% (n = 28). The majority of recurrences (93.2 %; n = 68; OR, 5.9) occurred in patients in whom no pathological response was obtained (Chevallier 3 and 4).Conclusions.Pathological response in locally advanced tumors is related to the molecular subtype of breast cancer, finding higher pCR rates in pure HER2 and triple‐negative tumors. A direct relationship was found between disease recurrences and the pathological response, evidencing greater tumor recurrence in patients who did not respond to NACT (Chevallier 3 and 4). EFS and OS were greater in patients with pCR, with statistical significance only in triple‐negative tumors.Implications for Practice.This research article is of scientific interest, because it describes the clinical and pathological features and analyzes the correlation between pathological response to neoadjuvant chemotherapy and the molecular classification of locally advanced breast cancer in patients treated in the National Cancer Institute in Bogotá, Colombia. It was found that pathological response is related to the molecular subtype of breast cancer. In addition, there is a direct relationship between disease recurrences and pathological response. The survival results were greater in patients with pathological complete response.
Sandra Esperanza Diaz-Casas, Jorge Alberto Castilla-Tarra, Esperanza Pena-Torres, Martha Orozco-Ospino, Sara Mendoza-Diaz, Marcela Nunez-Lemus, Oscar Garcia-Angulo, Mauricio Garcia-Mora, Luis Guzman-AbiSaab, Carlos Lehmann-Mosquera, Javier Angel…

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs

3 weeks 5 days ago
AbstractFollicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early‐ and advanced‐stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first‐line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs.Implications for Practice.In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first‐line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies.
Matthew J. Matasar, Stefano Luminari, Paul M. Barr, Stefan K. Barta, Alexey V. Danilov, Brian T. Hill, Tycel J. Phillips, Mats Jerkeman, Massimo Magagnoli, Loretta J. Nastoupil, Daniel O. Persky, Jessica Okosun

Chemotherapy Toxicity in BRCA Mutation Carriers Undergoing First‐Line Platinum‐Based Chemotherapy

3 weeks 5 days ago
AbstractObjective.BRCA mutations are the most frequent mutations causing homologous recombination defects in epithelial ovarian cancers (EOC). Germline mutation carriers are heterozygous for the mutation and harbor one defective allele in all cells. This has been hypothesized to cause increased susceptibility to DNA damage in healthy cells as well as neoplastic ones. Our objective was to assess chemotherapy‐associated toxicities in patients with epithelial ovarian cancer with and without a germline BRCA mutation.Mateials and Methods.A retrospective cohort study of patients with EOC receiving first‐line platinum‐based chemotherapy at a single center between 2006 and 2016. Indices of chemotoxicity, including blood counts, transfusion requirements, granulocyte colony‐stimulating factor (gCSF) prescriptions, episodes of febrile neutropenia, and treatment delays were compared for BRCA mutation carriers and noncarriers.Results.A total of 90 women met the inclusion criteria, including 31 BRCA mutation carriers (34%) and 59 noncarriers (66%). Mean hemoglobin, neutrophil count, and platelet counts during treatment were comparable for the two patient groups. There was a trend toward a higher frequency of hematological events in BRCA mutation carriers (neutropenia <1500 per mL: 6% vs. 0%, p = .12; thrombocytopenia <100,000 per mL: 23% vs. 9%, p = .07), but these differences were not statistically significant. Similarly, no significant differences were found in surrogates of bone marrow toxicity such as blood transfusions, use of gCSF, episodes of febrile neutropenia, or treatment delays.Conclusion.BRCA mutation carriers and noncarriers receiving first‐line platinum‐based chemotherapy for EOC have similar hematologic toxicity profiles. Clinicians treating these patients can be reassured that chemotherapy dosing or schedule do not require adjustment in patients carrying BRCA mutations.Implications for Practice.Patients with ovarian cancer carrying BRCA mutations are more likely to have serous tumors and present with higher CA125 levels. Germline BRCA mutation status is not associated with increased frequency of adverse hematologic events among patients with ovarian cancer being treated with first‐line platinum‐based chemotherapy. Germline BRCA mutations are also not associated with more treatment delays or a lower number of courses completed in this patient population. These findings should reassure practitioners engaged in care for patients with ovarian cancer that BRCA mutation status most likely will not affect chemotherapy dosing or schedule.
Omar Weitzner, Yael Yagur, Yfat Kadan, Mario E. Beiner, Ami Fishman, Emilie Ben Ezry, Daphna Amitai Komem, Limor Helpman

