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Watanabe T, Oka H, Nagashima K, Nishi H, Kumai Y, Iijima H, Okami K, Shimizu Y, Kano S, Ito K, Yamazaki T, Takahashi H, Oridate N, Yokota T, Koyama T, Kiyota N, Sato Y, Takahashi S, Kato K, Kadowaki S, Honma Y. Clinical outcomes of recurrent or metastatic head and neck cancer after failure of platinum and nivolumab: a multicenter retrospective study. Oncologist 2025; 30:oyaf018. [PMID: 40163686 PMCID: PMC11957247 DOI: 10.1093/oncolo/oyaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 12/20/2024] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Platinum and anti-PD-1 antibodies are the front-line systemic therapy for recurrent or metastatic head and neck squamous cell carcinoma (RM-HNSCC). However, limited data are available on clinical outcomes and appropriate regimens for patients with RM-HNSCC following treatment failure with these agents. PATIENTS AND METHODS We retrospectively analyzed the clinical data of patients with RM-HNSCC from 10 Japanese institutions in whom platinum and nivolumab treatment failed. RESULTS Of the 480 patients included in the study, 236 were treated with the best supportive care and had a median overall survival of 3.1 months. The remaining 244 patients received salvage-line chemotherapy, which was paclitaxel + cetuximab in 72 (30%), paclitaxel or docetaxel in 89 (36%), and tegafur/gimeracil/oteracil in 48 (20%); the respective objective response rates were 54.9%, 27.9%, and 25.5%, with median progression-free survival of 5.4 months and median overall survival of 13.0 months. Multivariable analysis identified disease stabilization or response on prior nivolumab and paclitaxel + cetuximab as salvage-line chemotherapy to be associated with encouraging progression-free and overall survival. CONCLUSION This study sheds light on clinical outcomes and prognostic factors in patients with RM-HNSCC after failure of platinum and anti-PD-1 antibody therapy. The findings provide essential baseline data for future therapeutic development in salvage-line settings.
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Affiliation(s)
- Takane Watanabe
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, 104-0045, 5-1-1, Tsukiji, Chuo-ku, Tokyo, Japan
| | - Hiroki Oka
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, 104-0045, 5-1-1, Tsukiji, Chuo-ku, Tokyo, Japan
| | - Kengo Nagashima
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo 160-0016, Japan
| | - Hideaki Nishi
- Otorhinolaryngology/Head and Neck Surgery, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Yoshihiko Kumai
- Otorhinolaryngology/Head and Neck Surgery, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Hiroaki Iijima
- Otorhinolaryngology/Head and Neck Surgery, Tokai University Hospital, Isehara 259-1193, Japan
| | - Kenji Okami
- Otorhinolaryngology/Head and Neck Surgery, Tokai University Hospital, Isehara 259-1193, Japan
| | - Yasushi Shimizu
- Department of Medical Oncology, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Satoshi Kano
- Otorhinolaryngology, Head and Neck Surgery, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Kazue Ito
- Head and Neck Oncology, Miyagi Cancer Center, Natori 981-1239, Japan
| | - Tomoko Yamazaki
- Head and Neck Oncology, Miyagi Cancer Center, Natori 981-1239, Japan
| | - Hideaki Takahashi
- Otorhinolaryngology, Yokohama City University Hospital, Yokohama 236-0004, Japan
| | - Nobuhiko Oridate
- Otorhinolaryngology, Yokohama City University Hospital, Yokohama 236-0004, Japan
| | - Tomoya Yokota
- Gastrointestinal Oncology Department, Shizuoka Cancer Center, Shizuoka 411-8777, Japan
| | - Taiji Koyama
- Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe 650-0017, Japan
| | - Naomi Kiyota
- Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe 650-0017, Japan
| | - Yasuyoshi Sato
- Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Shunji Takahashi
- Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Kyoko Kato
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Yoshitaka Honma
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, 104-0045, 5-1-1, Tsukiji, Chuo-ku, Tokyo, Japan
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Fasano M, Pirozzi M, Vitale P, Damiano V, Ronzino G, Farese S, Carfora V, Ciccarelli G, Di Giovanni I, Facchini S, Cennamo G, Caraglia M, Ciardiello F, Addeo R. Paclitaxel for second-line treatment of squamous cell carcinoma of the head and neck: A multicenter retrospective Italian study. World J Clin Oncol 2024; 15:1468-1480. [PMID: 39720642 PMCID: PMC11514375 DOI: 10.5306/wjco.v15.i12.1468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 08/02/2024] [Accepted: 08/26/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND Squamous cell carcinoma of the head and neck (SCCHN) accounts for 3% of all malignant tumors in Italy. Immune checkpoint inhibitors combined with chemotherapy is first-line treatment for SCCHN; however, second-line treatment options are limited. Taxanes are widely used for combination therapy of SCCHN, as clinical trials have shown their efficacy in patients with this disease, particularly in patients with prior therapy. AIM To perform a multicenter retrospective study on the efficacy and safety of weekly paclitaxel for SCCHN. METHODS All patients were previously treated with at least one systemic therapy regimen, which included platinum-based therapy in the vast majority. No patient received prior immunotherapy. RESULTS Median progression-free survival (mPFS) was 3.4 months and median overall survival (mOS) was 6.5 months. Subgroup analysis was performed according to three principal prognostic factors: Smoking, alcohol consumption, and body mass index. Analysis demonstrated reduced survival, both mOS and mPFS, in the unfavorable prognostic groups, with the biggest deltas observed in mOS. CONCLUSION Weekly paclitaxel provided favorable survival and disease control rates, with low severe adverse events. Paclitaxel is a safe and valid therapeutic option for patients with SCCHN who received prior therapy.
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Affiliation(s)
- Morena Fasano
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80120, Italy
| | - Mario Pirozzi
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80120, Italy
| | - Pasquale Vitale
- Oncology Operative Unit, Hospital of Frattamaggiore, ASL Napoli 2 Nord, Naples 80027, Italy
| | - Vincenzo Damiano
- Department of Integrated Activities of Oncoematology, Diagnostica Per Immagini E Morfologica E Medicina Legale, Medical Oncology Unit, University Federico II, Naples 80120, Italy
| | | | - Stefano Farese
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80120, Italy
| | - Vincenzo Carfora
- Department of Radiation Oncology, ‘San Pio’ Hospital, Benevento 82100, Italy
| | | | - Ilaria Di Giovanni
- Oncology Operative Unit, Hospital of Frattamaggiore, ASL Napoli 2 Nord, Naples 80027, Italy
| | - Sergio Facchini
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80120, Italy
| | - Gregorio Cennamo
- Oncology Operative Unit, Hospital of Frattamaggiore, ASL Napoli 2 Nord, Naples 80027, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy
- Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Contrada Camporeale, Ariano Irpino, Avellino 83031, Italy
| | - Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80120, Italy
| | - Raffaele Addeo
- Oncology Operative Unit, Hospital of Frattamaggiore, ASL Napoli 2 Nord, Naples 80027, Italy
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Sakuma K, Kii T, Machida T, Kikuchi Y, Yoda M, Toya S, Tanaka A. Efficacy of Paclitaxel and Cetuximab in Recurrent/Metastatic Oral Cancer Cases Following Superselective Intraarterial Chemoradiotherapy: A Retrospective Cohort Study. CANCER DIAGNOSIS & PROGNOSIS 2024; 4:769-774. [PMID: 39502613 PMCID: PMC11534039 DOI: 10.21873/cdp.10394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 11/08/2024]
Abstract
Background/Aim The therapeutic efficacy of the paclitaxel (PTX) + cetuximab (Cmab) combination regimen was investigated in patients with recurrence or metastasis after superselective intraarterial chemoradiotherapy (SSIACRT) for oral cancer, and the safety was retrospectively examined. Patients and Methods All enrolled patients with advanced oral cancer or who had refused surgery over 10 years from December 2012 to December 2022 underwent SSIACRT for 6 to 9 weeks [cisplatin (CDDP): total 160-630 mg/m2 and radiotherapy: total 50-70 Gy]. Nine cases (tongue cancer, maxillary gingival cancer, and mandibular gingival cancer; three cases each) were subjected to PTX + Cmab therapy. Recurrence or metastases were observed within six months after the onset of treatment, complicating the conduct of salvage surgery. Cmab (first dose: 400 mg/m2 and second and following doses: 250 mg/m2) and PTX (80 mg/m2) were administered weekly. Results The overall response rate was 44.4% (four of nine cases), and the disease control rate was 88.9% (eight of nine cases), whereas the median progression-free survival was seven months, and the overall survival was 11 months. Grade 3-4 adverse events were neutropenia in 33.3% of the cases, leukopenia in 55.6%, anemia in 22.2%, and acneiform skin rash in 22.2%. Based on the above, PTX + Cmab therapy for recurrent and metastatic cases after SSIACRT had comparable results to other second-line modalities and enabled to cope with the side effects of myelosuppression. Conclusion PTX + Cmab therapy may be an effective treatment mode for recurrent or metastatic head and neck cancer resistant to CDDP after SSIACRT treatment.
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Affiliation(s)
- Kaname Sakuma
- Department of Oral and Maxillofacial Surgery, The Nippon Dental University School of Life Dentistry at Niigata, Niigata, Japan
| | - Tomoyuki Kii
- Department of Oral and Maxillofacial Surgery, The Nippon Dental University School of Life Dentistry at Niigata, Niigata, Japan
| | - Toko Machida
- Department of Oral and Maxillofacial Surgery, The Nippon Dental University School of Life Dentistry at Niigata, Niigata, Japan
| | - Yosuke Kikuchi
- Oral and Maxillofacial Surgery, The Nippon Dental University in Niigata Hospital, Niigata, Japan
| | - Masaki Yoda
- Oral and Maxillofacial Surgery, The Nippon Dental University in Niigata Hospital, Niigata, Japan
| | - Shuji Toya
- Oral and Maxillofacial Surgery, The Nippon Dental University in Niigata Hospital, Niigata, Japan
| | - Akira Tanaka
- Department of Oral and Maxillofacial Surgery, The Nippon Dental University School of Life Dentistry at Niigata, Niigata, Japan
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Liu L, Pan Y, Ye L, Liang C, Mou X, Dong X, Cai Y. Optical functional nanomaterials for cancer photoimmunotherapy. Coord Chem Rev 2024; 517:216006. [DOI: 10.1016/j.ccr.2024.216006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Jiang J, Wu B, Sun Y, Xiang J, Shen C, He X, Ying H, Xia Z. Anlotinib reversed resistance to PD-1 inhibitors in recurrent and metastatic head and neck cancers: a real-world retrospective study. Cancer Immunol Immunother 2024; 73:199. [PMID: 39105897 PMCID: PMC11303650 DOI: 10.1007/s00262-024-03784-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/17/2024] [Indexed: 08/07/2024]
Abstract
Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6-66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3-4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.
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Affiliation(s)
- Jianyun Jiang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Bin Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Radiology, Fudan University Shanghai Cancer Centre, Shanghai, 200032, China
| | - Ying Sun
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jun Xiang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Chunying Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Xiayun He
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Hongmei Ying
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China.
| | - Zuguang Xia
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.
