FLASH radiotherapy (FLASH-RT) is a technology that could modify the way radiotherapy is delivered in the future. This technique involves the ultra-fast delivery of radiotherapy at dose rates several orders of magnitude higher than those currently used in routine clinical practice. This very short time of exposure leads to the striking observation of relative protection of normal tissues that are exposed to FLASH-RT as compared with conventional dose rate radiotherapy. Here we summarise the current knowledge about the FLASH effect and provide a synthesis of the observations that have been reported on various experimental animal models (mice, zebrafish, pig, cats), various organs (lung, gut, brain, skin) and by various groups across 40 years of research. We also propose possible mechanisms for the FLASH effect, as well as possible paths for clinical application.
Non-melanoma skin cancer (NMSC) represents the most frequently diagnosed malignancy worldwide, most being cutaneous basal cell and squamous cell carcinoma The global incidence of NMSC continues to increase as the global population ages. Numerous treatment options are available for NMSC patients, with radiotherapy an efficacious and tissue-preserving non-surgical option. External beam radiotherapy and brachytherapy are modalities with specific indications and advantages in treating NMSC. Where excision is not an option (medically/technically inoperable) or considered less ideal (e.g. cosmetic or functional outcome), radiotherapy offers an excellent alternative. Inoperable elderly and/or co-morbid patients of poor performance status can benefit from short-course hypofractionated radiotherapy, with very acceptable toxicity. Adjuvant radiotherapy in patients with unfavourable pathology can decrease the risk of local and regional recurrence and associated morbidity and mortality. Radiotherapy has advantages and disadvantages and it is important for clinicians to understand these. Managing patients with NMSC is carried out by clinicians from multiple disciplines but it is imperative that they are all aware of the role of radiotherapy in their patients in various clinical settings. Here we aim to discuss the role and indications for recommending radiotherapy in patients with NMSC.
The surgical management of non-melanoma skin cancers has seen some significant changes over the past 20 years, as a result of developments in three equally important and overlapping specialties that deal with this specific pathology: plastic and reconstructive surgery, surgical oncology and dermatological surgery. Better understanding of vascular and particularly microvascular anatomy, coupled with technological advances in operating microscopes, microsurgical instrumentation and preoperative planning via advanced imaging, allows functional and aesthetic restoration of any radical oncological skin and soft-tissue surgery defect from head to toe. As reconstruction has practically lost its technical boundaries, resectional surgery can be executed without compromising on surgical margins, thus reducing rates of local recurrences and metastatic spread. The increasing use of Mohs surgery and its several advantages for difficult high-risk non-melanoma skin cancer in facial sites especially, offers optimal cure rates while reducing functional impairment and optimising cosmetic outcomes. Advances in preoperative planning utilising computed tomography and magnetic resonance imaging scans can help to predict the degree of resectability and tailor further treatments, including radiotherapy, accordingly. From the reconstructive point of view, these techniques provide a roadmap to select the best blood supply for the transplanted flap, thereby reducing complications and increasing success rates. The focus of skin cancer surgery has therefore shifted from pure cancer clearance and flap survival, to a high degree of functional and aesthetic reconstruction.
Although surgery and radiotherapy remain the most commonly used treatments for non-melanoma skin cancer, there are a variety of alternatives. Here we discuss the use of electrochemotherapy and ablative treatments and examine the evidence for their effectiveness against a number of non-melanoma skin cancers.
Transplant recipients have a significantly higher risk of developing non-melanoma skin cancers compared with the general population and squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most common post-transplant malignancies. Although in the general population BCC outnumbers SCC 4:1, in transplant patients this ratio is reversed and SCC is more common, with a 65- to 250-fold increased incidence. As patients in immunosuppressed states are living longer after transplants, the incidence of skin cancer in this population continues to increase. The skin cancers in transplant patients also tend to be more aggressive, with higher morbidity and mortality. Preventive strategies play an important role in transplant recipients given their increased frequency of developing both premalignant and malignant skin lesions. Sun protection and regular skin cancer screening are critical. In addition, chemoprophylaxis with systemic retinoids, nicotinamide and capecitabine can significantly reduce the development of new skin cancers. Topical 5-fluorouracil, imiquimod, photodynamic therapy and cyclooxygenase inhibitors have all been investigated in transplant patients for the treatment of field cancerisation. Adjusting the immunosuppressive regimen is also an important adjuvant therapeutic strategy for managing skin cancers in transplant recipients and requires integrated multidisciplinary care with the entire transplant team. This article reviews the epidemiology of non-melanoma skin cancer in transplant patients, discusses the prevention strategies and highlights the management and treatment strategies of both field cancerisation and non-melanoma skin cancers.