Analysis of Differentially Expressed MicroRNAs and Circulating Tumor Cells as Predictive Biomarkers of Platinum Chemoresistance in Primary Ovarian Carcinomas: A Prospective Study

3 weeks 5 days ago
AbstractLesson Learned. Circulating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials.Background.Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor‐based predictive biomarkers of platinum resistance.Methods.Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs).Results.The average age of the patients was 64 years, and 82.6% had high‐grade epithelial carcinomas. The baseline median CA‐125 was 464 (range 32–2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum‐resistant/refractory versus platinum‐sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance.Conclusion.Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.
Emil Lou, Rachel I. Vogel, Spencer Hoostal, Phillip Wong, Aaron Grad, Minnu Monu, Tomasz &#x0141;ukaszewski, Jaai Deshpande, Elizabeth L. Dickson, Molly Klein, Michael A. Linden, Subbaya Subramanian, Deanna Teoh, Melissa A. Geller

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen‐Activated Protein Kinase Pathway Alterations

3 weeks 5 days ago
AbstractBackground.Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.Materials and Methods.We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.Results.Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)‐like or high‐grade glioma (HGG)‐like. PXA‐like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG‐like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen‐activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG‐like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.Conclusion.We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high‐grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen‐activated protein kinase pathway.Implications for Practice.Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma‐like ABM cases show a favorable prognosis whereas high‐grade glioma (glioblastoma and diffuse midline gliome)‐like ABM show significantly worse clinical courses. These results call for in‐depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.
William Boisseau, Philipp Euskirchen, Karima Mokhtari, Caroline Dehais, Mehdi Touat, Khe Hoang-Xuan, Marc Sanson, Laurent Capelle, Aurelien Nouet, Carine Karachi, Franck Bielle, Justine Guegan, Yannick Marie, Nadine Martin-Duverneuil, Luc Taillandier,…

18F‐FES PET/CT Influences the Staging and Management of Patients with Newly Diagnosed Estrogen Receptor‐Positive Breast Cancer: A Retrospective Comparative Study with 18F‐FDG PET/CT

4 weeks ago
AbstractPurpose.We compared the clinical value of 16a‐18F‐fluoro‐17b‐estradiol (18F‐FES) positron emission tomography (PET)/computed tomography (CT) and 18F‐fluoro‐2‐deoxy‐D‐glucose (18F‐FDG) PET/CT and investigated whether and how 18F‐FES PET/CT affects the implemented management of newly diagnosed estrogen receptor positive breast cancer patients.Materials and Methods.We retrospectively analyzed 19 female patients newly diagnosed with immunohistochemistry‐confirmed estrogen receptor (ER)‐positive breast cancer who underwent 18F‐FES and 18F‐FDG PET/CT within 1 week in our center. The sensitivity of 18F‐FES and 18F‐FDG in diagnosed lesions were compared. To investigate the definite clinical impact of 18F‐FES on managing patients with newly diagnosed ER positive breast cancer, we designed two kinds of questionnaires. Referring physicians completed the first questionnaire based on the 18F‐FDG report to propose the treatment regime, and the second was completed immediately after reviewing the imaging report of 18F‐FES to indicate intended management changes.Results.In total, 238 lesions were analyzed in 19 patients with newly diagnosed ER‐positive breast cancer. Lesion detection was achieved in 216 sites with 18F‐FES PET and in 197 sites with 18F‐FDG PET/CT. These results corresponded to sensitivities of 90.8% for 18F‐FES versus 82.8% for 18F‐FDG PET/CT in diagnosed lesions. Thirty‐five physicians were given the questionnaires referring to the treatment strategy, with 27 of them completing both questionnaires. The application of 18F‐FES in addition to 18F‐FDG PET/CT changed the management in 26.3% of the 19 patients with newly diagnosed ER‐positive breast cancer.Conclusion.Performing 18F‐FES PET/CT in newly diagnosed ER‐positive breast cancer patients increases the value of diagnosis equivocal lesions and treatment management compared with 18F‐FDG PET/CT.Implications for Practice.This study investigated whether 16a‐18F‐fluoro‐17b‐estradiol (18F‐FES) positron emission tomography (PET)/computed tomography (CT) affects the clinical management of patients with newly diagnosed estrogen receptor (ER)‐positive breast cancer. Physicians completing two questionnaires comparing the clinical impact of 18F‐FES and 18F‐FDG on individual management plans in patients with newly diagnosed ER‐positive breast cancer confirmed that 18F‐FES scans led to change in management in 26.3% of the 19 patients with newly diagnosed ER positive breast cancer. This retrospective study indicates the potential impact of 18F‐FES PET/CT on intended management of patients with newly diagnosed estrogen receptor positive breast cancer in comparison to 18F‐fluoro‐2‐deoxy‐D‐glucose PET/CT.
Cheng Liu, Chengcheng Gong, Shuai Liu, Yingjian Zhang, Yongping Zhang, Xiaoping Xu, Huiyu Yuan, Biyun Wang, Zhongyi Yang

