Role of radiotherapy in the management of hepatocellular carcinoma:A systematic review

Many patients with hepatocellular carcinoma(HCC) present with advanced disease,not amenable to curative therapies such as surgery,transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization(TACE) and radiation therapy. Especially TACE,delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy,has given favorable results on local control and survival. Radiotherapy,as a therapeutic modality of internal radiation therapy with radioisotopes,has also achieved efficacious tumor control in advanced disease. On the contrary,the role of external beam radiotherapy for HCC has been limited in the past,due to the low tolerance of surrounding normal liver parenchyma. However,technological innovations in the field of radiotherapy treatment planning and delivery,have provided the means of delivering radical doses to the tumor,while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy,evaluated for efficacy and safety for HCC,report encouraging results. In this review,we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.

Combined chemo-radiotherapy in locally advanced nasopharyngeal carcinomas

AIM:To provide efficacy and safety data about the combined use of radiotherapy and chemo-radiotherapy in nasopharyngeal carcinoma(NPC).METHODS:We reviewed data of 40 patients with locally advanced NPC treated with induction chemotherapy followed by concomitant chemo-radiotherapy(CCRT)(22/40 patients)or CCRT alone(18/40)from March 2006 to March 2012.Patients underwent fiberoscopy with biopsy of the primitive tumor,and computed tomography scan of head,neck,chest and abdomen with and without contrast.Cisplatin was used both as induction and as concomitant chemotherapy,while 3D conformal radiation therapy was delivered to the nasopharynx and relevant anatomic regions(total dose,70 Gy).The treatment was performed using 6 MV photons of the linear accelerator administered in 2 Gy daily fraction for five days weekly.This retrospective analysis was approved by the review boards of the participating institutions.Patients gave their consent to treatment and to anonymous analysis of clinical data.RESULTS:Thirty-three patients were males and 7 were females.Median follow-up time was 58 mo(range,1-92 mo).In the sub-group of twenty patients with a follow-up time longer than 36 mo,the 3-year survival and disease free survival rates were 85%and 75%,respectively.Overall response rate both in patients treated with induction chemotherapy followed by CCRT and in those treated with CCRT alone was 100%.Grade 3 neutropenia was the most frequent acute side-effect and it occurred in 20 patients.Grade 2 mucositis was seen in 29 patients,while grade 2 xerostomia was seen in 30 patients.Overall toxicity was manageable and it did not cause any significant treatment delay.In the whole sample population,long term toxicity included grade 2 xerostomia in 22 patients,grade 1 dysgeusia in 17 patients and grade 1 subcutaneous fibrosis in 30 patients.CONCLUSION:Both CCRT and induction chemotherapy followed by CCRT showed excellent activity in locally advanced NPC.The role of adjuvant chemotherapy remains to be defined.

Adjuvant chemotherapy and acute toxicity in hypofractionated radiotherapy for early breast cancer

AIM: To evaluate the effect of chemotherapy to the acute toxicity of a hypofractionated radiotherapy(HFRT) schedule for breast cancer. METHODS: We retrospectively analyzed 116 breast cancer patients with T1, 2N0 Mx. The patients received3-D conformal radiotherapy with a total physical dose of 50.54 Gy or 53.2 Gy in 19 or 20 fractions according to stage, over 23-24 d. The last three to four fractions were delivered as a sequential tumor boost. All patients were monitored for acute skin toxicity according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group criteria. The maximum monitored value was taken as the final grading score. Multivariate analysis was performed for the contribution of age, chemotherapy and 19 vs 20 fractions to the radiation acute skin toxicity.RESULTS: The acute radiation induced skin toxicity was as following: grade Ⅰ 27.6%, grade Ⅱ 7.8% and grade Ⅲ 2.6%. No significant correlation was noted between toxicity grading and chemotherapy(P = 0.154, χ2 test). The mean values of acute toxicity score in terms of chemotherapy or not, were 0.64 and 0.46 respectively(P = 0.109, Mann Whitney test). No significant correlation was also noted between acute skin toxicity and radiotherapy fractions(P = 0.47, χ2test). According to univariate analysis, only chemotherapy contributed significantly to the development of acute skin toxicity but with a critical value of P = 0.05. However, in multivariate analysis, chemotherapy lost its statistical significance. None of the patients during the 2-years of follow-up presented any locoregional relapse.CONCLUSION: There is no clear evidence that chemotherapy has an impact to acute skin toxicity after an HFRT schedule. A randomized trial is needed for definite conclusions.