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Reyes-Gibby CC, Qdaisat A, Ferrarotto R, Fadol A, Bischof JJ, Coyne CJ, Lipe DN, Hanna EY, Shete S, Abe JI, Yeung SCJ. Cardiovascular events after cancer immunotherapy as oncologic emergencies: Analyses of 610 head and neck cancer patients treated with immune checkpoint inhibitors. Head Neck 2024; 46:627-635. [PMID: 38151809 PMCID: PMC10922978 DOI: 10.1002/hed.27604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/24/2023] [Accepted: 12/06/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Cardio-oncology and emergency medicine are closely collaborative, as many cardiac events in cancer patients require evaluation and treatment in the emergency department (ED). Immune checkpoint inhibitors (ICIs) have become a common treatment for patients with head and neck cancer (HNC). However, the immune-related adverse events (irAEs) from ICIs can be clinically significant. METHODS We reviewed and analyzed cardiovascular diagnoses among HNC patients who received ICI during the period April 1, 2016-December 31, 2020 in a large tertiary cancer center. Demographics, clinical and cancer-related data were abstracted, and billing databases were queried for cardiovascular disease (CVD)-related diagnosis using International Classification of Disease-version10 (ICD-10) codes. We recorded receipt of care at the ED as one of the outcome variables. RESULTS A total of 610 HNC patients with a median follow-up time of 12.3 months (median, interquartile range = 5-30 months) comprised our study cohort. Overall, 25.7% of patients had pre-existing CVD prior to ICI treatment. Of the remaining 453 patients without pre-existing CVD, 31.5% (n = 143) had at least one CVD-related diagnosis after ICI initiation. Tachyarrhythmias (91 new events) was the most frequent CVD-related diagnosis after ICI. The time to diagnosis of myocarditis from initiation of ICI occurred the earliest (median 2.5 months, 1.5-6.8 months), followed by myocardial infarction (3.7, 0.5-9), cardiomyopathy (4.5, 1.6-7.3), and tachyarrhythmias (4.9, 1.2-11.4). Patients with myocarditis and tachyarrhythmias mainly presented to the ED for care. CONCLUSION The use of ICI in HNC is still expanding and the spectrum of delayed manifestation of ICI-induced cardiovascular toxicities is yet to be fully defined in HNC survivors.
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Affiliation(s)
- Cielito C. Reyes-Gibby
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aiham Qdaisat
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anecita Fadol
- Department of Nursing, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason J. Bischof
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Christopher J. Coyne
- Department of Emergency Medicine, University of California San Diego, San Diego, California, USA
| | - Demis N. Lipe
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ehab Y Hanna
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sanjay Shete
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sai-Ching J. Yeung
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Horichi Y, Matsui H, Yamamura Y, Iwae S. Platinum resistance and sensitivity in recurrent/metastatic head and neck squamous cell carcinoma. Auris Nasus Larynx 2024; 51:132-137. [PMID: 37331819 DOI: 10.1016/j.anl.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/06/2023] [Accepted: 05/25/2023] [Indexed: 06/20/2023]
Abstract
OBJECTIVE For patients with recurrent/metastatic head and neck squamous cell carcinoma (R/MHNSCC), platinum-free interval (PFI)-based differences in the effectiveness of rechallenge with platinum-based chemotherapy (PBCT) remain unknown. We aimed to evaluate the difference in platinum sensitivity based on PFI in R/MHNSCC. METHODS We retrospectively examined 80 patients with R/MHNSCC who underwent PBCT between 2001 and 2020. Treatment efficacy was compared between patients with prior PBCT for treatment of recurrence/metastasis or concurrent chemoradiotherapy during radical treatment (rechallenge group) and those without (control group). Patients with prior PBCT (rechallenge group) were stratified by PFI. PFI was defined as the period from the last dosing date with the previous platinum agent to rechallenge with PBCT. RESULTS Of 80 patients, 55 had been with prior PBCT (rechallenge group) and 25 had been without prior PBCT (control group). The rechallenge group was divided into three groups: PFI <6 months (10), PFI 6-11 months (17), and PFI ≥12 months (28). The PFI <6-month group had shorter overall survival (p=0.047, the log-rank test) and lower disease control rate (p=0.02, Fisher's exact test) than the control group. The PFI 6-11- and ≥12-month group outcomes did not significantly differ from those of the control group. CONCLUSIONS Patients with PFI <6 months tend to have a poorer prognosis after rechallenge with PBCT than patients without prior PBCT, suggesting that PFI 6 months may be considered as a threshold of platinum resistance and rechallenge with PBCT may be a valid option in PFI ≥6 months.
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Affiliation(s)
- Yuto Horichi
- Department of Head and Neck Surgery, Hyogo Cancer Center, 13-70 Kitaohji, Akashi, Hyogo 673-8558, Japan.
| | - Hidetoshi Matsui
- Department of Head and Neck Surgery, Hyogo Cancer Center, 13-70 Kitaohji, Akashi, Hyogo 673-8558, Japan
| | - Yuta Yamamura
- Department of Head and Neck Surgery, Hyogo Cancer Center, 13-70 Kitaohji, Akashi, Hyogo 673-8558, Japan
| | - Shigemichi Iwae
- Department of Head and Neck Surgery, Hyogo Cancer Center, 13-70 Kitaohji, Akashi, Hyogo 673-8558, Japan
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Sakai A, Ebisumoto K, Iijima H, Yamauchi M, Teramura T, Yamazaki A, Watanabe T, Inagi T, Maki D, Okami K. Chemotherapy following immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma: clinical effectiveness and influence of inflammatory and nutritional factors. Discov Oncol 2023; 14:158. [PMID: 37642856 PMCID: PMC10465419 DOI: 10.1007/s12672-023-00774-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/18/2023] [Indexed: 08/31/2023] Open
Abstract
OBJECTIVE This study aimed to evaluate the clinical effectiveness of chemotherapy following immune checkpoint inhibitors (ICI). The association between inflammatory and nutritional factors and prognosis has also been investigated. METHODS We retrospectively reviewed the medical records of recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) patients who received chemotherapy following ICI therapy. The response rate and survival after chemotherapy, and nutritional and inflammatory factors, were examined. RESULTS The ICI before chemotherapy was nivolumab in 36 patients (70.6%) and pembrolizumab in 15 patients (29.4%). The chemotherapy regimens consisted of PTX in 32 patients (62.7%), PTX + Cmab in 9 (17.6%), and S1 in 10 (19.6%). The median overall survival (OS) was 20 months (95% CI 12-25), the estimated 12-month OS rate was 63.3%, the median progression-free survival (PFS) was 5 months (CI 4-6), and the 12-month PFS estimate was 8.9%. Univariate analysis significantly correlated Neutrophil-to-Lymphocyte Ratio (NLR), platelet-to-lymphocyte ratio (PLR), controlling nutritional status score (CONUT), and prognostic nutrition index (PNI) with OS and PFS. Additionally, these factors were significantly correlated with OS and PFS in the log-rank tests. CONCLUSIONS Chemotherapy following ICI is highly effective. There were no significant differences in the chemotherapy regimens. Inflammatory and nutritional factors may associate with patient prognosis after chemotherapy.
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Affiliation(s)
- Akihiro Sakai
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Koji Ebisumoto
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Hiroaki Iijima
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Mayu Yamauchi
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Takanobu Teramura
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Aritomo Yamazaki
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Takane Watanabe
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Toshihide Inagi
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Daisuke Maki
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Kenji Okami
- Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan
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Sharon S, Daher-Ghanem N, Zaid D, Gough MJ, Kravchenko-Balasha N. The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer. FRONTIERS IN ORAL HEALTH 2023; 4:1180869. [PMID: 37496754 PMCID: PMC10366623 DOI: 10.3389/froh.2023.1180869] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/27/2023] [Indexed: 07/28/2023] Open
Abstract
Although treatment modalities for head and neck cancer have evolved considerably over the past decades, survival rates have plateaued. The treatment options remained limited to definitive surgery, surgery followed by fractionated radiotherapy with optional chemotherapy, and a definitive combination of fractionated radiotherapy and chemotherapy. Lately, immunotherapy has been introduced as the fourth modality of treatment, mainly administered as a single checkpoint inhibitor for recurrent or metastatic disease. While other regimens and combinations of immunotherapy and targeted therapy are being tested in clinical trials, adapting the appropriate regimens to patients and predicting their outcomes have yet to reach the clinical setting. Radiotherapy is mainly regarded as a means to target cancer cells while minimizing the unwanted peripheral effect. Radiotherapy regimens and fractionation are designed to serve this purpose, while the systemic effect of radiation on the immune response is rarely considered a factor while designing treatment. To bridge this gap, this review will highlight the effect of radiotherapy on the tumor microenvironment locally, and the immune response systemically. We will review the methodology to identify potential targets for therapy in the tumor microenvironment and the scientific basis for combining targeted therapy and radiotherapy. We will describe a current experience in preclinical models to test these combinations and propose how challenges in this realm may be faced. We will review new players in targeted therapy and their utilization to drive immunogenic response against head and neck cancer. We will outline the factors contributing to head and neck cancer heterogeneity and their effect on the response to radiotherapy. We will review in-silico methods to decipher intertumoral and intratumoral heterogeneity and how these algorithms can predict treatment outcomes. We propose that (a) the sequence of surgery, radiotherapy, chemotherapy, and targeted therapy should be designed not only to annul cancer directly, but to prime the immune response. (b) Fractionation of radiotherapy and the extent of the irradiated field should facilitate systemic immunity to develop. (c) New players in targeted therapy should be evaluated in translational studies toward clinical trials. (d) Head and neck cancer treatment should be personalized according to patients and tumor-specific factors.
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Affiliation(s)
- Shay Sharon
- Department of Oral and Maxillofacial Surgery, Hadassah Medical Center, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Oral and Maxillofacial Surgery, Boston University and Boston Medical Center, Boston, MA, United States
| | - Narmeen Daher-Ghanem
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Deema Zaid
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Michael J. Gough
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Nataly Kravchenko-Balasha
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
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10
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Ettl T, Grube M, Schulz D, Bauer RJ. Checkpoint Inhibitors in Cancer Therapy: Clinical Benefits for Head and Neck Cancers. Cancers (Basel) 2022; 14:4985. [PMID: 36291769 PMCID: PMC9599671 DOI: 10.3390/cancers14204985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/07/2022] [Accepted: 10/08/2022] [Indexed: 11/20/2022] Open
Abstract
Recently, considerable progress has been achieved in cancer immunotherapy. Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages. With a better understanding of cellular responses to immune checkpoint therapies, it will soon be feasible to find targeted compounds which will make personalized medicine practicable. This is a great opportunity, but it also sets tremendous challenges on both the scientific and clinical aspects. Head and neck tumors evade immune surveillance through various mechanisms. They contain fewer lymphocytes (natural killer cells) than normal tissue with an accumulation of immunosuppressive regulatory T cells. Standard therapies for HNSCC, such as surgery, radiation, and chemotherapy, are becoming more advantageous by targeting immune checkpoints and employing combination therapies. The purpose of this review is to provide an overview of the expanded therapeutic options, particularly the combination of immune checkpoint inhibition with various conventional and novel therapeutics for head and neck tumor patients.