The burden of human papillomavirus (HPV)-related cancers worldwide is significant. Although the incidence of cervical cancer is decreasing due to cervical screening programmes, the incidences of oropharyngeal, anal and vulval cancers are increasing. The introduction of HPV vaccination programmes in many countries has had an impact on HPV infection rates but due to the time-lag from initial HPV infection to the development of invasive carcinoma, the impact on the incidence of HPV-related cancer will take more time to become evident. This review explores the common aspects of HPV-related cancers and how they differ from their HPV-negative counterparts, both clinically and molecularly. It also covers the implications this has on future treatment strategies, including the possible role of immunotherapy.
Oligoprogressive disease is a relatively new clinical concept describing progression at only a few sites of metastasis in patients with otherwise controlled widespread disease. In the era of well-tolerated targeted treatments, resistance inevitably occurs and overcoming this is a challenge. Local ablative therapy for oligoprogressive disease may allow the continuation of systemic treatments by overcoming the few sub-clones that have developed resistance. Stereotactic body radiotherapy is now frequently used in treating oligometastatic disease using ablative doses with minimally invasive techniques and acceptable toxicity. We discuss the current retrospective clinical evidence base supporting the use of local ablative therapy for oligoprogression in metastatic patients on targeted treatments within multiple tumour sites. As there is currently a lack of published prospective data available, the best management for these patients remains unclear. We discuss current trials in recruitment and the potential advancements in treating this group of patients with stereotactic radiotherapy.
Metastatic lung cancer encompasses a heterogenous group of patients in terms of burdens of disease, ranging from patients with extensive metastases to those with a limited number of metastatic lesions (oligometastatic disease). Histopathological heterogeneity also exists within two broad categories, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), portraying different patterns and evolution of disease. Local consolidative therapy to the primary tumour and metastatic sites, including surgery and/or radical dose radiotherapy, is increasingly being used to improve survival outcomes, particularly in the context of oligometastatic disease, with or without the use of molecular targeted therapy and immunotherapy. Recently, randomised studies in oligometastatic NSCLC have shown that local consolidative therapy may confer a survival advantage. This review explores whether treating just the primary tumour with radiotherapy may similarly produce improved clinical outcomes. Such a treatment strategy may carry less potential toxicity than treating multiple sites upfront. The biological rationale behind the potential benefits of treating just the primary in metastatic malignancy is discussed. The clinical evidence of such an approach across tumour sites, such as breast and prostate cancer, is also explored. Then the review focuses on treating the primary in NSCLC and SCLC with radiotherapy, by first exploring patterns of failure in metastatic NSCLC and second exploring evidence on survival outcomes from studies in metastatic NSCLC and SCLC. It is challenging to draw conclusions on the clinical benefit of treating the primary cancer in isolation from the evidence available. This highlights the need to collect data within the ongoing clinical trials on the clinical outcome and toxicity of radiotherapy delivery to primary thoracic disease specifically. This challenge also identifies the need to design future clinical trials to produce randomised evidence for such an approach.
These multidisciplinary guidelines aim to provide clinically helpful, evidence-based recommendations on the surgical management of the axilla in patients who have received neo-adjuvant chemotherapy for early breast cancer. Following a review of published evidence, a writing group representing all disciplines quorate within a breast cancer multidisciplinary meeting prepared the guidelines. In patients presenting with clinically node negative axillae, sentinel node biopsy (SNB) may be performed prior to or on completion of neo-adjuvant chemotherapy (NACT). In patients presenting with clinically node positive axillae, SNB may be safely considered following completion of NACT. Four nodes should be removed with dual mapping. If evidence of complete pathological response of previous metastases is seen, axillary radiotherapy may be offered. If residual cancer (isolated tumour cells, micro- or macrometastes) is seen within the SNB, offer axillary node dissection.
