J Natl Compr Canc Netw. Tumors with both PD-L1 and PD-L2 expression responded better than tumors with only PD-L1 expression, indicating that combinatorial scoring may be an attractive approach. 2014;371(3):21323. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. 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. These successes have led to checkpoint blockade therapies being testing in earlier treatment settings. Int J Radiat Oncol Biol Phys. Nat Rev Clin Oncol. JClin Oncol (2018) 36(31):307783. J Clin Oncol (2021) 39(15_suppl):60088. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. HE has provided clinical advice at Advisory Board meetings for Roche, Pfizer and Astra Zeneca. Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer? Spotlight on landmark oncology trials: the latest evidence and novel J Clin Oncol. N Engl J Med (2003) 349(22):20918. RU serves on an advisory board for Merck, Inc. Nat Med (2021) 27(2):3019. The immunological responses were analyzed using blood before and after treatment. He is the current Head of the Department of Soft Tissue/Bone Sarcoma and Melanoma, the Plenipotentiary Director of Institute for Clinical Trials at the Maria Sklodowska-Curie Memorial Cancer Center as well as the President of the Scientific Council of Maria Sklodowska-Curie Memorial Cancer Center. Xu Y, Zhu G, Maroun CA, Wu IXY, Huang D, Seiwert TY, et al. Frezza AM, Stacchiotti S, Gronchi A. Google Scholar. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). A meta-analysis by Pignon et al. Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. Ruffin AT, Cillo AR, Tabib T, Liu A, Onkar S, Kunning SR, et al. Landmark Trials in Selected Head and Neck Cancers. Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). BMC Med. ID: NCT03803774. Head Neck (2005) 27(10):84350. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Furthermore, the one-year relapse rate in high-risk patients was 16.7%, which was lower than historical data. Google Scholar. Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. The IMCISION study (NCT03003637) presented at ESMO 2020 is examining neoadjuvant nivolumab and ipilimumab for stage II-IVa HNSCC patients. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A, POPLAR Study Group. J Radiat Oncol Biol Phys. Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). doi: 10.1002/cncr.33471, 22. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. doi: 10.1038/nature14129, 11. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. J Clin Oncol (2019) 37(15_suppl):25755. The indications for IC are limited to those with significantly advanced disease and may result in a high frequency of severe adverse events. In Checkmate-141 phase III trial, there wasno correlation of survival extension and PD-L1 expression on tumors (PD-L1+ >1%, 5% and 10%) (12). The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. doi: 10.1200/JCO.2011.38.8595, 60. He has participated in several investigator-driven trials in melanoma and sarcoma. We and others have focused on HPV-negative, locally advanced disease patients with high-risk pathologic features (positive surgical margins or extra-nodal extension). No use, distribution or reproduction is permitted which does not comply with these terms. The goal of cytotoxic chemotherapy in this setting is to directly attack tumor cells to reduce tumor burden. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. The effects of checkpoint inhibitors are mainly derived from reinvigoration and activation of tumor-oriented antigen-specific T cells (15). IC resulted in larynx preservation but did not contribute to improved survival. In addition, CD8+ T cells with lymphocyte-activation gene 3 (LAG-3) or T cell immunoglobulin domain and mucin domain-3 (TIM-3) co-expression with PD-1 was higher among non-responders (52). A special article collection in BMC Medicine, Spotlight on landmark oncology trials, features articles from invited experts on recent clinical practice-changing trials. The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. Herbst RS, Baas P, Kim DW, Felip E, Prez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro Jr G, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. doi: 10.1200/JCO.2016.70.1524, 45. 2023 BioMed Central Ltd unless otherwise stated. Primary Chemotherapy in Resectable Oral Cavity Squamous Cell Cancer: A Randomized Controlled Trial. Eur J Cancer. N Engl J Med. In phase 3 trials, ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, showed efficacy over traditional salvage therapeutic options in patients with relapsed or refractory CLL [32]. Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect. Combenefit: an interactive platform for the analysis and visualization of drug combinations. 2016;375(1):1122. All authors read and approved the final manuscript. 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. Patients received two cycles of drug therapy. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Szturz P, Vermorken JB. In addition, the dynamic expression change of PD-L1 with tumor heterogeneity also makes it difficult to evaluate the expression of PD-L1 (41). 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. Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial. Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. New treatment destroys head and neck cancer tumours in trial Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazz D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. The FOCUS 4 trial in metastatic colorectal cancer uses group-sequential multi-arm, multi-stage methodology [46] to achieve similar matching of novel therapy and biomarker groups. doi: 10.1136/jitc-2021-002485, 67. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Biomarkers in Head and Neck Cancer an Update - PubMed Head and Neck Cancer | NEJM The pTR rate is calculated as the area of regions 1-3/(1-3)+area of any remaining tumor. 2014;370(12):110110. 2016;375(19):184555. SM does not have any conflict of interest to disclose. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. These studies with previously untreated tumors may enable establishment of predictive biomarkers to select appropriate patients and also define mechanistic pathways. N Engl J Med. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, high-risk HNSCC patients (3, 4). RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefbvre JL, Greiner RH, et al. J Natl Compr Canc Netw. Lancet (2019) 394(10212):191528. The November 3, 2021 "Clinical Trial Endpoint Development" (12pm - 5:00 pm ET) will address Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) Finally, biomarker and minimal residual disease assessment may ultimately be useful to guide the targeted agent or regimen of choice and the duration of treatment [38]. Signatures of Mutational Processes in Human Cancer. - 50.249.249.18. Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. NIRT did impact healing of wounds that all ultimately resolved. This was followed by BATTLE-2 [42], testing combination treatments in the same disease. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. Landmark Trials. J Clin Oncol (2021) 39(15_suppl):60533. J Clin Oncol (2003) 21(2):32733. Xiong Y, Neskey DM, Horton JD, Paulos CM, Knochelmann HM, Armeson KE, et al. In addition to the adjuvant chemotherapy, platinum-based neoadjuvant chemotherapy (induction chemotherapy; IC) has also been examined to augment subsequent (chemo)radiotherapy or surgery. 2014;32:273543. Nature (2014) 515(7528):57781. (NCT03021993), in which a total of 10 locally advanced OSCC patients were treated with neoadjuvant nivolumab (3 mg/kg on days 1, 14 and 28) (69). However, the proportion of CD4+ T cells were decreased while the rate of CD4+FoxP3+ regulatory T cells was increased with treatment. N Engl J Med. Pathological Response After Neoadjuvant Chemotherapy in Resectable Non-Small-Cell Lung Cancers: Proposal for the Use of Major Pathological Response as a Surrogate Endpoint. PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. Park JW, Liu MC, Yee D, Yau C, van t Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA, I-SPY 2 Investigators. Article N Engl J Med. California Privacy Statement, doi: 10.1200/JCO.2017.75.1644, 57. Redman JM, Gibney GT, Atkins MB. Mutational Landscape and Significance Across 12 Major Cancer Types. A study by Yamazaki et al. 2016;53:12534. HPV-related oropharyngeal HNSCC shows better survival related to HPV-negative oropharyngeal HNSCCs. Additionally, R/M HNSCC patients treated with pembrolizumab plus chemotherapy had significantly prolonged OS compared to the cetuximab with chemotherapy group. Geoffrois L, Martin L, De Raucourt D, Sun XS, Tao Y, Maingon P, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. 1998;16:13107. 2016;375(1):2334. Privacy Adjuvant Chemotherapy for Resectable Squamous Cell Carcinomas of the Head and Neck: Report on Intergroup Study 0034. The VA Larynx study, RTOG 91-11, a study by Bonner et al. Lancet. Nat Med (2020) 26(4):56676. Gutirrez Caldern V, Cantero Gonzlez A, Glvez Carvajal L, Aguilar Lizarralde Y, Rueda Domnguez A. Neoadjuvant Immunotherapy in Resectable Head and Neck Cancer: Oral Cavity Carcinoma as a Potential Research Model. Immunotherapy in head and neck cancer: aiming at EXTREME precision. Pembrolizumab Versus Methotrexate, Docetaxel, or Cetuximab for Recurrent or Metastatic Head-and-Neck Squamous Cell Carcinoma (KEYNOTE-040): A Randomised, Open-Label, Phase 3 Study. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. Lancet Oncol (2014) 15(1):e4250. Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, et al. Pathological Response and Survival With Neoadjuvant Therapy in Melanoma: A Pooled Analysis From the International Neoadjuvant Melanoma Consortium (INMC). Recently we reported an extension of this study with an additional 29 HNSCC patients treated with two cycles of neoadjuvant pembrolizumab. The Checkmate 358 phase I/II study examined clinical safety and efficacy of two doses of neoadjuvant nivolumab in HPV positive or negative HNSCC (NCT02488759) (67). that compared radiation therapy plus or minus cetuximab, and RTOG 0522 are included as landmark trials in the development of an organ preservation approach for the management of locoregionally advanced disease. doi: 10.1158/1078-0432.CCR-20-1695, 55. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). Rochester, Minn., Jacksonville, Fla. Development of Tumor Mutation Burden as an Immunotherapy Biomarker: Utility for the Oncology Clinic. Positive results from this study established the application of anti-PD-1 for R/M HNSCC treatment, and proved the existence of actionable, efficient anti-cancer immunity in HNSCC tumors. In addition to ongoing Phase II trials, KEYNOTE-689 is an international phase III study (NCT03765918) where surgically resectable locally advanced HPV-negative HNSCC patients are randomized to receive upfront surgery with SOC adjuvant treatment or neoadjuvant pembrolizumab (two doses) followed by surgery and SOC adjuvant treatment with pembrolizumab (76). Although a total of 21 patients experienced AEs, including grade 3/4 AEs in 2 (N) and 5 (N+I) patients, there were no surgical delays. In: Landmark Trials in Oncology. evaluated the role of measuring plasma EBV DNA and is included. Di Veroli et al. An important consideration in neoadjuvant immunotherapy approaches is clinical safety as the possibility of lifelong autoimmune complications in the definitive surgical setting needs to be weighed carefully. 2016;387(10028):162937. Furthermore, although distinct tumor-suppressor mutations including TP53, CDKN2A, NOTCH have been reported in HNSCC, cancer-promoting driver oncogenic mutations have not been detected (911), which makes it challenging to apply molecular targeted therapies. JCI Insight (2018) 3(4):113. N Engl J Med. 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. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. However, some immunological therapeutic effects can induce pseudo-progression or development of new lesions because of infiltration of immune cells into the primary tumor or lymph nodes, which makes it difficult to evaluate the treatment efficacy only with radiographical information (57). Considering the high-frequency of severe adverse events and lack of significant effect OS prolongation with induction chemotherapy, neoadjuvant immunotherapy thus represents an attractive option for advanced HNSCC treatment. In addition, as other checkpoints are testing, further improvements in pathologic responses and clinical outcomes are expected. Lancet Oncol (2013) 14(3):25764. doi: 10.1016/S0140-6736(18)31999-8, 14. Clin Cancer Res (2017) 23(12):315867. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. 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. Google Scholar. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. doi: 10.1056/NEJMoa1602252, 13. Friedman J, Moore EC, Zolkind P, Robbins Y, Clavijo PE, Sun L, et al. Differences in T-Cell Infiltrates and Survival Between HPV+ and HPV- Oropharyngeal Squamous Cell Carcinoma. PD-L1 expression in tumor cells and immune cells remains the most widely used biomarker in HNSCC and other cancers (40, 41). Combinations of chlorambucil with an anti-CD2O monoclonal antibody, such as rituximab, ofatumumab or obinutuzumab, are now the standard of care in patients unsuited to receive fludarabine, cyclophosphamide and rituximab [34,35,36]. Table1 Completed neoadjuvant immunotherapy clinical trials. Table2 Ongoing neoadjuvant immunotherapy clinical trials. Saad ED, Paoletti X, Burzykowski T, Buyse M. Precision medicine needs randomized clinical trials. Despite these efforts to improve clinical prognosis, the five-year survival rate of locally advanced stage III/IV HNSCC patients is still sub-optimal [53% in postoperative CCRT treated patients (7)], and half of advanced patients show recurrence within three years (8). 