1Medical Oncology and Immune-Related Tumors,
3Pharmacology and Clinical Toxicology,
7Medical oncology and Cancer prevention,
Correspondence Address: Dr. Giovanni Lo Re, Medical Oncology and Immune-Related Tumors, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Gallini 2, Aviano, PN 33081, Italy. E-mail: firstname.lastname@example.org
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
A 70-year-old female with metastatic cutaneous squamous cell carcinoma (cSCC) and low-grade non-Hodgkin’s lymphoma, not amenable to cisplatin combination therapy, was treated with cyclophoshamide (Cyc)-fluorouracil (FU)-interleukin-2 (IL-2) in light of high tumor immunogenicity and the potential activity of this regimen. Cyc 300 mg/m2 and FU 500 mg/m2 intravenously on day 1 and IL-2 4.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks; Carboplatin (C) AUC 2 and paclitaxel (P) 85 mg/m2 on days 1, 8 and 15 ± capecitabine (Cape) every 4 weeks. After partial remission (PR) of lung metastases and local control with two cycles of first therapy followed by PR with five cycles of CP ± Cape, right mastectomy was performed with evidence of viable tumor. Subsequently, the patient underwent 3 cycles of chlorambucil and is alive after 13 months of follow-up. Safety and activity of chemo-immunotherapy and salvage treatment can be achieved in cSCC.
Cutaneous squamous cell carcinoma, cyclophosphamide, fluorouracil, interleukin-2, regulatory T cells, myeloid-derived suppressor cells
In 2018, cutaneous squamous cell carcinoma (cSCC) was reported to be the 5th most common type of cancer with 5.8% and 0.7% rates of incidence and mortality respectively. It shows racial and gender differences with greater incidence in white than black subjects and in men than women. The incidence increases with age, with an average age around 60 years. Tumor aggressiveness is associated with histological type. In fact, well-differentiated histologic subtypes such as keratoacanthoma and verrucous carcinoma are associated with low metastatic potential and do not seem related to human papillomavirus (HPV) infection. On the contrary, there are histological variants characterized by greater tumor aggressiveness, metastatic potential and poor prognosis and are represented by desmoplastic and adenosquamous cSCC. However, the absence of negative features such as epithelial dysplasia and stromal invasion in verrucous carcinoma can determine differential diagnostic difficulties with other benign entities. The most important prognostic factors are tumor diameter > 2.0 cm, tumor depth (< 2 mm vs. > 2 mm) and perineural involvement, which are highly associated with local recurrence, nodal metastases and disease-specific death. Sun exposure, age, fair skin, and immunosuppression are the main risk factors. Immunosuppression, associated with organ transplantation or other lymphoproliferative or solid tumors, negatively affects the behavior of the disease and probably also the responsiveness to treatments. Surgery and radiotherapy are the main modalities of treatment once the diagnosis has been made or after loco-regional recurrence with good results in terms of relapse-free survival, which is influenced by the state of immunosurveillance. The treatment of metastatic disease up to now has been by chemotherapy[14-19], and it should be noted that cisplatin (DDP) and fluorouracil (FU) are the most active chemotherapeutic agents. Regarding anti-epidermal growth factor receptor (EGFR) therapy, cetuximab seems to be more active than panitumumab with complete response (CR) of 68% and 12.5%, overall response rate (ORR) of 78% and 31% and progression-free survival of 25 and 8 months, respectively.
