Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
3. Operable Locally Advanced CSCC (LACSCC)
3.1. The Parotid and Neck Issues
3.1.1. The Patterns of Relapse despite Radiotherapy
3.1.2. Facial Nerve Involvement, Positive Surgical Margins and the Debate about the Classification of the Parotid Gland as a Cervical Lymph Node Level
3.1.3. The Problem of the Occult Disease and How to Face It
3.1.4. The Therapeutic Gain by Radiotherapy over Surgery Alone, Especially in the Presence of Adverse Prognostic Factors
3.1.5. Radiotherapy in the Management of a Limited Burden of Regional Disease
3.1.6. The Effect of Adding Systemic Therapy to Radiotherapy
3.2. Radiotherapy for Non-Head and Neck cSCCs
Comments
4. Inoperable LACSCC: Definitive Radiotherapy Combined or Not with Systemic Therapies
4.1. The Combined Treatments Borrowed from the HNSCC Management
4.2. Immunotherapy or Chemotherapy Drugs to Be Associated with Radiotherapy
4.3. The Research Efforts to Maximize the Efficacy of Radiotherapy by Using New Radiosensitizers or Fully Combining with Chemotherapy and Immunotherapy
4.4. The Feasibility of Hypofractionation of Radiation Dose
4.5. Brachytherapy
Comments
5. Distantly Metastatic CSCC (M1 CSCC): Does Radiotherapy Have a Role?
Comments
6. Limitations
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
cSCC | cutaneous squamous cell carcinoma |
BCC | basal cell carcinoma |
RT | radiation therapy |
HNSCC | head and neck squamous cell carcinoma |
IT | immunotherapy |
DSS | disease-specific survival |
LACSCC | locally advanced cutaneous squamous cell carcinoma |
NCCN | National Comprehensive Cancer Network |
DSS | disease-specific survival |
DFS | disease-free survival |
PFS | progression-free survival |
OS | overall survival |
CR | complete response |
PR | partial response |
SD | stable disease |
3D-CRT | 3-dimensional conformal radiotherapy |
IMRT | intensity-modulated radiotherapy |
SBRT | stereotactic body radiotherapy |
END | elective neck dissection |
ENI | elective neck irradiation |
EGFR | epidermal growth factor |
PD-1 | programmed cell death protein 1 |
PD-L1 | programmed death-ligand 1 |
ICI | immune checkpoint inhibitors |
FDA | food and drug administration |
BED | biological effective dose |
Pt | platinum-based chemotherapy |
Cx | cetuximab |
CRT | chemoradiotherapy |
PET | positron emission tomography |
RECIST | response evaluation criteria in solid tumors |
PERCIST | positron emission tomography (PET) response criteria in solid tumors |
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Authors Year | Study Size | Surgery Type No. Patients (Percentage) | Radiation Protocol No. Patients (Percentage) | Systemic Therapy No. Patients (Percentage) | Outcomes | Adverse Events (Grade ≥ 3) No. Patients (Percentage) | |