Keratinocyte cancers – basal and cutaneous squamous cell carcinoma (BCC, cSCC) – are the most common forms of non-melanoma skin cancer (NMSC) and there has been a significant increase in their incidence globally in recent decades. Although the majority of BCC and cSCC are cured with conventional surgery or radiotherapy, certain tumour or patient-determined factors may result in these modalities being inadequate or inappropriate, for example, locally advanced or metastatic disease, high tumour multiplicity, patient comorbidities and patient preferences. In these clinical circumstances, systemic treatment may be indicated, and over the past 10 years a number of new systemic agents have been approved. Nonetheless, effective systemic therapy for keratinocyte cancers remains an area of significant unmet clinical need. Improved understanding of the molecular and immune pathogenesis underlying tumour growth and development is critical for driving future advances and is a research priority. The aim of this review is to provide clinicians with an overview of systemic treatments for BCC and cSCC and will focus on current evidence for conventional chemotherapy, targeted therapies, immunotherapy, adjuvant and neoadjuvant therapy, chemoprevention and future prospects for novel systemic treatment approaches.
Merkel cell carcinoma is a rare, aggressive neuroendocrine skin malignancy. Evidence for management comes from case series and single-arm trials. Optimal outcomes require assessment of the patient in a multidisciplinary team setting. Rapid diagnosis and staging are essential for locoregional control and may reduce metastasis. Sentinel lymph node biopsy (SLNB) adds prognostic information. FDG-positron emission tomography has high sensitivity and specificity and affects management in a quarter of cases. Surgical excision and radiotherapy provide good locoregional control even with positive margins. Wide surgical margins are needed if adjuvant radiotherapy is not used. It is uncertain whether adjuvant radiotherapy or elective surgery for uninvolved nodes or for patients selected by positive SLNB improves survival. Total doses of 50 Gy provide high levels of control for microscopic disease but at least 60 Gy should be given for macroscopic disease. Chemotherapy can be given safely with radiotherapy, but the benefit of adjuvant chemotherapy remains uncertain. Trials of adjuvant immune therapy are underway. Unresectable primaries might be controlled with radiotherapy alone or combination systemic therapy, radiotherapy and surgery. Metastatic disease often responds to chemotherapy, but the response duration can be short. Immunity is central to disease control. Immune checkpoint inhibitor treatment resulted in high response rates in chemotherapy-naive patients and lower rates in chemotherapy-refractory patients. Durable responses are observed.
A standardised classification of malignant skin appendageal (adnexal) tumours and sarcomas is required for improved patient management and prognosis. This has been hindered by considerable morphological variation both within and between tumour types, the use of many synonyms for the same tumour types and variation in classification between pathologists. This update uses the improved classification in the 2018 as the basis to discuss malignant skin appendageal tumours, sarcomas and cutaneous metastases that regularly present to skin cancer clinicians, multidisciplinary skin cancer teams and tumour boards, with current evidence for management, where appropriate.
Primary cutaneous lymphomas are the second most common form of extra-nodal lymphomas. They have special characteristics compared with other lymphomas. They are most frequently of T-cell origin and they generally have a much more indolent course than lymphomas of similar histology in other locations. Mycosis fungoides is the most common type of cutaneous lymphoma. Primary cutaneous lymphomas remain confined to the skin for a long time. Skin-directed therapies are the main treatments; systemic treatments are not very effective for the skin lesions. Skin-directed therapies used for the early and thin lesions are topical corticosteroids, phototherapy and topical retinoids and, for the more widespread or thick lesions, topical nitrogen mustard and radiation. Radiation therapy is highly effective and is indicated in virtually all cases of localised disease. Radiation therapy may be given to the whole skin surface, so-called total skin electron beam therapy. However, if the disease spreads to other organs, systemic treatments are indicated, often combined with skin-directed therapies. Conventional cytotoxic therapy is less effective in cutaneous lymphomas. The commonly used therapies, such as interferon, enhanced anti-tumour immunity and the recent advances in immune therapies may improve our treatments for cutaneous lymphomas.