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Affiliation(s)
- Tobias Ettl
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Matthias Grube
- Department of Hematology and Oncology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Daniela Schulz
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
- Center for Medical Biotechnology, Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Richard Josef Bauer
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
- Center for Medical Biotechnology, Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
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Oxaliplatin Induces Immunogenic Cell Death in Human and Murine Laryngeal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:3760766. [PMID: 36131787 PMCID: PMC9484908 DOI: 10.1155/2022/3760766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022]
Abstract
Background Cisplatin resistance is observed in patients with laryngeal cancer. The present study was designed to explore the efficacy of oxaliplatin on laryngeal cancer and elucidate the underlying mechanisms. Methods Cell viability was determined by using MTT assays. Cell apoptosis was determined by using annexin V and propidium iodide (PI) staining. Flow cytometry and immunofluorescence were applied to determine the levels of calreticulin (CALR) and DiD (1,1-dioctadecyl-3,3,3,3-tetramethylindodicarbocyanine). Flow cytometry was applied to analyze the levels of CD83, CD86, IFN-γ-producing CD8+ T cells, and CD4+CD25+FoxP3+ Tregs. The levels of adenosine triphosphate (ATP) were determined by using a chemiluminescent ATP kit and cytokines were determined by using specific enzyme-linked immunosorbent assays (ELISAs). The levels of HMGB1 were determined by using Western blot and ELISA, respectively. The xenograft animal model was constructed to evaluate the antitumor effects of oxaliplatin. Results Oxaliplatin inhibited cell growth, promoted cell apoptosis, and induced the levels of CALR, ATP, and high mobility group box protein 1 (HMGB1) in Hep-2 cells. Oxaliplatin-treated Hep-2 cells increased the intensity of DiD and the levels of CD83 and CD86 in dendritic cells (DCs), as well as induced the supernatant IL-6 and TNF-α. Oxaliplatin-treated primary laryngeal cancer cell-pulsed DCs increased the IFN-γ-producing CD8+ T cells and suppressed CD4+CD25+FoxP3+ Tregs. In vivo data showed that oxaliplatin suppressed tumor growth and increased the populations of CD86+CD80+ and CD8+CD45+ cells in the tumor tissues. Conclusion Treatment with oxaliplatin inhibited laryngeal cancer cells by inducing immunogenic cell death.
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12
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Zhao S, An L, Yang X, Wei Z, Zhang H, Wang Y. Identification and validation of the role of c-Myc in head and neck squamous cell carcinoma. Front Oncol 2022; 12:820587. [PMID: 36119473 PMCID: PMC9470836 DOI: 10.3389/fonc.2022.820587] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 08/10/2022] [Indexed: 12/09/2022] Open
Abstract
Background Many studies have shown that c-Myc plays a critical role in tumorigenesis. However, the molecular role of c-Myc in head and neck squamous cell carcinoma (HNSC) remains unclear. Methods Several biological databases, including UALCAN, TIMER2.0, TCGAportal, GEPIA, KM plotter, OncoLnc, LinkedOmics, GSCA, and TCIA, were used to analyze the molecular role of c-Myc in HNSC. The expression levels of c-Myc were validated by real-time PCR (RT–PCR) and Western blot in CAL-27 cells. Results The expression of c-Myc mRNA were significantly increased in HPV-negative HNSC tissues. The expression of c-Myc gene level was correlated with TP53 mutation status. HNSC also showed hypomethylated c-Myc compared with normal tissues. c-Myc was identified as an ominous prognostic factor for HNSC patients and correlated with immune infiltrating levels. Moreover, high c-Myc expression was associated with decreased expression of a series of immune checkpoints, resulting in a dampened immune response. c-Myc potentially mediated IL-17 signaling pathway and Th1 and Th2 cell differentiation. Inhibition of c-Myc expression increased apoptosis of CAL-27 cells. Conclusions These findings suggest a new mechanism of c-Myc in the prognosis of HNSC, implying the potential of c-Myc as a therapeutic target for HNSC patients.
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Affiliation(s)
- Sufeng Zhao
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- *Correspondence: Sufeng Zhao, ; Xudong Yang,
| | - Li An
- Department of Geriatrics, Zhongda Hospital Southeast University, Nanjing, China
| | - Xudong Yang
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- *Correspondence: Sufeng Zhao, ; Xudong Yang,
| | - Zheng Wei
- Department of Pediatric Dentistry, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - He Zhang
- Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yufeng Wang
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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Patients with Pulmonary Metastases from Head and Neck Cancer Benefit from Pulmonary Metastasectomy, A Systematic Review. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58081000. [PMID: 35893115 PMCID: PMC9332790 DOI: 10.3390/medicina58081000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/16/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022]
Abstract
Background and Objectives: The incidence of distant metastases in patients with head and neck cancer (HNC) is approximately 10%. Pulmonary metastases are the most frequent distant location, with an incidence of 70-85%. The standard treatment options are chemo-, immuno- and radiotherapy. Despite a benefit for long-term survival for patients with isolated pulmonary metastases, pulmonary metastasectomy (PM) is not the treatment of choice. Furthermore, many otorhinolaryngologists are not sufficiently familiar with the concept of PM. This work reviews the recent studies of pulmonary metastatic HNC and the results after pulmonary metastasectomy. Materials and Methods: PubMed, Medline, Embase, and the Cochrane library were checked for the case series' of patients undergoing metastasectomy with pulmonary metastases published since 1 January 2000. Results: We included the data of 15 studies of patients undergoing PM. The 5-year survival rates varied from 21% to 59%, with median survival from 10 to 77 months after PM. We could not identify one specific prognostic factor for long-term survival after surgery. However, at least most studies stated that PM should be planned if a complete (R0) resection is possible. Conclusions: PM showed reliable results and is supposedly the treatment of choice for patients with isolated pulmonary metastases. Patients not suitable for surgery may benefit from other non-surgical therapy. Every HNC patient with pulmonary metastases should be discussed in the multidisciplinary tumor board to optimize the therapy and the outcome.
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14
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Poulose JV, Kainickal CT. Immune checkpoint inhibitors in head and neck squamous cell carcinoma: A systematic review of phase-3 clinical trials. World J Clin Oncol 2022; 13:388-411. [PMID: 35662989 PMCID: PMC9153072 DOI: 10.5306/wjco.v13.i5.388] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/03/2021] [Accepted: 05/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field. AIM To evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials. METHODS We searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials. RESULTS Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy. CONCLUSION Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.
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Affiliation(s)
- Jissy Vijo Poulose
- National Fellowship in Palliative Medicine (Training Program), Institute of Palliative Medicine, Calicut 673008, Kerala, India
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15
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Wotman M, Gold B, Takahashi M, Draper L, Posner M. Treatment of Recurrent and Metastatic HPV-Associated Squamous Cell Carcinoma. CURRENT OTORHINOLARYNGOLOGY REPORTS 2022. [DOI: 10.1007/s40136-022-00402-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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16
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Nair V, Auger S, Kochanny S, Howard FM, Ginat D, Pasternak-Wise O, Juloori A, Koshy M, Izumchenko E, Agrawal N, Rosenberg A, Vokes EE, Skandari MR, Pearson AT. Development and Validation of a Decision Analytical Model for Posttreatment Surveillance for Patients With Oropharyngeal Carcinoma. JAMA Netw Open 2022; 5:e227240. [PMID: 35416988 PMCID: PMC9008506 DOI: 10.1001/jamanetworkopen.2022.7240] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IMPORTANCE Clinical practice regarding posttreatment radiologic surveillance for patients with oropharyngeal carcinoma (OPC) is neither adapted to individual patient risk nor fully evidence based. OBJECTIVES To construct a microsimulation model for posttreatment OPC progression and use it to optimize surveillance strategies while accounting for both tumor stage and human papillomavirus (HPV) status. DESIGN, SETTING, AND PARTICIPANTS In this decision analytical modeling study, a Markov model of 3-year posttreatment patient trajectories was created. The training data source was the American College of Surgeon's National Cancer Database from 2010 to 2015. The external validation data set was the 2016 International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S) study. Training data comprised 2159 patients with OPC treated with primary radiotherapy who had known HPV status and disease staging information. Patients with American Joint Committee on Cancer, 7th edition stage III to IVB disease and those with clinical metastases during the time of primary treatment were included. Data were analyzed from August 1 to October 31, 2020. MAIN OUTCOMES AND MEASURES Main outcomes included disease stage and HPV status, specific disease transition probabilities, and latency of surveillance regimens, defined as time between recurrence incidence and disease discovery. RESULTS Training data consisted of 2159 total patients (1708 men [79.1%]; median age, 59.6 years [range, 40-90 years]; 401 with stage III disease, 1415 with stage IVA disease, and 343 with stage IVB disease). Cohorts predominantly had HPV-negative disease (1606 [74.4%]). With model-optimized regimens, recurrent disease was discovered a mean of 0.6 months (95% CI, 0.5-0.8 months) earlier than with a standard surveillance regimen based on current clinical guidelines. Recurrent disease was discovered using the optimized regimens without significant reduction in sensitivity. Compared with strategies based on reimbursement guidelines, the model-optimized regimens found disease a mean of 1.8 months (95% CI, 1.3-2.3 months) earlier. CONCLUSIONS AND RELEVANCE Optimized, risk-stratified surveillance regimens consistently outperformed nonoptimized strategies. These gains were obtained without requiring any additional imaging studies. This approach to risk-stratified surveillance optimization is generalizable to a broad range of tumor types and risk factors.
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Affiliation(s)
- Vivek Nair
- University of Chicago Pritzker School of Medicine, Chicago, Illinois
| | - Samuel Auger
- Department of Surgery, University of Chicago, Chicago, Illinois
| | - Sara Kochanny
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
| | - Frederick M. Howard
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
| | - Daniel Ginat
- Department of Radiology, University of Chicago, Chicago, Illinois
| | | | - Aditya Juloori
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
| | - Matthew Koshy
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
| | - Nishant Agrawal
- Department of Surgery, University of Chicago, Chicago, Illinois
| | - Ari Rosenberg
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
| | - Everett E. Vokes
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
| | - M. Reza Skandari
- Centre for Health Economics and Policy Innovation, Imperial College Business School, Imperial College London, London, United Kingdom
| | - Alexander T. Pearson
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
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OUP accepted manuscript. Eur J Cardiothorac Surg 2022; 62:6529440. [DOI: 10.1093/ejcts/ezac098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/10/2022] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
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Huo XX, Wang SJ, Song H, Li MD, Yu H, Wang M, Gong HX, Qiu XT, Zhu YF, Zhang JY. Roles of Major RNA Adenosine Modifications in Head and Neck Squamous Cell Carcinoma. Front Pharmacol 2021; 12:779779. [PMID: 34899345 PMCID: PMC8657411 DOI: 10.3389/fphar.2021.779779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/09/2021] [Indexed: 11/13/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer malignancy worldwide and is known to have poor prognosis. The pathogenesis behind the development of HNSCC is not fully understood. Modifications on RNA are involved in many pathophysiological processes, such as tumor development and inflammation. Adenosine-related RNA modifications have shown to be linked to cancer and may play a role in cancer occurrence and development. To date, there are at least 170 different chemical RNA modifications that modify coding and non-coding RNAs (ncRNAs). These modifications affect RNA stability and transcription efficiency. In this review, we focus on the current understanding of the four major RNA adenosine modifications (N6-Methyladenosine, N1-Methyladenosine, Alternative Polyadenylation Modification and A-to-I RNA editing) and their potential molecular mechanisms related to HNSCC development and progression. We also touch on how these RNA modifications affect treatment of HNSCCs.
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Affiliation(s)
- Xing-Xing Huo
- Experimental Center of Clinical Research, Scientific Research Department, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Shu-Jie Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Hang Song
- Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Ming-de Li
- Experimental Center of Clinical Research, Scientific Research Department, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Hua Yu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Meng Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Hong-Xiao Gong
- Experimental Center of Clinical Research, Scientific Research Department, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Xiao-Ting Qiu
- Experimental Center of Clinical Research, Scientific Research Department, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Yong-Fu Zhu
- Experimental Center of Clinical Research, Scientific Research Department, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Jian-Ye Zhang
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Immunotherapy Approaches in HPV-Associated Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13235889. [PMID: 34884999 PMCID: PMC8656769 DOI: 10.3390/cancers13235889] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 11/15/2021] [Accepted: 11/20/2021] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.