---|---|---|---|---|---|---|---|
1 | Bron et al.—2003 [16] | 101 | Parotidectomy 101 (100%) Neck dissection 75 (74.3%) | EBRT 101 (100%) | N/A | LC 5-year 94% DSS 5-year 65% | N/A |
2 | Dona et al.—2003 [18] | 74 | Parotidectomy 74 (100%) Neck dissection 52 (70.3%) | EBRT Parotid 74 (100%), Neck 56 (75.7%) | N/A | LC 2-year 76%; 5-year 73% | 0 (0%) |
3 | Palme et al.—2003 [17] | 126 | Parotidectomy 88 (69.8%) Neck dissection 87 (69%) | EBRT 126 (100%) | N/A | LC 5-year 80% DSS 5-year 68% | N/A |
4 | Audet et al.—2004 [20] | 56 | Parotidectomy 44 (78.6%) Neck dissection 28 (50%) | EBRT 56 (100%) | N/A | DSS 3-year 72% Recurrence 29% | N/A |
5 | Southwell et al.—2006 [21] | 49 | Parotidectomy 46 (93.9%) Neck dissection 43 (87.8%) | EBRT 49 (100%) | N/A | Recurrence 56% OS 1-year 88%; 2-year 80% | N/A |
6 | Ch’ng et al.—2008 [24] | 170 | Parotidectomy 135 (79.4%) Neck dissection 150 (88.2%) | EBRT 170 (100%) 50–70 Gy | N/A | DFS 5-year 59% DSS 5-year 69% OS 5-year 48% Recurrence 36% | N/A |
7 | Howle et al.—2008 [22] | 27 | Parotidectomy 16 (59.3%) Neck dissection 29 (96.3%) | EBRT 27 (100%) 60 Gy in 30 fractions | N/A | Recurrence 48% PFS 6 months (2–29) OS 9 months (1–73) | N/A |
8 | Iyer et al.—2009 [25] | 176 | Parotidectomy 176 (100%) Neck dissection 136 (77.3%) | EBRT 176 (100%) 54 Gy (45–66) in 27 fr | N/A | LC 5-year 80% OS 5-year 60% | N/A |
9 | Oddone et al.—2009 [26] | 250 | Parotidectomy 152 (61%) Neck dissection 223 (89.2%) | EBRT 250 (100%) 60 Gy (50–74) in 30 fr | N/A | Recurrence 28% PFS 8 months (2–34) | N/A |
10 | Forest et al.—2010 [27] | 215 | Parotidectomy 198 (92.1%) Neck dissection 166 (77.2%) | EBRT 215 (100%) 54 Gy parotid, 50 Gy neck | N/A | OS 2-year 82%: 5-year 69% DSS 2-year 87%; 5-year 77% LC 2-year 81%; 5-year 73% | N/A |
11 | Goh et al.—2010 [48] | 26 | N/A | EBRT 26 (100%) 50 Gy (45–66) | Chemotherapy 2 (7.7%) | Recurrence 27% PFS 2.2 months (0.5–14.1) OS 18.5 months (0.5–74.5) | N/A |
12 | Turner et al.—2010 [19] | 43 | Parotidectomy 36 (83.7%) Neck dissection 35 (81.4%) | EBRT 43 (100%) 60 Gy (36–74) in 30 fr | N/A | Recurrence 35% PFS 5 months (4–20) OS 13 months (4–89) | N/A |
13 | Kirke et al.—2011 [28] | 51 | Parotidectomy 51 (100%) Neck dissection 34 (66.7%) | EBRT 51 (100%) 60 Gy in 30 fr | N/A | Recurrence 17.6% | N/A |
14 | Pramana et al.—2012 [23] | 75 | Parotidectomy 28 (37%) Neck dissection 47 (63%) | EBRT 75 (100%) 60 Gy (42–70) in 28 fr BED 72 Gy (50–84) | N/A | LC 5-year 67% DSS 5-year 66% OS 5-year 52% | Dermatitis 41 (55%) ORN 4 (5%) |