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. The current results of anti-PD-1 therapy with pembrolizumab or nivolumab monotherapy in melanoma indicated a median overall survival (OS) of approximately 2years, but the combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) was shown to be superior in terms of progression-free survival (PFS) and OS (Table1) [11,12,13,14,15]. doi: 10.1200/JCO.2014.58.6412, 3. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. CAS Article N Engl J Med. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. In the era of precision cancer medicine, innovative trial designs will also require the matching of novel drugs with putative targets. Rutkowski P, Kozak K. News from the melanoma sessions of the European Cancer Congress 2017. A limited number of drugs have shown activity in advanced disease, and due to the rarity of these tumours, clinical trials in sarcoma include many subtypes and are mainly initiated by academic research groups. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. These data indicate that PD-L1 expression on tumor cells is not a perfect biomarker to predict the clinical outcome. Cohen EEW, Soulires D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. A study by Lin et al. As described by ASO Editor-in-Chief, Kelly M. McMasters, MD, PhD, "The Landmark Series is designed to trace the origins of current multidisciplinary therapy for each type of solid tumor, and demonstrate the logical progression of clinical trials and other key evidence. 14 Articles, This article is part of the Research Topic, Rationale of Neoadjuvant Immunotherapy for HNSCC, Patient Selection for Neoadjuvant Immunotherapy, Biomarker Candidates for Neoadjuvant Immunotherapy, Pathologic Response Criteria for Neoadjuvant Immunotherapy, Clinical Studies of Neoadjuvant Immunotherapy for HNSCC, Immune Related Adverse Events in Neoadjuvant Immunotherapy Treated Patients, Creative Commons Attribution License (CC BY). A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. From a clinical standpoint, he is actively involved in the management and treatment of patients with hematological malignancies and, particularly, those suffering from lymphoproliferative disorders. These data together support further investigation in Phase III trials such as KEYNOTE-689 to define evidence for survival benefit and identify high-risk patients who may benefit from this approach. 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). In a landmark trial, a . examined neoadjuvant 1) nivolumab (N) or 2) nivolumab plus ipilimumab (N+I) in untreated 29 oral cavity cancer patients in a phase II trial (eligible for T2 or node positive) (NCT02919683) (68). 1. Understanding Patterns of Pathologic Response Following Neoadjuvant Immunotherapy for Solid Tumors. This diverse patient selection has been used primarily to define a signal of activity. Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson 3rd WE, Daniels GA, DiMaio D, Ernstoff M, Fields RC, Fleming MD, Gonzalez R, Guild V, Halpern AC, Hodi Jr FS, Joseph RW, Lange JR, Martini MC, Materin MA, Olszanski AJ, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Torres-Roca JF, Trisal V, Urist MM, McMillian N, Melanoma EA. Landmark Trials in Selected Head and Neck Cancers - ResearchGate Abstract CT075. Recent landmark trials in HER2-positive breast cancer include those using dual HER2-targeted therapy pertuzumab and trastuzumab with docetaxel. doi: 10.4155/fso.15.88, 44. RU: editing and supervising the manuscript, tables and figure. Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. doi: 10.1200/EDBK_280687, Keywords: head and neck squamous cell carcinoma, neoadjuvant immunotherapy, clinical trial, biomarker, pathological tumor response, Citation: Shibata H, Saito S and Uppaluri R (2021) Immunotherapy for Head and Neck Cancer: A Paradigm Shift From Induction Chemotherapy to Neoadjuvant Immunotherapy. Clinical Trial Endpoint Development for Locally Advanced Head and Neck Lancet. PR reports personal fees (honoraria for lectures and Advisory Board Member) from Novartis, BMS, Roche, MSD, GSK, Pfizer, and Amgen outside the submitted work. Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. Article BMC Med. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. 2015;372(26):252132. doi: 10.1056/NEJMoa1305133, 30. Remon J, Besse B, Soria JC. J Clin Oncol (2017) 35(14):15429. Epidemiology. 2012;366(15):138292. J Clin Oncol (2012) 30(15):1796804. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
Part Of Fortune Transits,
Coroners Court Listings,
Articles L