Stereotactic body radiotherapy (SBRT) is an option for the treatment of hepatocellular carcinoma (HCC) in patients ineligible for standard local therapies. This study reports on the safety and efficacy of SBRT in small HCC tumours (≤5 cm) in the province of British Columbia. Between March 2011 and July 2015, 31 patients with Child–Pugh Class A or B, with small HCCs measuring ≤5 cm were treated with SBRT at our institution. Primary end points were local control, progression-free survival, overall survival and toxicity. Thirty-four hepatomas (median size 3.3 cm, range 1.3–5.0 cm) were treated. The median follow-up was 18.3 months. Twenty-six patients (84%) had received previous liver-directed treatments. Most patients (88%) were treated with 45 Gy in three or five fractions. Six patients (19%) had worsened Child–Pugh score by two or more points during follow-up; overall 32% of patients experienced ≥ grade 3 + toxicities. One-year local control and overall survival were 94 and 84%, respectively. One-year progression-free survival was 49%; 81% of patients with disease progression received further HCC therapy. On univariate analysis, small tumour size predicted for improved overall survival ( = 0.01) whereas prescription biological equivalent dose (BED ) ≥100Gy approached significance ( = 0.06). SBRT provides high local control to small inoperable HCC. SBRT can be delivered safely even after previous liver-directed therapies and further liver therapies can follow treatment with SBRT. Although overall 32% of patients experienced ≥ grade 3 + toxicities, and 19% had a deterioration in Child–Pugh score of two or more points, these changes were mainly transient with minimal clinical impact. Despite excellent local control, disease progression outside of the irradiated site remains prominent. Further studies are warranted to examine combined therapy approaches to maximise disease control.
We present the first analysis of the management and outcomes of stage III non-small cell lung cancer (NSCLC) conducted in England using National Lung Cancer Audit data. Patients diagnosed with stage III NSCLC in 2016 were identified. Linked datasets (including Hospital Episode Statistics, the National Radiotherapy Dataset, the Systemic Anti-Cancer Dataset, pathology reports and death certificate data) were used to categorise the treatment received. Kaplan–Meier survival curves were obtained, with survival defined from the date of diagnosis to the date of death. In total, 6276 cases of stage III NSCLC were analysed: 3827 stage IIIA and 2449 stage IIIB; 1047 (17%) patients were treated with radical radiotherapy with 676 (11%) of these also receiving chemotherapy. Twenty per cent of patients with stage IIIA disease underwent surgery, with half of these also receiving chemotherapy, predominantly delivered in the adjuvant setting. Of note, 2148 (34%) patients received palliative-intent treatment and 2265 (36%) received no active anti-cancer treatment. The 1-year survival was 32.9% (37.4% for stage IIIA), with the highest survival seen for those patients receiving chemotherapy and surgery. We highlight important gaps in the optimal care of patients with stage III NSCLC in England. Multimodality treatment with either surgery or radical radiotherapy combined with chemotherapy was delivered to less than one-fifth of patients, even though these regimens are considered optimal. Timely access to specialist resources and staff, the practice of effective shared decision making and challenging preconceptions have the potential to optimise management.
Stereotactic ablative body radiotherapy (SABR) is now considered the standard of care for medically inoperable stage I non-small cell lung cancer (NSCLC). The English National Cancer Registration and Analysis Service (NCRAS) collects data on all patients diagnosed with lung cancer, including information on treatment. We wanted to compare outcomes for patients with stage I NSCLC treated with radical radiotherapy with either SABR or fractionated radiotherapy. All patients diagnosed with stage I NSCLC in 2015 and 2016 were identified from the NCRAS dataset, validated by the National Lung Cancer Audit, and their treatment data were collated. For patients who received radiotherapy, those receiving radical dose fractionations, including SABR, were identified through linkage to the national Radiotherapy Dataset. Clinical outcomes for those receiving SABR or more fractionated radical radiotherapy were compared using univariate and fully adjusted Cox proportional hazards models. In total, 12 384 patients with stage I NSCLC were identified during the study period; 53.5% underwent surgical resection, 24.3% received no documented treatment, 18.6% received radical radiotherapy and 3.5% received other non-curative-intent treatments. For those receiving radical radiotherapy, 69% received SABR and 31% received fractionated treatment. The hazard ratio of death for the 1587 patients who received SABR was 0.69 (95% confidence interval 0.61–0.79) compared with 717 patients who received radical fractionated radiotherapy; this benefit was seen for both stage Ia and stage Ib disease. The median overall survival was also longer for SABR versus radical radiotherapy (715 days versus 648 days). Exploratory travel time analysis shows that compared with stage I NSCLC patients receiving SABR, those receiving fractionated radiotherapy and those receiving no active treatment would have to travel longer and further to reach their nearest radiotherapy SABR centre. This study adds to the data that SABR has a survival benefit when compared with fractionated radical radiotherapy. Although the use of SABR increased in England over this study period, it has still not reached levels of use seen in other countries. This study also highlights that one quarter of stage I NSCLC patients overall received no active treatment.