15 | Sweeny et al.—2012 [46] | 56 | N/A | EBRT 56 (100%) | N/A | OS 2-year 64%; 5-year 56% | N/A |
16 | Wang et al.—2012 [32] | 122 | Neck dissection 122 (100%) | EBRT 122 (100%) 60 Gy in 30 fr | N/A | Recurrence 28% DFS 5-year 56% | N/A |
17 | Heath et al.—2013 [47] | 15 | Neck dissection 15 (100%) | EBRT 15 (100%) 60–66 Gy | Erlotinib 15 (100%) | OS 1-year 83%; 2-year 65% DFS 1-year 73%; 2-year 60% Recurrence 26.7% | Dermatitis 10 (67%) |
18 | Smith et al.—2016 [34] | 442 | N/A | EBRT 442 (100%) | N/A | Recurrence 17% | N/A |
19 | Hirshoren et al.—2018 [31] | 78 | Parotidectomy 78 (100%) Neck dissection 25 (32.1%) | EBRT 78 (100%) | N/A | LC 5-year 76% OS 5-year 46% | N/A |
20 | Porceddu et al.—2018 [45] | 310 | Neck dissection 310 (100%) | EBRT 310 (100%) 60 Gy in 30 fr | Carboplatin 153 (49.4%) | DFS 2-year 83%; 5-year 73% OS 2-year 88%; 5-year 79% | Hearing loss 17 (5.5%) ORN 10 (3.2%) Tinnitus 6 (1.9%) Neuropathy 4 (1.3%) Cataract 1 (0.3%) |
21 | Sood et al.—2019 [37] | 101 | Parotidectomy 78 (77.2%) Neck dissection 90 (89.1%) | EBRT 101 (100%) | N/A | Recurrence 24.8% | N/A |
22 | Trosman et al.—2020 [44] | 104 | N/A | EBRT 104 (100%) | Carboplatin 38 (37%) | OS 2-year 91%; 5-year 82% DFS 2-year 64%; 5-year 64% | N/A |
23 | Wilkie et al.—2020 [38] | 91 | Parotidectomy 71 (78%) Neck dissection 20 (22%) | EBRT 91 (100%) | N/A | Recurrence 36.3% PFS 9 months (3–38) OS 42 months (12–104) OS 5-year 43.8% DFS 5-year (36.2%) DSS 5-year 63.8% | N/A |
24 | Hazim et al.—2021 [43] | 21 | N/A | EBRT 21 (100%) Photon 11 (52%) 70 Gy Proton 10 (48%) 70 GyRBE | Cisplatin 10 (48%) Cetuximab 2 (10%) Cemiplimab 1 (5%) Paclitaxel 1 (5%) | Recurrence 40.8% PFS 2-year 44.5% OS 2-year 84.8% | Dermatitis 4 (19%) Thrombocytopenia 8 (38%) Mucositis 2 (9.5%) |
25 | Kampel et al.—2021 [42] | 74 | Parotidectomy 48 (65%) Neck dissection 63 (85%) | EBRT 74 (100%) | Chemotherapy 7 (9.5%) | OS 5-year 54.1% DFS 5-year 77% | N/A |
26 | Yang et al.—2021 [50] | 74 | N/A | EBRT 74 (100%) 50 Gy in 25 fr | N/A | DFS 2-year 49%; 5-year 49% OS 2-year 68%; 5-year 51% | N/A |
Authors Year | Study Size | Radiation Protocol No. Patients (Percentage) | Systemic Therapy No. Patients (Percentage) | Outcomes | Adverse Events (Grade ≥ 3) No. Patients (Percentage) | |
---|---|---|---|---|---|---|
1 | Samstein et al.—2014 [59] | 12 | EBRT 12 (100%) 60 Gy (12–80) in 30 fr | Cetuximab 12 (100%) | RR 64%; DC 91% DSS 2-year 51% OS 2-year 40% | Dermatitis 2 (16.7%) Thrombocytopenia 2 (16.7%) Mucositis 1 (8.3%) |
2 | Lu et al.—2015 [58] | 23 | EBRT 23 (100%) 60 Gy in 30 fr | N/A | Recurrence 12 (52%) PFS 8 months (1-31) | N/A |