In comparison, ORR of patients treated with DDP is 45% comprising 22% CR with a median disease-free survival of 14.6 months. One of the mechanisms of DDP resistance could be linked to MiR-3619-5p downregulation, responsible for cell proliferation. To overcome drug resistance, considering the synergistic action between different types of chemotherapeutic agents such as DDP and fluoropyrimidines [e.g., FU or capecitabine (Cape)], DDP and taxanes, and taxanes and fluoropyrimidines, there is a rationale for a combination of these drugs. Recently, we have witnessed an explosion in research on new immunotherapeutic agents that have come into clinical practice both in solid and hematological tumors. In 2018, the US FDA approved cemiplimab-rwlc, a human anti-programmed death 1 (PD-1) monoclonal antibody, which blocks the interaction of PD-1 with programmed death ligand-1 (PD-L1) and represents the first and sole treatment specifically approved and available for advanced cSCC. The approval of cemiplimab-rwlc was based on a combined analysis of data from a phase II trial (EMPOWER-CSCC-1 Study 1540) and a phase I trial with two advanced cSCC expansion cohorts (Study 1423). In 108 patients with metastatic or locally advanced disease, there was a 47.2% objective response, and G ≥ 3 SAE was observed in 29% of cases. Regarding other anti-PD1 agents such as nivolumab[24-28] and pembrolizumab[29-35], there are positive reports with small series [Table 1].
Anti-PD-1 agents in cSCC
|Agent||Study||Drug dose||No. PTS||RR (CR)||PFS (mo)||Toxicity G ≥ 3 SAE|
|Cemiplimab||1,540||59||41(7)||(n.r.) MDR > 6 mo 57%||29%|
|Ipilimumab Nivolumab||case||n.d.||1||Path CR||5||Allograft rejection|
|Nivolumab||case||3 mg/kg/2 weeks||3||PR 2, SD 1||12+||--|
|Nivolumab||case||3 mg/kg/2 weeks||3||PR 1, SD 2||5.5-7+||--|
|Nivolumab||case||3 mg/kg/2 weeks||1||PR||4.5||--|
|Pembrolizumab||cases||2 mg/kg/3 weeks||1||PR||5+||--|
|Pembrolizumab||cases||2 mg/kg/3 weeks||5||CR 1, PR SD 1, PD 1||3-21||Severe weakness (2)|
|Pembrolizumab||case||2 mg/kg/3 weeks||2||PR 1, SD 1||4+, 7+||--|
|Pembrolizumab||case||2 mg/kg/3 weeks||2||PR 2||--||--|
|Pembrolizumab||case||2 mg/kg/3 weeks||1||PR||11+||--|
|Pembrolizumab||phase 2||200 mg IV/3 weeks||10||40%||n.r.||hepatitis and pneumonitis|
|Pembrolizumab||case||2 mg/kg/3 weeks||1||PR||n.r.||--|
|Pembrolizumab||case||2 mg/kg/3 weeks||1||CR||24+||--|
Regarding the negative effect of immunosuppressive cells such as regulatory T lymphocytes (Tregs) and myelo-derived suppressor cells (MDSCs) on resistance to treatment with clinically unfavorable outcome and in light of the possible inhibitory interference of cyclophoshamide (Cyc) and FU on this cell population, the aim of the study was to evaluate an innovative chemo-immunotherapy modality including interleukin-2 (IL-2) in the treatment of cSCC.
Our patient with low performance status had advanced cSCC originating from the right breast and concomitant non-Hodgkin lymphoma (NHL), and was therefore not amenable to combination chemotherapy including DDP. Taking into consideration the high immunogenicity of cSCC, even if burdened by the immunosuppressive effect of NHL, this depletion strategy on Tregs and MDSCs by Cyc and FU could allow effective immune stimulation by IL-2. An alternative treatment with carboplatin, paclitaxel ± Cape was foreseen in case of intolerance or ineffectiveness of the therapy to reach palliative mastectomy.