Meta‐Analysis of Randomized Clinical Trials Comparing Active Treatment with Placebo in Metastatic Neuroendocrine Tumors

4 weeks 1 day ago
AbstractBackground.Most guidelines still recommend active surveillance for patients with asymptomatic, unresectable neuroendocrine tumors (NETs). However, recent findings from several randomized placebo‐controlled trials suggest that most patients would benefit from active treatment. We conducted a meta‐analysis of pooled outcomes from clinical trials in which an active treatment arm was compared with placebo to determine whether active treatment provides a survival advantage.Materials and Methods.This meta‐analysis evaluated six trials that compared a medication with placebo in patients with an asymptomatic, metastatic NET. The trials were heterogenous with regard to the active medication (octreotide, lanreotide, sunitinib, everolimus, Lu‐Dotatate) and tumor localizations (gastrointestinal, pancreas, lung). Overall survival (OS) and progression‐free survival (PFS) for the placebo and active treatment arms were obtained from individual trial data and combined to obtain pooled outcomes.Results.The individual trials all reported significantly better PFS outcomes for active treatment. The pooled data confirmed this advantage. At months 3, 6, 12, 18, and 24, pooled PFS rates for the placebo and treatment arms, respectively, were 92.9% versus 96.9%; 54.3% versus 83.7%; 35.5% versus 68.5%; 25.1% versus 54.7%; and 17.7% versus 61.0%. OS was also higher in the active treatment groups. At months 6, 12, 24, 36, 48, and 60, OS rates (placebo vs. active treatment), respectively, were 88.1% versus 93.4%; 84.1% versus 86.2%; 67.4% versus 76%; 56.6% versus 64.4%; 49.9% versus 61.0%; and 41.7% versus 45.9%.Conclusion.This meta‐analysis confirms findings from recent clinical trials indicating that active treatment yields better survival outcomes than placebo. Importantly, these findings were obtained across a wide range of patient profiles and diverse medical treatments for metastatic NETs. Given the lack of reliable prognostic factors to determine a priori which patients are unlikely to benefit from active treatment, these findings support early treatment in most patients.Implications for Practice.Although most guidelines still recommend active surveillance for patients diagnosed with metastatic neuroendocrine tumors, the results of this meta‐analysis, together with recent data from key clinical trials, suggest that most patients could benefit from upfront active treatment. However, more data are needed to confirm this.
Jaume Capdevila, Jorge Hernando, Santiago Perez-Hoyos, Ale&#x0237;andro Roman-Gonzalez, Enrique Grande

Randomized Phase II Study of Weekly Paclitaxel plus Carboplatin Versus Biweekly Paclitaxel plus Carboplatin for Patients with Previously Untreated Advanced Non‐Small Cell Lung Cancer

4 weeks 1 day ago
AbstractLessons Learned. This clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3‐weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non‐small cell lung cancer (NSCLC).The weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3‐weekly regimen in Japanese patients with NSCLC.Background.Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non‐small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients.Methods.Chemonaive patients with IIIB/IV NSCLC and a performance status of 0–1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks).Results.A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression‐free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W).Conclusion.The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3‐weekly regimen in NSCLC treatment.
Koichi Takayama, Masao Ichiki, Shoji Tokunaga, Koji Inoue, Masayuki Kawasaki, Junji Uchino, Yoichi Nakanishi

Inclusion of Older Patients with Cancer in Clinical Trials: The SAGE Prospective Multicenter Cohort Survey