Predictability and Management of OARs Toxicity in Patients with Prostate Cancer Treated with High-Dose Radiotherapy

Aim: To evaluate the predictability of toxicity analyzing the dose-volume histograms (DVHs) and to verify the effectiveness of preventive measures limiting side toxicity considering the evolution of the radiation techniques for prostate cancer treatment. Materials and Methods: 208 patients with localized prostate cancer were treated with exclusive radiotherapy until 73.8 Gy (group A) or 79.2 Gy (group B) with the dose escalation technique. Preventive measures to minimize the side effects were recommended in group B. Results: The assessment of genitourinary toxicity was similar while gastrointestinal toxicity was better in group B. Valuating the treatment plans, we found that most of the patients developing toxicity had “borderline” DVHs. Conclusion: Our analysis led to the establishment of a protocol for the management of patients with “border-line” DVH.

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients

A cohort study was conducted based on clinical records for 5248 women treated for breast cancer in Florence (Italy), with continuous follow up from 1965 to 1994. The subjects were categorised into groups such as no radiation treatment;breast dose only;and radiation doses in one, two, three or four of the following fields: namely internal mammary chain, supraclavicular nodes, axillary lymph nodes and chest wall. The Cox proportional hazards model for ungrouped survival data was used to estimate the relative risk for second cancer after radiotherapy delivered to different regions. The relative risk for all second cancers combined was statistically significantly raised if the internal mammary chain and supraclavicular nodes were irradiated. However, we found that the relative risk of the second malignancies could be reduced if all the locoregional lymph nodes (the internal mammary chain, supraclacicular nodes, axillary nodes) and chest wall are irradiated at the same time. If this finding can be verified by other large cohort studies or randomized clinical trials, it may have implications in clinical practice when deciding upon the targeted areas for radiotherapy;partial radiation treatment of the locoregional lymph nodes could raise the risk of second malignancies and should ideally be avoided.

Focal liver lesions detection and characterization: The advantages of gadoxetic acid-enhanced liver MRI

Since its clinical introduction, several studies in literature have investigated gadolinium ethoxybenzhyl diethylenetriaminepentaacetic acid or gadoxetic acid(Gd-EOB-DTPA) properties. Following contrast injection, it provides dynamic vascular phases(arterial, portal and equilibrium phases) and hepatobiliary phase, the latter due to its uptake by functional hepatocytes. The main advantages of Gd-EOB-DTPA of focal liver lesion detection and characterization are discussed in this paper. Namely, we focus on the possibility of distinguishing focal nodular hyperplasia(FNH) from hepatic adenoma(HA), the identification of early hepatocellular carcinoma(HCC) and the pre-operative assessment of metastasis in liver parenchyma. Regarding the differentiation between FNH and HA, adenoma typically appears hypointense in hepatobiliary phase, whereas FNH is isointense or hyperintense to the surrounding hepatic parenchyma. As for the identification of early HCCs, many papers recently published in literature have emphasized the contribution of hepatobiliary phase in the characterization of nodules without a typical hallmark of HCC. Atypical nodules(no hypervascularizaton observed on arterial phase and/or no hypovascular appearance on portal phase) with low signal intensity in the hepatobiliary phase, have a high probability of malignancy. Finally, regarding the evaluation of focal hepatic metastases, magnetic resonance pre-operative assessment using gadoxetic acid allows for more accurate diagnosis.