A 70-year-old female patient, a teacher by profession and of the Caucasian race, underwent hysterectomy for fibromatosis in 1995. In December 2017, she went to the emergency room because of the presence of exophytic vegetation 10 cm in diameter and localized in the right hemithorax. The lesion had appeared a year before and showed recent bleeding. After biopsy resection, the pathological diagnosis of a cSCC with lymph node metastasis (pT2L1V1N2) was made. A simultaneous marginal low-grade NHL (stage IV) was diagnosed. The patient was treated with radiotherapy on the right chest wall, 50 Gy/20 fractions, which were completed in August 2018. In September 2018, mammography detected local recurrence of a 35-mm nodule with polylobed contours in the right breast. The lesion was confirmed by ultrasound, which detected retroareolar ductal ectasia with dense intraductal content and satellite node of 0.6 cm in the upper internal quadrant of the breast. No significant focal lesions in the left breast were evident. Multiple bilateral axillary lymph nodes were detected. A needle biopsy of the right breast lesion was performed and confirmed the pathological diagnosis of poorly differentiated cSCC, polypoid, ulcerated, initially infiltrating the hypodermis. Thereafter, the immunohistochemistry for programmed death ligand-1 (PDL-1) and microsatellite instability were negative. Considering the new efficacy of anti-PD-1, at present not yet available, the ineligibility for DDP-containing regimen due to weight loss and poor performance status and the chance of low efficacy of alternative chemotherapy, after health authorization of chemo-immunotherapeutic regimen, from November 2018 to January 2019, she was treated with Cyc-FU-IL-2. The treatment was well tolerated, and the only reported problem was flu-like symptoms, which were controlled with paracetamol. On physical examination after two cycles of therapy, the patient showed initial local response [Figure 1A-C, Figure 3A and B] and size reduction of lung metastasis on CT scan [Figure 3D and E]. However, after a short-lasting response [Figure 1C] due to local progression [Figure 1D] from February to March 2019, the patient was treated with weekly low-dose carboplatin (C) AUC 2 and paclitaxel (P) 85 mg/m2 (CP) on days 1, 8 and 15 every 4 weeks with initial objective response [Figure 2A] followed by progression [Figure 2B]. Thereafter, from March to June 2019, Cape 1000 mg/day for 14 days was combined with CP for 3 cycles. From response evaluation by physical examination and radiological back-up, there was a reduction in size and thickness of the skin lesion in the right breast [Figure 2C and D, Figure 3C] with good tolerance and a further reduction of lung metastasis [Figure 3F]. After 5 cycles of chemotherapy, in June 2019, the patient was submitted to right simple radical mastectomy and the pathological diagnosis was poorly differentiated cSCC G3 according to WHO. Nipple, margins of resection and muscle level were free from tumor. However, after three months in September 2019, progression of disease was detected in multiple lymph nodes sites, on the chest wall along with the appearance of new pleural and lung metastatic lesions (not shown). Considering the progression and supposed negative impact of NHL, she then underwent three cycles of therapy with chlorambucil, aiming to improve the immunosuppressive role of lympho-proliferative disease. The patient is alive and in a rather good shape after 13 months from the beginning of systemic therapy.