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de Sousa LG, Ferrarotto R. Pembrolizumab in the first-line treatment of advanced head and neck cancer. Expert Rev Anticancer Ther 2021; 21:1321-1331. [PMID: 34689660 DOI: 10.1080/14737140.2021.1996228] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is associated with dismal prognosis and has limited therapeutic options. PD-1/PD-L1 axis blockade was initially shown to improve outcomes in platinum-refractory HNSCC. More recently, pembrolizumab monotherapy or pembrolizumab combined with chemotherapy resulted in better overall survival than platinum, 5-fluorouracil, and cetuximab (EXTREME regimen) as first-line therapy for R/M HNSCC, establishing a new standard-of-care therapy for this disease. AREAS COVERED We review pembrolizumab in the first-line treatment of R/M HNSCC and summarize the impact of PD-L1 expression, tumor and symptom burden, and patient's performance status on treatment decisions. Future perspectives are summarized. EXPERT OPINION The standard-of-care first-line therapy for R/M HNSCC is pembrolizumab monotherapy for patients with a PD-L1 combined positive score (CPS)≥1 or pembrolizumab combined with platinum and 5-fluorouracil for patients with any PD-L1 status. Addition of chemotherapy to pembrolizumab increases the response rate but also toxicity and is preferred for patients with good performance status and significant tumor and symptom burden. For patients with a PD-L1 CPS <1, the EXTREME regimen should be considered. New strategies combining pembrolizumab with targeted therapies and immune checkpoints inhibitors are being explored to synergize or overcome resistance to anti-PD-1.
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Affiliation(s)
- Luana Guimaraes de Sousa
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas Md Anderson Cancer Center, Houston, Texas, USA
| | - Renata Ferrarotto
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas Md Anderson Cancer Center, Houston, Texas, USA
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Patil VM, Singhai P, Noronha V, Bhattacharjee A, Deodhar J, Salins N, Joshi A, Menon NS, Abhyankar A, Khake A, Dhumal SB, Tambe R, Muckaden MA, Prabhash K. Effect of Early Palliative Care on Quality of Life of Advanced Head and Neck Cancer Patients: A Phase III Trial. J Natl Cancer Inst 2021; 113:1228-1237. [PMID: 33606023 DOI: 10.1093/jnci/djab020] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/30/2020] [Accepted: 02/03/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Early palliative care (EPC) is an important aspect of cancer management but, to our knowledge, has never been evaluated in patients with head and neck cancer. Hence, we performed this study to determine whether the addition of EPC to standard therapy leads to an improvement in the quality of life (QOL), decrease in symptom burden, and improvement in overall survival. METHODS Adult patients with squamous cell carcinoma of the head and neck region planned for palliative systemic therapy were allocated 1:1 to either standard systemic therapy without or with comprehensive EPC service referral. Patients were administered the revised Edmonton Symptom Assessment Scale and the Functional Assessment of Cancer Therapy for head and neck cancer (FACT-H&N) questionnaire at baseline and every 1 month thereafter for 3 months. The primary endpoint was a change in the QOL measured at 3 months after random assignment. All statistical tests were 2-sided. RESULTS Ninety patients were randomly assigned to each arm. There was no statistical difference in the change in the FACT-H&N total score (P = .94), FACT-H&N Trial Outcome Index (P = .95), FACT-general total (P = .84), and Edmonton Symptom Assessment Scale scores at 3 months between the 2 arms. The median overall survival was similar between the 2 arms (hazard ratio for death = 1.01, 95% confidence interval = 0.74 to 1.35). There were 5 in-hospital deaths in both arms (5.6% for both, P = .99). CONCLUSIONS In this phase III study, the integration of EPC in head and neck cancer patients did not lead to an improvement in the QOL or survival.
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Affiliation(s)
- Vijay Maruti Patil
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Pankaj Singhai
- Department of Palliative Medicine, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Atanu Bhattacharjee
- Section of Biostatistics, Centre for Cancer Epidemiology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Jayita Deodhar
- Department of Palliative Medicine, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Naveen Salins
- Department of Palliative Medicine, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Nandini Sharrel Menon
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Anuja Abhyankar
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Ashwini Khake
- Department of Palliative Medicine, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sachin Babanrao Dhumal
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rupali Tambe
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Mary Ann Muckaden
- Department of Palliative Medicine, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
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22
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Shaikh H, Karivedu V, Wise-Draper TM. Managing Recurrent Metastatic Head and Neck Cancer. Hematol Oncol Clin North Am 2021; 35:1009-1020. [PMID: 34226077 DOI: 10.1016/j.hoc.2021.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) treatment is often associated with high morbidity especially in the recurrent and/or metastatic (R/M) setting, limiting effective treatment options. Local disease control is important. Therefore, local therapies including reirradiation and salvage surgery, either alone or in combination with systemic treatment, may be used for selected patients with R/M HNSCC. Although chemotherapy and targeted agents have modest efficacy in HNSCC, the advent of immunotherapy has revolutionized the treatment paradigm of R/M HNSCC. Multiple trials have resulted in the past 5 years advocating for its use alone or in combination with chemotherapy.
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Affiliation(s)
- Hira Shaikh
- Division of Hematology/Oncology, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0562, USA
| | - Vidhya Karivedu
- Division of Medical Oncology, The Ohio State University, 1335 Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210, USA
| | - Trisha M Wise-Draper
- Division of Hematology/Oncology, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0562, USA.
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23
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De Keukeleire SJ, Vermassen T, De Meulenaere A, Deron P, Huvenne W, Duprez F, Creytens D, Van Dorpe J, Rottey S, Ferdinande L. Tumour infiltrating lymphocytes in oropharyngeal carcinoma: prognostic value and evaluation of a standardised method. Pathology 2021; 53:836-843. [PMID: 34217516 DOI: 10.1016/j.pathol.2021.03.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/12/2021] [Accepted: 03/22/2021] [Indexed: 01/04/2023]
Abstract
Tumour infiltrating lymphocytes (TILs) have been described as a biomarker for the host immune response against the tumour with prognostic properties. The International Immuno-Oncology Biomarkers Working Group (IBWG) proposed a standardised method for quantifying TILs in solid tumours to improve consistent and reproducible scoring. In this study, the methodology was tested in a retrospective population of oropharyngeal squamous cell carcinoma (OPSCC). TIL quantification was performed on 92 OPSCC samples (2004-2013) by four independent observers as described by the IBWG. Interobserver variability was assessed and results were correlated with clinicopathological variables and survival. TIL evaluation turned out to be challenging in OPSCC due to heterogeneity of TILs distribution, presence of pre-existing lymphoid tissue, surface ulceration or erosion and insufficient amount of intertumoural stroma in biopsies. Nonetheless, interobserver variability proved to be good to excellent. High stromal TILs (TILstr) and intratumoural TILs (TILtum) were both correlated to favourable overall survival and multivariate analysis showed TILstr to be the sole independent prognostic factor in OPSCC. The IBWG-proposed TIL quantification method is feasible and reproducible in OPSCC and provides valuable prognostic information regarding clinicopathological characteristics and overall survival. The use of this standardised methodology may facilitate implementation of TILs scoring as a prognostic biomarker in OPSCC.
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Affiliation(s)
| | - Tijl Vermassen
- Ghent University Hospital, Department of Medical Oncology, Ghent, Belgium; Ghent University Hospital, Drug Research Unit Ghent, Ghent, Belgium
| | | | - Philippe Deron
- Ghent University Hospital, Department of Head and Neck Surgery, Ghent, Belgium
| | - Wouter Huvenne
- Ghent University Hospital, Department of Head and Neck Surgery, Ghent, Belgium
| | - Fréderic Duprez
- Ghent University Hospital, Department of Radiation Oncology, Ghent, Belgium
| | - David Creytens
- Ghent University Hospital, Department of Pathology, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Jo Van Dorpe
- Ghent University Hospital, Department of Pathology, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Sylvie Rottey
- Ghent University Hospital, Department of Medical Oncology, Ghent, Belgium; Ghent University Hospital, Drug Research Unit Ghent, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Liesbeth Ferdinande
- Ghent University Hospital, Department of Pathology, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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24
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Arribas L, Plana M, Taberna M, Sospedra M, Vilariño N, Oliva M, Pallarés N, González Tampán AR, Del Rio LM, Mesia R, Baracos V. Predictive Value of Skeletal Muscle Mass in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients Treated With Immune Checkpoint Inhibitors. Front Oncol 2021; 11:699668. [PMID: 34249760 PMCID: PMC8267860 DOI: 10.3389/fonc.2021.699668] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/08/2021] [Indexed: 12/26/2022] Open
Abstract
Background Reduced muscle mass has been associated with increased treatment complications in several tumor types. We evaluated the impact of skeletal muscle index (SMI) on prognosis and immune-related adverse events (IrAEs) in a cohort of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoints inhibitors (ICI). Methods A single-institutional, retrospective study was performed including 61 consecutive patients of R/M HNSCC diagnosed between July 2015 and December 2018. SMI was quantified using a CT scan at L3 to evaluate body composition. Median baseline SMI was used to dichotomize patients in low and high SMI. Kaplan-Meier estimations were used to detect overall survival (OS) and progression-free survival (PFS). Toxicity was recorded using Common Terminology Criteria for Adverse Event v4.3. Results Patients were 52 men (85.2%) with mean of age 57.7 years (SD 9.62), mainly oral cavity (n = 21; 34.4%). Low SMI was an independent factor for OS in the univariate (HR, 2.06; 95% CI, 1.14–3.73, p = 0.017) and multivariate Cox analyses (HR, 2.99; 95% CI, 1.29–6.94; p = 0.011). PFS was also reduced in patients with low SMI (PFS HR, 1.84; 95% CI, 1.08–3.12; p = 0.025). IrAEs occurred in 29 (47.5%) patients. There was no association between low SMI and IrAEs at any grade (OR, 0.56; 95% CI, 0.20–1.54; p = 0.261). However, grades 3 to 4 IrAEs were developed in seven patients of whom three had low SMI. Conclusions Low SMI before ICI treatment in R/M HNSCC patients had a negative impact on OS and PFS. Further prospective research is needed to confirm the role of body composition as a predictive biomarker in ICI treatment.
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Affiliation(s)
- Lorena Arribas
- Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Head and Neck Cancer Unit, Bellvitge University Hospital, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,University of Barcelona, Barcelona, Spain
| | - Maria Plana
- Head and Neck Cancer Unit, Bellvitge University Hospital, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Miren Taberna
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Head and Neck Cancer Unit, Bellvitge University Hospital, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Sospedra
- Unitat de Nutrició Clínica i Dietètica, Hospital Universitari Germans Trias i Pujol (HUGTiP), Barcelona, Spain
| | - Noelia Vilariño
- Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Marc Oliva
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Head and Neck Cancer Unit, Bellvitge University Hospital, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Natalia Pallarés
- Unitat de Bioestadística (UBiDi), Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ana Regina González Tampán
- Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Head and Neck Cancer Unit, Bellvitge University Hospital, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
| | | | - Ricard Mesia
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Head and Neck Cancer Unit, Bellvitge University Hospital, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona, B-ARGO group, Barcelona, Spain
| | - Vickie Baracos
- Division of Palliative Care Medicine, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
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25
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Tahara M, Okano S, Enokida T, Ueda Y, Fujisawa T, Shinozaki T, Tomioka T, Okano W, Biel MA, Ishida K, Hayashi R. A phase I, single-center, open-label study of RM-1929 photoimmunotherapy in Japanese patients with recurrent head and neck squamous cell carcinoma. Int J Clin Oncol 2021; 26:1812-1821. [PMID: 34165660 PMCID: PMC8449763 DOI: 10.1007/s10147-021-01960-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/03/2021] [Indexed: 12/09/2022]
Abstract
Background To determine the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of a single cycle of RM-1929 photoimmunotherapy, an anti-EGFR antibody cetuximab conjugated with a light-activatable dye (IRDye®700DX), in Japanese patients with recurrent head and neck squamous cell carcinoma (rHNSCC).