3 | Tanvetyanon et al.—2015 [57] | 61 | EBRT 61 (100%) 60–66 Gy in 30 fr | Carboplatin or Cisplatin 61 (100%) | Recurrence 50% PS 23.5 months (7.4–39.5) | Leukopenia 3 (4.9%) Mucositis 3 (4.9%) Neurological 3 (4.9%) |
4 | Nottage et al.—2017 [61] | 21 | EBRT 21 (100%) 70 Gy in 35 fr | Cisplatin 21 (100%) | LC 1-year 61.9% OS 1-year 80.2% DFS 1-year 100% | Thrombocytopenia 6 (28.6%) Anemia/Fibrosis 5 (23.8%) Hearing loss 4 (19%) Leukopenia/ORN 2 (9.5%) |
5 | Joseph et al.—2018 [60] | 8 | EBRT 8 (100%) 55–66 Gy in 22–30 fr | Cetuximab 8 (100%) | DFS 2-year 87.5% PFS 2-year 83.3% OS 2-year 87.5% | Dermatitis 4 (50%) ACS/fatigue/mucositis 1 (12.5%) |
6 | Cowey et al.—2019 [63] | 82 | EBRT 82 (100%) | Carboplatin and Paclitaxel 22 (26.8%) Cetuximab 20 (24.4%) Cisplatin and 5-FU 6 (7.3%) Cisplatin 5 (6.1%) CarboP, PacliT and Cetux 5 (6.1%) CisP, Cetux and 5-FU 3 (2.7%) Other 21 (25.6%) | OS 1-year 56.1%; 2-year 30.2%; 3-year 15.6% | N/A |
7 | Lavaud et al.—2019 [67] | 4 | Hypofractionated EBRT 4 (100%) 26 Gy in 4 fr | Pembrolizumab 4 (100%) | PFS 14.4 months OS 15.6 months | 0 (0%) |
8 | Fan et al.—2020 [70] | 166 | Hypofractionated EBRT 166 (100%) Photon 92 (55%) Proton 74 (45%) 45 Gy in 12 fr | Cetuximab 32 (39%) Chemotherapy 30 (36%) Immunotherapy 11 (13%) Combination 10 (12%) | RR 66% OS 1-year 25.3% PFS 1-year 17.7% | Dysphagia 11 (6.6%) Trismus 5 (3%) Dermatitis 3 (1.8%) Mucositis/ORN/OSM 1 (0.9%) |
9 | Ogata et al.—2020 [64] | 130 | EBRT 62 (48%) | Carbo/Cisplatin 74 (57%) Cetuximab 5 (3.8%) Other 51 (39.2%) | PFS 5-year platinum 14%, no 22% OS 5-year platinum 29%, no 26% PFS 5-year non-RT 8%, RT 29% OS 5-year non-RT 15%, RT 42% PFS 5-year RT-plat 20%, RT-no 41% OS 5-year RT-plat 25%, RT-no 48% | Skin ulcer 3 (2.3%) Anemia/Hyponatriemia 2 (1.5%) Duodenal ulcer/Heart failure/Febrile neutropenia/Erythema multiforme 1 (0.8%) |
10 | De Felice et al.—2021 [68] | 18 | Ultra-hypofractionated EBRT 18 (100%) 56-64 Gy in 7–8 fr | N/A | OS 1-year 66%; 2-year 26.4% PFS 1-year 58.7%; 2-year 23.5% | 0 (0%) |
11 | Voruganti et al.—2021 [71] | 77 (out of 106 various skin cancers) | SBRT 106 (100%) | N/A | OS 1-year 44%; 2-year 26% PFS 1-year 60%; 2-year 44% | Dermatitis 31 (29.2%) Mucositis 1 (1%) Skin ulceration 1 (1%) Fibrosis 7 (6.6%) ORN 1 (1%) |
Authors Year | Study Size | Radiation Protocol No. Patients (Percentage) | Systemic Therapy No. Patients (Percentage) | Outcomes | Adverse Events (Grade ≥ 3) No. Patients (Percentage) | |
---|---|---|---|---|---|---|
1 | Foote et al.—2014 [91] | 16 | Previous EBRT 14 (87.5%) | Panitumumab 16 (100%) | PFS 8 months OS 11 months OS 2-year 37.5% | Dermatitis 4 (25%) Fatigue 1 (6%) |