Figure 1. Clinical presentation and course of breast neoplastic lesion during chemo-immunotherapy with cyclophosphamide, fluorouracil and interleukin-2. A: (November 2018): presence of polylobed and ulcerated neoplastic mass of 7 cm × 7 cm and overlying vegetative lesion of 4 cm located on the right breast; B: (December 2018): 2 weeks, after chemo-immunotherapy reduction in size and consistency of the neoplastic mass of 5 cm × 7 cm and of polylobed overlying vegetative lesion of 3 cm located in the right breast; C: (December 2018): 5 weeks after chemo-immunotherapy, further reduction in size and thickness of nodules in the right breast; D: (January 2019): increase in size of the polylobed and ulcerated neoplastic mass of 8 cm × 8 cm with nodules above greater than 4.5 cm located in the right breast after chemo-immunotherapy
Figure 2. Clinical presentation and course of breast neoplastic lesion during chemotherapy with carboplatin, paclitaxel ± capecitabine. A: reduction in size and thickness of the nodules with ulcerated area and fibrous material in the right breast after chemotherapy (February 2019); B: progression in size and thickness of nodules with ulcerated area and fibrous material within the neoplastic mass in the right breast after chemotherapy (March 2019); C: initial reduction in thickness of the polylobed nodules with ulcerated and necrotic areas and fibrin-hemorrhagic material above the neoplastic mass in the right breast (April 2019); D: reduction in size of the polylobed and ulcerated neoplastic mass of 6 cm × 6 cm located in the right breast after chemotherapy (June 2019)
Figure 3. CT scan presentation and clinical course of local and metastatic lesions during chemo-immunotherapy with cyclophosphamide, fluorouracil and interleukin-2 and salvage carboplatin, paclitaxel ± capecitabine regimen. A: neoplastic masses of 19 mm × 13 mm to the infero-lateral quadrant and 40 mm × 35 mm to the medial quadrant of the right breast. Metastatic lesion of 11 mm × 25 mm to the middle lung lobe anteriorly (November 2018); B: dimensional increase of the heterogeneous lesion localized in the right central breast of 63 mm × 34 mm, with current ulcerative aspects of the overlying skin after chemo-immunotherapy (February 2019); C: partial reduction of density due to necrosis and size of the polylobed and ulcerated neoplastic mass of 7 cm located in the right breast after salvage chemotherapy (June 2019); D: metastatic lesion of 11 mm × 25 mm to the middle lung lobe anteriorly (November 2018); E: reduction in size of metastatic lesion of 11 mm × 7 mm to the middle lung lobe anteriorly after chemo-immunotherapy (February 2019); F: further reduction in size of metastatic lesion of 10 mm × 6 mm to the middle lung lobe anteriorly after salvage chemotherapy (June 2019)
The chemo-immunotherapy combination included intravenous Cyc 300 mg/m2 and FU 500 mg/m2 on day 1 and subcutaneous low-dose IL-2 4.5 MIU/day on days 3-6 and 17-20 every 4 weeks. A premedication with metoclopramide and paracetamol was planned. The cycle was repeated every 4 weeks for three cycles. If an objective response (CR) or PR or disease stabilization was documented upon clinical and radiological back-up every two months, in the absence of serious toxicities or refusal of treatment, the therapy was continued for another three cycles.Blood count, creatinine, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (γ-GT), bilirubin, calcium, lactic dehydrogenase (LD), alkaline phosphatase, peripheral blood lymphocyte immunophenotype CD3+, CD4+, CD8+, CD19+, CD16+, HLA-DR+/CD3+/CD8+ and Treg (CD3+/CD4+/CD25+/CD127-) were determined before every cycle, and blood count, creatinine, ALT, bilirubin and blood lymphocyte immunophenotype (CD3+, CD4+, CD8+, CD19+, CD16+), HLA-DR+/CD3+/CD8+ and Treg (CD3+/CD4+/CD25+/CD127-) on days 3 and 17 of each cycle.
Salvage therapy: carboplatin (C) AUC 2 and paclitaxel (P) 85 mg/m2 (CP) day 1, 8 and 15 every 4 weeks. In the presence of further disease progression, the addition of Cape 1000 mg/day for 14 days to CP was expected. A premedication with ondansetron during treatment was employed.
Blood count, creatinine, ALT, γ-GT, bilirubin, calcium, LD, alkaline phosphatase were determined before every cycle and blood count, creatinine, ALT, bilirubin on days 1 and 8. Radiological response was determined every 3 months.