Methods Patients received a single fixed dose (640 mg/m2) of RM-1929 and a fixed light treatment dose (50 J/cm2 for superficial illumination; 100 J/cm fiber diffuser length for interstitial illumination). Safety, tumor response (modified RECIST v1.1 by central radiology review), pharmacokinetics, and immunogenicity were evaluated.
Results Three Japanese patients were enrolled who had failed ≥ 3 prior lines of therapy including radiation, chemotherapy, cetuximab, and immunotherapy. Target lesions were: submental lesion; right superficial cervical node lesion and oropharynx lesion; and external auditory canal lesion. All patients experienced ≥ 1 treatment-emergent adverse event (TEAE), but none were considered dose-limiting. TEAEs were mild to moderate in severity except for one grade 3 application-site pain, which was transient, resolved without sequelae within 24 h, and did not affect study treatment administration. Thirteen of 17 TEAEs reported were possibly or probably related to study treatment. Three patient reports of application-site pain and localized edema were deemed probably related to study treatment. Objective response was observed in two patients (both partial responses). The third patient had disease progression. RM-1929 concentrations and pharmacokinetic parameters were similar in all patients. No patients tested positive for anti-drug antibodies.
Conclusions RM-1929 photoimmunotherapy showed a manageable safety profile in rHNSCC. Tumor response in these heavily pre-treated patients was clinically meaningful and warrants further investigation. Clinical trial registration The trial was registered with the Japanese registry of clinical trials as jRCT2031200133. Supplementary Information The online version contains supplementary material available at 10.1007/s10147-021-01960-6.
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Affiliation(s)
- Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| | - Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Tomohiro Enokida
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yuri Ueda
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takao Fujisawa
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takeshi Shinozaki
- Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Toshifumi Tomioka
- Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Wataru Okano
- Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Merrill A Biel
- Clinical Development, Rakuten Medical Inc., 900 Concar Drive, San Mateo, CA, 94402, USA
| | - Kosuke Ishida
- Clinical Development, Rakuten Medical Japan, K.K., Futako Tamagawa Rise Office, 2-21-1, Tamagawa, Setagaya-ku, Tokyo, Japan
| | - Ryuichi Hayashi
- Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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26
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Hayman TJ, Bhatia AK, Jethwa KR, Young MR, Park HS. Combinations of immunotherapy and radiation therapy in head and neck squamous cell carcinoma: a narrative review. Transl Cancer Res 2021; 10:2571-2585. [PMID: 35116571 PMCID: PMC8798834 DOI: 10.21037/tcr-20-2096] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 07/23/2020] [Indexed: 12/24/2022]
Abstract
Radiation therapy and systemic therapy are the primary non-surgical treatment modalities for head and neck squamous cell carcinoma (HNSCC). Despite advances in our biologic understanding of this disease and the development of novel therapeutics, treatment resistance remains a significant problem. It has become increasingly evident that the innate and adaptive immune systems play a significant role in the modulation of anti-tumor responses to traditional cancer-directed therapies. By inducing DNA damage and cell death, radiation therapy appears to activate both innate and adaptive immune responses. Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) also have yielded promising results, particularly in the recurrent/metastatic setting. In this review, we will discuss the rationale for combining radiotherapy with immunotherapy to harness the immunomodulatory effects of radiation therapy on HNSCC, as well as biomarkers for immune response. We will also review recent preclinical and clinical data exploring these combinations in various contexts, including recurrent/metastatic and locally advanced disease. Among those with locally advanced HNSCC, we will discuss clinical trials employing immunotherapy either concurrently with radiation therapy or as maintenance following chemoradiation in both the definitive and postoperative settings, with or without the use of cisplatin-based or non-cisplatin-based chemotherapy.
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Affiliation(s)
- Thomas J. Hayman
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
| | - Aarti K. Bhatia
- Section of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Krishan R. Jethwa
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
| | - Melissa R. Young
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
| | - Henry S. Park
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
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27
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Okada T, Okamoto I, Sato H, Ito T, Miyake K, Tsukahara K. Efficacy and Safety of Paclitaxel Combined With Cetuximab for Head and Neck Squamous Cell Carcinoma. In Vivo 2021; 35:1253-1259. [PMID: 33622928 PMCID: PMC8045122 DOI: 10.21873/invivo.12376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM For recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), popular regimens containing platinum-based anticancer agents and immune checkpoint inhibitors are impractical for platinum-intolerant patients. Herein, the efficacy and safety of paclitaxel and cetuximab combination therapy in R/M SCCHN were evaluated. PATIENTS AND METHODS In this retrospective study, paclitaxel (80 mg/m2) and cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) were administered in 28-day cycles on days 1, 8, and 15. RESULTS Thirty-eight patients were treated. The overall response and disease control rates of first-line therapy were 43% and 79%, respectively, while those of second-line and later therapies were 20% and 90%, respectively. The median progression-free and overall survival were 5.3 and 12.5 months, respectively. All adverse events were manageable, including grade 3/4 neutropenia and anaemia affecting 8-13% of patients. CONCLUSION Paclitaxel and cetuximab combination therapy may be suitable for treating R/M SCCHN.
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Affiliation(s)
- Takuro Okada
- Department of Otorhinolaryngology and Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Isaku Okamoto
- Department of Otorhinolaryngology and Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Hiroki Sato
- Department of Otorhinolaryngology and Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Tatsuya Ito
- Department of Otorhinolaryngology and Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Keitaro Miyake
- Department of Otorhinolaryngology and Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kiyoaki Tsukahara
- Department of Otorhinolaryngology and Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
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28
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Nör F, Nör C, Bento LW, Zhang Z, Bretz WA, Nör JE. Propolis reduces the stemness of head and neck squamous cell carcinoma. Arch Oral Biol 2021; 125:105087. [PMID: 33639480 DOI: 10.1016/j.archoralbio.2021.105087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To evaluate the effect of Brazilian propolis on head and neck cancer stem cells in vitro. METHODS Head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-17B and UM-SCC-74A), human keratinocytes (HK), and primary human dermal microvascular endothelial cells (HDMEC) were treated with 0.5, 5.0, or 50 μg/mL green, brown or red Brazilian propolis or vehicle control for 24, 36, and 72 h. Cell viability was evaluated by Sulforhodamine B assay. Western blots evaluated expression of cancer stem cell (CSC) markers (i.e. ALDH, CD44, Oct-4, Bmi-1) and flow cytometry was performed to determine the impact of propolis in the fraction of CSC, defined as ALDHhighCD44high cells. RESULTS propolis significantly reduced cell viability of HNSCC and HDMEC cells, but not HK. Notably, red propolis caused a significant reduction in the percentage of CSC, reduced the number of orospheres, and downregulated the expression of stem cell markers. CONCLUSIONS Collectively, our data demonstrate an anti-CSC effect of propolis, and suggest that propolis (i.e. red propolis) might be beneficial for patients with head and neck cancer.
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Affiliation(s)
- Felipe Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of Oral Pathology, Radiology & Medicine, University of Iowa College of Dentistry, Iowa City, IA, USA.
| | - Carolina Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada
| | - Letícia W Bento
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Zhaocheng Zhang
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | | | - Jacques E Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA
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29
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Green SE, McCusker MG, Mehra R. Emerging immune checkpoint inhibitors for the treatment of head and neck cancers. Expert Opin Emerg Drugs 2020; 25:501-514. [PMID: 33196319 DOI: 10.1080/14728214.2020.1852215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Introduction: The benefits of immune checkpoint inhibitors (ICIs) in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have been demonstrated through multiple studies to improve overall survival (OS) with decreased side effects when compared to the standard of care (SOC) treatment regimens in place for decades, leading to the approval of two ICIs, nivolumab and pembrolizumab. There has been a subsequent influx in the development of novel immunotherapy agents for the treatment of HNSCC. Areas covered: Data for anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies in treatment of R/M HNSCC will be reviewed. Emerging immune checkpoint inhibitors as well as combined therapies in HNSCC will be discussed. The role of predictive biomarkers, HPV-status, PD-L1 expression, and challenges related to treating patients with ICIs will be summarized. Expert opinion: A shift toward ICIs as SOC for the treatment of R/M HNSCC will continue as emerging immune checkpoints and combination therapies are evaluated. Response rates are variable in this patient population underlying the importance of identifying predictive biomarkers to aid in patient selection for ICI treatment.
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Affiliation(s)
- Sarah E Green
- University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center , Baltimore, MD, USA
| | - Michael G McCusker
- University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center , Baltimore, MD, USA
| | - Ranee Mehra
- University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center , Baltimore, MD, USA
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30
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Lee YG, Chang H, Keam B, Chun SH, Park J, Park KU, Shin SH, An HJ, Lee KE, Lee KW, Kim HR, Kim SB, Ahn MJ, Hwang IG. Outcomes and Biomarkers of Immune Checkpoint Inhibitor Therapy in Patients with Refractory Head and Neck Squamous Cell Carcinoma: KCSG HN18-12. Cancer Res Treat 2020; 53:671-677. [PMID: 33285051 PMCID: PMC8291197 DOI: 10.4143/crt.2020.824] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 12/04/2020] [Indexed: 12/31/2022] Open
Abstract
Purpose This study was conducted to determine the effectiveness of immune checkpoint inhibitors (ICIs) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum-containing chemotherapy. We also identified clinical biomarkers which may be predictive of patient prognosis. Materials and Methods We analyzed 125 patients with R/M HNSCC who received ICIs, retrospectively. Overall response rate (ORR) was the primary study outcome. Overall survival (OS) and progression-free survival (PFS) were the secondary study outcomes. Results The patients received anti–programmed cell death protein-1 (PD-1) (n=73, 58%), anti–programmed death-ligand 1 (PD-L1) (n=24, 19%), or a combination of anti–PD-1/PD-L1 and anti–cytotoxic T-lymphocyte antigen 4 (n=28, 22%). The median age was 57 years (range, 37 to 87). The location of the primary tumor was in the oral cavity in 28% of the cases, followed by oropharynx (27%), hypopharynx (20%), and larynx (12%). The ORR was 15% (19/125). With 12.3 months of median follow-up, median PFS was 2.7 months. Median OS was 10.8 months. A neutrophil-to-lymphocyte ratio (NLR) > 4 was significantly associated with poor response to ICIs (odds ratio, 0.30; p=0.022). A sum of the target lesions > 40 mm (hazard ratio [HR], 1.53; p=0.046] and a NLR > 4 (HR, 1.75; p=0.009) were considered to be predictive markers of short PFS. A poor performance status (HR, 4.79; p < 0.001), a sum of target lesions > 40 mm (HR, 1.93; p=0.025), and an NLR > 4 (HR, 3.36; p < 0.001) were the significant predictors for poor survival. Conclusion ICIs exhibited favorable antitumor activity in R/M HNSCC. Clinically, our findings can be used to recognize patients benefit from receiving ICI.
