A Study to Evaluate Fractionated Radiation Therapy Utilizing GRID Therapy for Locally-advanced Bulky Tumors. quantification of plasma epstein-barr virus DNA in patients with advanced nasopharyngeal carcinoma. doi: 10.1080/2162402X.2019.1581530, 34. A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane cen Merlino DJ, Johnson JM, Tuluc M, Gargano S, Stapp R, Harshyne L Jr., et al. Uppaluri R, Lee NY, Westra W, Cohen EEW, Haddad RI, Temam S, et al. 2014;14:31723. The landmark VA Larynx study compared IC (cisplatin and fluorouracil) followed by RT versus total laryngectomy followed by RT in advanced laryngeal cancer (22). It has become clear that neoadjuvant immunotherapy, especially checkpoint inhibitors, are safe and have shown signals of clinical efficacy in HNSCC. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. Note, there are institution specific protocols where induction chemotherapy prior to surgery is still used for larger tumors to achieve more rapid control (21). Intriguing findings from this study reported discordant responses between primary tumor and regional metastatic lymph nodes (NCT03238365) (65). strategies for preserving the quality of life during and after treatment. Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. Mandal R, enbabaolu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. The expression level of PD-L1 in the tumor does not necessarily correlate withthe response to CPIs. Beitler J, et al. 2014;370(12):110110. Patients with high-TMB have more effective clinical responses with improved survival in lung, bladder, and head and neck cancer patients (47, 48). Spotlight on landmark oncology trials: the latest evidence and novel New treatment destroys head and neck cancer tumours in trial Updated results of a phase II neoadjuvant pembrolizumab trial prior to surgery followed by adjuvant concurrent pembrolizumab and radiation along with cisplatin for clinically high-risk (T3/4 stage and/or 2+ LNs) HPV-negative HNSCC patients (NCT02641093) were recently presented (74). 2010;11:218. doi: 10.1016/S1470-2045(10)70017-6, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Clin Cancer Res (2020) 26(3):67989. Induction Chemotherapy in Advanced Head and Neck Tumors. With the advent of novel oral agents that are well tolerated and highly efficacious, the therapeutic landscape of CLL underwent radical changes [31]. JCI Insight (2016) 1(17):e89829. Contact: Elizabeth Akoth, 240-858-3154. HNSCC shows a relatively high tumor-mutational burden (TMB) (16) and immune infiltration (17), consistent with a potential to achieve therapeutic efficacy from cancer immunotherapy. Notably, any pTR after neoadjuvant pembrolizumab correlated with baseline tumor PD-L1, immune infiltration, and IFN- activity, but not TMB. A meta-analysis which examined the results of clinical trials including Checkmate 141, KEYNOTE-012, KEYNOTE-055 showed that HPV infection status was associated with the response rate to anti-PD-1 treatment independently of PD-L1 expression and TMB in HNSCC (45). Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. CAS Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. J Clin Oncol (2015) 33(8):83645. 2023 BioMed Central Ltd unless otherwise stated. Abstract CT075. RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. doi: 10.1056/NEJM199106133242402, 23. 2017;15:57. The landmark phase III trials in high-grade serous ovarian cancer are testing PARP inhibitors as maintenance therapy after response to platinum-based therapy in relapsed disease. In the KEYNOTE-048 phase III trial, significant survival benefit of pembrolizumab for patients was seen with PD-L1 expression 1% and 20% by CPS (14). In this trial, primary endpoints are rate of major pathological response (10% tumor cells in resected primary and lymph nodes on central review) and event-free survival (EFS). Median PFS was 9.5months in the fulvestrant plus palbociclib group and 4.6months in the fulvestrant plus placebo group with a hazard ratio of 0.46, which was highly statistically significant. Sci Rep (2019) 9(1):13404. doi: 10.1038/s41598-019-49771-0, 46. In conclusion, the RESONATE-2 trial demonstrates that ibrutinib is a new important player in the treatment of elderly unfit patients and in those with high-risk disease. PubMedGoogle Scholar. Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al. doi: 10.4155/fso.15.88, 44. In conclusion, we provided here an overview of the history of neoadjuvant immunotherapies in HNSCC starting with chemotherapy extending to exciting frontiers using immunotherapy. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. 