Advanced cSCC is an orphan disease and the main treatment is represented by radiotherapy, anti-EGFR antibodies and chemotherapy. Unfortunately, these treatments do not offer long-lasting results with a range of 8 to 25 months. The disease becomes more resistant especially when it is associated with a state of immunosuppression resulting from post-transplant therapy or neoplastic disease such as lymphomas. This scenario becomes permissive to the immunosuppression exercised above all by Tregs and MDSCs, as well as by tumor-associated macrophages. cSCC shows a high tumor mutation burden (TMB), a condition that makes immunotherapy effectiveness highly possible. Recently, cemiplimab-rwlc, an anti PD-1 checkpoint agent was approved by the FDA for the treatment of cSCC. Regarding other immunotherapeutic agents such as IL-2, which has been shown to be effective in metastatic renal cell carcinoma and cutaneous melanoma, it has not been tested in this disease in human subjects. However, in the animal model, subcutaneous perilesional administration of IL-2 resulted in a high remission rate and long-lasting response, which was significantly satisfactory when administering high doses instead of low ones. IL-2 is a 15.5 kDa cytokine secreted predominantly by CD4+, CD8+ T cells, natural killer cells, and activated dendritic cells. IL-2 can stimulate cells expressing both a high affinity for the trimeric receptor α, β, γ chains or a low affinity dimeric receptor α, γ chains for IL-2. IL-2 can stimulate cell growth in CD8+ cells and differentiation of memory lymphocytes, and maintain and expand the CD41+ Tregs, reducing the risk of uncontrolled immune activity and autoimmunity. Furthermore, it has a differentiating effect on CD4 T cells, and its action can be stimulatory or inhibitory in the different T helper subtypes. The immunosuppressive effect seems to be exerted also by MDSCs. It can occur indirectly through the increase in Tregs and for the expression of indoleamine 2, 3-dioxygenase (IDO) on MDSCs and through the production of TGF-β and retinoic acid. Similarly the overexpression of IDO by the dendritic cells with consequent depletion of tryptophan determines immunosuppression through their blocking of the maturation and induction of T cell apoptosis.
Considering the key immunosuppressive role played by these cells, with Tregs and MDSCs being the most studied, and their negative relationship with tumor stage, prognosis, and resistance to treatment, preliminary experience with Cyc and FU, active on both types of suppressive cells, combined with IL-2 was reported in heavily pre-treated solid tumors, with interesting results both from a clinical and laboratory point of view.
Our patient with advanced cSCC showed for the first time how a chemo-immunotherapy regimen including IL-2 was able to produce a fleeting response even on the primary and more-lasting tumor response on the metastatic lesion. Furthermore, the blood count and immunophenotype showed an initial increase in white blood cells, neutrophilic granulocytes and lymphocytes followed by their decrease [Figure 4A] and a transient decrease in the Treg count during chemo-immunotherapy [Figure 4B], respectively. In addition, a subsequent decrease in Tregs was observed during salvage chemotherapy [Figure 4B]. This transient effect could be explained by the concomitant presence of lymphomas and Treg stimulation by IL-2 with detrimental effect on the immune system with consequent unfavorable response to chemo-immunotherapy. A more favorable outcome could be hypothesized in the presence of adequate immunosurveillance especially in a high TMB tumor such as cSCC. A confirmation of the poor efficacy of chemotherapy along with the combination of carboplatin and paclitaxel employed after chemo-immunotherapy failure, despite the theoretical synergism and additive antitumor activity for increase of carboplatin-DNA adduct formation, has been reported. Noteworthy is the ability of a fluoropyrimidine (Cape) to reverse resistance to the previous carboplatin combination therapy through the upregulation of thymidine phosphorylase activity by paclitaxel and subsequent Cape activation[22,46], the decrease of Treg count and tumor response.