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Affiliation(s)
- Yun-Gyoo Lee
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Chang
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Sang Hoon Chun
- Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Jihyun Park
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Keon Uk Park
- Department of Hemato-Oncology, Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Seong Hoon Shin
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Ho Jung An
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyoung Eun Lee
- Department of Hematology and Oncology, Ewha Womans University Hospital, Seoul, Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Ryun Kim
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Sung-Bae Kim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Myung-Ju Ahn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - In Gyu Hwang
- Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
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Rajan S, Kumar V, Akhtar N, Gupta S, Chaturvedi A. Metronomic chemotherapy for scheduling oral cancer surgery during the COVID-19 pandemic. Indian J Cancer 2020; 57:481-484. [PMID: 33078758 DOI: 10.4103/ijc.ijc_553_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Worldwide, hospitals are facing problems in managing cancer patients during the ongoing COVID-19 pandemic. Given the immense cancer burden of oral cancer in India, scheduling surgeries are becoming increasingly difficult. Upfront surgeries are recommended for curative treatment of oral cancers and postponing them raises the fear of progression. Metronomic chemotherapy can be considered during the waiting period given its potential oncological benefits and ease of administration without much toxicity.
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Affiliation(s)
- Shiv Rajan
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Vijay Kumar
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Naseem Akhtar
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Sameer Gupta
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Arun Chaturvedi
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
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Seliger B, Massa C, Yang B, Bethmann D, Kappler M, Eckert AW, Wickenhauser C. Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2020; 21:ijms21197032. [PMID: 32987799 PMCID: PMC7582858 DOI: 10.3390/ijms21197032] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/25/2022] Open
Abstract
Immunotherapy has been recently approved for the treatment of relapsed and metastatic human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC). However, the response of patients is limited and the overall survival remains short with a low rate of long-term survivors. There exists growing evidence that complex and partially redundant immune escape mechanisms play an important role for the low efficacy of immunotherapies in this disease. These are caused by diverse complex processes characterized by (i) changes in the expression of immune modulatory molecules in tumor cells, (ii) alterations in the frequency, composition and clonal expansion of immune cell subpopulations in the tumor microenvironment and peripheral blood leading to reduced innate and adaptive immune responses, (iii) impaired homing of immune cells to the tumor site as well as (iv) the presence of immune suppressive soluble and physical factors in the tumor microenvironment. We here summarize the major immune escape strategies of HNSCC lesions, highlight pathways, and molecular targets that help to attenuate HNSCC-induced immune tolerance, affect the selection and success of immunotherapeutic approaches to overcome resistance to immunotherapy by targeting immune escape mechanisms and thus improve the HNSCC patients’ outcome.
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Affiliation(s)
- Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (C.M.); (B.Y.)
- Fraunhofer Institute of Cell Therapy and Immunology, 04103 Leipzig, Germany
- Correspondence:
| | - Chiara Massa
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (C.M.); (B.Y.)
| | - Bo Yang
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (C.M.); (B.Y.)
| | - Daniel Bethmann
- Institute of Pathology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (D.B.); (C.W.)
| | - Matthias Kappler
- Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (M.K.); (A.W.E.)
| | - Alexander Walter Eckert
- Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (M.K.); (A.W.E.)
- Klinik für Mund-, Kiefer- und Plastische Gesichtschirurgie, Universitätsklinik der Paracelsus Medizinischen Privatuniversität; 90471 Nürnberg, Germany
| | - Claudia Wickenhauser
- Institute of Pathology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (D.B.); (C.W.)
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Patil V, Noronha V, Dhumal SB, Joshi A, Menon N, Bhattacharjee A, Kulkarni S, Ankathi SK, Mahajan A, Sable N, Nawale K, Bhelekar A, Mukadam S, Chandrasekharan A, Das S, Vallathol D, D'Souza H, Kumar A, Agrawal A, Khaddar S, Rathnasamy N, Shenoy R, Kashyap L, Rai RK, Abraham G, Saha S, Majumdar S, Karuvandan N, Simha V, Babu V, Elamarthi P, Rajpurohit A, Kumar KAP, Srikanth A, Ravind R, Banavali S, Prabhash K. Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial. Lancet Glob Health 2020; 8:e1213-e1222. [PMID: 32827483 DOI: 10.1016/s2214-109x(20)30275-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/20/2020] [Accepted: 05/27/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings. METHODS We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m2 methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m2 intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed. FINDINGS Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6-12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 [95% CI 0·615-0·97, p=0·026]). In the per-protocol analysis population, median overall survival was 7·5 months (4·7-12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 [95% CI 0·616-0·974, p=0·029]). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01). INTERPRETATION Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible. FUNDING Tata Memorial Center Research Administration Council. TRANSLATIONS For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section.
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Affiliation(s)
- Vijay Patil
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Sachin Babanrao Dhumal
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Atanu Bhattacharjee
- Section of Biostatistics, Centre for Cancer Epidemiology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Suyash Kulkarni
- Department of Radiodiagnosis, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Suman Kumar Ankathi
- Department of Radiodiagnosis, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Abhishek Mahajan
- Department of Radiodiagnosis, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Nilesh Sable
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Kavita Nawale
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Arti Bhelekar
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Sadaf Mukadam
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Arun Chandrasekharan
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Sudeep Das
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Dilip Vallathol
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Hollis D'Souza
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Amit Kumar
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Amit Agrawal
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Satvik Khaddar
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Narmadha Rathnasamy
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Ramnath Shenoy
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Lakhan Kashyap
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Rahul Kumar Rai
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - George Abraham
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Saswata Saha
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Swaratika Majumdar
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Naveen Karuvandan
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Vijai Simha
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Vasu Babu
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Prahalad Elamarthi
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Annu Rajpurohit
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | | | - Anne Srikanth
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Rahul Ravind
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Shripad Banavali
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India.
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Park JH, Chun SH, Lee YG, Chang H, Lee KW, Kim HR, Shin SH, An HJ, Lee KE, Hwang IG, Ahn MJ, Kim SB, Keam B. Hyperprogressive disease and its clinical impact in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with immune-checkpoint inhibitors: Korean cancer study group HN 18-12. J Cancer Res Clin Oncol 2020; 146:3359-3369. [PMID: 32671504 DOI: 10.1007/s00432-020-03316-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Although immune-checkpoint inhibitors (ICIs) have emerged as therapeutic options for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), concerns have been raised on exceptional acceleration of tumor growth during treatment with ICIs, a condition described as hyperprogressive disease (HPD). This study examined the incidence, potential predictors, and clinical impact of HPD in R/M-HNSCC. METHODS We retrospectively collected data of patients with R/M-HNSCC treated with ICIs between January 2013 and June 2018 from 11 medical centers in Korea. HPD was defined as tumor growth kinetics ratio (TGKr) > 2, which was calculated by comparing TGK on ICIs with that before treatment with ICIs. RESULTS Of 125 patients, 68 (54.4%) obtained progressive disease as their best responses (progressors). HPD was identified in 18 (26.5% of progressors, 14.4% of total) patients. Relatively younger age, primary tumor of oral cavity, and previous locoregional irradiation were significant predictors of HPD according to multivariable analysis (p = 0.040, 0.027, and 0.015, respectively). Compared to patients without HPD, patients with HPD had significantly shorter median progression-free survival (PFS) (1.2 vs. 3.4 months, p < 0.001) and overall survival (OS) (3.4 vs. 10.7 months, p = 0.047). However, interestingly, HPD did not significantly affect the therapeutic benefit of post-ICIs chemotherapy. CONCLUSIONS Younger patients with oral cavity cancer or prior treatment with locoregional radiotherapy could be regarded potential risk groups for HPD in patients with R/M-HNSCC treated with ICIs. Although HPD could consistently predict poorer survival outcomes, patients who experienced HPD with ICIs should not be excluded from the subsequent salvage chemotherapy treatments.
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Affiliation(s)
- Ji Hyun Park
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Chun
- Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Yun-Gyoo Lee
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyun Chang
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Republic of Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hye Ryun Kim
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seong Hoon Shin
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Ho Jung An
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Kyoung Eun Lee
- Department of Hematology and Oncology, Ewha Woman's University Hospital, Seoul, Republic of Korea
| | - In Gyu Hwang
- Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Myung-Ju Ahn
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung-Bae Kim
- Department of Internal Medicine, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Liu Y, Yang M, Luo J, Zhou H. Radiotherapy targeting cancer stem cells "awakens" them to induce tumour relapse and metastasis in oral cancer. Int J Oral Sci 2020; 12:19. [PMID: 32576817 PMCID: PMC7311531 DOI: 10.1038/s41368-020-00087-0] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 02/05/2023] Open
Abstract
Radiotherapy is one of the most common treatments for oral cancer. However, in the clinic, recurrence and metastasis of oral cancer occur after radiotherapy, and the underlying mechanism remains unclear. Cancer stem cells (CSCs), considered the “seeds” of cancer, have been confirmed to be in a quiescent state in most established tumours, with their innate radioresistance helping them survive more easily when exposed to radiation than differentiated cancer cells. There is increasing evidence that CSCs play an important role in recurrence and metastasis post-radiotherapy in many cancers. However, little is known about how oral CSCs cause tumour recurrence and metastasis post-radiotherapy. In this review article, we will first summarise methods for the identification of oral CSCs and then focus on the characteristics of a CSC subpopulation induced by radiation, hereafter referred to as “awakened” CSCs, to highlight their response to radiotherapy and potential role in tumour recurrence and metastasis post-radiotherapy as well as potential therapeutics targeting CSCs. In addition, we explore potential therapeutic strategies targeting these “awakened” CSCs to solve the serious clinical challenges of recurrence and metastasis in oral cancer after radiotherapy.
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Affiliation(s)
- Yangfan Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Miao Yang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jingjing Luo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Preventive Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Beyond conventional chemotherapy, targeted therapy and immunotherapy in squamous cell cancer of the oral cavity. Oral Oncol 2020; 105:104673. [PMID: 32272385 DOI: 10.1016/j.oraloncology.2020.104673] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 03/28/2020] [Accepted: 03/28/2020] [Indexed: 11/22/2022]
Abstract
The focus of this review article is to throw light on non-conventional systemic chemotherapy that affects the tumour microenvironment and potentially has a favourable impact on the management of squamous cell cancer of the oral cavity. A metronomic combination of weekly methotrexate and celecoxib seems equally effective to single agent cisplatin in the palliative setting, but needs phase III testing. The same metronomic combination seems inferior to paclitaxel-cetuximab. Triple drug metronomic chemotherapy (methotrexate, celecoxib, and erlotinib) is still under development with promising data from pilot studies. Metronomic chemotherapy also seems beneficial in the curative setting but results of confirmatory studies are eagerly awaited. The low rate of adverse events and low cost make this regimen an attractive alternative. Both in vivo and in-vitro data suggests that numerous drugs like anthelmintics, DMARDs, antimalarials can be repurposed for Head and Neck Cancers. However, there is a dearth of clinical studies reported till date.