1 month ago
AbstractBackground.The primary objective was to evaluate the rates of older patients with colorectal cancer (CRC) who were eligible for a clinical trial, invited to participate, and, ultimately, included. The secondary objective was to assess the reasons for ineligibility, noninvitation, and noninclusion and factors associated.Materials and Methods.The Sujets AGés dans les Essais Cliniques (SAGE; Older Subjects in Clinical Trials) multicenter prospective cohort was established in seven centers (10 departments of medical oncology, digestive oncology, and digestive surgery) between 2012 and 2016. All patients with CRC aged 65 or older were studied. The endpoints were clinical trial availability, patient's eligibility, invitation, and enrollment in a trial.Results.We included 577 older patients (mean age ± SD: 75.6 ± 7 years; males: 56%; metastasis: 41%). Thirty‐seven trials were ongoing (one trial for older patients). Of the 474 patients with at least one available trial for their cancer stage and site, 127 (27%) were eligible; 84 of these 127 (66%) were invited to participate, and 70 of these 84 (83%) were included. In a multivariate analysis, noninvitation was found to be associated with older age (p = .016): adjusted relative risk (95% confidence interval), 0.14 (0.02–0.60) for ≥80 vs. 65–69; 0.54 (0.18‐1.04) for 75–79 vs. 65–69; 0.47 (0.17‐0.93) for 70–74 vs. 65–69.Interpretation.Three‐quarters of older patients with CRC were ineligible for a clinical trial. One‐third of the eligible patients were not invited to participate in a trial, and 17% of invited patients were not included. Few trials are reserved for older patients. Patients aged 80 or older were significantly less likely to be eligible for a trial and invited to participate. Clinical trial identification number: NCT01754636.Implications for Practice.The results of this study suggest that barriers to participation of older patients in clinical trials are particularly marked at age 80 years or older. Secondly, the results emphasize the need for trials for older patients. Thirdly, there is also a need for more pragmatic “real‐world” trials, rather than solely randomized trials performed in idealized settings with strictly selected patients. Large prospective observational cohorts with a precise follow‐up of toxicity, functional decline, and quality of life may constitute one way of generating more data on the risk‐benefit ratio for cancer treatments in older patients.
Florence Canoui-Poitrine, Astrid Lievre, Florent Dayde, Daniel Lopez-Trabada-Ataz, Isabelle Baumgaertner, Olivier Dubreuil, Francesco Brunetti, Romain Coriat, Karin Maley, Simon Pernot, Christophe Tournigand, Meoin Hagege, Thomas Aparicio, Elena Paillaud…

Median Survival or Mean Survival: Which Measure Is the Most Appropriate for Patients, Physicians, and Policymakers?

1 month ago
AbstractIntroduction.Understanding the efficacy of treatments is crucial for patients, physicians, and policymakers. Median survival, the most common measure used in the outcome reporting of oncology clinical trials, is easy to understand; however, it describes only a single time point. The interpretation of the hazard ratio is difficult, and its underlying statistical assumptions are not always met. The objective of this study was to evaluate alternative measures based on the mean benefit of novel oncology treatments.Materials and Methods.We reviewed all U.S. Food and Drug Administration (FDA) approvals for oncology agents between 2013 and 2017. We digitized survival curves as reported in the clinical trials used for the FDA approvals and implemented statistical transformations to calculate for each trial the restricted mean survival time (RMST), as well as the mean survival using Weibull distribution. We compared the mean survival with the median survival benefit in each clinical trial.Results.The FDA approved 83 solid tumor indications for oncology agents between 2013 and 2017, of which 27 approvals based on response rates, whereas 49 approvals were based on survival endpoints (progression‐free survival and overall survival). The average improvement in median overall survival or progression‐free survival was 4.6 months versus 3.6 months improvement in the average RMST and 6.1 months improvement in mean survival using Weibull distribution.Conclusion.Mean survival may supply valuable information for different stakeholders. Its inclusion should be considered in the reporting of prospective clinical trials.Implications for Practice.Mean survival may supply valuable information for different stakeholders. Its inclusion should be considered in the reporting of clinical trials.
Omer Ben-Aharon, Racheli Magnezi, Moshe Leshno, Daniel A. Goldstein

Individualized Prediction of Survival Benefit from Postmastectomy Radiotherapy for Patients with Breast Cancer with One to Three Positive Axillary Lymph Nodes