Despite best available therapy, many children with cancer develop recurrence after multimodal treatment, including initial radiation therapy. Re-irradiation is defined as the use of a second course of radiation therapy with a retreatment volume that overlaps substantially with that of a previously delivered course of radiation therapy. Re-irradiation is an important part of salvage treatment for patients with recurrent ependymoma, diffuse intrinsic pontine glioma, medulloblastoma and germinoma. In patients with ependymoma, conventionally fractionated re-irradiation (1.8 Gy/day) can provide long-term disease control with low rates of high-grade toxicity. For children with progressive diffuse intrinsic pontine glioma, re-irradiation provides effective palliation of symptoms and a survival gain as compared with those treated without re-irradiation. Repeat radiation therapy that includes craniospinal irradiation, if safe to deliver, may provide long-term tumour control in patients with medulloblastoma. Patients with recurrent intracranial germinoma can be effectively salvaged with re-irradiation that includes craniospinal irradiation. Finally, the emerging role of re-irradiation in non-brainstem high-grade glioma and extracranial solid tumours requires further study regarding its efficacy and safety. When given, re-irradiation should be delivered with care so that doses to organs at risk are minimised. In all cases, re-irradiation should be considered as an option alongside, or concurrently with, other salvage treatments, including surgery or systemic therapy, to maximise the likelihood of durable disease control.
Recent studies suggest that the treatment response and survival from head and neck tumours can be stratified according to biomarker status, particularly human papillomavirus (HPV) status and p16 expression, but the evidence for predictive biomarkers in anal squamous cell carcinoma (ASCC) remains limited. The aim of this study was to determine which biomarkers were associated with locoregional recurrence (LRR), overall survival and disease-free survival (DFS) in ASCC. A systematic search was undertaken of the MEDLINE, Embase, Cochrane Library, CINAHL and Web of Science databases using validated terms for ASCC, biomarkers and prognosis. Biomarkers were included in the meta-analysis if they were reported by at least four studies and provided sufficient data to permit the calculation of survival effect estimates. HPV status, p16, p53 and epidermal growth factor receptor (EGFR) met the inclusion criteria for meta-analysis and were reported by 17 retrospective cohort studies describing 1635 patients. When compared with HPV-negative tumours, HPV-positive tumours were associated with reduced LRR (pooled hazard ratio = 0.27 [95% confidence interval 0.16–0.48]; < 0.001), improved overall survival (hazard ratio =0.26 [0.12–0.59]; = 0.001) and DFS (hazard ratio = 0.33 [0.16–0.70]; = 0.003). Likewise, p16-positive tumours were associated with reduced LRR (hazard ratio = 0.26 [0.13–0.52]; < 0.001), improved overall survival (hazard ratio = 0.44 [0.24–0.81]; = 0.009) and DFS (hazard ratio = 0.44 [0.23–0.83]; = 0.012) when compared with p16-negative tumours. HPV-positive/p16-positive tumours had improved overall survival when compared with HPV-negative/p16-negative tumours (hazard ratio = 0.27 [0.15–0.48], < 0.001), but not HPV-negative/p16-positive tumours (hazard ratio = 0.64 [0.21–1.90]; = 0.421). p53 mutation was associated with worse DFS (hazard ratio = 1.63 [1.33–2.01]; = 0.003). There was no association between EGFR status and any survival outcome. HPV status, p16 and p53 expression are of prognostic utility in ASCC. Future studies should prospectively validate these findings with a view to conducting subsequent randomised controlled trials where patients are stratified according to biomarker status and randomised to different treatment regimens.