2016;375(19):184555. Although neither baseline CD8+ T cell infiltration status nor PD-L1 expression level correlated with overall response, there was a trend in which greater CD8+ T cells infiltrated patients tended to show MPR. In addition, as other checkpoints are testing, further improvements in pathologic responses and clinical outcomes are expected. Expert Rev Hematol. N Engl J Med. J Clin Oncol. J Clin Oncol (2017) 35(14):15429. In the KEYNOTE-055 phase II trial, the response rate to pembrolizumab was 22% for p16 positive patients and 16% for p16 negative patients (44). doi: 10.1016/S1470-2045(13)70011-1, 20. HE, SM and PR contributed equally to drafting, editing and revision of the manuscript. We also highlight selected and recent practice-changing trials in chronic lymphocytic leukaemia as well as breast and gynaecological cancers, and review the advances offered by the development of novel clinical trial designs. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomized trial, and relation between cetuximab-induced rash and survival. PDF Spotlight on landmark oncology trials: the latest evidence and novel 2016;34(8):78693. Uppaluri R, Chernock R, Mansour M, Jackson R, Rich J, Pipkorn P, et al. The effects of checkpoint inhibitors are mainly derived from reinvigoration and activation of tumor-oriented antigen-specific T cells (15). SM does not have any conflict of interest to disclose. For example, radiological tumor examination is widely used in Response Evaluation Criteria In Solid Tumors (RECIST) after organ preservation therapy including radiotherapy and chemotherapy. Twenty-nine HNSCC patients with locoregionally recurrent disease who were surgically resectable were treated with neoadjuvant nivolumab and lirilumab, an anti-KIR blocking antibody focused on NK cell checkpoint inhibition. evaluated the role of measuring plasma EBV DNA and is included. statement and She is an Editorial Board Member for BMC Medicine. Lancet Oncol. J Clin Oncol. doi: 10.1056/NEJMoa032641, 8. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). J Cancer Res Clin Oncol (1997) 123(9):46977. Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. Similarly, the Keynote-040 randomized phase III trial compared the efficacy of pembrolizumab (anti-PD-1) versus SOC (methotrexate, docetaxel, or cetuximab) (13) for R/M HNSCC patients after platinum-containing treatment. doi: 10.1016/0360-3016(92)90642-U, 4. Understanding Patterns of Pathologic Response Following Neoadjuvant Immunotherapy for Solid Tumors. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. doi: 10.1200/JCO.2019.37.15_suppl.TPS6090, 77. These results clearly demonstrate the superiority of dual HER2-directed therapy. doi: 10.1016/S0140-6736(19)32591-7, 15. There are three major potential benefits to use CPIs in the neoadjuvant setting. 2015;373:5219. Schffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha SY, Blay JY, Hohenberger P, DAdamo D, Guo M, Chmielowski B, Le Cesne A, Demetri GD, Patel SR. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Cookies policy. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Although only 15-20% of patients benefit, immunotherapies have been approved and widely used for recurrent and metastatic HNSCC. Histological Assessment. However, a potential setback is represented by the control arm since chlorambucil is no longer regarded an adequate therapy in CLL [26]. Readers are encouraged to refer to the full manuscript of these trials for a greater understanding. Pathologic responses were evaluated in 34 patients (17 HPV+ and 17 HPV-negative). He has published more than 180 peer-reviewed papers primarily in the field of CLL and CLL-related disorders. 2016;32(18):28668. Forastiere A, et al. Recent landmark trials in HER2-positive breast cancer include those using dual HER2-targeted therapy pertuzumab and trastuzumab with docetaxel. Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, et al. Landmark Trials | Division of Cancer Prevention These data show that two doses or the longer neoadjuvant window (3 versus 6 weeks) resulted in an increased rate of pTR but did not increase the total proportion of patients with pTR. 2016;128(24):27703. Leidner R, Crittenden M, Young K, Xiao H, Wu Y, Couey MA, et al. In the era of precision cancer medicine, innovative trial designs will also require the matching of novel drugs with putative targets. CAS Weissferdt A, Pataer A, Vaporciyan AA, Correa AM, Sepesi B, Moran CA, et al. Lancet Oncol. Provided by the Springer Nature SharedIt content-sharing initiative. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. Front Immunol (2021) 12:645170. doi: 10.3389/fimmu.2021.645170, 47. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Part of Springer Nature. Head and Neck Cancer Clinical Trials and Research Topalian SL, Taube JM, Pardoll DM. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Notably, the treatments were safe and 16/26 patients (61.5%) had pathologic responses (>20%) and 8/26 (31%) of patients experienced complete response (72). Based on KEYNOTE-048, the FDA approved use of pembrolizumab monotherapy in the first-line for R/M HNSCC with CPS 1 and pembrolizumab plus platinum-based chemotherapy for those with CPS<1 R/M HNSCC (31). McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. A study by Lin et al. Pignon J-P, et al. Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Dhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. Mol Cancer Ther (2017) 16(11):2598608. The era of precision medicine has led to significant developments in the therapy of advanced soft tissue sarcomas (STS), breast cancer, ovarian cancer and haematological neoplasms, among others. N Engl J Med. N Engl J Med. Clin Lung Cancer (2020) 21(4):3418. He is also Coordinator of the Polish Clinical GIST Registry, and a reviewer for several international scientific journals, as well as a member of the Editorial Board of Annals of Surgical Oncology, BMC Medicine and European Journal of Surgical Oncology. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. doi: 10.1200/JCO.2003.06.146, 27. Xiong Y, Neskey DM, Horton JD, Paulos CM, Knochelmann HM, Armeson KE, et al. In: Landmark Trials in Oncology. Friedman J, Moore EC, Zolkind P, Robbins Y, Clavijo PE, Sun L, et al. Despite optimal local treatment, approximately 50% of adult patients with localised STS develop distant metastases and die of metastatic disease. Another meta-analysis showed that HPV positive HNSCC patients display significant improved outcomes with PD-1/PD-L1 axis blockage treatment compared to HPV negative HNSCC patients (46). Google Scholar. Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The phase II Checkpoint Inhibitors Assessment in Oropharynx cancer (CIAO) trial (NCT03144778) tested a combination of durvalumab (1500 mg) and tremelimumab (75 mg) in the neoadjuvant setting, preceding SOC (surgery with or without radiation therapy) (70). A special article collection in BMC Medicine, Spotlight on landmark oncology trials, features articles from invited experts on recent clinical practice-changing trials. Landmark Trials in Selected Head and Neck Cancers HPV-related oropharyngeal HNSCC shows better survival related to HPV-negative oropharyngeal HNSCCs. Status: Open - Recruiting. We classified pTR into pTR-0 (10%), pTR-1 (10-49%), and pTR-2 (50%) (54). First, neoadjuvant immunotherapies will enhance systemic T cell responses for tumor-specific antigens before surgery (34). With the positive responses in the R/M HNSCC setting, several trials have reported results with neoadjuvant checkpoint immunotherapy prior to surgery (Table1). PubMed Central It is meant to be an educational resource . The premise of neoadjuvant immunotherapy is to use the existing tumor mass as an in-situ source of tumor-specific antigens to enhance systemic immunity via dendritic cell antigen presentation to rejuvenate T cells and priming especially for cytotoxic T cells (34). Results from the CLEOPATRA trial in the metastatic setting of the same treatment have produced remarkable results [25]; the same combination produced a 56.5-month median OS compared with 40.8months achieved with trastuzumab and docetaxel alone, showing an increase of 15.7months to OS in the pertuzumab group. Nature (2014) 515(7528):57781. Science (2011) 333(6046):115760. Lancet. Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Nature (2013) 502(7471):3339. Recent landmark immunotherapy trials - melanoma, Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients With Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck. PR reports personal fees (honoraria for lectures and Advisory Board Member) from Novartis, BMS, Roche, MSD, GSK, Pfizer, and Amgen outside the submitted work. PubMed Sholl LM. RU: editing and supervising the manuscript, tables and figure. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebb C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. The indications for IC are limited to those with significantly advanced disease and may result in a high frequency of severe adverse events. doi: 10.1056/NEJMoa032646, 6. However, translational research did not discover any predictive biomarker subgroups [27] for the palbociclib effect. Key pathological findings after neoadjuvant immunotherapy include 1) keratinous debris, 2) giant cells, histiocytic reaction and 3) tumor necrosis. These data suggest that virus infection status impacts TMB as a biomarker. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. 2014;32:294050. A study by Yamazaki et al. Pignon JP, le Matre A, Maillard E, Bourhis J. Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): An Update on 93 Randomised Trials and 17,346 Patients. Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR, Tsao A, Stewart DJ, Hicks ME, Erasmus J, Gupta S. The BATTLE trial: personalizing therapy for lung cancer.

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