1 month ago
AbstractPurpose.There still exist some arguments regarding the use of postmastectomy radiotherapy (PMRT) for patients with breast cancer carrying one to three positive axillary lymph nodes considering the heterogeneity of this cohort. Here, we developed a prognostic nomogram to estimate the probability of long‐term outcome in patients receiving or not receiving PMRT in order to assist in making individually locoregional treatment decisions for this particular cohort.Methods.Altogether, 20,336 women, aged 18 to 80 years, diagnosed with breast cancer, and carrying one to three positive nodes were identified in the Surveillance, Epidemiology, and End Results (SEER) database. We applied multivariant Cox hazard model to determine the impact of covariates on disease‐specific survival (DSS) and overall survival (OS). Then, the nomogram was built accordingly. Internal and external validations were performed to examine the accuracy of nomograms.Results.Age of diagnosis, tumor grade, size, estrogen and progesterone receptor status, and number of positive nodes were independent factors of DSS and OS in the multivariate analysis. Incorporating these factors into the constructed nomogram showed high accuracy when predicting 5‐ and 10‐year survival, with internally and externally bootstrap‐corrected concordance indexes in the range of 0.6 to 0.8.Conclusion.Besides the number of involved nodes, extra variables existed as predictors of survival outcomes in this cohort; therefore, the recommendation of PMRT or no PMRT requires comprehensive consideration. This clinically validated nomogram provided a useful tool that could aid decision making by estimating DSS and OS benefits from PMRT, useful in predicting 5‐ and 10‐year DSS and OS for patients with one to three positive nodes after mastectomy.Implications for Practice.This study evaluated population‐based data to identify prognostic factors associated with patients with breast cancer with one to three lymph nodes and help clinicians to weigh the benefit of postmastectomy radiotherapy (PMRT). Surveillance, Epidemiology, and End Results (SEER) data were used to develop a prognostic nomogram to predict the likelihood of long‐term survival with and without PMRT in order to optimize the individual locoregional control strategy for this particular cohort. This clinically validated nomogram provides a useful tool to predict 5‐ and 10‐year disease‐specific survival and overall survival for patients with one to three positive nodes and can aid tailored clinical decision making by estimating predicted benefit from PMRT.
Ning Zhang, Jiashu Zhang, Hanwen Zhang, Ying Liu, Wenjing Zhao, Lijuan Wang, Bing Chen, Meena S. Moran, Bruce G. Haffty, Qifeng Yang

Adjuvant Trastuzumab Therapy: Can We Balance Efficacy and Safety?

1 month ago
AbstractTrastuzumab is an effective treatment for HER2‐positive breast cancer. Current guidelines recommend withholding trastuzumab in patients experiencing a significant asymptomatic decline in left ventricular function. In this commentary, we discuss the survival benefits afforded by trastuzumab juxtaposed against the risk of trastuzumab‐mediated cardiotoxicity. It is not known whether the net benefit of continuing trastuzumab in the setting of mild cardiotoxicity outweighs the associated risks. We describe a potential approach undertaken by our group, and others, and call for a randomized trial.
Carly C. Barron, Nidhi Kumar Tyagi, Muhammad Mustafa Alhussein, Som D. Mukher&#x0237;ee, Peter M. Ellis, Sukhbinder Dhesy-Thind, Darryl P. Leong

Role of Resection Following Focal Progression with Standard Doses of Imatinib in Patients with Advanced Gastrointestinal Stromal Tumors: Results of Propensity Score Analyses