Figure 4. Outcome of complete and differential blood count and immunophenotyping during chemo-immunotherapy and salvage chemotherapy. A: The blood count showed an initial increase in white blood cells (WBC), neutrophilic granulocytes (N) and lymphocytes (Lym) followed by their decrease during chemo-immunotherapy; B: An undulating trend of CD3+, CD4+, CD8+, CD19+, CD16+, HLA-DR+ and Tregs and a transient decrease in Treg count were observed after chemo-immunotherapy. Subsequently, after an increase in Treg count, there was a decrease during chemotherapy. CD3+: cluster of differentiation 3 T cell; CD4+: CD4+ (helper) T cell; CD8+: CD8+ (cytotoxic) T cells; CD19+: cluster of differentiation 19 B-lymphocyte; CD16+: type I transmembrane receptor mediating antibody-dependent cellular cytotoxicity (ADCC) by NK cells; HLA-DR+: histocompatibility class II allele T cell; Treg: regulatory T cells CD4(+)CD25(+)Foxp3(+)
In conclusion advanced spinocellular carcinoma of the skin remains a pathology with severe treatment difficulties due to primary resistance, worsened by a state of immunosuppression resulting from organ transplantation or other tumors. It is desirable to improve our knowledge of the resistance mechanisms and to investigate prospectively innovative therapeutic strategies to improve the therapeutic index and the control of the disease.
We warmly thank Dr. Federica G. Ravizza for editing. Finally, we thank the doctors and nurses who supported us in this study.Authors’ contributions
Conceptualization: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A
Data curation: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Formal analysis: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Investigation: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Project administration: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A
Software: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Supervision: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Validation: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Visualization: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Writing - original draft: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Writing - review and editing: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Used in attributes: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro SAvailability of data and materials
The source of the data is PUBMED and proceeding ASCO.Financial support and sponsorship
None.Conflicts of interest
All authors declared that there are no conflicts of interest.Ethical approval and consent to participate
Informed consent to treatment was accepted and signed by the patient after ethical approval by the competent facility.Consent for publication
Patient consent for publication.Copyright
© The Author(s) 2020.
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.DOIPubMed
2. Xiang F, Lucas R, Hales S, Neale R. Incidence of nonmelanoma skin cancer in relation to ambient UV radiation in white populations, 1978-2012: empirical relationships. JAMA Dermatol 2014;150:1063-71.DOIPubMed
3. del Pino M, Bleeker MC, Quint WG, Snijders PJ, Meijer CJ, et al. Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma. Mod Pathol 2012;25:1354-63.DOIPubMed
4. Breuninger H, Schaumburg-Lever G, Holzschuh J, Horny HP. Desmoplastic squamous cell carcinoma of skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer 1997;79:915-9.DOIPubMed
5. Azorín D, López-Ríos F, Ballestín C, Barrientos N, Rodríguez-Peralto JL. Primary cutaneous adenosquamous carcinoma: a case report and review of the literature. J Cutan Pathol 2001;28:542-5.DOIPubMed
6. van der Waal I, Reichart PA. Oral proliferative verrucous leukoplakia revisited. Oral Oncol 2008;44:719-21.DOIPubMed