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Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Palliative chemotherapy in head and neck cancer: balancing between beneficial and adverse effects. Expert Rev Anticancer Ther 2020; 20:17-29. [PMID: 31899993 DOI: 10.1080/14737140.2020.1708197] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer in the world. Almost 2/3rds of patients have recurrent or metastatic (R/M) HNSCC. Treatment options for R/M HNSCC have evolved, with relatively little change in survival. Thus, it is imperative that management decisions must balance efficacy with toxicity and emphasize the importance of maintaining the patient's quality of life (QOL).Areas covered: We cover the various chemotherapeutic options available for R/M HNSCC including single agent chemotherapy, platinum-based doublets and triplet options. The role of cetuximab, immunotherapy and oral metronomic chemotherapy (OMCT) is also reviewed. We discuss the management of patients with platinum-refractory disease.Expert opinion: In all patients with R/M HNSCC, we recommend assessment of extent of disease, patient symptomatology, performance status, affordability and availability of logistic and social support. In patients with PD-L1 CPS =/> 20, pembrolizumab is an option. In patients with PD-L1 CPS < 20, pembrolizumab/cisplatin/5FU or cisplatin/5FU/cetuximab (EXTREME) may be considered based on affordability and availability. Options available that have a lower toxicity and can help to maintain the patient's QOL include; single agent chemotherapy, carboplatin/paclitaxel combination chemotherapy, sequential combination chemotherapy followed by cetuximab, replacing 5FU with docetaxel (TPEx regime) and OMCT.
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Affiliation(s)
- Akhil Rajendra
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Vijay Maruti Patil
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
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Pai SI, Cohen EEW, Lin D, Fountzilas G, Kim ES, Mehlhorn H, Baste N, Clayburgh D, Lipworth L, Resteghini C, Shara N, Fujii T, Zhang J, Stokes M, Wang H, Twumasi-Ankrah P, Wildsmith S, Khaliq A, Melillo G, Shire N. SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Transl Med 2019; 17:429. [PMID: 31878938 PMCID: PMC6933901 DOI: 10.1186/s12967-019-02182-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
Background Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. Methods This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. Results 412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively). Conclusions PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015.
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Affiliation(s)
- Sara I Pai
- Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, GRJ 9-904G, Boston, MA, 02114, USA.
| | - Ezra E W Cohen
- UC San Diego Health System, Moores Cancer Center, La Jolla, CA, USA
| | - Derrick Lin
- Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, GRJ 9-904G, Boston, MA, 02114, USA.,Massachusetts Eye and Ear, Boston, MA, USA
| | | | - Edward S Kim
- Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
| | - Holger Mehlhorn
- Universitaetsklinikum Leipzig, Klinik und Poliklinik fur HNO-Heilkunde, Leipzig, Germany
| | - Neus Baste
- Department of Oncology, Hospital Universitari Vall d'Hebron & Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Loren Lipworth
- Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Nawar Shara
- MedStar Health Research Institute, Hyattsville, MD, USA
| | | | - Jun Zhang
- Baylor College of Medicine, Houston, TX, USA
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Cramer JD, Burtness B, Ferris RL. Immunotherapy for head and neck cancer: Recent advances and future directions. Oral Oncol 2019; 99:104460. [PMID: 31683169 PMCID: PMC7749717 DOI: 10.1016/j.oraloncology.2019.104460] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023]
Abstract
Three randomized phase III trials have now conclusively proven that exposure to a PD-1 inhibitor prolongs survival in recurrent/metastatic (R/M) HNSCC, and it is clear that such agents should be used in the management of all patients who do not have contraindications to their use. Two of these phase III randomized trials showed that the anti-PD1 antibodies nivolumab and pembrolizumab were superior to investigators' choice chemotherapy in second-line platinum-refractory R/M HNSCC. Recently, a third phase III randomized trial, KEYNOTE-048, showed that pembrolizumab with chemotherapy was superior to the EXTREME regimen (cis- or carboplatin, 5-fluorouracil (5-FU) and cetuximab) in all patients, and pembrolizumab monotherapy was superior in patients whose tumors express PD-L1 in first-line R/M HNSCC. Pembrolizumab is now approved as monotherapy in PD-L1 expressing disease (combined positive score ≥1) or in combination with chemotherapy for all patients with R/M HNSCC. Thus, PD-L1 biomarker testing will be routinely used in R/M HNSCC, and this employs a scoring system that incorporates immune cell staining, referred to as the combined positive score (CPS). Additionally, for the 85% of patients with PD-L1 CPS ≥1, clinical judgment will guide the choice of pembrolizumab monotherapy or pembrolizumab plus chemotherapy, until more detailed clinical data are forthcoming to better inform this decision. In this article we discuss the clinical trials leading to these therapeutic advances and we will review initial results from clinical trials in previously untreated, locally advanced disease, and those using novel combinations of checkpoint inhibitors, co-stimulatory agonists, and therapeutic vaccines.
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Affiliation(s)
- John D Cramer
- Department of Otolaryngology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Barbara Burtness
- Department of Medicine and Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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Harabuchi S, Kosaka A, Yajima Y, Nagata M, Hayashi R, Kumai T, Ohara K, Nagato T, Oikawa K, Ohara M, Harabuchi Y, Ohkuri T, Kobayashi H. Intratumoral STING activations overcome negative impact of cisplatin on antitumor immunity by inflaming tumor microenvironment in squamous cell carcinoma. Biochem Biophys Res Commun 2019; 522:408-414. [PMID: 31771883 DOI: 10.1016/j.bbrc.2019.11.107] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 11/16/2019] [Indexed: 01/26/2023]
Abstract
Although cisplatin (CDDP) has been used as a major chemotherapeutic drug for head and neck squamous cell carcinoma (HNSCC), its impact on T-cell functions is controversial. Therefore, we investigated the immunologic effects of CDDP and antitumor effects by combination therapy of CDDP with a ligand for stimulator of interferon genes, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Direct impacts of CDDP on T-cell functions were addressed by comparing T-cell functions between human subjects treated and untreated with CDDP. The immune responses and the efficacy of combination therapy using CDDP and cGAMP were assessed using BALB/c mice inoculated with mouse squamous cell carcinoma (SCC) cell lines. CDDP inhibited T-cell proliferation in a dose-dependent manner. T-cell functions of CDDP-treated HNSCC patients were comparable to those of healthy donors and CDDP-untreated HNSCC patients. In the mice bearing SCC cell lines, combination therapy using CDDP and cGAMP enhanced the gene expressions of CXCL9 and CXCL10 in the tumor tissues and inhibited tumor growth. The antitumor effect was cancelled by anti-CXCR3 monoclonal antibody. These findings suggest that the combination therapy using CDDP and an immunomodulating drug like cGAMP would be a rational cancer immunotherapy for patients with HNSCC.
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Affiliation(s)
- Shohei Harabuchi
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan; Department of Otolaryngology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Akemi Kosaka
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Yuki Yajima
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Marino Nagata
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Ryusuke Hayashi
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan; Department of Otolaryngology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Takumi Kumai
- Department of Otolaryngology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Kenzo Ohara
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan; Department of Otolaryngology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Toshihiro Nagato
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Kensuke Oikawa
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Mizuho Ohara
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Yasuaki Harabuchi
- Department of Otolaryngology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan
| | - Takayuki Ohkuri
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan.
| | - Hiroya Kobayashi
- Department of Pathology, Head and Neck Surgery Asahikawa Medical University, Asahikawa Midorigaoka-Higashi 2-1-1, Asahikawa, Japan.
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Cristina V, Herrera-Gómez RG, Szturz P, Espeli V, Siano M. Immunotherapies and Future Combination Strategies for Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:E5399. [PMID: 31671550 PMCID: PMC6862353 DOI: 10.3390/ijms20215399] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 10/26/2019] [Accepted: 10/28/2019] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives.
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Affiliation(s)
- Valerie Cristina
- Oncology Department, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
| | | | - Petr Szturz
- Oncology Department, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
| | - Vittoria Espeli
- Oncology Department, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland.
| | - Marco Siano
- Interdisciplinary Cancer Service-SIC, Hôpital Riviera-Chablais, 1847 Rennaz, Switzerland.
- Faculty of Medicine, University and Unive rsity Hospital of Zurich, 8032 Zurich, Switzerland.
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Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, Le QT, Lee NY, Leidner R, Lewis RL, Licitra L, Mehanna H, Mell LK, Raben A, Sikora AG, Uppaluri R, Whitworth F, Zandberg DP, Ferris RL. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer 2019; 7:184. [PMID: 31307547 PMCID: PMC6632213 DOI: 10.1186/s40425-019-0662-5] [Citation(s) in RCA: 478] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.
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Affiliation(s)
- Ezra E W Cohen
- Moores Cancer Center, University of California San Diego, San Diego, CA, USA
| | - R Bryan Bell
- Earle A. Chiles Research Institute at the Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, USA
| | - Carlo B Bifulco
- Earle A. Chiles Research Institute at the Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, USA
| | - Barbara Burtness
- Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA
| | - Maura L Gillison
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Nancy Y Lee
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rom Leidner
- Earle A. Chiles Research Institute at the Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, USA
| | | | - Lisa Licitra
- Fondazione IRCCS Istituto Nazionale dei Tumori Milan and University of Milan, Milan, Italy
| | - Hisham Mehanna
- Institute of Head and Neck Studies and Education, University of Birmingham, Birmingham, UK
| | - Loren K Mell
- Moores Cancer Center, University of California San Diego, San Diego, CA, USA
| | - Adam Raben
- Helen F. Graham Cancer Center, Newark, DE, USA
| | | | - Ravindra Uppaluri
- Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA
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Different responses to nivolumab therapy between primary and metastatic tumors in a patient with recurrent hypopharyngeal squamous cell carcinoma. Oral Oncol 2019; 101:104366. [PMID: 31300273 DOI: 10.1016/j.oraloncology.2019.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/04/2019] [Accepted: 07/06/2019] [Indexed: 12/23/2022]
Abstract
We report the case of a 70-year-old man with primary and metastatic tumors, showing clinically progressive disease and complete response to nivolumab therapy, respectively. He underwent total pharyngo-laryngectomy, bilateral neck dissection, and reconstruction with free-jejunum after nivolumab therapy failure, and had no recurrent or newly arising lesions 8 months after the surgery. Immunohistochemistry analysis revealed that metastatic neck tumor with the clinical complete response to nivolumab showed higher PD-L1 expression with higher CD8+ TIL density, while primary lesion with progressive disease showed lower PD-L1 expression with lower CD8+ TIL density. This represents the first case reported on head and neck squamous cell carcinoma treated with salvage surgery after nivolumab therapy failure.
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De La Chapa JJ, Singha PK, Self KK, Sallaway ML, McHardy SF, Hart MJ, McGuff HS, Valdez MC, Ruiz F, Polusani SR, Gonzales CB. The novel capsazepine analog, CIDD-99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1-independent induction of ER stress, mitochondrial dysfunction, and apoptosis. J Oral Pathol Med 2019; 48:389-399. [PMID: 30825343 DOI: 10.1111/jop.12843] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/21/2019] [Accepted: 02/27/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five-year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-tumor effects against OSCC via a unique mechanism-of-action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti-proliferative effects (CIDD-24, CIDD-99, and CIDD-111). METHODS Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti-cancer mechanism(s)-of-action were assessed by cell cycle analysis and mitochondrial depolarization assays. RESULTS CIDD-99 was the most potent analog demonstrating significant anti-tumor effects in vivo (P < 0.001). CIDD-24 was equipotent to the parent compound CPZ, but less potent than CIDD-99. CIDD-111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD-99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti-cancer effects. All analogs induced an S-phase block, dose-dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD-99 had the most dramatic anti-tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD-99 was non-noxious and demonstrated no observable adverse reactions CONCLUSION: This study describes a novel, highly efficacious, CPZ analog, CIDD-99, with dramatic anti-tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.