Use of probiotics for prevention of radiation-induced diarrhea

AIM： To investigate the efficacy of a high-potency probiotic preparation on prevention of radiation-induced diarrhea in cancer patients.METHODS： This was a double-blind, placebo-controlled trial. Four hundred and ninety patients who underwent adjuvant postoperative radiation therapy after surgery for sigmoid, rectal, or cervical cancer were assigned to either the high-potency probiotic preparation VSL#3 （one sachet t.i.d.,） or placebo starting from the first day of radiation therapy. Efficacy endpoints were incidence and severity of radiation-induced diarrhea, daily number of bowel movements, and the time from the start of the study to the use of Ioperamide as rescue medication. RESULTS： More placebo patients had radiation-induced diarrhea than VSL#3 patients （124 of 239 patients, 51.8%, and 77 of 243 patients, 31.6%; P 〈 0.001） and more patients given placebo suffered grade 3 or 4 diarrhea compared with VSL#3 recipients （55.4% and 1.4%, P 〈 0.001）. Daily bowel movements were 14.7 ± 6 and 5.1 ± 3 among placebo and VSL#3 recipients （P 〈 0.05）, and the mean time to the use of Ioperamide was 86 ± 6 h for placebo patients and 122 ± 8 h for VSL#3 patients （P 〈 0.001）. CONCLUSION： Probiotic lactic acid-producing bacteria are an easy, safe, and feasible approach to protect cancer patients against the risk of radiation-induced diarrhea.

Hepatocellular adenoma: An unsolved diagnostic enigma

Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1α-mutated HCA, inflammatory HCA,β-catenin-mutated HCA, and unclassified HCA.β-cateninmutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1α-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization.

Diffusion-weighted MRI in a liver protocol: Its role in focal lesion detection

AIM: To evaluate the role of diffusion-weighted imaging (DWI) in the detection of focal liver lesions (FLLs), using a conventional magnetic resonance imaging (MRI) protocol. METHODS: Fifty-two patients (22 males, average age 55.6 years, range: 25-82 years), studied using a 1.5 Tesla magnetic resonance scanner, were retrospectively analyzed; detection of FLLs was evaluated by considering the number of lesions observed with the following sequences: (1) respiratory-triggered diffusion-weighted single-shot echo-planar (DW SS-EP) sequences; (2) fat-suppressed fast spin-echo (fs-FSE) T2 weighted sequences; (3) steady-state free precession (SSFP) images; and (4) dynamic triphasic gadolinium-enhanced images, acquired with three-dimensional fast spoiled gradient-echo (3D FSPGR). Two radiologists independently reviewed the images: they were blinded to their respective reports. DW SS-EP sequences were compared to fs-FSE, SSFP and dynamic gadolinium-enhanced acquisitions using a t -test. Pairs were compared for the detection of: (1) all FLLs; (2) benign FLLs; (3) malignant FLLs; (4) metastases; and (5) hepatocellular carcinoma (HCC). RESULTS: Interobserver agreement was very good (weighted = 0.926, CI = 0.880-0.971); on the consensus reading, 277 FLLs were detected. In the comparison with fs-FSE, DW SS-EP sequences had a significantly higher score in the detection of all FLLs, benign FLLs, malignant FLLs and metastases; no statistical difference was observed in the detection of hepatocellular carcinoma (HCCs). In the comparison with SSFP sequences, DW SS-EP had significantly higher scores (P < 0.05) in the detection of all lesions, benign lesions, malignant lesions, metastases and HCC. All FLLs were better detected by dynamic 3D FSGR enhanced acquisition, with P = 0.0023 for reader 1 and P = 0.0086 for reader 2 in the comparison with DW SS-EP sequences; with reference to benign FLLs, DW SS-EP showed lower values than 3D FSPGR enhanced acquisition (P < 0.05). No statistical differences were observed in the detection of malignant lesions and metastases; considering HCCs, a very slight difference was reported by reader 1 (P = 0.049), whereas no difference was found by reader 2 (P = 0.06). CONCLUSION: In lesion detection, DWI had higher scores than T2 sequences; considering malignant FLLs, no statistical difference was observed between DWI and dynamic gadolinium images.

Role of MGMT as biomarker in colorectal cancer

O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.

Optimal management of a patient with recurrent nasopharyngeal carcinoma

Nasopharyngeal carcinoma is rare in western countries, accounting for less than 1% of all malignancies. Despite prognosis is satisfactory for newly diagnosed, non-metastatic disease, management of recurrent disease is challenging, with a survival expectancy of approximately 6 mo with the use of chemotherapy as the sole salvage treatment. We report a case of recurrent nasopharyngeal carcinoma treated with a combination of chemotherapy, radiotherapy and surgery in the context of a multidisciplinary approach. A durable complete response was achieved.