7. Thompson AK, Kelley BF, Prokop LJ, Murad MH, Baum CL. Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis. JAMA Dermatol 2016;152:419-28.DOIPubMedPMC
8. Farasat S, Yu SS, Neel VA, Nehal KS, Lardaro T, et al. A new American Joint Committee on cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol 2011;64:1051-9.DOIPubMedPMC
9. Carter JB, Johnson MM, Chua TL, Karia PS, Schmults CD. Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study. JAMA Dermatol 2013;149:35-41.DOIPubMed
10. Puza CJ, Beasley GM, Barbas AS, Mosca PJ. Type of organ transplanted impacts the risk and presentation of cutaneous squamous cell carcinoma in transplant recipients. Exp Clin Transplant 2020;18:93-7.DOIPubMed
11. Quaglino P, Nardò T, Fierro MT, Massaia M, Orsucci L, et al. Clinicopathologic spectrum of cutaneous diseases in patients with hematologic malignancies with or without allogeneic bone marrow transplantation: an observational cohort study in 101 patients. G Ital Dermatol Venereol 2013;148:453-63.PubMed
12. Rosenberg CA, Greenland P, Khandekar J, Loar A, Ascensao J, et al. Association of nonmelanoma skin cancer with second malignancy. Cancer 2004;100:130-8.DOIPubMed
13. Manyam BV, Garsa AA, Chin RI, Reddy CA, Gastman B, et al. A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck. Cancer 2017;123:2054-60.DOIPubMed
14. Trodello C, Pepper JP, Wong M, Wysong A. Cisplatin and cetuximab treatment for metastatic cutaneous squamous cell carcinoma: a systematic review. Dermatol Surg 2017;43:40-9.DOIPubMed
15. FitzGerald GB, Wick MM. Comparison of the inhibitory effects of hydroxyurea, 5-fluorodeoxyuridine, 3,4-dihydroxybenzylamine, and methotrexate on human squamous cell carcinoma. J Invest Dermatol 1987;88:66-70.DOIPubMed
16. Gil S, Yébenes M, Luelmo J, Alsina M, Sabés M. A comparative study of the effectiveness of cisplatin and 5-fluorouracil on cutaneous squamous human carcinoma cell line: potential chemotherapy alternative to surgery. Dermatol Ther 2016;29:341-4.DOIPubMed
17. Hitt R, Jimeno A, Rodríguez-Pinilla M, Rodríguez-Peralto JL, Millán JM, et al. Phase II trial of cisplatin and capecitabine in patients with squamous cell carcinoma of the head and neck, and correlative study of angiogenic factors. Br J Cancer 2004;91:2005-11.DOIPubMedPMC
18. Khansur T, Kennedy A. Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin. Cancer 1991;67:2030-2.DOIPubMed
19. Zhang M, Luo H, Hui L. MiR-3619-5p hampers proliferation and cisplatin resistance in cutaneous squamous-cell carcinoma via KPNA4. Biochem Biophys Res Commun 2019;513:419-25.DOIPubMed
20. Foote MC, McGrath M, Guminski A, Hughes BG, Meakin J, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Ann Oncol 2014;25:2047-52.DOIPubMed
21. Huang GC, Liu SY, Lin MH, Kuo YY, Liu YC. The synergistic cytotoxicity of cisplatin and taxol in killing oral squamous cell carcinoma. Jpn J Clin Oncol 2004;34:499-504.DOIPubMed
22. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998;4:1013-9.PubMed
23. Markham A, Duggan S. Cemiplimab: first global approval. Drugs 2018;78:1841-6.DOIPubMed
24. Chen A, Ali N, Boasberg P, Ho AS. Clinical remission of cutaneous squamous cell carcinoma of the auricle with cetuximab and nivolumab. J Clin Med 2018;7:10.DOIPubMedPMC
25. Miller DM, Faulkner-Jones BE, Stone JR, Drews RE. Complete pathologic response of metastatic cutaneous squamous cell carcinoma and allograft rejection after treatment with combination immune checkpoint blockade. JAAD Case Rep 2017;3:412-5.DOIPubMedPMC
26. Blum V, Müller B, Hofer S, Pardo E, Zeidler K, et al. Nivolumab for recurrent cutaneous squamous cell carcinoma: three cases. Eur J Dermatol 2018;28:78-81.DOIPubMed
27. Borradori L, Sutton B, Shayesteh P, Daniels GA. Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases. Br J Dermatol 2016;175:1382-6.DOIPubMed