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Affiliation(s)
- Jorge J De La Chapa
- Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas
| | - Prajjal K Singha
- Department of Pathology, School of Medicine, UT Health San Antonio, San Antonio, Texas
| | - Kristen K Self
- Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas
| | - McKay L Sallaway
- Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas
| | - Stanton F McHardy
- Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas.,Mays Cancer Center, UT Health San Antonio, San Antonio, Texas
| | - Matthew J Hart
- Mays Cancer Center, UT Health San Antonio, San Antonio, Texas.,Center for Innovative Drug Discovery, HTS Facility, Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, Texas
| | - Howard Stan McGuff
- Department of Pathology, School of Medicine, UT Health San Antonio, San Antonio, Texas
| | - Matthew C Valdez
- Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas
| | - Francisco Ruiz
- Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas
| | - Srikanth R Polusani
- Center for Innovative Drug Discovery, HTS Facility, Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, Texas
| | - Cara B Gonzales
- Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas.,Mays Cancer Center, UT Health San Antonio, San Antonio, Texas
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Zandberg DP, Algazi AP, Jimeno A, Good JS, Fayette J, Bouganim N, Ready NE, Clement PM, Even C, Jang RW, Wong S, Keilholz U, Gilbert J, Fenton M, Braña I, Henry S, Remenar E, Papai Z, Siu LL, Jarkowski A, Armstrong JM, Asubonteng K, Fan J, Melillo G, Mesía R. Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy. Eur J Cancer 2018; 107:142-152. [PMID: 30576970 DOI: 10.1016/j.ejca.2018.11.015] [Citation(s) in RCA: 190] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/09/2018] [Accepted: 11/10/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. PATIENTS AND METHODS Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). RESULTS Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. CONCLUSION Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
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Affiliation(s)
- Dan P Zandberg
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA.
| | - Alain P Algazi
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Antonio Jimeno
- Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - James S Good
- Institute of Head and Neck Studies and Education, Queen Elizabeth Hospital, Birmingham, UK
| | - Jérôme Fayette
- Clinical Oncology, Cancer Center Centre Léon Bérard, University of Lyon, Lyon, France
| | - Nathaniel Bouganim
- Department of Oncology, McGill University Health Centre, Montréal, QC, Canada
| | | | - Paul M Clement
- Department of Oncology, Leuven Cancer Institute, KU Leuven, Belgium
| | - Caroline Even
- Department of Head and Neck Oncology, Institut Gustave Roussy, Villejuif, France
| | - Raymond W Jang
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Stuart Wong
- Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | | | - Moon Fenton
- The West Cancer Center, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Irene Braña
- Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Stephanie Henry
- Department of Oncology-Hematology, Radiotherapy, and Nuclear Medicine, CHU UCL Namur, Namur, Belgium
| | - Eva Remenar
- National Institute of Oncology (Országos Onkológiai Intézet), Budapest, Hungary
| | - Zsuzsanna Papai
- State Health, Center Higatian Defanse Forses, Budapest, Hungary
| | - Lillian L Siu
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | | | | | | | - Jean Fan
- AstraZeneca, Gaithersburg, MD, USA
| | | | - Ricard Mesía
- Medical Oncology Department, Catalan Institute of Oncology, University of Barcelona, IDIBELL, Barcelona, Spain
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Enokida T, Okano S, Fujisawa T, Ueda Y, Uozumi S, Tahara M. Paclitaxel Plus Cetuximab as 1st Line Chemotherapy in Platinum-Based Chemoradiotherapy-Refractory Patients With Squamous Cell Carcinoma of the Head and Neck. Front Oncol 2018; 8:339. [PMID: 30211118 PMCID: PMC6119881 DOI: 10.3389/fonc.2018.00339] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 08/06/2018] [Indexed: 11/13/2022] Open
Abstract
Purpose: We sought to evaluate the efficacy and safety of the combination of cetuximab (Cmab) and paclitaxel (PTX) in patients with squamous cell carcinoma of the head and neck (SCCHN) who had unresectable recurrent or metastatic (R/M) disease after platinum-based chemoradiotherapy. Materials and Methods: Data on 23 patients with SCCHN who received paclitaxel and cetuximab (Cmab) for R/M disease no more than 6 months after CRT completion were retrospectively reviewed. PTX and Cmab were given in a 28-day cycle (PTX, 80 mg/m2 on days 1, 8, and 15; Cmab, loading dose 400 mg/m2 followed by a weekly 250 mg/m2). The differences in prognosis between subgroups in different clinical settings were also assessed. Results: CRT had been delivered as definitive treatment in 13 cases (57%) and as adjuvant treatment in 10 (43%). Median time from CRT completion to disease recurrence or metastasis was 73 days (1-152). The best objective response and disease control rates were 52 and 83%, respectively, with 12 partial responses and seven cases of stable disease by Response Evaluation Criteria in Solid Tumors (RECIST). A total of 17 of 23 patients (74%) achieved a degree of tumor shrinkage. Median progression-free survival (PFS) and overall survival (OS) were 7.0 (95% confidence interval [CI]: 3.7-8.4) and 16.3 months (95% CI: 7.8-23.3), respectively. Patients with a longer duration (≥60 d) from CRT completion to disease progression had a statistically significantly longer OS than the others (median OS 22.3 vs. 8.1 months, log-rank test; p = 0.034). Main Grade 3 toxicities included neutropenia (13%), anemia (13%), and hypomagnesemia (13%). No Grade 4 toxicity or treatment-related death was seen. Conclusion: PTX and Cmab is a tolerable and effective option in SCCHN patients with symptomatic CRT-refractory disease. Its favorable effects on tumor shrinkage will help relieve tumor-associated symptoms.
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Affiliation(s)
- Tomohiro Enokida
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takao Fujisawa
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yuri Ueda
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinya Uozumi
- Division of Pharmacy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Segrelles C, Contreras D, Navarro EM, Gutiérrez-Muñoz C, García-Escudero R, Paramio JM, Lorz C. Bosutinib Inhibits EGFR Activation in Head and Neck Cancer. Int J Mol Sci 2018; 19:ijms19071824. [PMID: 29933569 PMCID: PMC6073167 DOI: 10.3390/ijms19071824] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/15/2018] [Accepted: 06/19/2018] [Indexed: 01/17/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and although new therapeutic approaches have been recently evaluated, overall patient survival is still poor. Thus, new effective and selective clinical treatments are urgently needed. An analysis of data from large-scale, high-throughput drug screening cell line projects identified Bosutinib, a Src/Abl inhibitor that is currently used for the treatment of chronic myelogenous leukemia, as a candidate drug to treat HNSCC. Using a panel of HNSCC-derived cell lines, we found that treatment with Bosutinib reduced cell proliferation and induced apoptosis of sensitive cell lines. The drug rapidly inhibited Src and EGFR (epidermal growth factor receptor) phosphorylation, and sensitivity to Bosutinib was correlated with the activation status of EGFR. Similar findings were observed in in vivo xenograft assays using HNSCC derived cells. Moreover, in the presence of mutations in PIK3CA, the combination of Bosutinib with the PI3Kα inhibitor Alpelisib showed a synergistic effect. These results suggest that Bosutinib could be a new effective drug for the treatment of HNSCC, particularly in tumors with high EGFR activity. Its combination with Alpelisib could especially benefit patients bearing activating mutations of PIK3CA.
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Affiliation(s)
- Carmen Segrelles
- Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
- Molecular Oncology, University Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - David Contreras
- Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
| | - Elena M Navarro
- Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
| | | | - Ramón García-Escudero
- Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
- Molecular Oncology, University Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Jesús M Paramio
- Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
- Molecular Oncology, University Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Corina Lorz
- Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
- Molecular Oncology, University Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
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Abstract
PURPOSE OF REVIEW Discussion of current strategies targeting the immune system related to solid tumors with emphasis on head and neck squamous cell carcinoma (HNSCC).This review will outline the current challenges with immunotherapy and future goals for treatment using these agents. RECENT FINDINGS Agents targeting immune checkpoint receptors (IR) such as program death 1 (PD1) have been used in the clinical realm for melanoma and non-small cell lung cancer (NSCLC), and the use of these agents for these malignancies has provided crucial information about how and why patients respond or not to inhibitory checkpoint receptor blockade therapy (ICR). The anti PD1 agent, nivolumab, was recently approved by the FDA as a standard of care regimen for patients with platinum refractory recurrent/metastatic (R/M) HNSCC. Molecular pathways leading to resistance are starting to be identified, and work is underway to understand the most optimal treatment regimen with incorporation of immunotherapy. ICR has renewed interest in the immunology of cancer, but resistance is not uncommon, and thus understanding of these mechanisms will allow the clinician to appropriately select patients that will benefit from this therapy.
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Affiliation(s)
- Jessica Moskovitz
- Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jennifer Moy
- Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert L Ferris
- Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, USA. .,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. .,Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. .,University of Pittsburgh Eye and Ear Institute, 200 North Lothrop Street, Suite 500, Pittsburgh, PA, 15213, USA.
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Kim HS, Chen YC, Nör F, Warner KA, Andrews A, Wagner VP, Zhang Z, Zhang Z, Martins MD, Pearson AT, Yoon E, Nör JE. Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels. Oncotarget 2017; 8:100339-100352. [PMID: 29245982 PMCID: PMC5725024 DOI: 10.18632/oncotarget.22225] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 10/13/2017] [Indexed: 12/31/2022] Open
Abstract
Recent evidence suggests that the metastatic spread of head and neck squamous cell carcinomas (HNSCC) requires the function of cancer stem cells endowed with multipotency, self-renewal, and high tumorigenic potential. We demonstrated that cancer stem cells reside in perivascular niches and are characterized by high aldehyde dehydrogenase (ALDH) activity and high CD44 expression (ALDHhighCD44high) in HNSCC. Here, we hypothesize that endothelial cell-secreted interleukin-6 (IL-6) contributes to tumor progression by enhancing the migratory phenotype and survival of cancer stem cells. Analysis of tissue microarrays generated from the invasive fronts of 77 HNSCC patients followed-up for up to 11 years revealed that high expression of IL-6 receptor (IL-6R) (p=0.0217) or co-receptor gp130 (p=0.0422) correlates with low HNSCC patient survival. We observed that endothelial cell-secreted factors induce epithelial to mesenchymal transition (EMT) and enhance invasive capacity of HNSCC cancer stem cells. Conditioned medium from CRISPR/Cas9-mediated IL-6 knockout primary human endothelial cells is less chemotactic for cancer stem cells in a microfluidics-based system than medium from control endothelial cells (p<0.05). Blockade of the IL-6 pathway with a humanized anti-IL-6R antibody (tocilizumab) inhibited endothelial cell-induced motility in vitro and decreased the fraction of cancer stem cells in vivo. Notably, xenograft HNSCC tumors vascularized with IL-6-knockout endothelial cells exhibited slower tumor growth and smaller cancer stem cell fraction. These findings demonstrate that endothelial cell-secreted IL-6 enhances the motility and survival of highly tumorigenic cancer stem cells, suggesting that endothelial cells can create a chemotactic gradient that enables the movement of carcinoma cells towards blood vessels.
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Affiliation(s)
- Hong Sun Kim
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Yu-Chih Chen
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA
- Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Felipe Nör
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
- Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Kristy A. Warner
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - April Andrews
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Vivian P. Wagner
- Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Zhaocheng Zhang
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Zhixiong Zhang
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA
| | - Manoela D. Martins
- Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Alexander T. Pearson
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA
- Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Euisik Yoon
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
| | - Jacques E. Nör
- Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
- Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
- Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA
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Yun MR, Choi HM, Kang HN, Lee Y, Joo HS, Kim DH, Kim HR, Hong MH, Yoon SO, Cho BC. ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma. Oncogene 2017; 37:377-388. [DOI: 10.1038/onc.2017.339] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 08/08/2017] [Accepted: 08/12/2017] [Indexed: 02/07/2023]
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