Chemoradiation as definitive treatment for primary squamous cell cancer of the rectum

In this report,we present a case of advanced squamous cell cancer located in the rectum of a 78-year-old woman treated with chemoradiation with curative intent.The patient showed a complete clinical response to chemoradiation;multiple biopsies were performed at the site of the previous mass 5 mo after the end of treatment and histological examination showed no residual tumour in the specimens.Surgical intervention was avoided and the patient was free of disease 12 mo after the diagnosis of cancer.Primary chemoradiation should be considered as the treatment of choice for this rare malignancy.

免疫疗法联合立体定向放疗治疗非小细胞肺癌脑转移:一项AIRO多中心回顾性研究

背景与目的 通过意大利放射治疗和临床肿瘤学学会(Italian Association of Radiotherapy and Clinical Oncology, AIRO)的一项多中心回顾性研究,明确免疫疗法(immunotherapy, IT)和立体定向放疗(stereotactic radiotherapy,SRT)包括放射外科治疗(radiosurgery, RS)或大分割立体定向放疗(hypofractionated stereotactic radiotherapy, HFSRT)治疗非小细胞肺癌(non-small cell lung cancer, NSCLC)脑转移的疗效和毒性。方法 对来自19个意大利中心接受SRT+IT的NSCLC伴脑转移患者进行分析,并与单独接受SRT的对照组患者进行比较。结果 共纳入SRT+IT组100例和单独SRT组50例。接受SRT+IT的患者有更长的颅内局部无进展生存期(intracranial local progression-free survival, i LPFS)(经倾向性评分调整后,P=0.007)。在诊断为脑转移时接受IT合并有颅外进展的患者中(n=24),接受SRT后再进行IT与较好的总生存期(overall survival, OS)相关(P=0.037)。多因素分析显示组织学类型为非腺癌、卡氏体能状态(Karnofsky performance status,KPS)评分=70分以及接受HFSRT与显著减少的生存期相关(P值分别为0.019、0.017和0.007)。与SRT和IT治疗间隔>7天(n=10)相比,治疗间隔≤7天(n=90)与更长的OS相关(经倾向性评分调整后,P=0.008)。联合治疗耐受性良好。在放射性坏死方面,接受SRT+IT的患者与单独SRT的患者无显著差异。SRT和IT的治疗间隔对毒性发生率无影响。结论 SRT+IT是一种安全的联合治疗方法,与单独SRT相比,具有更长的i LPFS。

Accuracy of Ultrasound Examination of Loco-Regional Lymph Nodes in Breast Cancer Follow-Up and Its Role in the Axillary Surgical Management

Objective: Major international guidelines have not standardized the sequence of diagnostic examinations during the follow-up of a patient with a diagnosed breast cancer. The aim of this study is to investigate the accuracy of sonography in the diagnosis of loco-regional lymphatic recurrences in comparison to the core needle biopsy results. Materials and Methods: Among 6455 patients who were followed up with clinical examination, mammography and ultrasound between January 2004 and November 2011, 125 (1.93%) patients had to be investigated with a core needle biopsy of a sonographically suspicious loco-regional lymph node. Results: Among the whole series, a total of 142 ultrasound-guided core needle biopsies were performed. Follow-up for the primary tumor lasted for a median time of 6.1 years (range 1 - 27 years). Ultrasound of suspicious loco-regional lymph nodes showed a sensitivity of 89.5%, a specificity of 87.1% and a positive predictive value of 89.5%. Conclusions: In our experience, ultrasound of suspicious loco-regional lymph nodes showed good accuracy and it should be a part of the standard examinations performed during follow-up for breast cancer.