1 month ago
AbstractBackground.There are limited data on the clinical benefits of adding surgical resection in patients with focally progressive gastrointestinal stromal tumor (GIST). This study aims to compare the clinical outcomes of resection plus imatinib dose escalation or maintenance (S group) with imatinib dose escalation alone (NS group) in patients with advanced GIST following focal progression (FP) with standard doses of imatinib.Materials and Methods.A total of 90 patients with advanced GISTs who experienced FP with standard doses of imatinib were included in this retrospective analysis. The primary endpoints were time to imatinib treatment failure (TTF) and overall survival (OS).Results.Compared with the NS group (n = 52), patients in the S group (n = 38) had a higher proportion of primary tumor site involvement and lower tumor burden at FP. With a median follow‐up duration of 31.0 months, patients in the S group had significantly better TTF and OS than patients in the NS group (median TTF: 24.2 vs. 6.5 months, p < .01; median OS: 53.2 vs. 35.1 months, p = .009). Multivariate analysis showed that S group independently demonstrated better TTF (hazard ratio [HR], 0.29; p < .01) and OS (HR, 0.47; p = .01). Even after applying inverse probability of treatment‐weighting adjustments, S group demonstrated significantly better TTF (HR, 0.36; p < .01) and OS (HR, 0.58; p = .049).Conclusion.Our results suggested that resection following FP with standard doses of imatinib in patients with advanced GIST provides additional benefits over imatinib dose escalation alone.Implications for Practice.This is the first study to compare the clinical outcomes of resection plus imatinib dose escalation or maintenance (S group) with imatinib dose escalation alone (NS group) in patients with advanced gastrointestinal stromal tumor (GIST) following focal progression (FP) with standard doses of imatinib. These findings suggest that resection can be safely performed following FP, and the addition of surgical resection provides further clinical benefit over imatinib dose escalation alone. Based on these results, the authors recommend resection following FP in patients with advanced GIST provided that an experienced multidisciplinary team is involved in the patient's treatment.
Hyungwoo Cho, Min-Hee Ryu, Yong&#x0237;une Lee, Young Soo Park, Ki-Hun Kim, Jwa Hoon Kim, Yangsoon Park, Sun Mi Lee, Chan Wook Kim, Beom Soo Kim, Moon-Won Yoo, Yoon-Koo Kang

Incorporating MicroRNA into Molecular Phenotypes of Circulating Tumor Cells Enhances the Prognostic Accuracy for Patients with Metastatic Breast Cancer

1 month 1 week ago
AbstractBackground.The molecular phenotype of circulating tumor cells (CTCs) was associated with clinical outcome of patients with breast cancer. CTCs isolated from patients with metastatic breast cancer (MBC) display a unique microRNA (miRNA) expression profile. The aim of this study was to enhance the prognostic accuracy of the CTC phenotype in patients with MBC, by incorporating miRNA into a combined prediction model.Subjects, Materials, and Methods.CTCs were detected by CellSearch and enriched by magnetic cell sorting. miRNA deep sequencing and quantitative polymerase chain reaction were used to screen and verify potentially CTC‐specific miRNA candidates. Patients with MBC were enrolled from two independent cohorts, and overall survival (OS) and chemotherapy response were analyzed.Results.We screened and identified that miR‐106b was an upregulated molecule in patients with MBC with CTC ≥5/7.5 mL (n = 16) compared with patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8). The expression of CTC‐specific miR‐106b correlated with vimentin and E‐cadherin in CTC and acted as an independent factor for predicting OS (hazard ratio 2.157, 95% confidence interval [CI] 1.098–4.239, p = .026). Although CTC‐specific miR‐106b, E‐cadherin, and vimentin showed a prognostic potential independently, the prognostic performance for OS based on the combination of three markers was significantly enhanced in Cohort 1 (area under the curve [AUC] 0.752, 95% CI 0.658–0.847, n = 128) and further validated in Cohort 2 (AUC 0.726, 95% CI 0.595–0.856, n = 91). Besides, a combined model incorporating miR‐106b was associated with therapy response.Conclusion.The phenotypic assemblies of CTC incorporating miR‐106b show enhanced prognostic accuracy of overall survival in patients with MBC.Implications for Practice.In order to enhance the prognostic accuracy of the circulating tumor cell (CTC) phenotype in patients with metastatic breast cancer (MBC), this study screened and identified a CTC‐specific microRNA (miRNA), miR‐106b, as an upregulated molecule based on the comparison of miRNA profile between CTCs, primary tumors, and healthy blood donors. By incorporating miR‐106b into a combined prediction model, the prognostic accuracy of the CTC phenotype for patients with MBC was greatly improved in both the training and validation cohorts. This work provides clinical evidence supporting the prognostic potential of CTC‐specific miRNA for patients with MBC. These results indicate that developing CTC‐specific miRNAs as new biomarkers will help to further optimize personalized therapy.
Weige Tan, Gehao Liang, Xinhua Xie, Wenguo Jiang, Luyuan Tan, Andrew J. Sanders, Zihao Liu, Yun Ling, Wenjing Zhong, Zhenluan Tian, Wanyi Lin, Chang Gong
1 hour 5 minutes ago
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