28. Pandey A, Liaukovich M, Joshi K, Avezbakiyev BI, O’Donnell JE. Uncommon presentation of metastatic squamous cell carcinoma of the skin and treatment challenges. Am J Case Rep 2019;20:294-9.DOIPubMedPMC
29. Chang ALS, Tran DC, Cannon JGD, Li S, Jeng M, et al. Pembrolizumab for advanced basal cell carcinoma: An investigator-initiated, proof-of-concept study. J Am Acad Dermatol 2019;80:564-6.DOIPubMedPMC
30. Tran DC, Colevas AD, Chang AL. Follow-up on programmed cell death 1 inhibitor for cutaneous squamous cell carcinoma. JAMA Dermatol 2017;153:92-4.DOIPubMed
31. Degache E, Crochet J, Simon N, Tardieu M, Trabelsi S, et al. Major response to pembrolizumab in two patients with locally advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol 2018;32:e257-8.DOIPubMed
32. Stevenson ML, Wang CQ, Abikhair M, Roudiani N, Felsen D, et al. Expression of programmed cell death ligand in cutaneous squamous cell carcinoma and treatment of locally advanced disease with pembrolizumab. JAMA Dermatol 2017;153:299-303.DOIPubMed
33. Kudchadkar RR, Yushak ML, Lawson DH, Delman KA, Lowe MC, Goings M, et al. Phase II trial of pembrolizumab (MK-3475) in metastatic cutaneous squamous cell carcinoma (cSCC). J Clini Oncol 2018;36:9543.DOI
34. Deinlein T, Lax SF, Schwarz T, Giuffrida R, Schmid-Zalaudek K, et al. Rapid response of metastatic cutaneous squamous cell carcinoma to pembrolizumab in a patient with xeroderma pigmentosum: case report and review of the literature. Eur J Cancer 2017;83:99-102.DOIPubMed
35. Assam JH, Powell S, Spanos WC. Unresectable cutaneous squamous cell carcinoma of the forehead with MLH1 mutation showing dramatic response to programmed cell death protein 1 inhibitor therapy. Clin Skin Cancer 2016;1:26-9.DOIPubMedPMC
36. Den Otter W, Hill FW, Klein WR, Koten JW, Steerenberg PA, et al. Therapy of bovine ocular squamous-cell carcinoma with local doses of interleukin-2: 67% complete regressions after 20 months of follow-up. Cancer Immunol Immunother 1995;41:10-4.DOIPubMed
37. Rosenberg SA. Interleukin-2 and the development of immunotherapy for the treatment of patients with cancer. Cancer J Sci Am 2000;6 Suppl 1:S2-7.PubMed
38. Chinen T, Kannan AK, Levine AG, Fan X, Klein U, et al. An essential role for the IL-2 receptor in Treg cell function. Nat Immunol 2016;17:1322-33.DOIPubMedPMC
39. Liao W, Lin JX, Wang L, Li P, Leonard WJ. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol 2011;12:551-9.DOIPubMedPMC
40. Zoso A, Mazza EM, Bicciato S, Mandruzzato S, Bronte V, et al. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur J Immunol 2014;44:3307-19.DOIPubMed
41. Hoechst B, Gamrekelashvili J, Manns MP, Greten TF, Korangy F. Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells. Blood 2011;117:6532-41.DOIPubMed
42. Bracho-Sanchez E, Hassanzadeh A, Brusko MA, Wallet MA, Keselowsky BG. Dendritic cells treated with exogenous indoleamine 2,3-dioxygenase maintain an immature phenotype and suppress antigen-specific T cell proliferation. J Immunol Regen Med 2019;5:100015.DOIPubMedPMC
43. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009;58:49-59.DOIPubMedPMC
44. Lo Re G, Lo Re F, Doretto P, Del Conte A, Amadio M, et al. Cyclophosphamide with or without fluorouracil followed by subcutaneous or intravenous interleukin-2 use in solid tumors: a feasibility off-label experience. Cytokine 2019;113:50-60.DOIPubMed
45. Jiang S, Pan AW, Lin TY, Zhang H, Malfatti M, et al. Paclitaxel enhances carboplatin-DNA adduct formation and cytotoxicity. Chem Res Toxicol 2015;28:2250-2.DOIPubMedPMC
46. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998;4:1013-9.PubMed
Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S. Cyclophosphamide, fluorouracil and low-dose interleukin-2 and salvage combination chemotherapy in advanced cutaneous squamous cell carcinoma. J Cancer Metastasis Treat 2020;6:17. http://dx.doi.org/10.20517/2394-4722.2020.11