Complete pathological response in locally advanced non-small-cell lung cancer patient: A case report

BACKGROUND Chemotherapy and radiotherapy followed by durvalumab is currently the standard treatment for locally advanced node-positive non-small-cell lung cancer(NSCLC).We describe the case of a patient with locally advanced node-positive NSCLC(LA-NSCLC)treated in a phase II prospective protocol with chemotherapy,accelerated hypofractionated radiotherapy(AHRT)and surgery in the preimmunotherapy era.CASE SUMMARY A 69-year-old male,ex-smoker(20 PY),with a Karnofsky performance status of 90,was diagnosed with locally advanced squamous cell lung carcinoma.He was staged by total body computed tomography(CT)scanning,and integrated 18Ffluorodeoxyglucose positron emission tomography/CT scan[cT4 cN3 cM0,stage IIIC according to TNM(tumor-node-metastasis)8th edition]and received AHRT between chemotherapy cycles,in accordance with the study protocol(EudractCT registration 2008-006525-14).At the end of the study the patient underwent surgery,which was not part of the protocol,and showed a complete pathological response.CONCLUSION This case report confirms that AHRT can be used successfully to treat primary LA-NSCLC with bilateral mediastinal lymph node involvement.Our case is of particular interest because of the pathological response after AHRT and the lack of surgical complications.We hypothesize that this radiotherapeutic approach,with its proven efficacy,could be delivered as a short course reducing treatment costs,increasing patient compliance and reducing toxicity.We are currently investigating the possibility of combining hypofractionation,chemotherapy and immunotherapy for patients with LA-NSCLC.

Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer:A multicenter retrospective observational comparative study

BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer.AIM To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer.METHODS This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer(stage Ⅲ and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128(59%) of them were treated with CHT(no-mEHT) and 89(41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT.RESULTS Median patients’ age was 67 years(range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group(20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses(45% vs 24%, P = 0.0018) and a lower number of progressions(4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions.CONCLUSION mEHT seems safe and has beneficial effects on survival and tumor response of stage Ⅲ-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Long-term results of suppressing thyroid-stimulating hormone during radiotherapy to prevent primary hypothyroidism in medulloblastoma/PNET and Hodgkin lymphoma:a prospective cohort study

Primary hypothyroidism commonly occurs after radiotherapy(RT),and coincides with increased circulating thyroid-stimulating hormone(TSH)levels.We tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma(HL)in a prospective cohort study.From 1998 to 2001,a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL,scheduled for craniospinal irradiation and mediastinum/neck radiotherapy,respectively,underwent thyroid ultrasound and free triiodothyronine(FT3),free thyroxine(FT4),and TSH evaluation at the beginning and end of craniospinal iiradiation.From 14 days before and up to the end of radiotherapy,patients were administered L-thyroxine checking every 3 days TSH to ensure a value<0.3μIU/mL.During follow-up,blood tests and ultrasound were repeated;primary hypothyroidism was considered an increased TSH level greater than normal range.Twenty-two/37 patients with medulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels˂0.3μIU/mL and well matched for other variables.Twenty years on,hypothyroidism-free survival rates differed significantly,being 60%±15%and 15.6%±8.2%in TSH-suppressed vs.not-TSH suppressed patients,respectively(P=0.001).These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae,but it should be confirmed in a larger cohort.

Optimizing the Dose Distribution in Stereotactic Body Radiotherapy with Standard Multileaf Collimator(MLC) ： A Planning Study

导读：体部立体定向放射治疗（SBRT）可实现靶区剂量的集中、精准和生物有效性，同时避开重要的正常器官。它在当今放疗世界扮演着越来越重要的地位。为了得到更好的剂量优化，目前有很多关于定位、处方剂量技术的研究，运用IMRT可实现SBRT的剂量优化，但各个放疗中心的结果却不尽相同，尚未完全统一。

Current focal therapies for the treatment of low-and intermediate-risk prostate cancer

Active surveillance (AS) and radical treatment (such as radical prostatectomy [RP] or external radiotherapy [RT]/brachytherapy [BRT]) are the standard therapeutic options for treatment in localized prostate cancer (PCa).

Cyclophosphamide,fluorouracil and low-dose interleukin-2 and salvage combination chemotherapy in advanced cutaneous squamous cell carcinoma

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/m^(2)and FU 500 mg/m^(2)intravenously on day 1 and IL-24.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks;Carboplatin(C)AUC 2 and paclitaxel(P)85 mg/m^(2)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.