2 | Gold et al.—2018 [92] | 39 | Previous EBRT 32 (82%) | Erlotinib 39 (100%) | DC 72% PFS 4.7 months (3.5–6.2) OS 13 months 88.4–20.5) OS 1-year 53%; 3-year 19% | Fatigue 4 (10%) Dermatitis 3 (8%) |
3 | Hanna et al.—2020 [93] | 61 | Previous EBRT 36 (59%) | Cemiplimab/Nivolumab/Pembrolizumab 61 (100%) | PFS 6-month 50.3% OS 1-year 46.1% | Gastrointestinal 5 (8.2%) Rheumatologic 4 (6.6%) Skin 2 (3.3%) Muscular 1 (1.6%) Neurologic 1 (1.6%) |
4 | In et al.—2020 [95] | 26 | Previous EBRT 10 (38.5%) | Cemiplimab 13 (50%) Pembrolizumab 7 (26.9%) Nivolumab 6 (23.1%) | PFS 5.4 months RR 42.3% DR 7.6 months (2.8–28.8) | DKA 2 (7.7%) Cardiomyopathy 1 (3.8%) Coagulopathy 1 (3.8%) Pneumonitis 1 (3.8%) |
5 | Rischin et al.—2020 [96] | 115 | Previous EBRT 88 (76.5%) | Cemiplimab 26 (100%) | DC 67.8% DR 1-year 90%) OS 1-year 80.7% | Anemia 7 (6.1%) Fatigue 4 (3.5%) Pneumonitis 3 (2.6%) Dyspnea 2 (1.7%) Rash 1 (0.9%) |
6 | Salzmann et al.—2020 [94] | 46 | - | Pembrolizumab 28 (61%) Nivolumab 19 (22%) Cemiplimab 8 (17%) | RR 58.7% DC 80.4% PFS 1-year 58.8%; 2-year 52.3% OS 1-year 79.3%; 2-year 67.1% | Myositis 2 (4.3%) Pneumonitis 2 (4.3%) Arthritis 1 (2.2%) Dermatitis 1 (2.2%) Thyreoiditis 1 (2.2%) |
7 | Hughes et al.—2021 [90] | 105 | Previous CT-RT 17 (16.2%) | Pembrolizumab 105 (100%) | RR 35.2% DC 52.4% DR 1-year 77.8% PFS 1-year 36.4% OS 1-year 48,4% | Hepatitis 2 (1.3%) Dermatitis 1 (0.6%) Fatigue 1 (0.6%) Nephritis 1 (0.6%) Pneumonitis 1 (0.6%) |
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Ferini, G.; Palmisciano, P.; Forte, S.; Viola, A.; Martorana, E.; Parisi, S.; Valenti, V.; Fichera, C.; Umana, G.E.; Pergolizzi, S. Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy. Cancers 2022, 14, 1871. https://doi.org/10.3390/cancers14081871
Ferini G, Palmisciano P, Forte S, Viola A, Martorana E, Parisi S, Valenti V, Fichera C, Umana GE, Pergolizzi S. Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy. Cancers. 2022; 14(8):1871. https://doi.org/10.3390/cancers14081871
Chicago/Turabian StyleFerini, Gianluca, Paolo Palmisciano, Stefano Forte, Anna Viola, Emanuele Martorana, Silvana Parisi, Vito Valenti, Corrado Fichera, Giuseppe Emmanuele Umana, and Stefano Pergolizzi. 2022. "Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy" Cancers 14, no. 8: 1871. https://doi.org/10.3390/cancers14081871
APA StyleFerini, G., Palmisciano, P., Forte, S., Viola, A., Martorana, E., Parisi, S., Valenti, V., Fichera, C., Umana, G. E., & Pergolizzi, S. (2022). Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy. Cancers, 14(8), 1871. https://doi.org/10.3390/cancers14081871